A rare, potentially lethal, autosomal recessive metabolic disease characterized by impaired glucose-galactose absorption resulting in severe watery diarrhea and dehydration with onset in the neonatal period.

Summary:
Epidemiology
Glucose-galactose malabsorption (GGM) is a rare disease, with fewer than 1,000 cases reported worldwide, which is most frequently reported in populations with a high incidence of consanguinity. The frequency of the Northern-Sweden founder mutation, Q457R, is 45-fold higher than other mutations linked to the disease in the general European population.
Clinical description
This disease usually presents within the first week of life with severe life-threatening diarrhea, metabolic acidosis, and hyperosmolar dehydration.
Etiology
GGM is due to mutations in the gene coding for the intestinal brush border sodium-glucose cotransporter protein SGLT1 (SLC5A1), disrupting the absorption of glucose and galactose from lactose in breast milk. As this disease is mainly reported in populations with high incidence of consanguinity, many mutations causing the disease are homozygous missense, nonsense, frame-shift, or splice-site mutations. In non-consanguineous probands, heterozygous mutations are inherited from each parent. Mutations producing premature stop codons result in non-functional truncated proteins, while missense mutations generally result in proteins that do not reach the brush border membrane. It should be cautioned that not all identified missense mutations produce inactive transporters. In the oldest known GGM pedigree -dating back to the 17th century in Northern Sweden- a homozygous missense mutation identified in 14 patients results in a non-functional protein in the brush border membrane.
Diagnostic methods
If the child is in hospital, i) a duodenal biopsy is frequently taken to ensure normal histology, and ii) an oral glucose tolerance test or a hydrogen breath test is conducted to evaluate glucose absorption. However, the most straightforward test in the hospital or at home is to eliminate lactose, glucose, and galactose from the feeds by withholding breast milk and feeding with a sugar-free formula. The diarrhea will cease but return immediately on refeeding breast milk or formula with glucose, but not with fructose. Sanger and next-generation sequencing methods are readily available. Molecular testing is not required if the intestinal biopsy is normal, and the child's diarrheal symptoms resolve on a glucose/galactose restricted-diet.
Differential diagnosis
The differential diagnosis GGM includes other forms of nutrient-specific congenital diarrhea such as congenital lactase deficiency and congenital sucrase-isomaltase deficiency.
Antenatal diagnosis
Antenatal diagnosis is possible when molecular testing has previously identified the mutation causing glucose malabsorption.
Genetic counseling
As GGM is an autosomal recessive disorder, the parents of children with GGM should be advised that additional children have a 25% chance of inheriting the disease. Carriers of GGM mutations have an extremely low chance of parenting children with the disease, as the frequency of mutation in the general population is less than 1 in 15,000. The only exception is where carriers are restricted by geography or culture to communities where GGM is prevalent, and in these cases, prospective partners ought to be screened for mutations.
Management and treatment
The symptoms of GGM are resolved on a diet free of glucose, galactose, and lactose, and several infant formulas are available for young children in Europe and North America. As children enter late infancy, it becomes more challenging to maintain a carbohydrate-free diet and parents are encouraged to consult a well-qualified-dietician or parent-support group.
Prognosis
After dealing with the challenges of dietary carbohydrates (lactose, sucrose, glucose, galactose) restriction to control diarrhea and dehydration in newborns and young children, the prognosis is excellent for adults who lead a normal healthy life.

                            Last update:
                            November 2023

                            - Expert reviewer(s):
                            Pr Martin MARTIN  - Pr Ernest WRIGHT


A disorder that is principally characterized by hemolytic anemia, (usually rather mild), however, the presence of neurological symptoms has also been reported.

Summary:
Epidemiology
Gamma-glutamylcysteine synthetase deficiency has been detected in nine patients from seven families worldwide.
Etiology
Gamma-glutamylcysteine synthetase catalyses the first and rate-limiting step in the synthesis of glutathione. Its deficiency results in low cellular levels of glutathione and gamma-glutamylcysteine. Four different mutations in the heavy subunit have been identified in four families affected by gamma-glutamylcysteine synthetase deficiency.
Diagnostic methods
The diagnosis consists of the following stages: clinical findings, the finding of low cellular levels of glutathione, low activity of gamma-glutamylcysteine synthetase, and mutation analysis of the gamma-glutamylcysteine synthetase genes.
Differential diagnosis
The differential diagnosis should include glutathione synthetase deficiency (see this term), which is also associated with low levels of glutathione.
Antenatal diagnosis
Antenatal diagnosis could be performed by measurement of gamma-glutamylcysteine synthetase activity or mutational analysis (if the mutation in the family is known) of chorionic villi samples or cultured amniocytes.
Genetic counseling
As transmission is autosomal recessive, families should be referred for genetic counselling.
Management and treatment
Patients with gamma-glutamylcysteine synthetase deficiency should avoid drugs known to precipitate hemolytic crises in patients with glucose-6-phosphate dehydrogenase deficiency, e.g. phenobarbital, acetylsalicylic acid and sulfonamides. It is possible that patients would benefit from treatment with anti-oxidants but no studies have been made.
Prognosis
The prognosis is difficult to predict, as only nine patients are known worldwide.

