A rare genetic neurodegenerative disorder characterized by congenital microphthalmia, sunken eyes, blindness, microcephaly, severe intellectual disability, progressive spasticity, and seizures. Psychomotor development is normal in the first 6-8 months of life and thereafter declines rapidly and continuously. Brain MRI reveals progressive and extensive degenerative changes, especially cortex, cerebellum, brainstem, and corpus callosum atrophy, with complete loss of cerebral white matter.


A rare lethal multiple congenital anomalies/dysmorphic syndrome characterized by the association of fetal akinesia sequence, bilateral microphthalmia, microtia, and persistent truncus arteriosus. Additional dysmorphic features include prominent forehead, small nose, micrognathia, as well as camptodactyly and symphalangism. Contractures of large joints and micropenis have also been reported.


Microphthalmia-retinitis pigmentosa-foveoschisis-optic disc drusen syndrome is a rare, genetic, non-syndromic developmental defect of the eye disorder characterized by the association of posterior microphthalmia, retinal dystrophy compatible with retinitis pigmentosa, localized foveal schisis and optic disc drusen. Patients present high hyperopia, usually adult-onset progressive nyctalopia and reduced visual acuity, and, on occasion, acute-angle glaucoma.


A rare inflammatory, necrotizing, systemic vasculitis that affects predominantly small vessels (i.e. small arteries, arterioles, capillaries, venules) in multiple organs, including the kidney, the lungs, the skin and the peripheral nerves.

Summary:
Epidemiology
Microscopic polyangiitis (MPA) has a prevalence of 1/40,000 adults in France. Pediatric-onset MPA (<10 years of age) is uncommon.
Clinical description
MPA affects small vessels (more rarely medium-sized arteries) in any organ, resulting in a wide variety of non-specific symptoms. The early clinical manifestations are indicative of systemic inflammation: fever, arthralgias, myalgias, fatigue, and/or loss of appetite. As the disease progresses, 90% of patients show renal involvement with pauci-immune necrotizing and crescentic glomerulonephritis that can have a rapidly progressive course if not treated promptly. Pulmonary involvement (alveolar hemorrhage) is frequent and manifests with symptoms such as dyspnea, cough or hemoptysis. The most severe manifestation is combined pulmonary and renal disease (pulmonary-renal syndrome). Gastro-intestinal involvement can present with abdominal pain, nausea, or vomiting, and can be life-threatening in case of peritonitis, ischemia or perforation. Neurological (mainly mononeuritis multiplex), dermatologic (mainly leukocytoclastic angiitis), musculoskeletal (arthralgias, myalgias) and ocular involvement (e.g. episcleritis, retinal vasculitis, uveitis) are also observed. Cardiovascular involvement (e.g. pericarditis, cardiac insufficiency) is rare.
Etiology
MPA is an antineutrophil cytoplasmic autoantibodies (ANCA)-associated auto-immune disease with little or no immune complex deposition. Evidence indicates that ANCA can activate neutrophils and monocytes, and cause them to attack vessel walls.
Diagnostic methods
Diagnosis can be difficult and is essentially made by exclusion of other diseases. Detection of ANCA is a useful serologic marker. Generally, 60% of patients have myeloperoxidase (MPO)-ANCA, 30% proteinase 3 (PR3)-ANCA and 10% are ANCA-negative. Blood tests can reveal elevated C-reactive protein, leukocytosis, and anemia. Urine tests can show proteinuria, hematuria, and leukocyturia. Renal, pulmonary and skin biopsy can support the diagnosis. Pathologically, MPA is characterized by segmental vascular necrosis with infiltration of neutrophils and monocytes, often with leukocytoclasia and accumulation of fibrin.
Differential diagnosis
The differential diagnosis includes granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis (distinguished from MPA by the presence of necrotizing granulomatous inflammation in the absence or presence of asthma, respectively), Henoch-Schönlein purpura and cryoglobulinemic vasculitis (distinguished from MPA by IgA-dominant and cryoglobulin immune deposits, respectively), and polyarteritis nodosa.
Management and treatment
Treatment consists of two phases: induction of remission and maintenance of remission. The first-line induction therapy consists of oral or intravenous administration of high dose corticosteroids with immunosuppressive treatment (e.g. cyclophosphamide, or rituximab) in severe cases. Milder forms can be treated with glucocorticoids alone. Maintenance treatment consists of semestral infusions of rituximab. Relapses are treated with increased or reinstituted immunosuppression. In case of renal failure, dialysis and/or renal transplantation are appropriate.
Prognosis
With early diagnosis and treatment, prognosis is improved. Induction of remission occurs in 90% of patients. Optimum treatment reduces relapses (10% of patients have a relapse within 2 years of remission). Five-year patient survival has significantly improved during the last decade.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Dr Xavier PUECHAL  - Pr Benjamin TERRIER


Microspherophakia - metaphyseal dysplasia is a very rare syndrome associating bone dysplasia with micromelic dwarfism and eye defects.

Summary:
Epidemiology
It has been reported in a father and his son.
Clinical description
Bone dysplasia is characterized by diaphyseal thickening of the long bones, metaphyseal deformation and epiphyseal irregularities. Eye defects consisted of myopia, microspherophakia, lens coloboma and luxation, and retinal detachment. The affected patients have normal mental development.
Etiology
The condition is most probably hereditary, transmitted as an autosomal dominant trait.

                            Last update:
                            August 2011

                            - Expert reviewer(s):
                            Dr Nicole MORICHON-DELVALLEZ


Microsporidiosis is a parasitosis caused by microsporidia (protozoan parasites).

Summary:
Epidemiology
The annual incidence of microsporidiosis is unknown and the geographical distribution of microsporidia remains to be defined. Immunodeficient patients (individuals with HIV, and patients who have undergone a bone marrow or organ transplant) are the main target.
Clinical description
The infection results in chronic diarrhea that leads to severe weight loss.
Etiology
Microsporidia are unicellular eukaryotic parasites without mitochondria and are responsible for opportunistic infections. Microsporidia are strictly intracellular parasites. The initial proliferative asexual stage (merogony) is followed by a disseminating stage (sporogony) that leads to spore development. Small spores (1 to 3 µm depending on the species) represent the most resistant and disseminating form and are characterized by a polar filament, which allows them to perforate the cell wall and inject nuclear material. They develop mainly in intestinal cells but may also develop in adipocytes, epithelium cells and blood cells. Several genera have been reported in humans, among which Encephalitozoon and Enterocytozoon are the most common. Contamination probably occurs after ingesting spores contained in water or food. Direct interhuman contamination is also likely.
Diagnostic methods
Diagnosis is based on the identification of spores through laboratory testing.
Differential diagnosis
Differential diagnoses include the other genera of microsporidia.
Management and treatment
Treatment with albendazole is well tolerated and successful, except for patients with Enterocytozoon bieneusi infections, for which only fumagillin is effective but hematotoxic.
Prognosis
The prognosis may be severe in immunodeficient patients.

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Dr Annick DATRY


Microtia-eye coloboma-imperforation of the nasolacrimal duct syndrome

This syndrome is characterised by the association of microtia, eye coloboma, and imperforation of the nasolacrimal duct.

Summary:
Epidemiology
So far, it has been described in only one family.
Etiology
The phenotype is associated with the presence of five copies of a copy-number-variable region (CNV) localised to 4pter. This is the first example of an amplified CNV being associated with a Mendelian disorder.
Genetic counseling
Transmission is autosomal dominant.

                            Last update:
                            May 2008


A congenital malformation of the external ear, seen more frequently in males, that occurs sporadically or is inherited, that is characterized by unilateral (79-93% of cases, 60% of which involve the right ear) or bilateral small and abnormally shaped auricles and that is often associated with atresia or stenosis of the ear canal, attention deficit disorders and delayed language development. The variation in auricle size ranges from grade I, where the auricle is simply smaller than normal, to grade IV, also known as anotia, where there is a complete absence of the external ear and of the auditory canal.


Microtriplication 11q24.1 is an extremely rare partial autosomal tetrasomy, resulting from a partial triplication of the long arm of chromosome 11, characterized by intellectual disability (with severe verbal impairment), short stature with small extremities, keratoconus and distinctive facial features (round, course face, upward slanting palpebral fissures, mild synophris, large nose with thick ala nasi and triangular tip, large mouth with broad lips, short and smooth philtrum, large protruded chin, ears with adherent lobules). Additionally, patients are overweight and present hypercholesterolemia.


Microvillus inclusion disease (MVID) is a very rare and severe intestinal disease characterized by intractable neonatal secretory diarrhea persisting at bowel rest and specific histological features of the intestinal epithelium.

Summary:
Epidemiology
Prevalence data are not available. Less than 200 cases have been reported to date. There is a male predominance, with a sex ratio of 1.5:1.
Clinical description
Two clinical forms of MVID have been described: an early-onset form, developing within hours or days of birth, and a late-onset form, occurring in the first months of life. In both, intractable, watery diarrhea is profuse and leads to severe metabolic acidosis, dehydration, malabsorption and failure to thrive. Total parenteral nutrition is necessary, however, in some later-onset cases, partial oral absorption has been described. The intestinal insufficiency is progressively life-threatening in the absence of rapid, appropriate hydroelectrolytic and nutritional compensation. Developmental delays may be present and rare associated anomalies (e.g. inguinal hernia, renal dysplasia) have been reported. Long-term parenteral nutrition may be complicated with specific liver cholestasis. Atypical forms of MVID, without detectable microvillus inclusions and less severe course, have been described.
Etiology
MVID is caused by mutations in the MYO5B gene (18q) resulting in perturbation of intestinal epithelial cell apical polarity. Disorganized microvilli impair the absorptive capacity of the enterocytes. A variant of the disorder, without microvillous inclusion vesicles, is caused by loss-of-function mutations in the syntaxin 3 (STX3) gene (11q12.1), and when associated with hemophagocytic lymphohistiocytosis, can also be caused by mutation of STXBP2 (19p13.2) gene. Some patients do not display mutations in any identified gene.
Diagnostic methods
The diagnosis is suspected based on clinical manifestations and is confirmed by histological analysis of small bowel biopsies showing villous atrophy and abnormal periodic acid-Schiff stain (PAS)-positive inclusion material in intestinal epithelium, without crypt hyperplasia. Electronic microscopy reveals microvillous atrophy and in most cases, microvillous inclusion vesicles in the cytoplasm of enterocytes. Molecular genetic testing has become essential to confirm the diagnosis.
Differential diagnosis
The differential diagnosis includes rare congenital enteropathies such as autoimmune enteropathy, chloride diarrhea, congenital sodium diarrhea, and congenital tufting enteropathy.
Antenatal diagnosis
As MVID is a rare disease with no specific and systematic prenatal signs. Prenatal diagnosis is possible only if the specific gene mutation has been identified in an affected member of the family.
Genetic counseling
The inheritance pattern of MVID is autosomal recessive (parents of an affected individual have a probability of 25 % to transmit the causal mutation to their offspring). Genetic counseling should be offered to affected families in order to provide more information about this genetic condition, its risk of recurrence and the necessity/availability of prenatal diagnosis.
Management and treatment
To date, there is no curative therapy for MVID. Treatment involves total parenteral nutrition, intestinal transplantation (when long-term parenteral nutrition is no longer possible) and, when required, associated liver transplantation.
Prognosis
Due to the severity and precocity of the symptoms, as well as the long-term parenteral nutrition's complications, prognosis for MVID is generally poor. Causes of death include severe dehydration and metabolic imbalance, malnutrition, and sepsis.

