Autosomal dominant neovascular inflammatory vitreoretinopathy

A rare, genetic, vitreoretinal degeneration characterized by a slowly progressive vitreoretinopathy with onset during the second or third decade of life. The disease initially presents as autoimmune uveitis with reduction in the b-wave on electroretinography, and progresses with development of photoreceptor degeneration, vitreous hemorrhage, cystoid macular edema, retinal neovascularization, intraocular fibrosis, secondary glaucoma, and retinal detachment leading to phthisis and complete blindness.


A rare seizure disorder characterized by intermittent dystonia and/or choreoathetoid movements that occur during sleep. The clusters of nocturnal motor seizures are often stereotyped and brief.

Summary:
Epidemiology
Over 100 families have been described in the literature to date. Males and females are affected equally.
Clinical description
The age of onset varies between 3 and 47 years (usually < 20 years, with a peak during childhood). Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is defined by different motor events of increasing complexity and duration, arising during non-rapid eye movement sleep (NREM), including short-lasting (2-4 sec) stereotyped movements involving the limbs, axial musculature, and/or the head; paroxysmal arousals characterized by sudden and brief arousals (5-10 sec) sometimes accompanied by stereotyped movements, vocalization, and fear; and major attacks (20-30 sec), featuring asymmetric tonic or dystonic posturing, or complex movements (pelvic thrusting, pedaling, choreoathetoid, and ballistic movements of the limbs). Some patients may show ictal deambulatory behaviors often associated with frightened expression. The frequency is highly variable ranging from 5 attacks per night to 5 times per year. Daytime dyskinesia, generalized seizures and auras may occur. Intellect is usually preserved or mildly reduced and psychiatric comorbidity may occur. Paroxysmal hypnogenic dyskinesia (PHD), which was previously characterized as a form of paroxysmal dyskinesia, is now considered to be ADNFLE.
Etiology
ADNFLE results from malfunction in the thalamo-cortical loops. The genes involved are CHRNA4 (20q13.33), CHRNB2 (1q21.3), CHRNA2 (8p21), KCNT1 (9q34.3), DEPDC5 (22q12.3), CRH (8q13), and CABP4 (11q13.2).
Diagnostic methods
Diagnosis relies principally on clinical history revealing at least one of the following four criteria: motor event duration of less than 2 minutes; unstructured vocalization during the episode; experience of an aura preceding the motor attack; history of tonic-clonic seizures during sleep. Diagnosis is also achieved by recording seizures by nocturnal video polysomnography (V-PSG) and confirmed by genetic screening.
Differential diagnosis
Differential diagnoses include paroxysmal dyskinesia, familial focal epilepsy with variable foci, restless legs syndrome, periodic limb movement disorders (PLMS), REM sleep behavior disorders (RBD), nocturnal panic attacks, non-REM parasomnias, obstructive sleep apnea syndrome, and arousal disorders.
Genetic counseling
Transmission is autosomal dominant with a penetrance ranging from 60 % to 80 %. High intra-familial heterogeneity has been described. Sporadic cases may occur.
Management and treatment
The treatment of choice for ADNFLE includes use of carbamazepine (200-1,000 mg/day). Carbamazepine abolishes seizures in 20% of cases, and gives significant relief (at least 50 % seizure reduction) in another 48%. Oxcarbamazepine, topiramate and acetazolamide (as add-on therapies) may also be used. Nicotine transdermal patches may be efficient in patients who are refractory to standard antiepileptic drugs. Quinidine, a potassium channel blocker, has been reported as a potential therapeutic agent in only a few patients with KCNT1 mutation implicated in ADNFLE and epilepsy of infancy with migrating focal seizures (EIMFS). Surgical treatment may be indicated for drug-resistant patients, both for seizures and for epilepsy-related sleep disturbances. Neuropsychological testing and psychiatric assessment are advised for ADNFLE affected individuals.
Prognosis
ADNFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Pr Shinichi HIROSE  - Dr Hirokazu KURAHASHI


Autosomal dominant optic atrophy and cataract

A form of autosomal dominant optic atrophy characterized by an early and bilateral optic atrophy leading to insidious visual loss of variable severity, followed by a late anterior and/or posterior cortical cataract. Additional features include sensorineural hearing loss and neurological signs such as tremor, extrapyramidal rigidity and absence of deep tendon reflexes. It is caused by mutations in the OPA3 gene (19q13.32).


Autosomal dominant optic atrophy and peripheral neuropathy

A rare form of autosomal dominant optic atrophy (ADOA) characterized by progressive and isolated visual loss in the first decade of life, decreased reflexes in the lower limbs and a mild cerebellar stance.


A rare neuro-ophthalmological disease associating the typical optic atrophy with other extra-ocular manifestations such as sensorineural deafness, myopathy, chronic progressive external ophthalmoplegia, ataxia and peripheral neuropathy. More rarely, other manifestations have been associated with this condition, such as spastic paraplegia or multiple-sclerosis like illness.

Summary:
Epidemiology
Autosomal dominant optic atrophy plus syndrome (ADOA plus) accounts for approximately 20% of all ADOA cases.
Clinical description
ADOA plus is characterized by bilateral and symmetric progressive visual loss (visual acuity ranging from 20/30 to 20/200) and color vision deficiency, occurring typically during the first decade of life. Sensorineural deafness usually occurs later, during the second or third decade of life, although it may also be diagnosed, in rare instances, prior to the optic neuropathy. From the third decade onwards, other extra-ocular manifestations may appear, such as chronic progressive external ophthalmoplegia, proximal myopathy, ataxia and axonal sensory motor polyneuropathy. Other manifestations have been more rarely associated with ADOA plus, such as multiple sclerosis-like illness, migraine, cardiomyopathy, late-onset diabetes mellitus, and spastic paraplegia.
Etiology
ADOA plus is caused by mutations in the OPA1 gene (3q29), encoding a dynamin-like GTPase involved in the fusion of the inner mitochondrial membrane, in energetic production and mitochondrial DNA stability.
Diagnostic methods
Ophthalmological examination is not specific and typically shows a moderate bilateral optic atrophy associated with bilateral central or paracentral scotomas. Diagnosis of ADOA plus relies both on the genetic screening of the OPA1 gene and on skeletal muscle biopsy to measure the enzymatic activity of the respiratory chain complexes, allowing histological examination (Gomori-modified trichrome and double cytochrome C oxidase/succinate dehydrogenase staining) which typically reveals features of mitochondrial myopathy (cytochrome C negative fibers and ragged red fibers). Laboratory findings may reveal hyperlactacidemia. Additional investigations may include an audiological work-up, peripheral nerve conduction studies, electromyography, electroencephalography, brain magnetic resonance imaging, according to the patient's symptoms.
Differential diagnosis
Differential diagnosis includes several other syndromic hereditary optic neuropathies that may have bilateral manifestations associated with extra ocular features and that presents with a similar phenotype, such as Autosomal dominant Charcot-Marie-Tooth disease type 2A, Leber hereditary optic neuropathy, Wolfram syndrome and Wolfram-like syndrome.
Antenatal diagnosis
Prenatal identification of a mutation may be proposed in families with previously known mutations, with the understanding that not all the carriers will manifest the disease.
Genetic counseling
Transmission is autosomal dominant with variable penetrance and genetic counselling is recommended.
Management and treatment
There is currently no efficient treatment for ADOA plus. Low-vision aids may be recommended and cochlear implants have been shown to improve audition in patients with sensorineural deafness. The role of idebenone has been anecdotally reported in ADOA. Physiotherapy for the muscular symptoms programs can be warranted for patients with multiple sensory and motor handicaps. Avoiding tobacco and alcohol intake as well as medications interfering with mitochondrial metabolism (certain antibiotics, antivirals) is recommended.
Prognosis
Vision seems to be more severely affected in patients with ADOA plus than in patients with no extra ocular involvement. If associated, hearing loss can further impair social communication.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Pr Dan MILEA  - Pr Pascal REYNIER


Autosomal dominant optic atrophy, classic form

A rare neuro-ophthalmological disease which is one of the most common forms of hereditary optic neuropathy characterized by progressive bilateral visual loss with an onset during the first decade of life, associated with optic disc pallor, visual acuity loss, visual field deficits and color vision defects.

Summary:
Epidemiology
The prevalence of Autosomal dominant optic atrophy (ADOA) is variable, commonly varying between 1/10,000 in Denmark (due to a founder effect) to 1/35,000 in the UK and probably worldwide.
Clinical description
ADOA is usually detected during the first decade of life, often by vision screening in school but later onset is possible. Visual impairment is usually moderate (visual acuity ranges from 20/80 to 20/120) but may range from mild to severe. Visual field defect is typically centrocecal, central, or paracentral. Color vision is often affected, usually but not always in the blue-yellow axis (tritanopia). Legal blindness is rare. Patients may also be asymptomatic, albeit bearing the mutation. In about 20% of cases, extra-ocular signs are present, such as sensorineural hearing loss or other severe neurological signs, that occur typically later in life, in young adults, such as myopathy, ataxia, peripheral neuropathy, chronic progressive external ophthalmoplegia (ADOA plus). Rare forms of the disease, similar to Behr syndrome have been reported with biallelic OPA1 mutations (Behr syndrome, OPA1).
Etiology
A majority, but not all ADOA patients harbor mutations in the gene OPA1 (3q29) which codes for an inner mitochondrial membrane protein intricately involved in mitochondrial biogenesis, mitochondrial DNA replication and mitochondrial dynamics. Visual impairment is highly variable both within and between families, even when considering the same mutation.
Diagnostic methods
ADOA is most often suspected in children with unexplained optic neuropathy, especially if associated with a similar family history (which may nevertheless be absent in 50% of cases). Fundus examination typically reveals bilateral and symmetrical pallor of the temporal side of the optic nerve head, pallor of the optic nerve rim and a temporal grey crescent, sometimes associated with abnormal optic disc cupping. Visual evoked potentials (VEP) are usually delayed and pattern electroretinogram shows an abnormal N95:P50 ratio, with reduction in the amplitude of the N95 waveform suggesting alterations of the retinal ganglion cells layer. Optical Coherence Tomography (OCT) discloses a global reduction of the peripapillary retinal nerve fiber layer thickness, mainly in the infero-temporal quadrant. The rest of the retinal is tipically normal. The diagnosis is confirmed by the genetic screening of OPA1.
Differential diagnosis
Differential diagnosis includes all the common causes of optic neuropathies: compressive, inflammatory, ischemic, toxic and metabolic causes. Other hereditary optic neuropathies such as Leber's hereditary optic neuropathy, Wolfram syndrome have different initial presentations (later onset, associated or not with other neurological or systemic signs), but the final clinical phenotype of optic neuropathy is not specific. Other genes involved in isolated or syndromic forms autosomal dominant optic atrophy are : ACO2, SPG7, AFG3L2, MFN2, OPA3, DRP1, and SSBP1.
Antenatal diagnosis
Prenatal identification of a mutation may be proposed in families with previously known mutations, with the understanding that not all the carriers will manifest the disease.
Genetic counseling
Transmission is autosomal dominant with a penetrance of 50%.
Management and treatment
There are currently no efficient treatments in ADOA. Low-vision aids may be recommended in patients with severely decreased visual acuity. Tobacco use, excessive alcohol intake and medications that may have mitochondrial toxicity should be avoided.
Prognosis
Visual impairment in ADOA is classically irreversible ; spontaneous recovery has been only exceptionally reported. Visual loss is usually mild, but can at times worsen later during lifetime. ADOA does not affect intellectual development or life span. Patients may have normal familial and social life although vocational integration may at times be problematic.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Pr Dan MILEA  - Pr Pascal REYNIER


A rare sclerosing bone disorder characterized by skeletal densification that predominantly involves the cranial vault.