                            Last update:
                            March 2007

                            - Expert reviewer(s):
                            Dr Agne LARSSON  - Dr Ellinor RISTOFF


A rare inborn error of metabolism characterized by abnormally high urinary excretion of glutaric acid due to peroxisomal glutaryl-CoA oxidase deficiency. There is no association with a specific clinical phenotype.


Glutaryl-CoA dehydrogenase (GCDH) deficiency (GDD) is an autosomal recessive neurometabolic disorder clinically characterized by encephalopathic crises resulting in striatal injury and a severe dystonic dyskinetic movement disorder.

Summary:
Epidemiology
Worldwide prevalence is estimated at 1 in 100,000 births. GDD is more prevalent in the old order Amish community, Canadian Oji-Cree natives, Irish travelers and Lumbee Native Americans.
Clinical description
Neonates are mainly asymptomatic, although 75 % present with macrocephaly and possibly show hypotonia and irritability. If undiagnosed, the initial acute encephalopathic crisis occurs between 3-36 months, typically precipitated by an intercurrent febrile illness, vaccination or a surgical intervention, and characterized by hypotonia, loss of motor skills and convulsions resulting in bilateral striatal injury with severe secondary dystonia and occasionally subdural and retinal hemorrhage. GDD can exceptionally present with hypoglycemia or acidosis. With age (>6 years) and with appropriate treatment, the risk of encephalopathic crises subsides. In some patients, hypotonia and dystonia develop gradually with no encephalopathic crisis, which is known as late-onset or insidious-onset GDD.
Etiology
GDD is caused by mutations in the GCDH gene, located to 19p13.2, and involved in L-lysine, L-hydroxylysine and L-tryptophane catabolic pathways. Over 200 GCDH mutations have been reported. GDD has a distinctive pathological appearance due to the accumulation of glutaric acid (GA), 3-hydroxyglutaric (3-OH-GA) and glutaconic acids and glutarylcarnitine in body fluids.
Diagnostic methods
Presymptomatic detection can be offered through routine newborn screening programs implemented in some countries. If not available, diagnosis should be suspected on the basis of clinical findings and can be supported by neuroradiological findings including widely open opercula and basal ganglia injury. Diagnosis is confirmed by genetic analysis or by measuring elevated levels of GA, 3-OH-GA, glutaconic acid and glutarylcarnitine by quantitative urinary organic acid analysis, gas chromatography-mass spectrometry and/or tandem mass spectrometry (acylcarnitines).
Differential diagnosis
GDD is often misdiagnosed. Differential diagnosis includes encephalitis, Reye's syndrome, familial infantile bilateral striatal necrosis, familial megalencephaly, postencephalitic Parkinsonism (see these terms), dystonic cerebral palsy, battered child syndrome with chronic subdural effusions, sudden infant death syndrome and vaccine induced brain-injury.
Antenatal diagnosis
Prenatal testing can be performed by genetic and GCDH enzyme analysis of chorionic villi sample or through measuring GA levels in amniotic fluid in at-risk families. Genetic testing is necessary to confirm antenatal diagnosis.
Genetic counseling
Genetic counseling is recommended and should be offered to affected families together with genetic testing, as inheritance is autosomal recessive.
Management and treatment
Daily management comprises a low lysine diet, carnitine supplementation in association with prompt emergency treatment during intercurrent illness. During acute episodes, management includes, most importantly, increasing energy supply (20-100 % above RDI); omission of natural protein for 24-48 hours followed by a gradual reintroduction; L-carnitine supplementation doubling and close monitoring of glucose, electrolyte and fluid balance, as well as urea and liver status by an informed skilled interdisciplinary team. Adherence to emergency treatment recommendations is imperative in preventing neuronal damage and subsequent secondary dystonia.
Prognosis
Prognosis depends on a timely diagnosis and consequential management and treatment. GDD is now regarded as a treatable neurometabolic disorder.