                            Last update:
                            October 2017

                            - Expert reviewer(s):
                            Pr Olivier GOULET  - Dr Julie SALOMON


Micturation-induced seizures is a rare neurologic disease characterized by tonic posturing or clonic movements triggered by micturition, with bilateral or unilateral involvement of the extremities and with or without loss of consciousness. Developmental delay is reported in some cases.


A rare, acquired, dermis elastic tissue disease characterized by asymptomatic, well-demarcated, symmetric patches and/or plaques of finely wrinkled skin arranged parallel to skin cleavage lines (type I), associated with perifollicular papular protrusions (type II) or with persistent reticular erythema (type III), occurring predominantly on the shoulders, trunk, back, and proximal extremities, associating, on histopathology, a selective loss of elastic tissue in the midreticular dermis. Erythema and/or urticaria may or may not precede wrinkly lesions.


A rare vascular anomaly characterized by the segmental narrowing of the abdominal and/or distal descending thoracic aorta, with varying involvement of the visceral and renal arteries, that commonly presents in children and young adults with early onset and refractory hypertension, abdominal angina, and lower-limb claudication, that can lead to life-threatening complications associated with severe hypertension (i.e. myocardial infarction, heart failure, aortic rupture, renal insufficiency and intracranial hemorrhage). It may be due to various congenital or acquired causes, but it is most often secondary to an acquired inflammatory disease (i.e. Takayasu arteritis or giant cell arteritis).


Middle ear neuroendocrine tumor is a rare, otorhinolaryngologic tumor characterized by a mixed glandular and non-glandular histological features and positive immunostaining for pancytokeratin, vimentin, synaptophysin and islet-1 protein. Common signs and symptoms are hearing loss, mass, pain, discharge, equilibrium disturbances, tinnitus and nerve paralysis.


A rare infectious disease caused by Middle East respiratory syndrome coronavirus (MERS‐CoV) and characterized by a spectrum of illness, ranging from mild upper respiratory symptoms to rapidly progressive lower respiratory infection/pneumonia potentially leading to acute respiratory distress syndrome (ARDS), multi-system organ failure, and death. Presenting signs and symptoms typically include fever, cough, shortness of breath, chills, dyspnea, myalgia, abdominal pain, nausea, vomiting, and diarrhea.


A rare neck malformation characterized by a congenital vertical atrophic and usually erythematous skin defect of variable length, lacking adnexal elements and located along the midline of the anterior neck. It typically presents with a superior skin tag, a midline subcutaneous fibrous cord which is often longer than the overlying skin defect, and an inferior blind sinus from which mucus can be expressed. The length of the defect increases with patients' age. Likewise, the fibrous cord becomes more prominent with age, potentially leading to restriction of neck extension if the malformation is left untreated. Other possible complications include microgenia, exostosis, torticollis, or infection.


Midline interhemispheric variant of holoprosencephaly (MIH) or syntelencephaly is a form of holoprosencephaly (HPE; see this term) characterized by non-separation of the posterior frontal and parietal lobes, normally-formed callosal genu and splenium, absence of the callosal body, normally-separated hypothalamus and lentiform nucleus, and frequent heterotopic gray matter.

Summary:
Epidemiology
About 2% to 15% of HPE patients have MIH type.
Clinical description
Patients have rather mild dysmorphic facial features such as ocular hypotelorism, flat or narrow nasal bridge or a relatively normal facial appearance.
Etiology
MIH has mainly been reported in patients with ZIC2 (13q32) mutations.
Prognosis
Prognosis is better than in classical forms of HPE.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Pr Sandra MERCIER  - Pr Sylvie ODENT


Mietens syndrome is a very rare syndrome consisting of corneal opacity, nystagmus, strabismus, flexion contracture of the elbows with dislocation of the head of the radius and abnormally short ulnae and radii.

Summary:
Epidemiology
To date, only nine cases have been reported.
Clinical description
Ocular findings are striking. Dysmorphic features are not characteristic except for a small pinched nose and a depressed nasal root. Intellectual deficit and growth delay are observed in the majority of patients.
Genetic counseling
An autosomal recessive pattern of inheritance is probable.

                            Last update:
                            July 2010


Mikati-Najjar-Sahli syndrome is characterized by microcephaly, hypergonadotropic hypogonadism, short stature and facial dysmorphism (a narrow forehead, hypertrophy and fusion of the eyebrows, micrognathia and pinnae abnormalities).

Summary:
Epidemiology
It has been described in five siblings (three males and two females) born to consanguineous parents.
Clinical description
Additional congenital anomalies present in some of the patients included cubitus valgus and genu valgum. Early tooth loss was also reported.
Genetic counseling
The mode of transmission appears to be autosomal recessive.

                            Last update:
                            May 2009


Mild Canavan disease (CD) is a neurodegenerative disorder characterized by mild speech delay or motor development.

Summary:
Epidemiology
Mild CD has been identified in only a few cases. The majority of patients with Canavan disease have the severe form (see this term). In contrast to the severe CD, most mild CD patients are not from Ashkenazi Jewish descent.
Clinical description
Mild CD usually presents in childhood with mild developmental delay or problems with speech or motor development. Head circumference is usually normal. Retinitis pigmentosa (see this term) may be present. .
Etiology
CD is caused by mutation in the ASPA gene (17p13.3), coding for the aspartoacylase enzyme. Mild CD is associated with heterozygous genotypes comprising a mild mutation and a severe one. Mild mutations include Y288C, R71H, P257R, I143T, and Y231C.
Diagnostic methods
The brain MRI usually demonstrates an increased signal intensity in the basal ganglia and the urine level of N-acetyl-L-aspartic acid (NAA) is slightly elevated. Mutation screening can be performed for molecular diagnosis.
Prognosis
Prognosis is good and children often attend normal school but may need speech therapy or a tutor. Life expectancy is normal.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Kimberlee MATALON  - Dr Reuben MATALON


A mild form of hemophilia A characterized by a small deficiency of factor VIII (biological activity between 5 and 40 IU/dL) leading to abnormal bleeding as a result of minor injuries or following surgery or tooth extraction. Spontaneous hemorrhages do not occur. Patients may be also labeled as having mild hemophilia A if they have a FVIII >40 IU/dL and a DNA change in the F8 gene and one of the following: (i) a family member with the same DNA change and FVIII of <40 IU/dL, and the DNA change is found in <1% of the population; and (ii) the international databases list the DNA change as being associated with hemophilia A and <40 IU/dL FVIII. The condition may affect males and female carriers of disease-causing mutations.


A mild form of hemophilia B characterized by a small deficiency of factor IX (biological activity between 5 and 40 IU/dL) leading to abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction. Spontaneous hemorrhages do not occur. The condition may affect males and female carriers of disease-causing mutations.


A rare form of phenylketonuria, an inborn error of amino acid metabolism, characterized by blood phenylalanine (Phe) concentrations of 120-600 micromol/L with or without clinical manifestations of impaired cognitive function, and behavioral and developmental disorders.


A mild to moderate form of phenylketouria (PKU), an inborn error of amino acid metabolism, characterized by blood phenylalanine concentrations of 600-1,200 micromol/L and manifests with reduced cognitive function and behavioral and developmental disorders. Dietary phenylalanine tolerance is 400-600 mg/day.


Mild phosphoribosylpyrophosphate synthetase superactivity

A mild form of phosphoribosylpyrophosphate (PRPP) synthetase superactivity, an X-linked disorder of purine metabolism, characterized by adolescent or early adult-onset hyperuricemia and hyperuricosuria, leading to urolithiasis and gout.

Summary:
Epidemiology
PRPP synthetase superactivity is a rare disorder with 30 families described in the literature. The mild form accounts for approximately 75% of cases. The disorder predominantly affects males.
Clinical description
Mild PRPP synthetase superactivity typically manifests in late adolescence or early adulthood, but may manifest earlier, with uric acid crystalluria and urinary stones (kidney and/or bladder), followed by the development of gouty arthritis and eventually renal failure as a result of obstructive uropathy from uric acid crystal deposition. This form is not associated with any neurodevelopmental anomalies.
Etiology
The disease is due to overactivity of PRPP synthetase 1 (PRS-I), an enzyme that catalyzes the synthesis of PRPP, a cofactor involved in the synthesis of purine and pyrimidine nucleotides. PRS-I overactivity results in overproduction of purine nucleotides and uric acid (a waste product of purine breakdown). The exact molecular mechanism leading to the mild form is not yet well understood, but it seems to be linked to increased rates of transcription of the gene PRSP1 (Xq22.3) encoding PRS-I .
Diagnostic methods
Diagnosis is based on blood and urine analysis showing hyperuricemia, hyperuricosuria, and uric acid crystalluria. Diagnosis is confirmed by a PRS enzyme assay showing increased PRS-I activity in fibroblasts, lymphoblasts, and erythrocytes.
Differential diagnosis
Differential diagnosis includes other causes urinary stones and gout.
Antenatal diagnosis
Prenatal genetic testing in male fetuses may be possible if the mutation has been previously identified in the family.
Genetic counseling
Although no genetic mutation has been identified in this mild form, the pattern of inheritance is thought to be X-linked with complete penetrance in males. Females are not typically affected, but some females may show a mild clinical presentation.
Management and treatment
Hyperuricemia and hyperuricosuria are treated with: allopurinol or febuxostat to reduce uric acid formation and thus serum urate and urinary uric acid. A high daily fluid intake is recommended; and, as needed, potassium citrate to alkalinize the urine. Dietary recommendations include emphasis on low-fat dairy and complex carbohydrate-containing foods.
Prognosis
Severe gout can lead to renal impairment, if not properly treated.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Arjan DE BROUWER


Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis is a type 2 collagen-related bone disorder characterized by precocious, generalized osteoarthritis (with onset as early as childhood) and mild, dysplastic spinal changes (flattening of vertebrae, irregular endplates and wedge-shaped deformities) resulting in a mildly short trunk.