Summary:
Epidemiology
It is extremely rare, as only 33 cases have been reported in 3 families.
Clinical description
The disease typically has onset in late childhood or adolescence. Clinical signs include chronic bone pain and disorders of the cranial nerves (trigeminal neuralgia, facial palsy, hearing loss). The risk of fracture is not increased and patients show normal or even increased trabecular bone strength. Twenty to forty percent of cases are asymptomatic.
Etiology
The disease is due to a gain-of-function mutation in the LRP5 gene (Low density lipoprotein receptor-related protein 5; 11q12-q13) which results in increased bone formation. Therefore, controversy exists whether Autosomal dominant osteopetrosis type 1 is truly a type of osteopetrosis (which is due to failure of osteoclast development or function) or whether it is more accurately described as a `high bone mass' disease.
Diagnostic methods
Diagnosis is based on clinical and radiographic evaluation. Radiographs show diffuse skeletal sclerosis, with marked thickening of the cranial vault, slight sclerosis of the spine with dense vertebral arches, and thickened long bone cortices. Bone mineral density (lumbar spine, femoral neck) has a Z-score ranging from +4 to +8 SD.
Genetic counseling
Transmission is autosomal dominant. Each child of an affected individual has a 50% risk of being affected. Autosomal dominant osteopetrosis type 1 is a fully penetrant disease.
Management and treatment
Treatment is symptomatic.
Prognosis
Life expectancy is normal.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Ravi SAVARIRAYAN  - Dr Zornitza STARK


Autosomal dominant otospondylomegaepiphyseal dysplasia

A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by craniofacial dysmorphism (midface hypoplasia, depressed nasal bridge, small nose with upturned tip, cleft palate, Pierre Robin sequence), bilateral, pronounced sensorineural hearing loss, and skeletal/joint anomalies (including spondyloepiphyseal dysplasia, arthralgia/arthropathy), in the absence of ocular abnormalities.


Autosomal dominant palmoplantar keratoderma and congenital alopecia

A rare genetic skin disorder characterized by absence of scalp and body hair and palmoplantar keratoderma, without other hand complications.

Summary:
Epidemiology
To date, ten individuals with a clinical diagnosis of autosomal dominant palmoplantar keratoderma and congenital alopecia (PPK-CA) have been reported.
Clinical description
Autosomal dominant PPK-CA usually presents during infancy. Its very early onset is often characterized by fading of facial, scalp and body hair within the first months of life without subsequent re-growth. Body and facial keratosis pilaris are additional features which appear in the following years. Palmoplantar keratoderma develops during infancy and may have an unusual pattern, affecting the two sides of fingers and palms, but usually sparing the palmar sides. Periungueal involvement is typical, leading to secondary nail dystrophy. Autosomal dominant PPK-CA seems to have a more benign course than autosomal recessive PPK-CA (see this term).
Etiology
The genetic basis of autosomal dominant PPK-CA is unknown. Transmission appears to be autosomal dominant.
Differential diagnosis
Palmoplantar keratoderma and congenital alopecia/hypotrichosis is also found in ectodermal dysplasias and keratinization disorders, including hydrotic ectodermal dysplasia; hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome; KID syndrome; odonto-onycho-dermal dysplasia; Lelis syndrome; mutilating palmoplantar keratoderma with periorificial keratotic plaques; and Schöpf-Schulz-Passarge syndrome.
Genetic counseling
Transmission appears to be autosomal dominant.

                            Last update:
                            July 2013

                            - Expert reviewer(s):
                            Dr Marco CASTORI


Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis

A rare contiguous gene syndrome involving a partial deletion of chromosome 16 and characterized by early-onset and severe polycystic kidney disease with various manifestations of tuberous sclerosis (multiple angiomyolipomas, lymphangioleiomyomatosis and periventricular calcifications of the central nervous system).


A rare, genetic, renal tubular disease characterized by progressive outgrowths of fluid-filled cysts from the renal epithelium, which can manifest with hematuria, urinary tract infections, hypertension, and abdominal or flank pain. The slowly progressive loss of kidney function may evolve to end stage kidney disease (ESKD).

Summary:
Epidemiology
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease, with estimated prevalence of 1/2,500 in Europe.
Clinical description
Symptoms typically manifests in adulthood; however, approximately 2-5% of cases present before 15 years of age. The renal phenotype ranges from patients in advanced age with preserved kidney function to rare cases of enlarged kidneys that are detected in utero. Clinical symptoms, including early-onset hypertension, abdominal fullness and pain, hematuria and urinary tract infections (UTIs), are usually observed decades before the onset of renal insufficiency. Renal insufficiency is slowly progressive leading to ESKD by 60 years of age in approximately half of patients. Up to a third of adult patients have nephrolithiasis. Extra-renal features often include polycystic liver disease, cardiovascular abnormalities (including left ventricular hypertrophy, aortic root dilatation, arterial aneurysms, heart valve abnormalities and intracranial aneurysms), bronchiectasis, seminal vesicle cysts, pancreatic cysts, and diverticulosis. Male infertility is also described.
Etiology
Mutations in PKD1 (16p13.3) and PKD2 (4q22.1) account for approximately 78% and 15% of affected individuals, respectively. The remaining ~7% of cases are genetically unresolved or are due to mutations in other recently identified genes, such as GANAB (11q12.3), DNAJB11 and ALG9, involved in the maturation and trafficking of the polycystins.
Diagnostic methods
Diagnosis is established by the presence of age-specific ultrasound criteria and an affected first-degree relative, or by genetic testing. Pre-symptomatic screening of ADPKD is not currently recommended for at-risk children. A positive family history is absent in 10-15% of patients. Where other causes of cystic disease have been excluded, a patient with bilaterally enlarged kidneys and innumerable cysts most likely has ADPKD.
Differential diagnosis
The differential diagnosis for early onset ADPKD is autosomal recessive polycystic kidney disease, renal cysts and diabetes syndrome (HNF1B), tuberous sclerosis complex (TSC), the TSC2/PKD1 contiguous gene syndrome, von Hippel-Lindau syndrome, medullary sponge kidney, simple renal cysts and acquired cystic kidney disease.
Antenatal diagnosis
Kidney cysts can be detected by prenatal ultrasound scans. Large hyperechogenic kidneys are also a possible early manifestation. Prenatal genetic testing may be possible in at risk families, where the mutation has been previously identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal dominant. The risk of inheriting the disease from an affected individual is 50%. However, penetrance is incomplete and intra-familial phenotypes can vary in progression and severity. PKD1 mutations are associated with more severe disease, larger kidneys, earlier onset and earlier development of ESKD, than PKD2 mutations. GANAB mutations are associated with mild cystic disease, usually without decline in kidney function. Mutations arising de novo are possible.
Management and treatment
Early treatment and management of symptoms and complications, such as arterial hypertension is important. ACE inhibitors are the first choice for treatment of hypertension. For children with a family history of ADPKD, screening for hypertension from the age of 5 years onward is recommended. Tolvaptan, the vasopressin V2 receptor antagonist, has shown to reduce the rates of growth in total kidney volume and renal function loss in ADPKD patients, but also leads to polyuria because of its aquaretic effect. It is currently recommended for adult ADPKD with a rapid disease progression.
Prognosis
Prognosis depends on the age of disease onset and the disease severity. Approximately half of affected individuals develop ESKD by 60 years of age. Presence of proteinuria and arterial hypertension in affected children correlate with much more severe disease progression.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Pr Djalila MEKAHLI | ERKNet*

                                * European Reference Network


Autosomal dominant popliteal pterygium syndrome

A rare genetic, multiple congenital anomalies syndrome characterized by cleft lip, with or without cleft palate, pits in the lower lip, contractures of the lower extremities, abnormal external genitalia, syndactyly of fingers and/or toes, and a pyramidal skin fold over the hallux nail.