                            Last update:
                            April 2013

                            - Expert reviewer(s):
                            Pr Georg HOFFMANN


A rare disorder characterised by hemolytic anemia, associated with metabolic acidosis and 5-oxoprolinuria in moderate forms, and with progressive neurological symptoms and recurrent bacterial infections in the most severe forms.

Summary:
Epidemiology
This disease has been detected in at least 70 patients in more than 50 families worldwide.
Etiology
Several mutations have been identified in the gene encoding glutathione synthetase, localized to chromosome 20q11.2. Glutathione synthetase catalyses the last step in the synthesis of glutathione and a deficiency results in low levels of glutathione. Acidosis is due to reduced feedback inhibition of gamma-glutamyl cysteine synthetase in the gamma-glutamyl cycle, which ultimately leads to overproduction and accumulation of 5-oxoproline.
Diagnostic methods
The diagnosis usually involves the following: clinical findings, the finding of 5-oxoprolinuria, low levels of glutathione, low activity of glutathione synthetase, and mutation analysis of the glutathione synthetase gene.
Differential diagnosis
Other causes of 5-oxoprolinuria include 5-oxoprolinase deficiency (see this term), diet (certain infant formulas and tomato juice), severe burns, Stevens-Johnson syndrome (see this term), inborn errors of metabolism not involving the gamma-glutamyl cycle, e.g. X-linked ornithine trancarbamylase deficiency, urea cycle defects, tyrosinemia, as well as homocystinuria (see these terms), drug metabolism (paracetamol, vigabatrin, flucloxacillin, netimicin), prematurity, malnutrition, pregnancy and nephropatic cystinosis.
Antenatal diagnosis
Antenatal diagnosis is possible.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Management includes correction of the acidosis, supplementation with antioxidants and avoidance of drugs known to precipitate hemolytic crises in patients with glucose-6-phosphate dehydrogenase deficiency, e.g. phenobarbital, acetylsalicylic acid and sulfonamides.
Prognosis
A long-term follow up study of 28 patients with glutathione synthetase deficiency has showed that the factors most predictive of survival and long-term outcome are early diagnosis, correction of acidosis and early supplementation with vitamin C and vitamin E.

                            Last update:
                            March 2007

                            - Expert reviewer(s):
                            Dr Agne LARSSON  - Dr Ellinor RISTOFF


A rare form of glycerol kinase deficiency (GKD) characterized by pseudohypertriglyceridemia in otherwise healthy adults and diagnosed fortuitously.


Glycerol kinase deficiency, juvenile form

Juvenile glycerol kinase deficiency (GKD) is an uncommon form of GKD (see this term) characterized by Reye-like clinical manifestations including episodic vomiting, acidemia, and disorders of consciousness.


Glycine encephalopathy (GE) is an inborn error of glycine metabolism characterized by accumulation of glycine in body fluids and tissues, including the brain, resulting in neurometabolic symptoms of variable severity.