A rare acquired peripheral neuropathy characterized by acute ophthalmoplegia, ataxia, and areflexia, typically manifesting with diplopia and unsteady gait, and generalized areflexia.

Summary:
Epidemiology
Annual incidence is estimated at 1/333,333.
Clinical description
Miller Fisher syndrome (MFS) is characterized by the clinical triad of acute onset of gait ataxia, areflexia, and ophthalmoplegia. Acute onset of external ophthalmoplegia is a cardinal feature of MFS. Facial and bulbar nerve palsies have also been reported.
Etiology
In the majority of cases, MFS occurs following upper respiratory tract or gastrointestinal infections. Although the exact pathological mechanism is not fully understood, MFS is associated with the presence of antiganglioside antibodies (primarily, anti-GQ1b).
Diagnostic methods
Diagnosis is based on the clinical findings, patient history, cerebrospinal fluid (CSF) analysis (revealing raised protein levels), detection of anti-GQ1b IgG antibodies (not present in all patients), brain MRI studies are usually unremarkable, and electromyography is normal.
Differential diagnosis
The clinical picture in MFS shows clinical overlap with Bickerstaff brainstem encephalitis (BBE), which is also associated with raised titers of anti-GQ1b antibodies, leading to the suggestion that BBE and MFS represent variable manifestations of the same clinical spectrum.
Management and treatment
If the severity is high (inability to walk, or complete ophthalmoplegia), management is based on immunotherapy with intravenous immunoglobulin (IVIg) or plasma exchange. In mild cases, spontaneous recovery is expected.
Prognosis
MFS is generally self-limiting and patients recover within a few months, however, cases of progression to respiratory failure have been reported in MFS patients with features of both MFS and other forms of GBS (MFS/GBS overlap syndrome).

                            Last update:
                            November 2023

                            - Expert reviewer(s):
                            Pr Satoshi KUWABARA


Miller-Dieker Syndrome (MDS) is a contiguous gene deletion syndrome of chromosome 17p13.3, characterised by classical lissencephaly (lissencephaly type 1) and distinct facial features. Additional congenital malformations can be part of the condition.

Summary:
Epidemiology
MDS is undoubtedly a rare condition with a reported estimate of 1 cases per 100 000 live births, although incidence and prevalence are probably higher.
Clinical description
Children with MDS present with severe developmental delay, usually have epilepsy, and feeding problems are common. The lissencephaly represents the severe end of the spectrum with generalized agyria, or agyria and some frontal pachygyria.
Etiology
Visible and submicroscopic deletions of 17p13.3, including the LIS1 gene, are found in almost 100% of patients.
Management and treatment
Management of children with MDS is symptomatic. To avoid the complications of feeding and swallowing problems (poor nutritional state, aspiration pneumonia), nasogastric tubes and gastrostomies (a more long-term solution) can be utilised. Seizure control is important.

                            Last update:
                            April 2005

                            - Expert reviewer(s):
                            Pr Daniela PILZ


A rare, acquired motor neuron disease characterized by a slowly progressive, unilateral, ascending or descending hemiplegia, associated to unilateral or asymmetrical pyramidal signs and no sensory loss. It is a diagnosis of exclusion and controversy exists regarding whether the presence of bulbar symptoms, sphincter disturbances, fasciculations or cognitive manifestations characterize the disease.


Milroy disease is a frequent form of primary lymphedema (see this term) characterized generally by painless, chronic lower-limb lymphedema found at birth or developing in the early neonatal period.


Minimal pigment oculocutaneous albinism type 1

An extremely rare form of Oculocutaneous albinism type 1 with minimal pigment present, characterized by blond hair (white at birth), variable iris transillumination (blue irides at birth followed by minimal development of pigment during the first decade of life), visual acuity ranging from 20/80-20/200 and white skin, with or without skin nevi.


A rare genetic disease characterized by pre- and postnatal growth restriction, developmental delay, adrenal hypoplasia, genital abnormalities (such as microphallus, hypospadias, or cryptorchidism), thrombocytopenia and/or anemia, recurrent severe invasive infections, and enteropathy with chronic diarrhea. Myelodysplastic syndrome and dysmorphic features (including downslanting palpebral fissures, low-set and posteriorly rotated ears, anteverted nares, camptodactyly, and arachnodactyly, among others) may also be observed.


A rare biliary tract disease characterized by external compression and subsequent obstruction of an extrahepatic biliary duct by one or more gallstones in the cystic duct or the gallbladder. Patients may present with acute or chronic cholecystitis with right upper abdominal pain, nausea, and vomiting, jaundice, or cholangitis. Cholecystobiliary or -enteric fistulae can arise due to chronic inflammation and ulceration.


Mirror polydactyly-vertebral segmentation-limbs defects syndrome

A rare disorder characterized by mirror polydactyly, vertebral hypersegmentation and severe congenital limb deficiencies. Duodenal atresia and absent thymus were also reported. So far, it has been described in four unrelated infants identified through a congenital malformation screening program carried out in Spain. The prevalence was estimated at around 1 in 330,000. The etiology is unknown but it was suggested that the syndrome is caused by defective expression of a developmental control gene.


A rare non-syndromic limb malformation characterized by a hand or foot with more than five digits that has a recognizable anterior/posterior axis of symmetry, either with a hallux- or thumb-like structure or an interdigital space in the middle. The most lateral digits on each side typically resemble fifth fingers or toes. The malformation may be unilateral or bilateral and may occur in isolation or in association with other congenital anomalies.


MiT family translocation renal cell carcinoma (t-RCC) is a rare subtype of renal cell carcinoma with recurrent genetic abnormalities, harboring rearrangements of the TFE3 (Xp11 t-RCC) or TFEB [t(6;11) t-RCC] genes. The t(6;11) t-RCC has distinctive histologic features of biphasic appearance with larger epitheloid and smaller eosinophilic cells. The symptoms are usually non-specific and include hematuria, flank pain, palpable abdominal mass and/or systemic symptoms of anemia, fatigue and fever.


MITF-related melanoma and renal cell carcinoma predisposition syndrome is an inherited cancer-predisposing syndrome due to a gain-of-function germline mutation in the MITF gene, associated with a higher incidence of amelanotic and nodular melanoma, multiple primary melanomas and increase in nevus number and size. It may also predispose to co-occurring melanoma and renal cell carcinoma and to pancreatic cancer.


Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria

A rare mitochondrial DNA depletion syndrome characterized by neonatal or infantile onset of global developmental delay, hypotonia, failure to thrive, progressive neurologic decline, sensorineural deafness, and movement disorder. Seizures, external ophthalmoplegia, polyneuropathy, cardiomyopathy, and renal tubular dysfunction have also been reported. Brain imaging may show T2-weighted hyperintensities in the basal ganglia, and laboratory examination may reveal lactic acidosis and mild methylmalonic aciduria.


Mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy

A rare mitochondrial DNA depletion syndrome characterized by neonatal or infantile onset of hypotonia, failure to thrive, global developmental delay, and persistent lactic acidosis. The disease course is variable and ranges from intractable diarrhea and respiratory failure with fatal outcome in early infancy to a milder phenotype with survival into childhood. Additional reported features include sensorineural hearing loss, microcephaly, seizures, pigmentary retinopathy, and renal tubulopathy.


Mitochondrial DNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies

A rare mitochondrial DNA depletion syndrome characterized by congenital or early-onset lactic acidosis, hypotonia, and severe global developmental delay with feeding difficulties and failure to thrive. It is frequently associated with variable dysmorphic facial features. Additional manifestations include seizures, movement disorders, and cardiac and ophthalmologic anomalies, among others. Brain imaging may show generalized atrophy and white matter abnormalities.


Mitochondrial DNA depletion syndrome, encephalomyopathic form is a group of mitochondrial DNA maintenance syndrome diseases characterized by predominantly neuromuscular manifestations with typically infantile onset of hypotonia, lactic acidosis, psychomotor delay, progressive hyperkinetic-dystonic movement disorders, external ophtalmoplegia, sensosineural hearing loss, generalized seizures and variable renal tubular dysfunction. It may be associated with a broad range of other clinical features.


A rare immune disease characterized by severely reduced mitochondrial DNA content due to DGUOK deficiency typically manifesting with early-onset liver dysfunction, psychomotor delay, hypotonia, rotary nystagmus that develops into opsoclonus, lactic acidosis and hypoglycemia.

Summary:
Epidemiology
Prevalence of Mitochondrial DNA depletion syndrome, hepatocerebral form due to DGUOK deficiency (DGUOK-MDS) is unknown. However, more than 100 cases of MDS have been described, DGUOK deficiency being one of the most common causes of hepatocerebral form of mitochondrial DNA depletion syndromes.
Clinical description
In most cases, DGUOK-MDS presents as a multi-organ disease in the first week of life with hypoglycemia and lactic acidosis followed by development of hepatic and neuromuscular dysfunction within weeks of birth. Neuromuscular manifestations include hypotonia, psychomotor delay which progresses to developmental regression, typical rotary nystagmus developing into opsoclonus, and severe myopathy. Liver involvement includes jaundice, cholestasis (usually intrahepatic), hepatomegaly, and elevated serum transaminases, conjugated bilirubinemia and ferritin. Hepatic dysfunction frequently progresses to neonatal- or infantile-onset liver failure with coagulopathy, ascites, and edema. In a minority of cases, patients initially present isolated liver disease (with onset in infancy or early childhood). Development of mild hypotonia and renal involvement in these latter patients may be observed.
Etiology
DGUOK-MDS results from mitochondrial DNA depletion resulting from biallelic mutations in the DGUOK (2p13.1) gene, which codes for mitochondrial deoxyguanosine kinase involved in the mitochondrial nucleotide synthesis. The mitochondrial DNA deletion leads to insufficient production of key subunits of mitochondrial respiratory chain complexes causing insufient energy production. The reasons for tissue-specific clinical expression of the disease are not yet understood.
Diagnostic methods
Diagnosis is suggested by the clinicopathological correlation of hepatoencephalopathic signs and symptoms with the finding of reduced mitochondrial DNA copy numbers in liver or muscle (typically >20% of control in liver). It is confirmed by the presence of biallelic pathogenic mutations in the DGUOK gene. Elevated serum concentration of tyrosine or phenylalanine on newborn screening is suggestive of the disease and should prompt further examination. Respiratory chain enzyme assays in liver reveal a combined deﬁciency of complex I, III, and IV. Liver histology typically shows microvesicular cholestasis while electron microscopy usually reveals increased number of mitochondria with abnormal cristae.
Differential diagnosis
Differential diagnosis includes the other hepatocerebral mitochondrial depletion syndromes, namely due to mutations in the POLG, MPV17 or TWNK genes.
Antenatal diagnosis
Prenatal testing is possible if pathogenic variants have been previously identified in the family.
Genetic counseling
DGUOK-MDS is inherited in an autosomal recessive manner. Parents of an affected child should be informed of the 25% risk of disease recurrence among future offspring.
Management and treatment
Treatment is mostly directed towards providing symptomatic management, as currently no efficacious treatment exists. Diet modulation (e.g. fractional meals, nocturnal enteric nutrition, uncooked cornstarch and formulas with enriched medium-chain triglyceride content), as well as cofactor supplementation, may be beneficial. Liver transplantation is usually reserved for patients with isolated liver disease, as in patients with multi-organ involvement transplantation provides no survival benefit.
Prognosis
Prognosis is generally poor. Vital prognosis is typically engaged before four years of age.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Dr Ayman EL-HATTAB