Summary:
Epidemiology
The prevalence of autosomal-dominant-popliteal pterygium syndrome (AD-PPS) is unknown. However, based on the occurence of cleft lip/palate in the general population, the prevalence at birth of popliteal pterygium syndrome (PPS) has been suggested at 1/300,000 with more than 200 cases of AD-PPS being reported worldwide.
Clinical description
Presentation may be as early as the first trimester, with detection of cleft lip and/or palate on ultrasound. In addition to facial clefts (91%-97%), patients may have lower lip pits or sinuses (45%), webbing of the skin extending from the ischial tuberosities to the heels (popliteal pterygium with contractures possibly impairing mobility) (58%), bifid scrotum and cryptorchidism in affected males and hypoplasia of the labia majora in females, finger and/or toe syndactyly, and skin abnormalities around the nails. Almost all patients have a pyramidal fold of skin overlying the nail of the hallux. Some may have missing teeth. Other occasional features include filiform synechiae connecting the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon), spina bifida occulta, retrognathia, accessory medial meniscus, and talipes. Growth and intellectual development are normal in patients with AD-PPS although there are some reports of delayed language acquisition and learning disabilities.
Etiology
AD-PPS is associated with mutations in the IRF6 gene (1q32.2-q32.3), involved in the formation of epithelial tissues, especially the periderm. Almost all affected patients harbor mutations in IRF6.
Diagnostic methods
Diagnosis is based on the presence of the characteristic range of clinical findings (cleft lip with or without cleft palate, popliteal pterygium, genital and nail anomalies), and can be confirmed by molecular genetic testing. AD-PPS is highly associated with missense mutations in the DNA Binding Domain of IRF6(encoded in exons 3 and 4) that alter residues that are predicted to interact directly with DNA.
Differential diagnosis
Mildly affected AD-PPS patients have significant clinical overlap with Van der Woude syndrome (VWS), a disorder caused by deletions and mutations in the same gene (IRF6). In fact, affected individuals in the same family, having the same mutation in IRF6, have been diagnosed with AD-PPS and with VWS. The cause of this variable expressivity is not known. Bartsocas-Papas syndrome, CHAND syndrome and multiple pterygium syndrome should also be considered.
Antenatal diagnosis
If the disease-causing mutation has been identified in the family, prenatal diagnosis for at-risk pregnancies is possible through molecular analysis following amniocentesis or chorionic villus sampling.
Genetic counseling
The pattern of inheritance is autosomal dominant with a 50% risk of disease transmission to offspring. However, penetrance is incomplete and expressivity is variable. De novo mutations have also been reported. Genetic counseling should be provided to affected families.
Management and treatment
In infants, nutritional intake and weight gain should be monitored. Cleft lip and/or palate should be treated surgically at an early stage and orthodontically by a specialized multidisciplinary team. Speech therapy as well as audiological and dental assessments should also be provided. Surgery may also be required for lip pits, popliteal pterygium, syndactyly and ankyloblepharon. Rarely, surgical correction of abnormal genitalia may be considered. Management of the other manifestations of AD-PPS is generally supportive and symptomatic.
Prognosis
Overall prognosis is good. Growth and intelligence are expected to be normal, and corrective surgeries are available, especially for orofacial clefts. However, the prognosis for physical activity depends on the severity of the pterygium and the success of corrective surgery. Genital anomalies may cause infertility.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Dr Elizabeth LESLIE  - Dr Brian SCHUTTE


Autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome

A rare genetic syndrome with limb malformations as a major feature characterized by preaxial polydactyly of the hands and feet with variable phenotypic expressivity in combination with hypertrichosis extending from the posterior hairline to the middle of the back. Reported limb malformations include triphalangeal thumbs, duplicated thumbs, preaxial extra ray, and syndactyly between digits I and II in the hands, and large or duplicated hallux and syndactyly between toes I and II in the feet.


A mild form of familial primary hypomagnesemia (FPH), characterized by extreme weakness, tetany and convulsions. Secondary disturbances in calcium excretion are observed.

Summary:
Epidemiology
To date, only one large pedigree with 18 affected individuals has been reported in the literature.
Clinical description
Autosomal dominant primary hypomagnesemia with hypocalciuria (ADPHH) can be detected in childhood or in adult life. Most affected individuals are asymptomatic but patients may suffer from generalized convulsions. In adulthood, chondrocalcinosis may be observed.
Differential diagnosis
Differential diagnosis includes all causes of renal hypomagnesemia, particularly diseases associated with hypocalciuria such as Gitelman syndrome, EAST syndrome and familial primary hypomagnesemia with normocalciuria and normocalcemia (see these terms).
Genetic counseling
Transmission is autosomal dominant. Genetic counseling may be proposed and the recurrence risk is 50%.
Management and treatment
Management is mainly symptomatic and includes oral magnesium supplements.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Rosa VARGAS-POUSSOU


A rare, genetic, non-syndromic, developmental defect during embryogenesis malformation syndrome characterized by a congenital, non-progressive, occipitofrontal head circumference that is 2 or more standard deviations below the mean for age, gender and ethnicity which is associated with normal brain architecture and uncomplicated by other abnormalities. Borderline to moderate intellectual disability, as well as early psychomotor delay, may or may not be associated.


A rare, genetic, developmental defect during embryogenesis disorder characterized by abnormal forward projection of the mandible beyond the standard relation to the cranial base, with lower incisors often overlapping the upper incisors, that is inherited in an autosomal dominant manner. Association with mildly everted lower eyelids, flat malar area, thickened lower lip and craniosynostosis has been reported.


Autosomal dominant progressive external ophthalmoplegia

A rare genetic, neuro-ophthalmological disease characterized by progressive weakness of the external eye muscles, resulting in bilateral ptosis and diffuse symmetric ophthalmoparesis. Additional signs may include skeletal muscle weakness, cataracts, hearing loss, sensory axonal neuropathy, ataxia, parkinsonism, cardiomyopathy, hypogonadism and depression. It is usually less severe than autosomal recessive form.


Autosomal dominant progressive nephropathy with hypertension

A rare, genetic hypertension characterized by an adult onset of increased blood pressure associated with nephropathy progressing to end-stage renal disease. Renal biopsy may show interstitial fibrosis, glomerulosclerosis and mild tubular atrophy. Increased serum creatinine and proteinuria have also been reported.


Autosomal dominant proximal renal tubular acidosis

A rare autosomal dominant form of proximal renal tubular acidosis (pRTA) characterized by an isolated defect in the proximal tubule leading to the decreased reabsorption of bicarbonate and consequently causing urinary bicarbonate wastage. Mild growth retardation and reduced bone density are extra-renal complications. Several fractures and delayed puberty are possible features.


Autosomal dominant proximal spinal muscular atrophy

A group of rare, genetic, motor neuron disease characterized by childhood or adult onset progressive, predominantly proximal, muscular weakness and wasting. Included diseases are Autosomal dominant adult-onset proximal spinal muscular atrophy, Lower motor neuron syndrome with late-adult onset, and Autosomal dominant childhood-onset proximal spinal muscular atrophy.


Autosomal dominant rhegmatogenous retinal detachment

A rare, hereditary, non-syndromic form of vitreoretinopathy characterized by retinal tears due to abnormal vitreous, and commonly present refractive errors. No other signs or symptoms of Stickler syndrome is present.


The more common type of Robinow syndrome (RS) characterized by mild to moderate limb shortening and abnormalities of the head, face and external genitalia.

Summary:
Epidemiology
About 100 cases of this type have been reported in the literature to date.
Clinical description
The clinical signs are generally milder in dominant cases of RS than in the AR form. In the presence of rib fusions, the recessive form of the syndrome should be considered.
Etiology
Mutations in WNT5A gene (3p14.3) have been reported in some patients (< 10%) with autosomal dominant Robinow syndrome.
Genetic counseling
Transmission is autosomal dominant.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Juliana MAZZEU


Autosomal dominant secondary polycythemia

A rare, genetic, hematologic disease characterized by increased levels of serum hemoglobin, hematocrit and erythrocyte mass, associated with elevated or inappropriately normal erythropoietin serum levels, occurring in various members of a family and with autosomal dominant inheritance.


Autosomal dominant severe congenital neutropenia

A rare primary immunodeficiency disorder characterized by autosomal dominant inheritance, absolute neutrophil counts below 0.5x10E9/L in the peripheral blood (on three separate occasions over a six month period), granulopoiesis maturation arrest at the promyelocyte/myelocyte stage and early-onset, severe, recurrent bacterial infections.


Autosomal dominant slowed nerve conduction velocity

A rare hereditary demyelinating motor and sensory neuropathy characterized by slowed nerve conduction velocities, in the absence of clinically apparent neurological deficits, gait abnormalities or muscular atrophy, associated with a germline mutation in the ARGHEF10 gene.


Autosomal dominant spastic ataxia type 1

A rare, genetic, autosomal dominant spastic ataxia disorder characterized by lower-limb spasticity and ataxia in the form of head jerks, ocular movement abnormalities, dysarthria, dysphagia and gait disturbances.


Autosomal dominant spastic paraplegia type 10

A rare, hereditary spastic paraplegia that can present as either a pure or complex phenotype. The pure form is characterized by lower limb spasticity, hyperreflexia and extensor plantar responses, presenting in childhood or adolescence. The complex form is characterized by the association with additional manifestations including peripheral neuropathy with upper limb muscle atrophy, moderate intellectual disability and parkinsonism. Deafness and retinitis pigmentosa have also been reported.


Autosomal dominant spastic paraplegia type 12

A pure form of hereditary spastic paraplegia characterized by a childhood- to adulthood-onset of slowly progressive lower limb spasticity and hyperreflexia of lower extremities, extensor plantar reflexes, distal sensory impairment, variable urinary dysfunction and pes cavus.


Autosomal dominant spastic paraplegia type 13

A rare, pure or complex form of hereditary spastic paraplegia characterized by progressive spastic paraplegia with pyramidal signs in the upper and lower limbs, and decreased vibration sense.


Autosomal dominant spastic paraplegia type 17

A complex hereditary spastic paraplegia characterized by progressive spastic paraplegia, upper and lower limb muscle atrophy, hyperreflexia, extensor plantar responses, pes cavus and occasionally impaired vibration sense. Association with hand muscles amyotrophy typical.


Autosomal dominant spastic paraplegia type 19

A pure form of hereditary spastic paraplegia characterized by a slowly progressive and relatively benign spastic paraplegia presenting in adulthood with spastic gait, lower limb hyperreflexia, extensor plantar responses, bladder dysfunction (urinary urgency and/or incontinence), and mild sensory and motor peripheral neuropathy.


Autosomal dominant spastic paraplegia type 29

A complex form of hereditary spastic paraplegia characterized by a spastic paraplegia presenting in adolescence, associated with the additional manifestations of sensorial hearing impairment due to auditory neuropathy and persistent vomiting due to a hiatal or paraesophageal hernia.


Autosomal dominant spastic paraplegia type 3

A rare, pure or complex form of hereditary spastic paraplegia, with variable phenotype, typically characterized by childhood-onset of minimally progressive, bilateral, mainly symmetric lower limb spasticity and weakness, associated with pes cavus, scoliosis, sphincter disturbances and/or urinary bladder hyperactivity. Rare additional associated manifestations may include mild intellectual disability, axonal motor neuropathy, and seizures.