Summary:
Epidemiology
In Finland, an incidence at birth of 1/55,000 is reported and in British Columbia, Canada, 1/63,000, with a calculated carrier rate of 1/125.
Clinical description
Three forms of GE have been recognized based on the age of onset: neonatal, infantile and atypical glycine encephalopathy (see these terms). Most patients have the life-threatening neonatal form and present mild to severe disease manifestations starting within a few days of birth including lethargy or even coma, hypotonia, hiccups, myoclonic jerks, and breathing/swallowing disorders, with subsequent intellectual deficit, spasticity and intractable seizures. A smaller proportion of patients show developmental delay and generally mild seizures in the infantile period, while others do not develop symptoms until late infancy or adulthood. Although patients usually have either a mild or severe course, there is a continuous clinical spectrum. Some patients develop choreic movements. Atypical glycine encephalopathy indicates hyperglycinemic patients whose clinical presentations are different from those of neonatal or infantile form, for example, transient or late-onset hyperglycinemia and patients with spastic paraparesis.
Etiology
Mutations in two genes are known to cause glycine encephalopathy: GLDC (9p22) and AMT (3p21.2-p21.1). These genes encode the P-protein and T-protein components of the enzymatic glycine cleavage system (GCS), respectively. Although GCSH is another GCS gene, no mutations have been identified in neonatal or infantile forms. Deficient GCS activity results in defective glycine metabolism and accumulation of the amino acid in body tissues. In some patients with deficient GCS enzyme activity no mutation could be identified by exon sequencing analysis of any GCS gene. The vast majority of patients have no detectable enzyme activity. Etiology of atypical forms remains largely unknown.
Diagnostic methods
GE should be suspected in cases of elevated glycine levels in blood and cerebrospinal fluid (CSF). Increased CSF-to-plasma glycine ratios also suggest the diagnosis. Measurement of GCS activity of biopsied liver sample or by 13C-glycine breath test and genetic testing may confirm diagnosis. Brain MRI may reveal hypogenesis of corpus callosum, abnormal gyrus, and hypogenesis of cerebellum in the neonatal form. Suppression burst and hypsarrhythmia are common in EEG. Subsequently, delayed myelination and atrophy may be observed.
Differential diagnosis
Differential diagnosis includes organic acidemias that may present hyperglycinemia such as D-glyceric acidemia, propionic acidemia, methylmalonic acidemia, isovaleric acidemia, and ketoacidosis due to beta-ketothiolase deficiency (see these terms). Conditions characterized by neonatal seizures should also be considered. Valproate treatment may cause hyperglycinemia.
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies can be performed either by molecular genetic testing of the causative genes or by GCS enzyme analysis of chorionic villi sample.
Genetic counseling
Glycine encephalopathy is inherited in an autosomal recessive manner.
Management and treatment
The following tests should be used to guide treatment: brain MRI, EEG, and developmental and neurological assessment. There are only supportive and symptomatic measures for GE including antiepileptics for seizure control, placement of a gastrostomy tube for swallowing disorders, and treatment for gastroesophageal reflux. Sodium benzoate is used to reduce plasma glycine levels. NMDA receptor antagonists may ameliorate neurological symptoms although it remains to be established whether they improve long term outcome.
Prognosis
Prognosis depends on disease severity. Most patients with neonatal or infantile forms have a severe outcome. In the neonatal form, early death sometimes occurs due to apnea. Prognosis in atypical cases is variable.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                             Shigeo KURE


Glycogen storage disease due to acid maltase deficiency, infantile onset is the most severe form of glycogen storage disease due to acid maltase deficiency, characterized by cardiomegaly with respiratory distress, muscle weakness and feeding difficulties. It is often fatal.


Glycogen storage disease due to acid maltase deficiency, late-onset

A rare form of glycogen storage disease due to acid maltase deficiency characterized by excessive accumulation of glycogen in lysosomes most notably in skeletal muscle, leading to slowly progressive muscle weakness with walking disability and reduced respiratory function. The late-onset form includes all cases in which hypertrophic cardiomyopathy did not manifest or was not diagnosed at or under the age of 1 year, as well as all cases with symptom onset above the age of 1 year.


Glycogen storage disease due to acid maltase deficiency

A rare lysosomal storage disease characterized by lysosomal accumulation of glycogen particularly in skeletal, cardiac, and respiratory muscles, as well as the liver and nervous system, due to acid maltase deficiency. The clinical spectrum comprises infantile-onset disease with severe hypertrophic cardiomyopathy, generalized muscle weakness, poor feeding and failure to thrive, and respiratory insufficiency, and late-onset disease manifesting before or after twelve months of age without cardiomyopathy, with proximal muscle weakness and respiratory insufficiency.


Glycogen storage disease due to aldolase A deficiency is an extremely rare glycogen storage disease (see this term) characterized by hemolytic anemia with or without myopathy or intellectual deficit. Myopathy can be severe enough to result in fatal rhabdomyolysis in some patients. A family with episodic rhabdomyolysis (triggered by fever) without hemolytic anemia has recently been reported.


Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia

Glycogenosis due to glucose-6-phosphatase deficiency (G6P) type a, or glycogen storage disease (GSD) type 1a, is a type of glycogenosis due to G6P deficiency (see this term).

Summary:
Epidemiology
Prevalence is unknown. Annual incidence at birth of glycogenosis due to G6P deficiency is around 1/100,000. Type a is the more frequent type, affecting about 80% of patients.
Clinical description
The disease may manifest at birth by enlarged liver or, more commonly, between the ages of three to four months by symptoms of fast-induced hypoglycemia (tremors, seizures, cyanosis, and apnea). Patients present disturbed glucose homeostasis usually characterized by poor tolerance to fasting, significant hepatomegaly (sometimes eight to ten cm below the right costal margin), growth retardation (short stature and delayed puberty), generally improved by an appropriate diet, osteopenia and, in some cases, osteoporosis, round doll-like facial appearance with full cheeks, mild hypotonia, nephromegaly, and platelet dysfunction that may lead to frequent epistaxis. Diarrhea may be encountered. Late complications are hepatic (adenomas with rare but possible transformation into hepatocellular carcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal failure), but also include anemia, sometimes severe, and a risk of hypoglycemic brain damage. Pulmonary hypertension has been reported in few cases.
Etiology
The disease is due to a dysfunction in the G6P system, a key step in glycemia regulation. Type a is due to mutations in the G6PC gene (17q21), which cause a deficit of the catalytic subunit G6P-alpha expressed in the liver, kidney and intestine. Many mutations have been identified, illustrating the allelic heterogeneity of the condition.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Management is similar in both types of glycogenosis due to G6P deficiency (see this term).