Mitochondrial DNA depletion syndrome, hepatocerebrorenal form

A rare, genetic, mitochondrial DNA depletion syndrome characterized by neonatal or early-infantile onset hepatopathy (manifesting with hepatomegaly, cholestasis, increased transaminases, coagulopathy, hypoalbuminemia, ascites, and/or liver failure), associated with renal tubulopathy and progressive neurodegenerative manifestations, which include muscular atrophy, hyporeﬂexia, ataxia, sensory neuropathy, epilepsy, sensorineural hearing impairment, psychomotor regression, athetosis, nystagmus, and/or ophthalmoplegia. Patients typically present with recurrent vomiting, severe failure to thrive, feeding difficulties, and fasting hypoglycemia.


Mitochondrial DNA depletion syndrome, myopathic form

A rare mitochondrial DNA depletion syndrome characterized by muscle weakness, and progressive, generalized hypotonia due to depletion of mtDNA in skeletal muscles. Clinical progression ranges from rapid and early fatal course due to respiratory failure, to slowly progressive myopathy over the course of childhood or even early adulthood.


A clinically heterogeneous group of mitochondrial disorders characterized by a reduction of the mitochondrial DNA copy number in affected tissues without mutations or rearrangements in the mitochondrial DNA. It is phenotypically heterogeneous, and can affect a specific organ or a combination of organs, with the main presentations described being either hepatocerebral (i.e. hepatic dysfunction, psychomotor delay), myopathic (i.e. hypotonia, muscle weakness, bulbar weakness), encephalomyopathic (i.e. hypotonia, muscle weakness, psychomotor delay) or neurogastrointestinal (i.e gastrointestinal dysmotility, peripheral neuropathy). Additional phenotypes include fatal infantile lactic acidosis with methylmalonic aciduria, spastic ataxia (early-onset spastic ataxia-neuropathy syndrome), and Alpers syndrome.


Mitochondrial DNA-associated Leigh syndrome

Maternally inherited Leigh syndrome is a rare subtype of Leigh syndrome (see this term) characterized clinically by encephalopathy, lactic acidosis, seizures, cardiomyopathy, respiratory disorders and developmental delay, with onset in infancy or early childhood, and resulting from maternally-inherited mutations in mitochondrial DNA.


Mitochondrial DNA-related cardiomyopathy and hearing loss

A rare mitochondrial disease that has a heterogeneous clinical presentation characterized by the association of progressive sensorineural hearing loss with hypertrophic cardiomyopathy and, in the majority of cases, encephalomyopathy symptoms such as ataxia, slurred speech, progressive external opthalmoparesis (PEO), muscle weakness, myalgia, and exercise intolerance.


Maternally-inherited mitochondrial dystonia is a rare neurological mitochondrial DNA-related disorder characterized clinically by progressive pediatric-onset dystonia with variable degrees of severity.


Mitochondrial DNA-related mitochondrial myopathy

A group of rare mitochondrial oxidative phosphorylation disorders due to mitochondrial DNA anomalies characterized by progressive, most commonly proximal, myopathy with variable degrees of weakness, exercise-induced muscle pain, and fatigue. Progressive external ophthalmoplegia is often observed. Additional features include neurological signs and symptoms (such as seizures, stroke-like episodes, or developmental delay), cardiomyopathy, involvement of liver, kidneys, and gastrointestinal tract, and diabetes. Lactic acidosis is frequently present, while recurrent rhabdomyolysis and myoglobinuria are rare. Muscle biopsy may reveal the presence of ragged-red fibers and a mosaic pattern of cytochrome c oxidase-negative fibers.


Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency

A rare mitochondrial oxidative phosphorylation disorder with complex I and IV deficiency characterized by lactic acidosis, hypotonia, hypertrophic cardiomyopathy and global developmental delay. Other clinical features include feeding difficulties, failure to thrive, seizures, optic atrophy and ataxia.


A rare neurodegenerative disorder characterized by iron accumulation in specific regions of the brain, usually the basal ganglia, and associated with slowly progressive pyramidal (spasticity) and extrapyramidal (dystonia) signs, motor axonal neuropathy, optic atrophy, cognitive decline, and neuropsychiatric abnormalities.

Summary:
Epidemiology
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an extremely rare disease with an estimated worldwide prevalence of about 1/1,000,000. MPAN accounts for approximately 6-10% of cases neurodegeneration with brain iron accumulation (NBIA) cases, with less than 80 cases reported to date.
Clinical description
MPAN usually manifests during childhood (mean age: 10 years), but cases during adolescence or adulthood have been reported too. It presents with gait difficulty, dysarthria and bilateral optic atrophy. Early upper motor neuron signs (pyramidal signs, e.g. spasticity) are constant findings and are later followed by signs of lower motor neuron dysfunction (deep tendon reflex loss, muscular weakness and atrophy). Progressive dystonia, parkinsonism, cognitive decline, and neuropsychiatric symptoms are present in more than half of the patients. Weight loss and bowel and/or bladder dysfunction are common.
Etiology
MPAN is caused by mutations in the chromosome 19 open reading frame 12 gene (C19orf12 ; 19q13.11). A founder mutation (c.204_214del11 (p.Gly69ArgfsX10)) has been described in Eastern Europe. The function of C19orf12 remains uncertain, but it may be involved in mitochondrial function, lipid homeostasis and coenzyme A metabolism.
Diagnostic methods
Diagnosis is based on neuroimaging that shows evidence of iron deposits mainly in the globus pallidus and substantia nigra, often with unique T2-hyperintense streaking between the hypointense internal globus pallidus and external globus pallidus. Ophthalmologic examinations and evoked visual potentials are important to identify optic atrophy. Neuropathologic examination shows axonal spheroids, Lewy bodies and hyperphosphorylated tau-containing inclusions. Mutation analysis of the C19orf12 gene confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes other NBIAs, more particularly fatty acid hydroxylase-associated neurodegeneration and PLA2G6-associated neurodegeneration. Spasticity, more prominent than dystonia, optic atrophy, motor neuropathy, and a slowly progressive course with cognitive decline help to differentiate MPAN from the other NBIAs.
Antenatal diagnosis
Prenatal diagnosis may be available for families in which disease-causing mutations have been identified in a previous affected sib.
Genetic counseling
MPAN is an autosomal recessive disorder. It is more common in consanguineous families or families of the same origin (i.e. both parents from the same small town). Parents of a patient with MPAN are obligate carriers. The risk of having an affected child in further pregnancies is of 25%.
Management and treatment
There is currently no curative treatment. Management strategies focus on the medical and surgical palliation of symptoms. Follow-up by a multidisciplinary team formed by neurologists, geneticists, ophthalmologists, physiotherapists, occupational therapists, speech and language therapists, orthopedic surgeons, and neurosurgeons is essential.
Prognosis
The progression of MPAN is usually slow and may lead to loss of independent ambulation due to spasticity, dystonia and parkinsonism; limited communication due to dysarthria and cognitive decline; and severe dementia. Life expectancy is variable. Premature death may occur due to secondary complications such as aspiration pneumonia.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Dr Carmen ESPINÓS


Mitochondrial myopathy and sideroblastic anemia belongs to the heterogeneous family of metabolic myopathies. It is characterised by progressive exercise intolerance manifesting in childhood, onset of sideroblastic anaemia around adolescence, lactic acidaemia, and mitochondrial myopathy.

Summary:
Epidemiology
Less than 10 cases have been described so far.
Etiology
A 656C-->T mutation in the nuclear pseudouridine synthase 1 gene (PUS1), localised to 12q24.33, has recently been identified in some patients. Deficient pseudouridylation of mitochondrial tRNAs may be responsible for the oxidative phosphorylation disorder.
Diagnostic methods
Muscle biopsy demonstrates low activity of complexes 1 and 4 of the respiratory chain and paracrystalline inclusions can be revealed in most mitochondria by electron microscopy.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            June 2006


Mitochondrial myopathy with reversible cytochrome C oxidase deficiency

A rare, genetic, mitochondrial oxidative phosphorylation disorder characterized by a potentially life-threatening, severe myopathy manifesting in the neonatal to early infantile period, followed by marked, spontaneous improvement of muscular function by early childhood. Associated biochemical findings include lactic acidosis and a transient, marked decrease in respiratory chain activity.


Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome

A rare mitochondrial myopathy characterized by motor developmental delay (in infancy), growth impairment and mostly proximal muscle weakness caused by a muscular dystrophy. Muscle biopsy presents myopathic abnormalities and decreased mtDNA content. Electromyography (EMG) shows a myopathic process and serum creatine kinase is increased. The disease is also characterized by early onset non-progressive cerebellar atrophy (particularly cerebellar vermis and hemispheres), corticospinal tract dysfunction, and global or partial cerebral atrophy on brain MRI. Additionally, some patients presented with cognitive deficiencies, skeletal abnormalities, tremors, and retinopathy.