Autosomal dominant spastic paraplegia type 31

A rare type of hereditary spastic paraplegia usually characterized by a pure phenotype of proximal weakness of the lower extremities with spastic gait and brisk reflexes, with a bimodal age of onset of either childhood or adulthood (>30 years). In some cases, it can present as a complex phenotype with additional associated manifestations including peripheral neuropathy, bulbar palsy (with dysarthria and dysphagia), distal amyotrophy, and impaired distal vibration sense.


Autosomal dominant spastic paraplegia type 36

A complex form of hereditary spastic paraplegia, characterized by an onset in childhood or adulthood of progressive spastic paraplegia (with spastic gait, spasticity, lower limb weakness, pes cavus and urinary urgency) associated with the additional manifestation of peripheral sensorimotor neuropathy.


Autosomal dominant spastic paraplegia type 37

A pure form of hereditary spastic paraplegia characterized by a childhood- to adulthood-onset of slowly progressive spastic gait, extensor plantar responses, brisk tendon reflexes in arms and legs, decreased vibration sense at ankles and urinary dysfunction. Ankle clonus is also reported in some patients.


Autosomal dominant spastic paraplegia type 38

A complex hereditary spastic paraplegia characterized by mild to severe lower limb spasticity, hyperreflexia, extensor plantar responses, impaired vibration sensation, pes cavus, and significant wasting and weakness of the small hand muscles. Temporal lobe epilepsy and cognitive dysfunction have been also reported.


Autosomal dominant spastic paraplegia type 4

A rare form of hereditary spastic paraplegia with high intrafamilial clinical variability, characterized in most cases as a pure phenotype with an adult onset (mainly the 3rd to 5th decade of life, but that can present at any age) of progressive gait impairment due to bilateral lower-limb spasticity and weakness as well as very mild proximal weakness and urinary urgency. In some cases, a complex phenotype is also reported with additional manifestations including cognitive impairment, cerebellar ataxia, epilepsy and neuropathy. A faster disease progression is noted in patients with a later age of onset.


Autosomal dominant spastic paraplegia type 41

A pure form of hereditary spastic paraplegia characterized by onset in adolescence or early adulthood of slowly progressive spastic paraplegia, proximal muscle weakness of the lower extremities and small hand muscles, hyperreflexia, spastic gait and mild urinary compromise.


Autosomal dominant spastic paraplegia type 42

A pure form of hereditary spastic paraplegia characterized by slowly progressive spastic paraplegia of lower extremities with an age of onset ranging from childhood to adulthood and patients presenting with spastic gait, increased tendon reflexes in lower limbs, extensor plantar response, weakness and atrophy of lower limb muscles and, in rare cases, pes cavus. No abnormalities are noted on magnetic resonance imaging.


Autosomal dominant spastic paraplegia type 6

A rare, pure or complex form of hereditary spastic paraplegia typically characterized by presentation in late adolescence or early adulthood as a pure phenotype of lower limb spasticity with hyperreflexia and extensor plantar responses, as well as mild bladder disturbances and pes cavus. Rarely, it can present as a complex phenotype with additional manifestations including epilepsy, variable peripheral neuropathy and/or memory impairment.


Autosomal dominant spastic paraplegia type 73

A pure form of hereditary spastic paraplegia characterized by adult onset of crural spastic paraparesis, hyperreflexia, extensor plantar responses, proximal muscle weakness, mild muscle atrophy, decreased vibration sensation at ankles, and mild urinary dysfunction. Foot deformities have been reported to eventually occur in some patients. No abnormalities are noted on brain magnetic resonance imaging and peripheral nerve conduction velocity studies.


Autosomal dominant spastic paraplegia type 8

A rare, pure or complex form of hereditary spastic paraplegia characterized by early adulthood onset of slowly progressive lower limb spasticity resulting in gait disturbances, hyperreflexia and extensor plantar responses, urinary urgency and/or incontinence, muscle weakness, decreased vibration sense and mild muscular atrophy in lower extremities. It may be associated with complicating signs, such as sensory neuropathy, ataxia (i.e. mild dysmetria, uncoordinated eye movement) and mild dysphagia.


Autosomal dominant spastic paraplegia type 9A

A rare complex hereditary spastic paraplegia characterized by juvenile to adult onset of slowly progressive spasticity mainly affecting the lower limbs, associated with spastic dysarthria and motor neuropathy. Additional manifestations include congenital bilateral cataract, gastroesophageal reflux, persistent vomiting, mild cerebellar signs, pes cavus, and occasionally short stature, among others.


Autosomal dominant spastic paraplegia type 9B

A rare predominantly pure hereditary spastic paraplegia characterized by juvenile or adult onset of slowly progressive spastic paraparesis, gait disturbances, and increased tendon reflexes. Additional variable manifestations include pes cavus, dysarthria, sensory impairment, and urinary symptoms. Cognition is normal.


Autosomal dominant spondylocostal dysostosis

A very rare and mild form of spondylocostal dysostosis characterized by vertebral and costal segmentation defects, often with a reduction in the number of ribs.


Autosomal dominant striatal neurodegeneration

An adult-onset movement disorder characterized by bradykinesia, dysarthria and muscle rigidity.

Summary:
Epidemiology
To date, ADSD has been observed in seven individuals in one family.
Clinical description
Onset of symptoms of ADSD is in the fourth to fifth decade of life with mild progressive dysarthria and hypokinesia. Mild bradykinesia presents predominantly as gait disturbance but also as a general slowing of movement. Dysdiadochokinesia is also present and muscle tone is slightly increased. Additional features include stiffness of the tongue and, in some patients, mild difficulties in swallowing. ADSD is characterized by dysfunction and changes of the striatal part of the basal ganglia, visible on MRI scans.
Etiology
It is caused by mutation in the PDE8B gene (5q13.3-q14.1) and is transmitted in an autosomal dominant manner with complete penetrance in the investigated family.
Diagnostic methods
Diagnosis is based on brain MRI which shows distinctive and characteristic symmetric lesions of the striatum that appear earlier than the onset of symptoms. A good correlation has been observed between clinical signs and the degree of MRI abnormalities.
Differential diagnosis
Differential diagnoses include other degenerative diseases causing hypokinesia (such as Parkinson's disease; see this term). However, unlike for these diseases, in ADSD, tremor is not observed. Differential diagnoses also include neuroferritinopathy (see this term). However, ADSD is characterized by hypokinesia whereas neuroferritinopathy is characterized by hyperkinesia. The characteristic MRI changes of the striatum can be regarded as pathognomonic for ADSD.
Antenatal diagnosis
Antenatal diagnosis is currently not available but is probably not necessary because of the mild course of the disease.
Management and treatment
There is currently no known treatment for ADSD and symptoms do not respond to treatment with levodopa.
Prognosis
The course of the disease is mild and allows affected individuals to lead a virtually normal life. Life expectancy does not appear to be affected.

                            Last update:
                            May 2010

                            - Expert reviewer(s):
                            Pr Gregor KUHLENBÄUMER


Autosomal dominant thrombocytopenia with platelet secretion defect

A rare isolated constitutional thrombocytopenia characterized by reduced platelet count and defective platelet ATP secretion, resulting in increased bleeding tendency. Clinical manifestations are easy bruising, gum bleeding, menorrhagia, spontaneous epistaxis, spontaneous muscle hematoma, and potential postpartum hemorrhage, among others.


Autosomal dominant tubulointerstitial kidney disease

A rare, genetic renal tubular disease characterized by tubular damage and interstitial fibrosis in absence of glomerular lesions and clinically manifesting with chronic kidney disease (CKD) and slow progression to end-stage kidney disease (ESKD).

Summary:
Epidemiology
Autosomal dominants tubulointerstitial kidney (ADTKD) is estimated to account for approximately 2-5% of monogenic causes of chronic kidney disease. In the Caucasian population, no geographic or sex differences are reported.
Clinical description
There are four clinical subtypes, classified due to the genetic mutation involved: UMOD-, MUC1-, REN- and HNF1B-related ADTKD. The typical clinical findings in ADTKD are a progressive loss of kidney function with bland urinary sediment, absent-to-mild proteinuria, urinary concentrating defects with low morning urine osmolality, normal or slightly elevated blood pressure, normal or small kidney size and a family history of CKD that is compatible with an autosomal dominant inheritance pattern. Presentation and age of onset varies according to clinical subtype. For ADTKD-UMOD, presentation may occur in adolescence with gout; hyperuricemia and gout are highly prevalent. CKD is often first diagnosed in the late adolescence or early adulthood. ADTKD-MUC1 typically presents with CKD in the early twenties. ADTKD-REN may present as early as infancy with anemia, hyperkalemia and CKD. ADTKD-HNF1B may present in childhood with genitourinary abnormalities, in the teenage years with gout or diabetes, and in the third decade of life with CKD; extrarenal anomalies are possible. All subtypes lead to progressive ESKD, occurring generally between 25 and 70 years of age. Renal cysts may occur but are not typical.
Etiology
Pathogenic variants are detected in 50-60% of cases and most commonly involve UMOD (16p12.3) and MUC1 (1q22). More rare variants include REN (1q32.1) and HNF1B (17q12), and different genes may be identified in the future.
Diagnostic methods
Diagnosis can be difficult due to the lack of distinct clinical features but should be suspected in individuals with a family history of CKD, gout and/or hyperuricemia, a bland urinary sediment and a renal ultrasound that excludes autosomal dominant polycystic disease (ADPKD). If available, kidney biopsy from the patient or an affected family member showing predominant tubulointerstitial fibrosis are supportive of a diagnosis. Genetic testing for a pathogenic variant in the patient or a family member can also be useful.
Differential diagnosis
The differential diagnoses include atypical ADPKD (DNAJB11-related), nephronophthisis (NPHP1-related), renal coloboma syndrome, tubulointerstitial nephritis and uveitis syndrome, and Sjögren syndrome. Mutations in SEC61A1 have been reported in a few cases with congenital anemia, neutropenia (in one family) and tubulointerstitial kidney disease; mitochondrial mutations have also been associated with an ADTKD phenotype.
Antenatal diagnosis
Genetic prenatal diagnosis may be possible where pathogenic variants have previously been identified in a family member.
Genetic counseling
The disease is autosomal dominant. Genetic counseling should be offered to affected individuals informing them that for each conception there is 50% risk of disease transmission. However, penetrance is incomplete and disease expression may vary between affected family members.
Management and treatment
There is no specific treatment for ADTKD; affected individuals should be treated according to established CKD guidelines, noting that specific recommendations are based on limited evidence in ADTKD. Children with ADTKD-HNF1B and ADTKD-REN disease are likely to benefit from early management by a pediatric nephrologist. Diuretics should be used with caution as they may aggravate salt loss, volume depletion and hyperuricemia. A low-salt diet is not recommended. NSAIDS are contraindicated in ADTKD patients. In patients with gout, urate-lowering treatment may prevent future attacks. Kidney transplantation is the preferred option for ESKD, and ADTKD does not recur in the renal transplant.
Prognosis
The quality of life in patients with ADTKD largely depends on the severity of CKD the presence of CKD-associated comorbidities and the existence of extrarenal manifestations.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Pr Olivier DEVUYST | ERKNet*

                                * European Reference Network


A rare, genetic, vitreous-retinal disease characterized by ocular developmental anomalies such as microcornea, a shallow anterior chamber, glaucoma and cataract. Abnormal chorioretinal pigmentation is present, usually lying between the vortex veins and the ora serrata for 360 degrees.