                            Last update:
                            November 2010

                            - Expert reviewer(s):
                            Pr Philippe LABRUNE


Glycogen storage disease due to glucose-6-phosphatase deficiency type Ib

Glycogenosis due to glucose-6-phosphatase deficiency (G6P) type b, or glycogen storage disease (GSD) type 1b, is a type of glycogenosis due to G6P deficiency (see this term).

Summary:
Epidemiology
Prevalence is unknown. Annual incidence at birth of glycogenosis due to G6P deficiency is around 1/100,000. Type b is the less frequent type, affecting about 20% of patients.
Clinical description
Clinical presentation is similar to that of glycogenosis due to G6P deficiency type a (see this term). In addition, in type b, neutropenia, and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphthous gingivostomatitis, and inflammatory bowel disease.
Etiology
The disease is due to a dysfunction in the G6P system, a key step in glycemia regulation. Type b is due to mutations in the SLC37A4 gene (11q23), which cause a deficit of the ubiquitously expressed G6P transporter, or G6P translocase (G6PT). Many mutations have been identified, illustrating the allelic heterogeneity of the condition.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Management is similar in both types of glycogenosis due to G6P deficiency (see this term). However, in type b, periodic antibiotic therapy may be needed, and, under careful monitoring, granulocyte colony-stimulating factor (G-CSF or GCSF) enables correction of neutropenia with reduction of infections and inflammatory bowel disease.

                            Last update:
                            November 2010

                            - Expert reviewer(s):
                            Pr Philippe LABRUNE


Glycogen storage disease due to glucose-6-phosphatase deficiency

A rare inherited metabolic disease (comprising two major subtypes: type Ia and Ib) characterized by poor tolerance to fasting, growth delay and hepatomegaly resulting from accumulation of glycogen and fat in the liver.

Summary:
Epidemiology
Prevalence is unknown. Annual incidence at birth is around 1/100,000. Type Ia affects 80% of patients, and type Ib 20%.
Clinical description
The disease may manifest at birth by hepatomegaly or, more commonly, between the ages of three to four months by symptoms of fast-induced hypoglycemia. Patients have enlarged liver, growth delay, osteopenia, sometimes osteoporosis, full-cheeked round face, nephromegaly and frequent epistaxis due to platelet dysfunction. In addition, in type b, infections and inflammatory bowel disease are due to neutropenia and neutrophil dysfunction. Late complications are hepatic (hepatocellular adenomas and more rarely hepatocellular carcinoma) and renal (proteinuria and sometimes renal insufficiency).
Etiology
The disease is due to a dysfunction in the G6P system, a key step in glycemia regulation. Mutations in the G6PC gene (17q21) cause a deficit of the catalytic subunit G6P-alpha restricted to expression in the liver, kidney and intestine (type a), and mutations in the SLC37A4 gene (11q23) cause a deficit of the ubiquitously expressed G6P transporter (G6PT) or G6P translocase (type b).
Diagnostic methods
Diagnosis is based on clinical presentation, and glycemia and lactacidemia levels, after a meal (hyperglycemia and hypolactacidemia), and after three to four hours fasting (hypoglycemia and hyperlactacidemia). Uric acid, triglycerides, and cholesterol serum levels are increased. There is no glycemic response to glucagon. Molecular genetic testing enables confirmation of diagnosis. Liver biopsy to measure G6P activity is no longer performed.
Differential diagnosis
Differential diagnoses include the other glycogenoses, in particular glycogen storage disease due to glycogen debranching enzyme deficiency (GDE deficiency) or GSD type III but in this case, glycemia and lactacidemia are high after a meal and low in a fasting period. Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but easily ruled out through clinical and ultrasound data.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
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 that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube or a gastrostomy (only in type Ia patients), and later oral addition of uncooked starch), acidosis (restricted fructose and galactose intake, oral supplementation in bicarbonate), hypertriglyceridemia (diet, cholestyramine, statines), hyperuricemia (allopurinol) and hepatic complications. Renal protection using converting enzyme inhibitors must be started should microalbuminuria be detected. Liver transplantation, performed on the basis of poor metabolic control or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type b. Kidney transplantation can be performed in case of severe renal failure. Combined liver-kidney grafts have been performed in a few cases.
Prognosis
With adapted management, prognosis is better: patients have almost normal life span.