Summary:
Epidemiology
Approximately 30 cases have been reported worldwide.
Clinical description
Onset generally occurs in newborns, children or adolescents. First symptoms are often observed during the postnatal period: ataxia (secondary to cerebellar atrophy) and proximal muscle weakness. The condition of patients progressively deteriorates during childhood with delayed motor (delayed walking between 2 and 8 years old) and cognitive development. Although cognitive capacities might be normal, most of the children present learning difficulties and intellectual disabilities. In early adolescence, patients show decreased height and weight compared to the average, with an inability to perform complex motor movements. Other symptoms include dysmetria, tremor, dysarthria, adiadochokinesia, and skeletal abnormalities. Pigmentary retinopathy is rarely reported. In patients carrying a dominant mutation, these clinical signs appear later (late adolescence or adulthood).
Etiology
The disease is caused by biallelic mutations in the MSTO1 gene located on chromosome 1q22 with autosomal recessive inheritance. Only one family was described with an apparently autosomal dominant inheritance (mutation c.22 G > A p.Val8Met). MSTO1 encodes for a mitochondrial fusion protein, localized in the cytoplasm and on the outer membrane of the mitochondria. The mutation inactivates the protein leading to a fragmented mitochondrial network.
Diagnostic methods
Diagnosis relies primarily on clinical presentation of cerebellar ataxia and mitochondrial myopathy. MRI shows hypotrophy or damage to the cerebellum. Electromyography confirms the muscular involvement. Muscle biopsies show marked variation in fiber size, with severe atrophy of type I fibers and decreased mtDNA content. Levels of the biomarker creatine kinase, fibroblast growth factor 21 or growth/differentiation factor-15 are increased. Despite the mitochondrial origin, diagnostic criteria based on oxygen consumption or respiratory chain complex activities are not informative for these patients. Cognitive capacities tests support the diagnosis. Sequencing of the MSTO1 gene confirms diagnosis.
Differential diagnosis
Differential diagnoses include Marinesco-Sjögren syndrome, alpha-dystroglycanopathies, Kearns-Sayre syndrome, mitochondrial myopathies, neurogenic muscle weakness-ataxia-retinitis pigmentosa (NARP) syndrome, some hereditary spastic paraplegia (AP5Z1 gene mutations), Leigh syndrome, PMM2-congenital glycosylation disorder, and Pelizaeus-Merzbacher-like 1 disease.
Antenatal diagnosis
Prenatal diagnosis is possible when MSTO1 variants have been previously identified in the family.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples informing them of the 25% risk of having an affected child at each pregnancy. In a very few cases, the pattern of inheritance is autosomal dominant. Genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
No curative treatments have been identified. Physiotherapy remains the best long-term management for patients.
Prognosis
Cerebellar atrophy progresses during childhood and stabilizes in early adolescence. After adolescence, the condition appears to stabilize. Above 50 years of age, prognostic data is limited.

                            Last update:
                            December 2021

                            - Expert reviewer(s):
                            Pr Alessandra FERLINI  - Dr Marcella NERI


Mitochondrial myopathy-lactic acidosis-deafness syndrome

A rare metabolic myopathy presenting during childhood, and characterized clinically by growth failure, severe muscle weakness, and moderate sensorineural deafness and biochemically by metabolic acidosis, elevated serum pyruvate concentration, hyperalaninemia and hyperalaninuria. There have been no further descriptions in the literature since 1973.


Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE) syndrome is characterized by the association of gastrointestinal dysmotility, peripheral neuropathy, chronic progressive external ophthalmoplegia and leukoencephalopathy.

Summary:
Epidemiology
So far, just under 100 sporadic and familial cases have been reported.
Clinical description
The first clinical manifestations generally appear between the ages of 10 and 40 (most often before 20 years of age). The symptoms are progressive and the clinical picture is dominated by severe gastrointestinal disorders (cramping, vomiting, diarrhea, intestinal pseudo-obstruction, dysphagia and gastroparesis) due to abnormal bowel motility. Gastrointestinal disorders gradually progress to chronic pseudo-obstruction leading to cachexia. Neurological involvement includes chronic progressive ophthalmoplegia with or without ptosis, and sensorimotor peripheral neuropathy. Cerebral imaging often reveals subclinical leukodystrophy. Deafness, pigmentary retinopathy, and cerebellar involvement are less frequent findings and are not defining features of the syndrome. Patients are usually thin with short stature. Morphological studies of the muscles reveal the presence of a low proportion of muscle fibers with mitochondrial proliferation (ragged-red fibers) or cytochrome c oxidase deficiency.
Etiology
MNGIE syndrome is inherited in an autosomal recessive manner and is caused by mutations in the TYMP gene (22q13.32-qter), encoding a protein involved in thymidine phosphorylation. These mutations lead to total abolition of enzyme activity, thymidine and deoxyuridine accumulation in body fluids and tissues, and imbalanced mitochondrial DNA replication and repair leading to multiple deletions and sometimes partial depletion.
Diagnostic methods
Diagnosis is based on measurement of thymidine phosphorylase activity in leukocytes (absence of activity in symptomatic individuals and reduced activity in asymptomatic heterozygous individuals), and on genetic analysis.
Differential diagnosis
Differential diagnoses include similar disorders with phenotypes that overlap between MNGIE and MELAS, MERRF or progressive external ophthalmoplegia (PEO; see these terms), for example patients with prominent gastrointestinal symptoms and genetic alterations either in the mitochondrial DNA (such as the MT-TL1 or MT-TK genes with the m.3243A>G ``MELAS'' mutation or the m.8313G>A ``MERRF'' mutation) or in the nuclear POLG gene encoding DNA polymerase gamma (responsible for mitochondrial DNA replication and implicated in PEO).
Management and treatment
Management is mainly symptomatic, involving treatment of the chronic intestinal pseudo-obstruction. Thymidine and deoxyguanosine clearance appears to be an efficient approach. However, hemodialysis is not an effective treatment due to the rapid re-accumulation of compounds between sessions. Bone marrow transplantation has been performed on a few patients with promising results (stabilization of the disease course).
Prognosis
The prognosis is unfavorable due to the severity of the digestive involvement with infections and the need for permanent parenteral nutrition.

                            Last update:
                            November 2009

                            - Expert reviewer(s):
                            Dr Anne LOMBES


A group of clinically heterogeneous diseases, commonly defined by lack of cellular energy due to defects of oxidative phosphorylation (OXPHOS), resulting from pathogenic mutations in the nuclear DNA. Mitochondrial oxidative phosphorylation disorder due to nuclear DNA anomalies includes diseases classified according to defects in: genes encoding structural components of OXPHOS complexes (such as Leigh syndrome, coenzyme Q10 deficiency); genes encoding assembly factors of OXPHOS complexes (such as GRACILE syndrome); genes altering the stability of mitochondrial DNA (such as autosomal dominant progressive external ophthalmoplegia, mitochondrial DNA depletion syndrome); mitochondrial protein synthesis.


Mitochondrial pyruvate carrier deficiency

A rare pyruvate metabolism disorder characterized by neonatal onset of a mitochondrial encephalopathy with global developmental delay and the biochemical characteristics of lactic acidosis and increased serum pyruvate with normal lactate/pyruvate ratio. Additional reported manifestations include epilepsy, peripheral neuropathy, hypotonia, nystagmus, extensor plantar responses, hepatomegaly, and craniofacial dysmorphism (such as progressive microcephaly, epicanthus, long philtrum, and thin upper lip).


Mitochondrial trifunctional protein deficiency

A rare disorder of fatty acid oxidation characterized by a wide clinical spectrum ranging from severe neonatal manifestations including cardiomyopathy, hypoglycemia, metabolic acidosis, skeletal myopathy and neuropathy, liver disease and death to a mild phenotype with peripheral polyneuropathy, episodic rhabdomyolysis and pigmentary retinopathy..

Summary:
Epidemiology
TFPD has been reported in less than 100 cases in the literature.
Clinical description
The neonatal onset, severe form manifests as hepatic steatosis, cardiomyopathy, skeletal myopathy and neuropathy and is usually fatal. A moderately severe form, with onset usually from the neonatal period to 18 months of age, presents primarily with hypoketotic hypoglycemia and metabolic acidosis which is often precipitated by prolonged fasting and/or intercurrent illness. Both forms can manifest with neuropathy with or without cardiomyopathy and can be fatal. The mild form merges with the moderately severe infantile form and can present from a few months of age until adolescence as a peripheral polyneuropathy with episodic rhabdomyolysis triggered by prolonged fasting, illness, exercise or exposure to heat or cold. There is respiratory failure associated with the episodes of rhabdomyolysis. A pigmentary retinopathy may also develop over time. Very occasionally, adults presenting for the first time with a previously unrecognized disease are described.
Etiology
The TFP, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids which are the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase (LCEH), and long-chain thiolase (LCTH) steps. The HADHA gene (2p23) encodes the LCEH and LCHAD enzymes and the HADHB gene (2p23) encodes the LCTH enzyme. Two mutations in either one of these two genes causes TFPD.
Diagnostic methods
Urine organic acids may show a C6-C14 (hydroxy) dicarboxylic aciduria, and blood acylcarnitine analysis often shows increased long chain hydroxyacyl carnitine species (C14-OH, C16-OH, C18-OH, C18:1-OH). Both urine and blood markers are less reliable and more variable than those seen in LCHAD deficiency (see this term). This is because defects in LCEH may block the formation of hydroxy-metabolites. Reduced enzyme activity in at least two (usually all 3) enzymes in cultured fibroblasts is seen. Molecular analysis confirming bi-allelic non-1528C>G mutations in the HADHA gene or bi-allelic mutations in the HADHBgene confirms diagnosis. Newborn screening is available in Austria, Czech Republic, Denmark, Germany, Hungary, Iceland, Netherlands and Portugal.
Differential diagnosis
Sudden infant death syndrome and isolated LCHAD deficiency (see this term) form part of the differential diagnosis. LCHAD deficiency is clinically indistinguishable from severe TFPD.
Antenatal diagnosis
Prenatal diagnosis is possible by analyzing enzyme activity in chorionic villi samples, once a deficiency of TFP has been established in the index case/family. Molecular analysis is the preferred option when two mutations have been identified in a family.
Genetic counseling
TFPD is an autosomal recessive disorder and genetic counseling is possible.
Management and treatment
Treatment involves adherence to a low fat diet with restriction of long chain fatty acid intake and substitution with medium chain fatty acids. Fasting and exposure to environmental extremes must be strictly avoided and exercise should be limited.
Prognosis
Prognosis for the severe neonatal form of TFPD is very poor. The later onset mild form has a far more favorable prognosis.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Simon OLPIN


A rare congenital non-syndromic heart malformation characterized by an imperforate or absent mitral valve. In most cases, there is a univentricular atrioventricular connection to a dominant right ventricle via a tricuspid valve, and a hypoplastic left ventricle. Morphologic heterogeneity is considerable, and hemodynamic picture and clinical manifestation depend on the type and severity of associated cardiovascular anomalies (such as ventricular septal defect or aortic atresia).