Summary:
Epidemiology
At least 3 pedigrees have been reported to have ADVIRC.
Clinical description
Age of onset is variable, but can occur in childhood. ADVIRC is associated with developmental ocular anomalies including microphthalmos/nanophthalmos, microcornea, hypermetropia/high myopia, shallow anterior chamber, angle closure glaucoma, iris dysgenesis, abnormal pupillary ruff, microspherophakia with mild lens opacities (congenital or early-onset posterior/subcapsular cataract), disc gliosis and optic nerve dysplasia. Some patients may experience vision loss. Color vision is generally normal. Discrete rotatory nystagmus may be present. Retinal edema due to vascular incompetence may also be observed. ADVIRC is characterized by a peripheral retinal circumferential hyperpigmented band, punctuate white retinal opacities, fibrillar condensation of the vitreous, vascular abnormalities and neovascularisation. There are no identifiable systemic or skeletal abnormalities.
Etiology
ADVIRC is caused by mutations in BEST1 (11q12) (Val86Met, Val235Ala and Tyr236Cys), which encodes bestrophin-1 (expressed specifically in the retinal pigment epithelium (RPE)) forming a calcium activated chloride channel involved in regulation of voltage-dependent calcium channels. These mutations may alter normal splicing of BEST1 and result in in-frame alteration of bestrophin-1. However, functional consequences of such in-frame protein alterations remain undefined.
Diagnostic methods
Diagnosis of ADVIRC is based on low normal to non-recordable amplitudes of cones and rods on full-field electroretinogram (generalized rod and cone dysfunction), an abnormal electro-oculogram (EOG) (the light rise of EOG is decreased giving a reduced Arden ratio), and normal macular thickness on optical coherence tomography. Funduscopy typically reveals a concentric band of hyperpigmentation in the extreme periphery of one quadrant, with well-defined posterior demarcation, midperipheral chorioretinal atrophy and optic nerve dysplasia. Fundus autofluorescence imaging may show a normal autofluorescence pattern. Goldmann perimetry is often initially normal; however visual field tends to constrict mildly with age. Diagnosis is confirmed by genetic screening of BEST1.
Differential diagnosis
MRCS syndrome (see this term) is generally more severe than ADVIRC. However, both of these BEST1-related conditions show retinal pigmentary abnormalities, retinal dystrophy, microcornea, and early-onset cataract, conditions that overlap and likely form a continuum. Differential diagnosis also includes Best vitelliform macular dystrophy (BVMD), adult-onset foveomacular vitelliform dystrophy and autosomal recessive bestrophinopathy (see these terms).
Genetic counseling
Transmission is autosomal dominant and genetic counseling is possible.
Management and treatment
Management is mainly symptomatic. When choroidal neovascularization occurs, treatment may require laser photocoagulation or intravitreal delivery of anti-vascular endothelial growth factor agents such as bevacizumab and ranibizumab. Cystoid macular edema can be treated with conventional carbonic anhydrase inhibitors (CAIs) either systemically or topically. If presentation is complicated by glaucoma, conventional treatment may require topical agents to lower intraocular pressure, such as CAIs. Laser iridotomy may be advocated if angle closure glaucoma is a risk. Some cases may require additional surgical intervention.
Prognosis
Most patients retain a fairly good visual acuity throughout life, although visual acuity may decrease considerably due to macular edema, chorioretinal atrophy, or rarely, retinal detachment and vitreous hemorrhage.

                            Last update:
                            January 2014

                            - Expert reviewer(s):
                             Stephanie CHAN  - Pr Ian MACDONALD


A rare hereditary disorder of the heme metabolic pathway characterized by accumulation of protoporphyrin in blood, erythrocytes and tissues, with photosensitive skin manifestations.

Summary:
Epidemiology
Erythropoietic protoporphyria (EPP) has been reported worldwide, with prevalence ranging from 1/17,000 to 1/100,000.
Clinical description
It usually begins in early childhood, with the first exposure to the sun. EPP manifests as acute painful photosensitivity of the skin with erythema and edema, sometimes petechiae, together with stinging and burning sensations without phlyctens, after exposure to sunlight or illumination in the visible spectrum (particularly in the Soret band [400 - 410 nm]). These episodes have a variable severity depending on the exposure duration and may result in chronic permanent lesions on exposed skin. As protoporphyrin is a lipophilic molecule excreted by the liver, patients with EPP are at risk of cholelithiasis with obstruction of the bile ducts, and chronic liver disease which may progress to acute liver failure.
Etiology
In most cases, EPP is due to a partial deficiency of the last enzyme in the heme biosynthesis pathway, ferrochelatase, encoded by the FECH gene (NM_000140.3). The pattern of inheritance of EPP is autosomal dominant where clinical expression is modulated by the presence of the hypomorphic IVS3-48C FECH allele in trans. Autosomal recessive transmission of two mutated alleles of the FECH gene has also been reported.
Diagnostic methods
Diagnosis is established by increased levels of protoporphyrin in plasma and red blood cells, and detection of a plasma fluorescence peak at 635 nm. Further analysis is recommended, including a search for liver damage and measurement of ferrochelatase activity levels. Genetic analysis (mutations in the FECH gene, presence of the hypomorphic IVS3-48C FECH allele in trans) and family screening are also recommended.
Differential diagnosis
Differential diagnosis includes X-linked erythropoietic protoporphyria, phototoxic drug reactions, hydroa vacciniforme, solar urticaria, contact dermatitis, and angioedema.
Antenatal diagnosis
Antenatal diagnosis is theoretically possible, but is not offered.
Genetic counseling
The pattern of inheritance is autosomal dominant. Genetic counseling should be offered to affected individuals informing them that there is a 50 % risk of transmitting the pathogenic variant. Autosomal recessive transmission of two mutated alleles of the FECH gene has also been reported.
Management and treatment
Treatment is based on preventive measures such as sun avoidance, protection against visible light (especially blue light) using a high UVA index sunscreen with a high critical wavelength (>370 nm), the use of protective filters on windows and the yellow filter on scialytics, short sessions of UVB TL01 before summer, reducing protoporphyrins (by reducing erythropoiesis with transfusions or by administration of cholestyramine, a bile acid chelator, or by careful phlebotomy), preventing the progression of liver damage to liver failure. Conventional analgesics and beta-carotene have limited effectiveness in EPP. Since liver disease is the major risk associated with EPP, regular monitoring of liver function is key. Sequential liver and bone marrow transplant should be considered in the treatment of severe cases presenting with liver damage.
Prognosis
EPP is a chronic disease, and its prognosis depends on the progression of liver disease. However, photosensitivity can affect patients' quality of life. The latter has been improved by the use of afamelanotide. Two molecules, dersimelagon and bitopertin, are currently under development. Patients with EPP should not be given iron supplements without expert medical advice.

                            Last update:
                            March 2024

                            - Expert reviewer(s):
                            Dr Neila TALBI | MetabERN*

                                * European Reference Network


Autosomal recessive anterior segment dysgenesis

A rare anterior segment developmental anomaly without extraocular manifestations characterized by predominant iris and lens abnormalities, including iris hypoplasia, iris transillumination defects, ectropion uveae, corectopia, iridodonesis with ectopia lentis, and cataracts, with bilateral involvement. Increased intraocular pressure is absent in most patients.


Autosomal recessive ataxia due to PEX10 deficiency

A rare genetic, peroxisomal disease characterized by childhood onset slowly progressive ataxia and axonal motor neuropathy due to PEX 10 deficieny. Marked cerebellar atrophy and pyramidal signs are evident. Patients may present mild cognitive disability, intentional tremor, decreased vibration sense and diabetes mellitus. Additional features may include nystagmus, mydriasis, hyperreflexia and involuntary head movement.


Autosomal recessive ataxia due to ubiquinone deficiency

This syndrome is characterised by childhood-onset progressive ataxia and cerebellar atrophy.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Exercise intolerance with elevated lactate levels and mild intellectual deficit may also be present.
Etiology
The syndrome is caused by ubiquinone deficiency. Mutations in the ADCK3/CABC1 gene have been detected in affected individuals. This gene is already known to play a role in ubiquinone biosynthesis in yeast.
Genetic counseling
The syndrome is transmitted as an autosomal recessive trait.

                            Last update:
                            May 2008


A rare disorder characterised by a slowly progressive pure cerebellar ataxia associated with dysarthria. It has been described in 53 individuals from 26 families of Canadian origin. The mode of transmission is autosomal recessive. Positional cloning has led to the identification of several  gene mutations.


Autosomal recessive axonal Charcot-Marie-Tooth disease due to copper metabolism defect

A rare autosomal recessive axonal hereditary motor and sensory neuropathy characterized by motor-predominant axonal polyneuropathy due to a defect in copper metabolism. Patients become symptomatic in infancy or childhood with subtle motor delay or regression, manifesting with progressive weakness, muscle wasting, and absent reflexes in the lower and upper extremities. In addition, vibratory sensation is mildly diminished. Involvement of the face with weakness and fasciculation of facial muscles has also been described.