                            Last update:
                            October 2023

                            - Expert reviewer(s):
                            Pr Philippe LABRUNE | MetabERN*

                                * European Reference Network


Glycogen storage disease due to glycogen branching enzyme deficiency

Glycogen branching enzyme (GBE) deficiency (Andersen's disease or amylopectinosis), or glycogen storage disease type 4 (GSD4), is a rare and severe form of glycogen storage disease which accounts for approximately 3% of all the glycogen storage diseases (see these terms).

Summary:
Clinical description
Clinical presentation is extremely heterogeneous and involves the liver or the neuromuscular system. In the classical form, children are normal at birth, but develop hepatomegaly, hypotonia, and developmental delay during their first months. The disease then rapidly progresses to cirrhosis with portal hypertension and ascites, ultimately causing death in early childhood. A non-progressing hepatic form has been reported in a few cases. In the neuromuscular presentation, the age of onset ranges from fetal to adult age. The most severe form starts before birth with decrease or absence of fetal movements, arthrogryposis, hypoplastic lungs, and perinatal death. Patients with congenital forms have severe hypotonia, cardiomyopathy, depressed respiration and neuronal involvement. Milder forms have been reported with later-onset, marked by muscular weakness or cardiomyopathy and heart failure. Neurological adult forms with central and peripheral nervous system dysfunction have also been described, such as Adult Polyglucosan Body Disease (APBD; see this term), which is characterized by widespread upper and lower motor neuron lesions.
Etiology
The disease is caused by mutations in the GBE1 gene (3p12) encoding GBE. GBE deficiency results in storage of abnormal glycogen that resembles an amylopectin-like structure (polyglucosan).
Diagnostic methods
The diagnosis is based on biochemical findings from a liver biopsy, revealing an abnormal glycogen content, and on the evidence of enzymatic deficiency in the liver, muscle, erythrocytes, or fibroblasts, and in the trophoblast or cultured amniotic cells.
Differential diagnosis
Differential diagnoses include galactosemia, hydrops fetalis, and tyrosinemia (see these terms).APBD can also present with or without GBE deficiency indicating that different biochemical defects could result in an identical phenotype.
Antenatal diagnosis
Prenatal diagnosis is possible by enzyme assay and/or DNA analysis.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
There is no specific treatment. A liver transplant can be proposed in severe forms without associated heart disease.
Prognosis
Prognosis is unfavorable for patients with perinatal onset and classic forms who do not undergo liver transplantation. Long-term prognosis for others depends on the extent, severity, and progression of the condition.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr Roseline FROISSART


Glycogen storage disease due to glycogen debranching enzyme deficiency

Glycogen debranching enzyme (GDE) deficiency, or glycogen storage disease type 3 (GSD 3), is a form of glycogen storage disease characterized by severe muscle weakness and hepatopathy.

Summary:
Epidemiology
Estimated prevalence is approximately 1/100,000 births (it may be higher among North Africans).
Clinical description
GSD 3 commonly occurs in early childhood. Children present with hepatomegaly, growth retardation and occasional seizures related to hypoglycemia. Hepatomegaly may disappear with adulthood. Muscle weakness is slowly progressive. Other frequently associated signs include muscular hypotonia and hypertrophic cardiomyopathy. Symptoms often improve at puberty, except in the few cases where cirrhosis or myopathy appears. Biological findings include hypoglycemia without acidosis, hypertriglyceridemia, and hypertransaminasemia during childhood.
Etiology
The disease is caused by mutations in the AGL gene (1p21), leading to a deficiency in the GDE that works with the glycogen phosphorylase to catabolize glycogen. The deficiency may occur in the liver and muscle (GSD 3a) or only in the liver (GSD 3b).
Diagnostic methods
The diagnosis is based on the evidence of enzymatic deficiency in fresh leukocytes, fibroblasts, or on a liver or a muscle biopsy. Unlike GSD type 1 (see this term), there is a response to glucagon after meals.
Differential diagnosis
Differential diagnoses include the other forms of glycogen storage diseases (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible by enzyme assay and/or DNA analysis.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment is based on a specific diet, with enteral nasogastric drip feeding at night in case of hypoglycemia, frequent meals, and uncooked starch supplements. For patients with myopathy, a high protein diet is also recommended.
Prognosis
Rarely, patients may develop complications such as hepatic failure or hepatocellular carcinoma.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr Roseline FROISSART


Glycogen storage disease due to hepatic glycogen synthase deficiency

A genetically inherited anomaly of glycogen metabolism and a form of glycogen storage disease (GSD) characterized by fasting hypoglycemia. This is not a glycogenosis, strictly speaking, as the enzyme deficiency decreases glycogen reserves.