Mitral valve agenesis is a rare congenital heart malformation defined as an agenesis or severe hypoplasia of both mitral valve leaflets (complete agenesis) or one of the leaflets (partial agenesis). Complete mitral valve agenesis presents in the neonatal period with symptoms of severe mitral regurgitation and is rapidly fatal unless surgically treated. It is frequently associated with other heart malformations. Partial mitral valve agenesis may present at various ages, usually with symptoms of mitral regurgitation.


Mixed autoinflammatory and autoimmune syndrome

A group of systemic diseases characterized by mixed patterns of dysregulated innate and/or adaptive immune responses, leading to chronic activation of the immune system and tissue inflammation, which presents clincally with a wide range of variable, concomitant, autoimmune and autoinflammatory manifestations in various organ systems.


Mixed connective tissue disease (MCTD) is a rare connective tissue disorder combining clinical features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis (PM) (see these terms) and/or rheumatoid arthritis (RA).

Summary:
Epidemiology
The exact prevalence of MCTD is unknown, except in Japan where it is estimated at 1/37,000. MCTD is found in all ethnic groups with a female-to-male ratio of approximately 10:1.
Clinical description
Onset usually occurs between 15 and 35 years old. Common clinical signs include Raynaud's phenomenon (see this term), arthralgia/arthritis, swollen hands/puffy fingers, sclerodactyly, and myositis. Some patients may also complain of esophageal hypomotility, lupus-like or dermatomyositis-like rashes, trigeminal neuralgia, pleuritis, pericarditis and/or pulmonary hypertension. Nonspecific constitutional symptoms such as fatigue, general malaise or low-grade fever (which should always prompt a careful search for infection) can also be observed during flares.
Etiology
The exact cause of MCTD is still unknown, but abnormal B- and T-cell immune responses against apoptotically modified self-antigens may be observed in MCTD patients.
Diagnostic methods
Most patients have high titers (often >1:1000) of anti-U1-ribonucleoprotein (RNP) and anti-U1-70 kd autoantibodies. The diagnosis of MCTD relies on overlapping features of SLE, SSc, PM, or RA (or when additional overlapping features are present in patients with a well-defined connective tissue disease) and on blood test results indicating high titers of anti-U1-RNP antibodies with normal titers of other connective tissue disease antibodies (except anti-SSA and/or anti-SSB antibodies in cases with secondary Sjögren syndrome; see this term).
Differential diagnosis
Differential diagnoses include other connective tissue diseases such as SLE, SSc, PM and/or RA, and other systemic diseases such as sarcoidosis, periarteritis nodosa, or Still's disease (see these terms).
Management and treatment
Management of MCTD is similar to that of the various overlapping connective tissue diseases. NSAIDs, antimalarials, or low-dose corticosteroids are effective for the minor or mild disease while corticosteroids (approximately 0.5-1mg/kg/day) are effective for moderate to severe disease. Higher doses of corticosteroids and additional immunosuppressants may be administered in case of severe visceral involvement. Symptomatic treatment (eg: treatment of Raynaud's phenomenon) is also of major importance.
Prognosis
MCTD is a chronic relapsing-remitting disease. The overall 10-year survival rate of the disease is approximately 80%. In general, the prognosis is favorable but it is largely dependent on which visceral manifestations of MCTD predominate. Patients with features of SSc or PM are thought to have the worst prognosis, and pulmonary hypertension has been recognized as the most frequent disease-associated cause of death.

                            Last update:
                            October 2009

                            - Expert reviewer(s):
                            Pr Zahir AMOURA  - Pr Laurent ARNAUD


A clinico-serological subtype of mixed cryoglobulinemia syndrome, an immune complex disorder, characterized by purpura, weakness and arthralgia and defined immunochemically by cryoglobulins composed of polyclonal IgGs (autoantigens) and monoclonal IgM (autoantibody).


A clinico-serological subtype of mixed cryoglobulinemia syndrome, is an immune complex disorder, characterized by purpura, weakness and arthralgia and defined immunochemically by cryoglobulins containing both polyclonal IgGs and polyclonal IgMs.


A rare common cystic lymphatic malformation characterized by a benign cystic lesion composed of dilated lymphatic channels. Mixed cystic lesions consist of cysts both larger (macrocystic) and smaller (microcystic) than 1 cm in diameter. They usually present at birth or during the first years of life and most often occur in the head and neck region but may affect any site. Symptoms depend on the location and extent of the lesion. Infection, trauma, or intracystic hemorrhage can lead to lesional expansion. Malignant transformation does not occur.


A rare germ cell tumor characterized by composition of two or more malignant germ cell components, the most common combination being dysgerminoma and yolk sac tumor. The tumors typically occur between childhood and young adulthood. They are usually located in the gonads, occasionally also in other regions. Clinical presentation corresponds to the individual germ cell components and the tumor location; manifestations may include abdominal pain, abdominal mass, and menstrual disorder in females, and a testicular mass in males. The most important prognostic factor is tumor stage.


Mixed neuroendocrine and non-neuroendocrine neoplasm of pancreas

A rare neuroendocrine neoplasm of pancreas characterized by morphologically recognizable neuroendocrine and non-neuroendocrine components, each constituting at least 30% of the tumor volume. Based on histopathology, mixed ductal- and mixed acinar-neuroendocrine carcinomas are distinguished. Patients usually present with unspecific symptoms related to tumor growth and/or metastasis, although occurrence of Zollinger-Ellison syndrome has been reported. Resectability of the tumor is the most important prognostic factor.


A group of rare acute leukemias of ambiguous lineage characterized by the presence of separate populations of blasts of more than one lineage (bilineal), a single population of blasts coexpressing antigens of more than one lineage (biphenotypic), or a combination thereof. The diagnosis relies on immunophenotyping, the T-cell component being characterized by strong expression of cytoplasmic CD3, usually in the absence of surface CD3, the B-cell component expressing CD19, almost always together with CD10, cCD79a, CD22, or PAX5, while the most specific hallmark of the myeloid component is the presence of myeloperoxidase in the blast cytoplasm.


Mixed sclerosing bone dystrophy with extra-skeletal manifestations

A rare, genetic, primary bone dysplasia with increased bone density disorder characterized by bone abnormalities, including metaphyseal plaques, osteopathia striata, marked cranial sclerosis, and sclerosis of the ribs and long bones, as well as macrocephaly, cleft palate, hearing loss, developmental delay, and facial dysmorphism (hypertelorism, prominent forehead, wide nasal bridge). Hypotonia, tracheo-/laryngomalacia, and astigmatic myopia are also associated.


Mixed autoimmune hemolytic anemia is a type of autoimmune hemolytic anemia (AIHA; see this term) defined by the presence of both warm and cold autoantibodies, which have a deleterious effect on red blood cells at either body temperature or at lower temperatures.

Summary:
Epidemiology
Mixed AIHA occurs in less than 10% of cases of AIHA, whose annual incidence is between 1/35,000-1/80,000 in North America and Western Europe.
Clinical description
Mixed AIHA can occur at any age but is rare in children. Patients with mixed AIHA usually present with abrupt onset severe hemolysis and anemia.
Etiology
Mixed AIHA can be idiopathic or secondary, mainly associated with systemic lupus erythematosus (SLE) and lymphoma.
Diagnostic methods
Diagnosis is based on clinical or laboratory evidence of hemolytic anemia and the detection of autoantibodies, usually both IgG and IgM, with the direct anti-globulin test (DAT) showing a pattern of IgG with complement C3, and the presence of cold agglutinins (IgM) in the serum at a significant titer.
Differential diagnosis
Erroneous diagnosis of mixed AIHA is sometimes made on the basis of inadequate serologic studies as a large proportion of patients with warm AIHA also have cold autoantibodies that are measured but are clinically insignificant. Unless a cold autoantibody with a high thermal amplitude (>30 degrees C) is observed in association with a warm autoantibody, a diagnosis of mixed AIHA is not warranted.
Management and treatment
The principles of management are comparable to that of warm AIHA (see this term), including corticosteroids and, if these are ineffective, splenectomy, but avoidance of cold must also be considered. Cautious transfusion is possible in cases with severe anemia. However, the best compatible or ``least incompatible'' packed red blood cell units must be identified by the blood centre to avoid post-transfusional hemolysis.
Prognosis
The disease responds to corticosteroids, and may be followed by remission, but usually runs a chronic course with intermittent exacerbations.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Pr Marc MICHEL


A recessive distal myopathy characterized by weakness in the distal lower extremity posterior compartment (gastrocnemius and soleus muscles) and associated with difficulties in standing on tip toes.

Summary:
Epidemiology
Miyoshi myopathy (MM) is the most common form of recessive distal myopathy in populations with founder mutations such as Libyan and Israeli Jewish population, Italian and Spanish populations.
Clinical description
The typical age of onset of MM lies between 15 and 30 years (median 19 years) and the disease is characterized by muscle atrophy usually symmetric especially of the calf muscles (soleus and gastrocnemius). Onset in the anterior tibial muscles has been rarely reported. Ankle muscle stretch reflexes are lost and difficulties for toe walking or climbing stairs are encountered. Exercise-induced myalgia and aching discomfort in the calves can be an early symptom. Anterior compartment muscles of the distal lower extremities eventually become weak as well. As the disease progresses, patients will develop proximal leg and arm weakness to varying degrees. Decrease in respiratory functions have been reported only in few patients with moderate to severe disease. Bulbar or symptoms have not been reported.
Etiology
MM is caused by mutations in the DYSF gene (2p13), which encodes dysferlin. The latter orchestrates skeletal muscle membrane repair and has also been associated with myogenesis, angiogenesis and microtubule dynamics.
Diagnostic methods
Diagnosis of MM relies on laboratory findings showing an elevated serum creatine kinase level (20 to 150 times the normal), muscle biopsy routine reveals dystrophic features. Western blotting may help in cases with uncertain immunohistochemistry findings. Magnetic resonance imaging (MRI) of calf muscles show typical fatty replacement. EMG reveals 'myopathic' motor units and recruitment patterns. Diagnosis is confirmed by the genetic screening of DYSF.
Differential diagnosis
Differential diagnosis includes autosomal recessive limb-girdle muscular dystrophy type 2L (LGMD2L), LGMD2B and qualitative or quantitative defects of caveolin-3.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.
Management and treatment
No definitive treatments for MM exist and management is mainly supportive. To prolong survival and improve quality of life, weight control to avoid obesity, physical therapy and stretching exercises to promote mobility and use of mechanical aids to help ambulation and mobility are recommended.
Prognosis
Progression is variable with some patients remaining fairly stable with distal weakness, while others can have a more aggressive pattern involving both proximal and distal muscles. Patients may become wheelchair bound 10-30 years after onset of symptoms. Disease progression is usually related to disease duration rather than age of onset of symptoms.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Dr Johanna PALMIO


MME-related autosomal dominant Charcot Marie Tooth disease type 2

A rare autosomal dominant hereditary axonal motor and sensory neuropathy characterized by adult onset of slowly progressive distal muscle weakness and atrophy, sensory impairment, and hyporeflexia beginning in the lower limbs. Progressive gait disturbance may lead to loss of independent ambulation in some patients at a higher age.