Autosomal recessive axonal neuropathy with neuromyotonia

A rare peripheral neuropathy characterized by slowly progressive axonal, motor greater than sensory, polyneuropathy combined with neuromytonia (including spontaneous muscular activity at rest (myokymia), impaired muscle relaxation (pseudomyotonia), and contractures of hands and feet) and neuromyotonic or myokymic discharges on needle EMG. It presents with distal lower limb weakness with gait impairment, muscle stiffness, fasciculations and cramps in hands and legs worsened by cold, decreased to absent tendon reflexes, intrinsic hand muscle atrophy and, variably, mild distal sensory impairment.


A rare retinal dystrophy, characterized by central visual loss in the first 2 decades of life, associated with an absent electrooculogram (EOG) light rise and a reduced electroretinogram (ERG).

Summary:
Epidemiology
The prevalence of ARB is still unknown; to date less than 20 cases have been described in the world literature.
Clinical description
ARB generally manifests in the first 2 decades of life, but patients may also first become symptomatic as late as the fifth decade of life. Most affected individuals initially present with central visual loss (visual acuity ranging from 20/200 to 20/25) and are usually mildly to highly hyperopic. Additional ocular findings may include short axial length with angle-closure glaucoma, amblyopia, anterior uveitis, strabismus, and color vision defects. Choroidal neovascularization (CNV) has been described in one case. Leukokoria and esotropia have also been reported.
Etiology
ARB is caused by compound heterozygous or homozygous mutations in the BEST1 gene (11q12) which encodes the chloride ion channel bestrophin-1 (expressed in the retinal pigment epithelium (RPE)). Mutations in BEST1 reduce or abolish the activity of the channel. It has been proposed that ARB may represent the null phenotype of bestrophin-1 in humans.
Diagnostic methods
Diagnosis of ARB relies on ophthalmologic examination, familial history and visual electrophysiology revealing an abnormal full-field ERG (reduced amplitudes and delayed implicit times of the rod and cone ERGs). Absent or severe reduction in EOG light rise (Arden ratio= 1.0) is commonly observed. Irregularity of the RPE throughout the posterior fundus, often with scattered punctate flecks (observed by autofluorescence imaging) is also found. Optical coherence tomography (OCT) imaging shows retinal edema, serous subretinal fluid, subretinal yellowish lesions and scars. Classic vitelliform lesions are not present. Fluorescein angiography reveals widespread patchy areas of hyperfluorescence and signs of mild perivascular leakage in the peripheral retina. Cystoid macular edema may be observed. Diagnosis is confirmed by the genetic screening of BEST1.
Differential diagnosis
Differential diagnosis includes Stargardt disease, familial drusen, Best vitelliform macular dystrophy, age-related macular degeneration (see these terms), central serous chorioretinopathy and chorioretinitis.
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
Management of ARB is mainly symptomatic and includes treatment of amblyopia, surgical strabismus correction, prophylactic laser (YAG) peripheral iridotomy to prevent angle closure and treat glaucoma, and intravitreal bevacizumab for the treatment for CNV. Cystoid macular edema may be treated with oral administration of acetazolamide. Gene therapy may offer a possible treatment for ARB in the future. Close monitoring of ARB patients is recommended, including repeated gonioscopy to judge the risk of angle closure.
Prognosis
Onset of vision loss in patients has been reported to vary between the ages of 4 to 40, and is coincident with initial presentation.

                            Last update:
                            March 2014

                            - Expert reviewer(s):
                             Stephanie CHAN  - Pr Ian MACDONALD


Brachyolmia, recessive type is a form of brachyolmia (see this term), a group of rare genetic skeletal disorders, characterized by short-trunked short stature with platyspondyly and scoliosis. Corneal opacities and precocious calcification of the costal cartilage are rare syndromic components. Premature pubarche may occur.

Summary:
Epidemiology
The precise prevalence of this form of brachyolmia is not known. About 20 cases have been reported. Cases have been reported in various ethnic groups (Japan, Korea, Turkey), sometimes related to consanguineous unions. However, a majority of cases reported so far were of Turkish origin.
Clinical description
Patients with Brachyolmia, recessive type generally have a normal birth weight and length. Platyspondyly is present in early childhood but patients usually come to medical attention in late childhood or early puberty as a result of stunted growth and short trunk. The radiographic features include platyspondyly with rectangular vertebral bodies and irregular end plates, broad ilia, short femoral neck, and broad proximal interphalangeal joints. Longitudinal striations in the femoral neck are occasionally seen. Precocious calcifications of the costal cartilage are described. The condition is described as relatively benign with the exception of mild non-specific backache and mild scoliosis beginning in young adulthood. However, reports are limited about the final outcome of musculoskeletal morbidity. Mental status and facies are reported to be normal. Some patients are reported to have peripheral punctuate opacities in the cornea found on slit lamp examination (formerly Toledo type).
Etiology
A number of different mutations in the PAPSS2 gene (10q23.2-q23.3) have been reported in affected patients. PAPPS2 encodes PAPS (3'-phosphoadenosine 5'-phosphosulfate) synthase 2. PAPSS2 mutations were also reported to cause two other disorders: spondyloepimetaphyseal dysplasia, PAPSS2 type (see this term), and spondylodysplasia and premature pubarche before the discovery of the molecular basis of brachyolmia, recessive type (Hobaek/Toledo type).
Genetic counseling
Genetic counseling should be provided to affected families based on the observed autosomal recessive pattern of inheritance.

                            Last update:
                            February 2016

                            - Expert reviewer(s):
                            Dr Gen NISHIMURA


Autosomal recessive centronuclear myopathy

A rare autosomal recessive congenital myopathy characterized by numerous centrally placed nuclei on muscle biopsy and clinical features of a congenital myopathy including facial weakness, ocular abnormalities (ptosis and external ophthalmoplegia) and predominant proximal muscle weakness of variable severity with possible distal involvement.

Summary:
Epidemiology
The exact prevalence remains unknown.
Clinical description
The age of onset varies from birth to childhood. AR-CNM is characterized by facial weakness including severe involvement of the masticatory muscles, and ocular abnormalities such as ptosis and external ophthalmoplegia. Muscle weakness is observed with variable severity. It is usually prominently proximal, but there may be additional distal weakness and wasting in the lower limbs. Foot abnormalities are frequent and other skeletal deformities (including high arched palate and scoliosis) are common. Respiratory involvement may be severe. An associated cardiomyopathy has been documented in a few, genetically unresolved cases. Urinary incontinence may be an associated feature.
Etiology
The disease is associated with mutations in BIN1 (2q14), encoding Myc box-dependent-interacting protein 1. AR- CNMs can be also related to biallelic mutation in RYR1 (19q13.2) , SPEG (2q35) and TTN (2q31.2) genes.
Diagnostic methods
Diagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features. Genetic testing is required to confirm the diagnosis. Muscle MRI may be helpful to distinguish AR-CNM from other forms of CNM.
Differential diagnosis
The main differential diagnoses include other congenital myopathies, myotonic dystrophy and, if facial involvement is prominent, facioscapulohumeral dystrophy.
Antenatal diagnosis
Prenatal diagnosis is possible where the mutation has previously been identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal recessive. The risk to siblings of inheriting the disease is 25%. Offspring of affected individuals are obligate carriers. Genetic counseling should be offered to all patients and their families.
Management and treatment
There is no curative treatment currently available. Management is supportive and based on a multidisciplinary approach.
Prognosis
In the absence of severe cardiorespiratory involvement, the prognosis appears favorable, with mild progressive proximal weakness.

                            Last update:
                            May 2020

                            - Expert reviewer(s):
                            Pr Enrico BERTINI  - Dr Adele D'AMICO  - Pr Fabiana FATTORI


Autosomal recessive cerebellar ataxia due to CWF19L1 deficiency

A rare autosomal recessive cerebellar ataxia characterized by early onset of slowly progressive cerebellar atrophy, clinically manifesting with extremity and truncal ataxia, global developmental delay, intellectual impairment, nystagmus, dysarthria, intention tremor, and pyramidal signs, among others.


Autosomal recessive cerebellar ataxia due to STUB1 deficiency

A rare hereditary ataxia characterized by progressive truncal and limb ataxia resulting in gait instability. Dysarthria, dysphagia, nystagmus, spasticity of the lower limbs, mild peripheral sensory neuropathy, cognitive impairment and accelerated ageing have also been associated.


Autosomal recessive cerebellar ataxia with late-onset spasticity

A rare, genetic neurodegenerative disease characterized by childhood or adolescent-onset of cerebellar ataxia with dysarthria which slowly progresses and associates pyramidal signs, including lower limb spasticity, brisk reflexes, and Babinski and Hoffman signs. Patients typically present cerebellar ataxia with development of increasing asymmetric spasticity in upper and lower limbs, and variable axonal sensory or sensorimotor neuropathy. Additional heterogeneous features, including pes cavus, scoliolis, and abnormalities of the brain (e.g. cerebral atrophy), may also be associated.


Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to RUBCN deficiency

An extremely rare, autosomal recessive, hereditary cerebellar ataxia disorder characterized by early onset of progressive, mild to moderate gait and limb ataxia, moderate to severe dysarthria, and nystagmus or saccadic pursuit, frequently associated with epilepsy, moderate intellectual disability, delayed speech acquisition, and hyporeflexia in the upper extremities. Hyperreflexia in the lower extremities may also be associated.


Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency

A rare hereditary ataxia characterized by an early onset symptomatic generalized epilepsy, progressive cerebellar ataxia resulting in significant difficulties to walk or wheelchair dependency, and intellectual disability.


Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency

A rare autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome characterized by early-childhood onset of cerebellar ataxia associated with generalized tonic-clonic epilepsy and psychomotor development delay, dysarthria, gaze-evoked nystagmus and learning disability. Other features in some patients include upper motor neuron signs with leg spasticity and extensor plantar responses, and mild cerebellar atrophy on brain MRI.


Autosomal recessive cerebellar ataxia-movement disorder syndrome

A rare hereditary ataxia characterized by a progressive cerebellar ataxia associated with disruption of visual fixation by saccadic intrusions (overshooting horizontal saccades with macrosaccadic oscillations and increased velocity of larger saccades). It presents with progressive gait, trunk and limb ataxia with pyramidal tract signs (increased tendon reflexes and Babinski sign), myoclonic jerks, fasciculations, cerebellar dysarthria, sensorimotor axonal neuropathy with impaired joint position, vibration, temperature, pain sensations, pes cavus, and saccadic intrusions with characteristic overshooting horizontal saccades, macrosaccadic oscillations, and increased velocity of larger saccades, without other eye movement disturbances.