Summary:
Epidemiology
It is an extremely rare disease; about 20 cases have been reported in the literature so far.
Clinical description
It commonly appears in infancy or in early childhood. Patients present with morning fatigue and fasting hypoglycemia (without hepatomegaly) associated with hyperketonemia but without hyperalaninemia or hyperlactacidemia. After meals, major hyperglycemia associated with lactate and alanine increase and hyperlipidemia is observed.
Etiology
Glycogen synthetase deficiency is caused by mutations in the GYS2 gene (12p12.2).
Diagnostic methods
Biological results after glucose loading test strongly suggest the diagnosis, but formal diagnosis requires a liver biopsy showing a slightly decreased glycogen concentration and evidence of the enzyme deficiency (it is not expressed in muscles, erythrocytes, leukocytes, or fibroblasts). Molecular analysis revealing a mutation in the GYS2 gene confirms the diagnosis. Mutation analysis is an alternative to liver biopsy.
Differential diagnosis
Differential diagnoses include fructose intolerance, GSD type 1 (see these terms), and hypoglycemia.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
The condition is treated with a specific diet that includes frequent meals with high protein intake during the day and addition of uncooked starch in the evening.
Prognosis
Prognosis is favorable when the disease is correctly managed.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr Roseline FROISSART


Glycogen storage disease due to lactate dehydrogenase deficiency

A rare genetic glycogen storage disease characterized by either lactate dehydrogenase (LDH) M- or H-subunit deficiency. Main features of LDH M-subunit deficiency are exertional fatigue and muscle pain potentially accompanied by myoglobinuria. Some patients may develop pustular psoriasis-like skin lesions. Complications of pregnancy, such as frequent abdominal pains and increased uterine tone with a risk of dystocia have also been described. LDH H-subunit deficiency manifests with low serum LDH activity of unclear clinical relevance.


Glycogen storage disease due to lactate dehydrogenase M-subunit deficiency

A rare glycogen storage disease characterized by easy fatigue, exertional myalgia, painful muscle stiffness, and cramps, with or without myoglobinuria. Pustular psoriasis-like eruptions with antecedent annular scaly plaques may be observed in some patients. In affected women, pregnancy may be complicated by abdominal pain and dystocia.


Glycogen storage disease due to liver and muscle phosphorylase kinase deficiency

A benign inborn error of glycogen metabolism. It is the mildest form of GSD due to PhK deficiency.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The disease manifests in childhood. Patients have marked hepatomegaly and mild muscular hypotonia. Hypoglycemia may occur only after prolonged fasting. These symptoms improve with age and adults are generally asymptomatic.
Etiology
Phosphorylase kinase (PhK) is an enzyme which plays a key role in the regulation of glycogenolysis as it is required for glycogen phosphorylase activation. It consists of four copies of each four subunits (alpha, beta, gamma and calmoduline) encoded by different genes on different chromosomes and differentially expressed in various tissues. GSD due to liver and muscle PhK deficiency is due to mutations in the PHKB gene (16q12-q13) which encodes the beta subunit.
Diagnostic methods
Biochemical diagnosis can be made by measuring phosphorylase kinase activity in blood cells or in a liver or muscle biopsy. Serum transaminase levels may also be elevated. Genetic testing is useful to confirm or establish the diagnosis.
Differential diagnosis
Differential diagnoses include other glycogen storage diseases such as GSD due to liver phosphorylase deficiency (GSD type VI), GSD due to glycogen debranching enzyme deficiency (GSD type III), and GSD due to glucose-6-phosphatase (GSD type I) (see these terms).
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Most patients do not require any specific treatment; a few patients may need to use cornstarch snacks.
Prognosis
Prognosis is good.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Roseline FROISSART  - Pr Philippe LABRUNE


Glycogen storage disease due to liver glycogen phosphorylase deficiency

Liver phosphorylase deficiency, or glycogen storage disease type 6b (Hers' disease, GSD 6b) is a benign and rare form of glycogen storage disease.