The MMEP syndrome is a congenital syndromic form of split-hand/foot malformation (SHFM; see this term). It is characterized by microcephaly, microphthalmia, ectrodactyly of the lower limbs and prognathism. Intellectual deficit has been reported. MMEP syndrome is considered to be a very rare condition, although the exact prevalence remains unknown. The etiology is not completely understood. Disruption of the sorting nexin 3 gene (SNX3; 6q21) has been shown to play a causative role in MMEP, although this was not confirmed in recent studies.


Moderate and severe traumatic brain injury

A rare neurologic condition characterized by brain damage caused by an external mechanical force, with a Glasgow Coma Scale score of 9 to 12 in moderate traumatic brain injury (TBI), or 3 to 8 in severe TBI, respectively. TBI can be closed (with the dura mater remaining intact) or open (with penetration of the dura mater) and may lead to focal damage, such as cerebral contusion and hemorrhage, as well as diffuse axonal injury and secondary damage due to increased intracranial pressure. Signs and symptoms are highly variable, depending on the nature, severity, localization, and extent of the trauma.


A moderately severe form of hemophilia A characterized by factor VIII deficiency (biological activity between 1 and 5 IU/dL) leading to abnormal bleeding as a result of minor injuries, or following trauma, surgery or tooth extraction. Spontaneous hemorrhages are rare. The condition primarily affects males but may also be observed in female carriers of disease-causing mutations.


A moderately severe form of hemophilia B characterized by factor IX deficiency (biological activity 1-5 IU/dL) leading to abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction. Spontaneous hemorrhages are rare. The condition primarily affects males but may also be observed in female carriers of disease-causing mutations.


MODY (maturity-onset diabetes of the young) is a rare, familial, clinically and genetically heterogeneous form of diabetes characterized by young age of onset (generally 10-45 years of age) with maintenance of endogenous insulin production, lack of pancreatic beta-cell autoimmunity, absence of obesity and insulin resistance and extra-pancreatic manifestations in some subtypes.

Summary:
Epidemiology
MODY is the most common form of monogenic diabetes. Prevalence is estimated to be about 1/10,000 in adults and 1/23,000 in children. No specific ethnic predilection has been reported. It has been estimated that around 80% of cases are misdiagnosed as type 1 or type 2 diabetes, thus complicating prevalence and incidence estimations.
Clinical description
The clinical features of MODY vary depending on the genetic etiology. The most frequent subtypes are HNF1A-MODY (30-50%), GCK-MODY (30-50%), HNF4A-MODY (10%), and HNF1B-MODY (1-5%). The latter is also known as renal cysts and diabetes syndrome (see this term). At least 9 other genetic subtypes have been described but are very rare. Patients with HNF1A and HNF4A mutations have slowly progressing beta-cell dysfunction and respond well to treatment with low-dose sulfonylureas, which are recommended as first line therapy. Vascular complications of diabetes are observed with a similar frequency to type 1 or type 2 diabetes. Low C-Reactive Protein is seen in HNF1A-MODY and neonatal hypoglycaemia and macrosomia are reported in babies with HNF4A-MODY. GCK-MODY is characterized by asymptomatic non-progressing mild fasting hyperglycemia with low post-prandial glucose excursions from birth, is not associated with vascular complications and does not require treatment.
Etiology
Mutations in at least 13 genes have been reported to be associated with a MODY phenotype: common causes (>5% of cases): HNF1A (12q24.31), GCK (7p15.3-p15.1), HNF4A (20q13.12); rare causes (about 1% of cases): KCNJ11 (11p15.1), ABCC8 (11p15.1), INS (11p15.5), HNF1B (17q12); and very rare (described in only a few families, genetic evidence not compelling for some): CEL (9q34.3),  PDX1 (13q12.1), NEUROD1 (2q32), PAX4 (7q32.1), KLF11 (2p25) and BLK (8p23-p22).
Genetic counseling
Criteria for genetic testing for MODY include diabetes onset in adolescence or young-adulthood, maintenance of endogenous insulin production, and usually a significant family history of diabetes. Subjects will also have absence of typical features of type 1 or type 2 diabetes. Although de novo mutations can arise, cascade screening of family members is essential to ensure that those with diabetes get the correct diagnostic label and those at risk of inheriting the mutation are tested for diabetes and/or consider predictive genetic testing.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Dr Katharine OWEN


Moebius syndrome-axonal neuropathy-hypogonadotropic hypogonadism syndrome

A rare syndromic neurological disorder characterized by the association of Möbius syndrome (congenital facial palsy with impaired ocular abduction) with peripheral axonal neuropathy and hypogonadotropic hypogonadism. There have been no further reports since 1996.


A very rare congenital cranial dysinnervation disorder characterized by unilateral or bilateral non progressive congenital facial palsy (VII cranial nerve) with impairments of ocular abduction (VI cranial nerve). It can also be associated with other cranial nerves palsies, orofacial anomalies and limb defects.

Summary:
Epidemiology
Epidemiological data on Moebius syndrome (MBS) is limited. The prevalence at birth is estimated at 1/47,250 in the Netherlands. MBS occurs equally in both sexes.
Clinical description
MBS is a non-progressive disease, present at birth, characterized by high clinical heterogeneity, with frequent asymmetrical presentations. The main feature of the disorder is the paralysis of the VII cranial nerve, responsible for the facial diplegia, often asymmetric and incomplete, sparing the lower face and platysma, resulting in a mask-like facial appearance. The ocular manifestations include alterations of ocular motility with uni- or bilateral abduction defects (esotropia is the most common), ectropion, epiphora and exposure keratopathy, ophthalmoplegia and ptosis. Feeding difficulties and drooling at birth and in infancy are common. Other associated manifestations, due to other cranial nerves deficiencies include: deafness, trigeminal nerve sensitivity disorders, dysphagia, dysphonia and tongue hypoplasia. MBS may be accompanied by hypotonia and global developmental delay with infants demonstrating motor, emotional and speech difficulties. Development tends to normalize at 3 years of age but weakness in hand-eye coordination persists. Minor facial anomalies may include small palpebral fissures, epicanthic folds, hypertelorism, bifid uvula, micrognathia, and microstomia. Clubfoot is described in about 45% of cases. Hand anomalies (syndactyly, brachydactyly, ectrodactyly) and agenesis of the pectoral muscle (Poland-Moebius syndrome) are associated occasionally.
Etiology
The etiology of MBS is currently unknown. It is thought to involve abnormal development of the brainstem, intrauterine hypoxia, teratogen exposure (e.g. misoprostol or cocaine), genetically determined vascular rhombencephalic disturbances in development or an acquired ischemic event occurring after the fifth week of pregnancy. De novo mutations in the PLXND1 (3q21.3) and REV3L (6q22) genes involved in hindbrain development have been found in about 6% of cases.
Diagnostic methods
The diagnosis of MBS is based exclusively on clinical criteria, although recent studies are beginning to document causative genetic patterns. MBS can be recognized and diagnosed early during the neonatal period with electromyographic examination and brain MRI. Key clinical findings include poor or absent sucking due to incomplete closure of the lips, lack of facial mimicking (especially while crying), fixed gaze, incomplete eyelid closure during sleep and ptosis.
Differential diagnosis
Differential diagnoses include Carey-Fineman-Ziter syndrome, Oro-Mandibular-Limb hypogenesis syndrome (OMLH), Moebius-like syndrome, hypoglossia-hypodactyly syndrome and glossopalatine ankylosis.
Antenatal diagnosis
Prenatal genetic diagnosis is possible if pathogenic mutations responsible for the disease have been identified in the family (very rare cases). Clubfeet may be detected by prenatal ultrasound but is non-specific.
Genetic counseling
Most of cases of MBS follows a sporadic pattern of occurrence. Familial cases represent about 2% of all affected individuals. Recurrence in siblings of affected individuals is therefore extremely rare.
Management and treatment
Treatment and management are supportive and symptomatic. A multidisciplinary clinical approach is important in order to optimize the diagnosis, treatment and advice given to these patients. The microneurovascular transfer of a free-muscle transplant is the procedure of choice for facial paralysis and midfacial animation. Ocular manifestations are treated with standard methods. Rehabilitation therapy (physiotherapy, oral motor, psychomotor/speech therapy) must start soon as possible and adapted over time in response to functional assessments. Psychological aspects relate to the patient's facial appearance. Communication between affected infants and their parents should be taken into consideration.
Prognosis
Prognosis is strongly correlated with the degree of brainstem involvement. It is non-progressive. Most of cases with MBS have normal life expectancy; although in severe cases, early demise shortly after birth is possible.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Dr Maria Francesca BEDESCHI | ITHACA* - Dr Odoardo PICCIOLINI

                                * European Reference Network


MOGS-CDG is a form of congenital disorders of N-linked glycosylation characterized by generalized hypotonia, craniofacial dysmorphism (prominent occiput, short palpebral fissures, long eyelashes, broad nose, high arched palate , retrognathia), hypoplastic genitalia, seizures, feeding difficulties, hypoventilation, severe hypogammaglobulinemia with generalized edema, and increased resistance to particular viral infections (particularly to enveloped viruses). The disease is caused by loss-of-function mutations in the gene  MOGS  (2p13.1).


A rare X-linked syndromic intellectual disability characterized by clinical manifestations commencing with early childhood onset hearing loss, followed by adolescent onset progressive dystonia or ataxia, visual impairment from early adulthood onwards and dementia from the 4th decade onwards.