Autosomal recessive cerebellar ataxia-psychomotor delay syndrome

A rare, hereditary, cerebellar ataxia disorder characterized by late-onset spinocerebellar ataxia, manifesting with slowly progressive gait disturbances, dysarthria, limb and truncal ataxia, and smooth-pursuit eye movement disturbance, associated with a history of psychomotor delay from childhood. Mild atrophy of the cerebellar vermis and hemispheres is observed on brain imaging.


Autosomal recessive cerebellar ataxia-pyramidal signs-nystagmus-oculomotor apraxia syndrome

A rare, genetic, slowly progressive neurodegenerative disease characterized by delayed psychomotor development beginning in infancy, mild to profound intellectual disability, gait and stance ataxia, pyramidal signs (hyperreflexia, extensor plantar responses), dysarthria, and ocular abnormalities (e.g. nystagmus, oculomotor apraxia, abduction deficits, esotropia, ptosis). Brain imaging reveals progressive, generalized cerebellar atrophy, mild ventriculomegaly and, in some, retrocerebellar cysts.


A heterogeneous group of rare neurological disorders involving both the central and peripheral nervous system (and in some cases other systems and organs), and characterized by degeneration or abnormal development of the cerebellum and spinal cord and, in most cases, early onset occurring before the age of 20 years.

Summary:
Epidemiology
This group encompasses a large number of rare diseases, the most frequent in the Caucasian population being Friedreich ataxia (estimated prevalence 2-4/100,000), ataxia-telangiectasia (1-2.5/100,000) and early onset cerebellar ataxia with retained tendon reflexes (1/100,000). Other forms ARCA are much less common.
Clinical description
Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorders), ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features.
Etiology
These diseases are caused by mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, alpha-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED), aprataxin in ataxia with oculomotor apraxia (AOA1), and senataxin in ataxia with oculomotor apraxia (AOA2).
Diagnostic methods
Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, computed tomography scanning), electrophysiological examination, and mutation analysis when the causative gene has been identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to the autosomal recessive mode of inheritance, a familial history of affected individuals is unlikely.
Genetic counseling
These diseases are transmitted in an autosomal recessive manner.
Management and treatment
For most ARCA there is no specific drug treatment, except for coenzyme Q10 deficiency and abetalipoproteinemia.

                            Last update:
                            November 2006

                            - Expert reviewer(s):
                            Dr Carmen ESPINÓS  - Pr Francesc PALAU


Autosomal recessive cerebelloparenchymal disorder type 3

A rare autosomal recessive cerebellar ataxia characterized by early onset of non- or slowly progressive cerebellar signs and symptoms including truncal and gait ataxia, dysarthria, dysmetria, dysdiadochokinesis, tremor, and nystagmus. Delayed psychomotor development and intellectual disability are variable. Additional reported features are spasticity, hypotonia, cataracts, and sensorineural hearing loss, among others. Brain imaging shows cerebellar atrophy.


A rare, genetic, neurodegenerative disorder characterized by ventriculomegaly and progressive, symmetrical atrophy of the cerebral cortex grey and white matter (sparing the midbrain, brainstem, cerebellum and infratentorial segments), manifesting in early infancy with acquired microcephaly, irritability, regression of developmental milestones, feeding difficulties, akathisia, exaggerated startle response, spasticity (fisted hands, stiff arms, leg scissoring), abnormal muscle tone with hypotonic trunk and hypertonic extremities, visual impairment and seizures.


Autosomal recessive Charcot-Marie-Tooth disease type 2X

A rare autosomal recessive axonal hereditary motor and sensory neuropathy characterized by childhood to adult onset of slowly progressive, sometimes asymmetric distal muscle weakness and atrophy, as well as sensory impairment, predominantly of the lower limbs. Additional common features include pes cavus, kyphoscoliosis, ankle contractures, tremor, or urogenital dysfunction. Fasciculations and proximal involvement may be seen in some cases. Patients usually remain ambulatory.


Autosomal recessive Charcot-Marie-Tooth disease with hoarseness

A severe, early-onset form of axonal CMT peripheral sensorimotor polyneuropathy.

Summary:
Epidemiology
ARCMT2K was originally described in three Spanish families and has since been described in five additional Spanish kindreds, as well as in families from Morocco, France and Poland.
Clinical description
Onset occurs in the neonatal period or early infancy with a clinical picture similar to that seen in CMT4A (another autosomal recessive form of CMT4 but with a demyelinating phenotype; see this term) including hypotonia, scoliosis, a hoarse voice, vocal cord paralysis and respiratory insufficiency. However, nerve conduction velocities and pathological findings from sural nerve biopsies in ARCMT2K patients are indicative of a predominantly axonal neuropathy with some demyelinating features.
Etiology
ARCMT2K is caused by mutations in the GDAP1 gene (8q13.3), encoding a protein required for mitochondrial fission. Mutations in the same gene are associated with CMT4A and with a milder, later-onset autosomal dominant axonal form of CMT, CMT2K (see this term).
Prognosis
The prognosis for ARCMT2K may be severe, with two of the reported patients dying during in the fifth decade of life.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Dr Carmen ESPINÓS  - Pr Francesc PALAU


Autosomal recessive chorioretinopathy-microcephaly syndrome

A rare neuro-opthalmological disease characterized by severe microcephaly of prenatal onset (with diminutive anterior fontanelle and sutural ridging), growth retardation, global developmental delay and intellectual disability (ranging from mild to profound), dysmorphic features (sloping forehead, micro/retrognathia, prominent ears) and visual impairments (including microphthalmia to anophtalmia, generalized retinopathy or multiple punched-out retinal lesions, retinal folds with retinal detachment, optic nerve hypoplasia, strabismus, nystagmus). Brain MRI may show reduced cortical size, cerebral hemispheres, corpus callosum, pachygyria, symplified gyral folding or normal pattern. Other associated features include epilepsy and neurological deficits.


Autosomal recessive complex spastic paraplegia due to Kennedy pathway dysfunction

A rare genetic neurological disorder characterized by progressive spastic paraparesis and delayed gross motor development with an onset in infancy or early childhood. Patients also show variable degrees of intellectual disability, speech delay, and dysarthria. Other reported features include microcephaly, seizures, bifid uvula with or without cleft palate, and ocular anomalies. Brain imaging shows white matter abnormalities in the periventricular and other regions.


Autosomal recessive congenital cerebellar ataxia due to GRID2 deficiency

A rare, genetic, slowly progressive neurodegenerative disease resulting from GRID2 deficiency characterized by motor, speech and cognitive delay, hypotonia, truncal and appendicular ataxia, and eye movement abnormalities (tonic upgaze, nystagmus, oculomotor apraxia). Intention tremor may also be associated. Brain imaging reveals progressive cerebellar atrophy with cerebellar flocculus particularly affected.


Autosomal recessive congenital cerebellar ataxia due to MGLUR1 deficiency

A rare, genetic, slowly progressive neurodegenerative disease resulting from MGLUR1 deficiency characterized by global developmental delay (beginning in infancy), mild to severe intellectual deficit with poor or absent speech, moderate to severe stance and gait ataxia, pyramidal signs (e.g. hyperreflexia) and mild dysdiadochokinesia, dysmetria, tremors, and/or dysarthria. Oculomotor signs, such as nystagmus, strabismus, ptosis and hypometric saccades, may also be associated. Brain imaging reveals progressive, generalized, moderate to severe cerebellar atrophy, inferior vermian hypoplasia, and/or constitutionally small brain.


A generalized connective tissue disorder characterized by the association of wrinkled, redundant and sagging inelastic skin with severe systemic manifestations (lung atelectesias and emphysema, vascular anomalies, and gastrointestinal and genitourinary tract diverticuli).

Summary:
Epidemiology
The prevalence of ARCL1 is unknown but around 60 cases have been reported in the literature so far.
Clinical description
The skin manifestations affect the whole body and are usually recognizable from birth. The excessive lax skin is particularly prominent around the axillae, groins and neck and on the face (giving patients an aged appearance with eyelid ptosis and drooping cheeks). Pulmonary emphysema develops early in life (during the neonatal period or by early childhood), often leading to respiratory failure. Common vascular anomalies include arterial aneurysms, fibromuscular artery dysplasia and stenosis leading to progressive heart failure. Genitourinary tract diverticuli lead to vesicoureteral reflux and recurrent infections. Less frequent findings include late closure of the fontanel, joint laxity, hip dislocation, inguinal hernia, arachnodactyly, bone fragility, vascular tortuosity and aortic aneurysm. Intelligence is normal.
Etiology
ARCL1 is genetically heterogeneous and, although the etiology remains unknown in the majority of cases, mutations have been identified in some patients in the FBLN5 (14q31) and EFEMP2 (11q13) genes, encoding the extracellular matrix proteins fibulin-5 and EGF-containing fibulin-like extracellular matrix protein 2 (Fibulin-4), respectively. Arachnodactyly, bone fragility, vascular tortuosity and aortic aneurysms are common findings in patients carrying EFEMP2 mutations.
Diagnostic methods
Detailed clinical evaluation and histological studies of skin biopsies (revealing a moth-eaten appearance, abnormal elastin fiber branching and lose microfibrils associated with reduced elastin synthesis) are usually diagnostic in ARCL1. Molecular testing, available on a research basis only, may confirm the diagnosis in carriers of FBLN5 and EFEMP2 mutations.
Differential diagnosis
The differential diagnosis should include other forms of CL (autosomal recessive type 2, autosomal dominant and X-lined CL) and related syndromes (gerodermia osteodysplastica, Cantu syndrome, wrinkly skin syndrome and De Barsy syndrome), together with the Ehlers-Danlos syndromes and Costello syndrome (see these terms).
Genetic counseling
Genetic counseling should be provided to affected families and prenatal diagnosis through molecular testing is feasible for families in which the disease-causing mutation has been identified.
Management and treatment
There are no effective therapeutic strategies available for ARCL1. Care should be multidisciplinary with symptomatic treatment of pulmonary emphysema, prophylactic therapy for infections and hernia repair.
Prognosis
The disease course in ARCL1 is severe, with most patients dying in childhood from cardiac or respiratory failure.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS


A spectrum of connective tissue disorders characterized by the association of wrinkled, redundant and sagging inelastic skin with growth and developmental delay, and skeletal anomalies. The spectrum ranges from patients with classic autosomal recessive cutis laxa type 2 (ARCL2, Debré type) to patients with a milder form of the disease, wrinkled skin syndrome (WSS).

Summary:
Epidemiology
Around 40 patients with classic ARCL2 have been reported so far.
Clinical description
Patients with ARCL2 present with generalized cutis laxa at birth but the skin manifestations become less pronounced and may disappear completely with age. Pre- and postnatal growth delay is common. Patients have a characteristic facial appearance (down-slanting palpebral fissures, a broad flat nasal bridge and short nose with anteverted nostrils, large ears and a small mouth). The most common ocular anomalies are strabismus and myopia. Congenital hip dislocation, increased joint laxity, congenital or progressive microcephaly, delayed closure of large fontanels, osteoporosis and decreased bone density are frequent findings. Developmental delay is observed in the majority of patients (mainly due to muscle hypotonia and joint laxity) but congenital brain anomalies are rare (although developmental anomalies such as cobblestone-like brain dysgenesis have been reported in some patients). Intellectual deficit and seizures have been reported in older patients. The systemic manifestations are mild in ARCL2 and pulmonary emphysema and cardiac anomalies are rare.
Etiology
The underlying etiology in the majority of ARCL2 cases remains unknown. However, a combined disorder of N- and O-linked glycosylation (congenital disorder of glycosylation type II) has been detected in some patients and is associated with mutations in the ATP6V0A2 gene (12q24.31). Mutations in ATP6V0A2 have also been identified in patients with WSS. There are no specific clinical features that distinguish ARCL2 patients with glycosylation defects from those without any metabolic anomalies. Mutations in the PYCR1 gene have recently been identified in patients with ARCL2 and in patients with a phenotype (wrinkly skin, osteopenia and progeroid features) overlapping with classic ARCL2 and WSS, and the closely related syndromes, gerodermia osteodysplastica (GO) and de Barsy syndrome (DBS; see these terms).
Diagnostic methods
Diagnosis is made on the basis of physical and developmental examination, skeletal surveys, imaging studies, histological analysis of skin biopsies (decreased amounts of structurally abnormal elastin fibers) and biochemical tests (plasma transferrin and apolipoprotein CIII isoelectric focusing for detection of abnormal glycosylation). Molecular testing is available on a clinical basis for families with ATP6V0A2 mutations.
Differential diagnosis
Differential diagnoses should include other forms of CL (ARCL type 1, autosomal dominant CL and X-linked CL), as well as the clinically overlapping entities GO and DBS (see these terms).
Genetic counseling
Genetic counseling should be proposed and prenatal diagnosis through molecular testing is feasible for families in which the disease-causing mutation has been identified.
Management and treatment
There are no effective therapeutic strategies available for ARCL2 and care should be multidisciplinary with symptomatic management of the ocular and skeletal manifestations, and supportive and educational care for developmental and learning problems.
Prognosis
The prognosis for patients is variable: life expectancy is generally not reduced. Although the skin manifestations improve with age, cognitive decline has been reported in some older patients.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS


A rare, genetic, dermis elastic tissue disease characterized by redundant, overfolded skin of variable severity, ranging from wrinkly skin to cutis laxa associated with pre- and post-natal growth retardation, hypotonia, mild to moderate developmental delay, late closure of anterior fontanelle, and craniofacial dysmorphism (including microcephaly, hypertelorism, downslanting palpebral fissures, large, prominent nasal root with funnel nose, small, low-set ears, long philtrum, drooping facial skin). Additional manifestations may include seizures, intellectual disability, congenital hip dislocation, inguinal hernia, and cortical and cerebellar malformations. Pretibial pseudo-ecchymotic skin lesions have occasionally been associated.


A rare, hereditary, developmental defect with connective tissue involvement characterized by cutis laxa of variable severity, in utero growth restriction, congenital hip dislocation and joint hyperlaxity, wrinkling of the skin, in particular the dorsum of hands and feet, and progeroid facial features. Hypotonia, developmental delay, and intellectual disability are common. In addition, cataracts, corneal clouding, wormian bones, lipodystrophy and osteopenia have been reported.


Autosomal recessive distal osteolysis syndrome

An early-onset distal osteolysis characterised by severe resorption of the hands and feet and absence of the distal and middle phalanges. It has been described in a son and daughter born to consanguineous parents. Other manifestations include distal muscular hypertrophy, flexion contractures, short stature, mild intellectual deficit and characteristic facies (maxillary hypoplasia, exophthalmos, and a broad nasal tip). It is transmitted as an autosomal recessive trait.


Autosomal recessive distal renal tubular acidosis

A rare autosomal recessive form of proximal renal tubular acidosis (pRTA) characterized by an isolated defect in the proximal tubule leading to the decreased reabsorption of bicarbonate and consequently causing urinary bicarbonate wastage. Mild growth retardation and reduced bone density are extra-renal complications. Several fractures and delayed puberty are possible features.


Autosomal recessive dopa-responsive dystonia

A very rare neurometabolic disorder characterized by a spectrum of symptoms ranging from those seen in dopa-responsive dystonia (DRD) to progressive infantile encephalopathy.

Summary:
Epidemiology
The estimated European prevalence of DRD ranges from 1/1,000,000-1/200,000. DYT5b is much less frequent than autosomal dominant DRD (DYT5a); fewer than 50 patients have been described worldwide to date.
Clinical description
Disease presents in infancy (most frequently in the first year of life) with a progressive hypokinetic-rigid syndrome with generalized dystonia, involuntary jerky movements, postural tremor, or gait disturbances that may fluctuate during the day and show good or excellent responsiveness to levodopa (L-dopa) in most cases (>80%). Eye-rolling movements and/or mild, non-progressive intellectual deficit may be present in some cases. Less frequently, a more severe phenotype of complex encephalopathy can present before the age of 6 months, with marked hypokinesia and progressive truncal hypotonia, combined with focal or generalized dystonia, sometimes with dystonic crises over several days and (often excessive) jerky movements like myoclonus and tremor without diurnal fluctuations. Autonomic disturbances are frequent, such as excessive salivation and sweating, lethargy, constipation, poor feeding and ''pyrexia of unknown origin''. Intellectual deficit, developmental motor delay, bilateral ptosis and oculogyric crises are also frequent.
Etiology
DYT5b is caused by mutations in the tyrosine hydroxylase TH gene (11p15.5) encoding tyrosine hydroxylase, an enzyme responsible for catalyzing the conversion of L-tyrosine to L-dopa, the precursor of dopamine. For the two most common missense mutations (c.698G>A and c.707T>C) and for heterozygous truncating mutations, no genotype-phenotype correlation has been observed, but mutations in the promoter region are apparently associated with a milder phenotype.
Diagnostic methods
Diagnosis is based on clinical findings and the improvement of symptoms with the administration of oral L-dopa. The finding of homozygous TH mutations confirms diagnosis. Low levels of the dopamine metabolite homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) are found in the cerebrospinal fluid (CSF) of patients with DYT5b. HVA concentrations and the HVA/5-HIAA ratio in CSF appear to correlate with the age of onset and the severity of the phenotype.
Differential diagnosis
Differential diagnoses include different forms of DRD (e.g. autosomal dominant DRD), early onset torsion dystonia, myoclonic dystonia and other types of early-onset parkinsonism. It can also be mistaken for cerebral palsy or spastic paraplegia. Differential diagnoses that need to be considered for the more severe, encephalopathy-like phenotype include febrile infection-related epilepsy syndrome, neonatal hypoxic and ischemic brain injury, other tetrahydrobiopterin (BH4)-related enzyme deficiencies and mitochondrial disorders.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known TH  mutation.
Genetic counseling
DYT5b is inherited in an autosomal recessive manner. Genetic counseling is possible and recommended.
Management and treatment
L-dopa, usually in combination with carbodopa, is the treatment of choice. The less severe phenotype typically shows a significant positive and quick response, but patients with the more severe phenotype frequently show hypersensitivity to L-dopa, with only moderate or no benefit, even after prolonged treatment and careful dosage adjustment, and are more prone to side effects. Dosage should be monitored for side effects and adjusted as necessary. Inhibitors of dopamine degradation like selegiline may be considered alternatively or in addition to L-dopa, but are rarely used in clinical practice.
Prognosis
Prognosis depends on the severity of the disease and if/when patients receive treatment.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Christoph KAMM


Autosomal recessive epidermolytic ichthyosis

A rare, inherited, non-syndromic ichthyosis characterized by congenital, generalized erythroderma with cutaneous blistering and erosions, resembling collodion presentation at birth, replaced by progressive hyperkeratosis later in life without palmoplantar involvement. The ultrastructural pathology consists of sparse keratin filaments and keratin clumps that show a nearly homogeneous, amorphous structure.


Autosomal recessive extra-oral halitosis

A rare inborn error of metabolism characterized by cabbage-like breath odor with high levels of methanethiol and dimethylsulfide in oral and nasal breath, due to methanethiol oxidase deficiency. Laboratory examination shows elevated levels of dimethylsulfide, dimethylsulfoxide, and dimethylsulfone in blood, cerebrospinal fluid (CSF), and urine.


Autosomal recessive faciodigitogenital syndrome

A very rare syndrome including short stature, facial dysmorphism, hand abnormalities and shawl scrotum.

Summary:
Epidemiology
It has been observed in 16 subjects from five distantly related sibships of a large Kuwaiti Bedouin tribe.
Clinical description
Dysmorphic features include triangular or elongated face, hypertelorism, wide palpebral fissures, short, stubby nose with anteverted nostrils, long philtrum and ear anomalies. The hands are small, broad with mild interdigital webbing, 5th finger clinodactyly and lax joints. In one sibship, affected patients had coarse, dry, and hypopigmented hair. The affected patients had no intellectual deficit.
Genetic counseling
In this tribe, the condition is transmitted as an autosomal recessive trait.

                            Last update:
                            October 2010


Autosomal recessive frontotemporal pachygyria

A cerebral malformation characterized by symmetric, bilateral pachygyria with normal head circumference and without polymicrogyria. Clinical manifestations include developmental delay, moderate intellectual disability, normal or slightly decreased muscle tone and deep-tendon reflexes, telecanthus or hypertelorism.