Summary:
Epidemiology
Mohr-Tranebjaerg syndrome (MTS) prevalence is unknown. More than 90 cases (37 families) are known, but not all cases have been reported in the literature.
Clinical description
The onset of rapidly progressive prelingual or postlingual sensorineural hearing loss, the only typical symptom, occurs in early childhood (18 months). The audiological phenotype is characterized by auditory neuropathy, characterized by preserved OAE (oto- acoustic emissions,) abnormal ABR (Auditory brain stem response), very poor speech discrimination, worsening in noisy environment and questionable benefit of treatment with cochlear implants (very few cases reported). Neuropsychologic manifestations, such as personality changes, paranoia, and mild intellectual deficit may emerge at the same time. A slowly progressive movement disorder, appearing as gegenhalten (diffuse resistance to limb movement), dystonia (mostly generalized or focal) or ataxia develops from early adolescence and is associated with brisk tendon reflexes, ankle clonus and extensor plantar responses. Patients experience reduced visual acuity, photophobia, acquired color vision defect and central scotomas starting from about 20 years of age and leading to legal blindness at around age 30 to 40. Slowly progressive dementia develops from the 4th decade onwards. In those with a contiguous gene deletion syndrome (CGS), recurrent infections may be present. Carrier females may be mildly affected with mild hearing impairment and focal dystonia. Despite the X linked recessive inheritance of the disease, there are a few cases where the proband was a female with dystonia.
Etiology
MTS is caused by either a mutation in the TIMM8A gene (located to Xq22) or by a CGS at Xq22, resulting in a deafness-dystonia peptide 1 (DDP1) deficiency. If the CGS includes the Bruton agammaglobulinemia tyrosine kinase (BTK) gene, recurrent infections secondary to this X-linked agammaglobulinemia (XLA) are present.
Diagnostic methods
A combination of hearing impairment and recurrent infections due to XLA in a male patient should elicit sequencing of the TIMM8A gene. Neuroimaging is employed to verify the presence of cerebral atrophy. In cases of suspected CGS; testing for XLA is possible.
Differential diagnosis
Differential diagnosis includes MELAS syndrome; mitochondrial DNA depletion syndrome (encephalomyopathic form with methylmalonic aciduria); Arts syndrome; X-linked spinocerebellar ataxia type 3 and 4; McLeod neuroacanthocytosis syndrome; Usher syndrome type 1 and 2; Wolfram syndrome; autosomal recessive nonsyndromic sensorineural deafness type DFNB; Pendred syndrome; and other forms of dystonia or rarely Friedreich ataxia.
Antenatal diagnosis
Prenatal diagnosis may be proposed to affected couples or parents for further pregnancies.
Genetic counseling
The pattern of inheritance is X-linked recessive and gentic counselling should be offerend to affected families. Where the female is a carrier, the risk to male offspring inheriting the disease is 50%, female offspring have a 50% risk of being carriers. Where a male is affected, female offspring are obligate carriers, and male offspring do not inherit the pathogenic mutation.
Management and treatment
Treatment of MTS is symptomatic and evolves over time. Hearing aids are used with variable success. For mild hearing loss, a hearing device and cochlear implants are an option whereas hearing aids with visual clues are used in cases with more severe hearing loss. The management of the hearing impairment is challenged by the fact that it is an auditory neuropathy. Management of dystonia and ataxia includes treatment with GABA-agonists together with psycho-motor re-education and physical therapy. Other supportive measures include therapies for the deaf-blind, addressing progressive sensory deficits, such as tactile sign language. In those with secondary complications, intravenous immunoglobulin may prevent infections in XLA. Furthermore, live viral vaccines should be avoided in cases of XLA. In adulthood, regular neurological evaluation (assessment for dementia and/or psychiatric manifestations) should be maintained.
Prognosis
Prognosis is poor. The combination of deafness and blindness severely affects communication, while the ongoing movement disorder results in an increasingly unstable gait. Life expectancy is highly variable and can range from death in the teenage years (after a rapidly progressive dystonia) to those that live into their 60's.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Lisbeth TRANEBJAERG


MOMO syndrome is a very rare genetic overgrowth/obesity syndrome (see this term) characterized by macrocephaly, obesity, mental (intellectual) disability and ocular abnormalities. Other frequent clinical signs include macrosomia, downslanting palpebral fissures, hypertelorism, broad nasal root, high and broad forehead and delay in bone maturation, in association with normal thyroid function and karyotype.


A rare genodermatosis characterized by a hair shaft dysplasia resulting in hypotrichosis.

Summary:
Epidemiology
The prevalence and incidence are not known.
Clinical description
Monilethrix has an early onset in infancy. Alopecia, associated with follicular hyperkeratosis and perifollicular erythema, can involve only the occiput and the nape of the neck or, in severe forms, the entire scalp, the eyebrows and eyelashes, and secondary hair. Infants show a characteristic hair shaft dysplasia: dystrophic constrictions regularly separated by elliptical nodes of normal thickness, giving a beaded appearance of affected hair. The thin internodal region shows a high propensity to break. In some cases, nail dystrophy (koilonychia) on fingers and toes has been reported. This symptomatic triad (moniliform hair, follicular hyperkeratosis and nail dystrophy), when associated with other ectodermal defects, such as as neurological, dental, and ophthalmological alterations, constitute the ''moniliform hair syndrome''.
Etiology
Four genes have been associated with monilethrix: KRT81, KRT83 and KRT86, coding for the type II hair keratins Hb1, Hb3 and Hb6, and are responsible for the autosomal dominant form of the disease. An autosomal recessive form has also been described in a few families, caused by mutations in the DSG4 gene, coding for the desmoglein 4 protein, also involved in hypotrichosis simplex (see this term) that has clinical overlap with monilethrix.
Diagnostic methods
A trichogram shows the characteristic moniliform hairs. Trichoscopy is another approach to detect the characteristic hair shaft dysplasia of monilethrix. An electron microscopy-based diagnostic test is available.
Differential diagnosis
Differential diagnosis includes pseudomonilethrix that presents with diffuse alopecia or alopecia limited to the occipital area. However, using trichogram analysis, pseudomoniletrix hair does not present with dystrophic constrictions but with flattened irregular beading.
Genetic counseling
In severe forms with alopecia and hyperkeratosis on the body, genetic counseling would be necessary.
Management and treatment
Treatment is disappointing. The best measure is to avoid the mechanical action of combing and brushing. Depilation only achieves repopulation with normal looking hair for a short while. Temporary improvement has been described with daily doses of 125 mg of griseofulvin, zinc-sulfate, X-ray depilation, and topical application of retinoid acid. There have also been improvements with the application of minoxidil and tretinoin, and with the administration of 0.5-1 mg/kg/day of etretinate.
Prognosis
The course of the localized form of monilethrix can be favorable with a reduction of hypotrichosis with time. In general, hypotrichosis improves with age, although remissions have been noted during puberty or pregnancy.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Pr Francisco CAMACHO-MARTÍNEZ


Monoamine oxidase-A deficiency is a very rare recessive X-linked biogenic amine metabolism disorder characterized clinically by mild intellectual deficit, impulsive aggressiveness, and sometimes violent behavior and presenting from childhood.


Monoclonal mast cell activation syndrome

A rare hematologic disease characterized by symptoms of mast cell activation in the absence of cutaneous findings, as well as absence of diagnostic criteria of systemic mastocytosis with tryptase levels of less than 20 ng/ml and normal to low burden of mast cells. Bone marrow biopsy reveals the presence of monoclonal mast cells carrying the KIT D816V mutation and/or expressing CD25. Patients present with recurrent episodes of flushing, headache, hypotension, abdominal cramping, nausea, diarrhea, cardiac arrhythmias, bronchoconstriction, and bleeding diathesis, among others.


Monomelic amyotrophy (MA) is a rare benign lower motor neuron disorder characterized by muscular weakness and wasting in the distal upper extremities during adolescence followed by a spontaneous halt in progression and a stabilization of symptoms.

Summary:
Epidemiology
The prevalence is unknown. It is seen mainly in Asian countries (particularly in Japan and India) with only a very few cases reported in Europe and the United States. A nation-wide survey conducted from 1996 to 1998 in Japan found 333 identified cases with the estimated prevalence being approximately 1/33, 300.
Clinical description
MA is seen more frequently in males (male to female ratio of 20:1) with an age of onset in the second to third decade of life (ages 14-25). Muscle weakness and wasting begins in the hand or forearm on one side. There is no pain associated with this muscular atrophy, nor sensory changes. Progression is slow, usually over a 3-9 year time span, followed by a halt and stabilization of symptoms. Occasionally it can destabilize and continue progression after the age of 40. In rare cases it can progress to the opposite limb. Additional rare manifestations include worsening of symptoms with exposure to cold (cold paresis), muscle cramps, cold hands, irregular coarse tremor and/or contraction fasciculations. O'Sullivan-McLeod syndrome (see this term), considered to be a variant of MA, presents with weakness in the intrinsic hand muscles. It begins unilaterally but eventually spreads to the opposite limb with an asymmetrical distribution.
Etiology
The exact etiology is unknown. One theory is that MA is caused by the anterior shift of the cervical dural sac, due to repeated neck flexion, leading to the compression of the anterior aspect of the spinal cord against the posterior margin of the vertebral body. Autoimmunity, toxins and infections have been proposed as possible causes, but more evidence is needed. Since there have been several familial cases of MA reported (<1% of MA patients), genetic susceptibility could also be a factor.
Diagnostic methods
Diagnosis is based on clinical imaging and electromyography findings. Magnetic resonance imaging (MRI) shows distinctive images of the anterior horn being compressed when a patient is in the maximum cervical anteflexion position (snake eyes sign). Atrophy in the lower cervical spinal cord is also visible. Nerve conduction tests show reduced compound muscle action potential of the median and ulnar nerves in the affected limb and F-wave studies show reduced frequency and prolonged minimum latency in these muscles.
Differential diagnosis
Poliomyelitis, multifocal motor neuropathy with conduction block, syringomyelia (see these terms), anterior interosseous or deep ulnar neuropathy, cervical vertebral abnormalities, spinal cord tumors, brachial plexopathy and trauma must be excluded.
Management and treatment
There is no cure for MA. Treatment is conservative and with early detection aims to slow the progression of muscle wasting. A cervical collar worn in the early stages of disease has been shown to halt progress of the disease in some cases, as it prevents neck flexion. Muscle strengthening exercises and hand coordination training can also be helpful.
Prognosis
MA is not life threatening but can cause a social disability in those with a complete loss of hand function. Early intervention can minimize progression of disease.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Pr Satoshi KUWABARA


Mononen-Karnes-Senac syndrome is characterized by skeletal dysplasia associated with finger malformations (brachydactyly with short and abducted thumbs, short index fingers, and markedly short and abducted great toes), variable mild short stature, and mild bowleg with overgrowth of the fibula. It has been described in two males, their mothers, and a maternal aunt. Females are less severely affected than males. X-linked dominant inheritance is suggested.