Summary:
Clinical description
The disease usually occurs in childhood and is characterized by hepatomegaly and growth delay. Hypoglycemic episodes are mild or absent, and hypertransaminasemia and hyperlipidemia are moderate and unconstant. Hepatomegaly usually improves with age and disappears entirely at puberty.
Etiology
Transmission is autosomal recessive and mutations in the PYGL gene (14q21-q22) have been identified in patients.
Diagnostic methods
Diagnosis is based on biochemical findings revealing excess glycogen and partial deficiency of total and active phosphorylase in liver biopsy.
Management and treatment
A diet with high carbohydrate intake and regular meals prevents hypoglycemia in children, but most patients require no specific treatment.
Prognosis
Prognosis is usually good.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr Roseline FROISSART


Glycogen storage disease due to liver phosphorylase kinase deficiency

Glycogen storage disease (GSD) due to liver phosphorylase kinase (PhK) deficiency is a benign inborn error of glycogen metabolism characterized by hepatomegaly, growth retardation, and mild delay in motor development during childhood.

Summary:
Epidemiology
It is the most common presentation of glycogen storage disease due to PhK deficiency (see this term) with an incidence estimated at less than 1/100,000 births.
Clinical description
Patients usually present in early childhood with hepatomegaly, growth retardation, and mild delay in motor development. Fast-induced hypoglycemia and hyperlipidemia are variable and, if present, are generally mild. Adults are generally asymptomatic. Full-cheeked round face and osteopenia have been reported on exceptional occasions in cases with an X-linked inheritance. An increased risk of cirrhosis due to liver fibrosis is observed in cases with autosomal recessive inheritance.
Etiology
Phosphorylase kinase (PhK) is an enzyme which plays a key role in the regulation of glycogenolysis as it is required for glycogen phosphorylase activation. It consists of four copies of each four subunits (alpha, beta, gamma and calmodulin) encoded by different genes on different chromosomes and differentially expressed in various tissues. The most frequent type of GSD due to liver PhK deficiency is the X-linked recessive (XLG) type that is due to mutations in the PHKA2 gene (Xp22.2-p22.1) encoding the liver isoform of the alpha-subunit. When the enzymatic deficiency is found both in erythrocytes and liver cells, the disorder is classified as XLG1, whereas when the deficiency can only be demonstrated in liver cells, it is classified as XLG2, although studies have shown that, in both cases, mutations occur within the same subunit. The autosomal recessive type is due to mutations in the PHKG2 gene (16p12.1-p11.2) encoding the liver isoform of the gamma-subunit. PhK deficiency due to all these mutations leads to glycogen accumulation in the liver.
Diagnostic methods
Biochemical diagnosis is made by measuring phosphorylase kinase activity in blood cells or in a liver biopsy. Some patients may have normal activity in red blood cells (XLG2 variant). Serum transaminase levels may be elevated. Genetic testing is useful to confirm or establish the diagnosis.
Differential diagnosis
Differential diagnoses include other glycogen storage diseases such as GSD due to liver phosphorylase deficiency (GSD type VI), GSD due to glycogen debranching enzyme deficiency (GSD type III), and GSD due to glucose-6-phosphatase deficiency (GSD type I) (see these terms).
Management and treatment
Most patients require no specific treatment. Hypoglycemia can be controlled by adequate dietary treatment (frequent meals rich in carbohydrates, and supplements of uncooked starch).
Prognosis
The clinical course is benign with patients reaching their full height and weight during adulthood. Life expectancy is normal.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Roseline FROISSART  - Pr Philippe LABRUNE


Glycogen storage disease due to muscle and heart glycogen synthase deficiency is characterised by muscle and heart glycogen deficiency. It has been described in three siblings (two brothers and their younger sister). The older brother died at 10.5 years of age as a result of sudden cardiac arrest and the younger brother presented with hypertrophic cardiomyopathy, abnormal heart rate and blood pressure during exercise, and muscle fatigability. The sister showed no symptoms but a lack of glycogen was identified through muscle biopsy. The syndrome is caused by homozygous missense mutations in the gene encoding muscle glycogen synthase.


Glycogen storage disease due to muscle beta-enolase deficiency

A rare glycolysis disorder characterized clinically by exercise intolerance and myalgia due to severe enolase deficiency in muscle.


Glycogen storage disease due to muscle glycogen phosphorylase deficiency

Myophosphorylase deficiency (McArdle's disease), or glycogen storage disease type 5 (GSD5) , is a severe form of glycogen storage disease characterized by exercise intolerance.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Onset occurs in childhood. Patients present with a syndrome of muscular exercise intolerance with myalgia, cramps, fatigue, and muscle weakness. Massive elevation of creatine-kinase and rhabdomyolysis with myoglobinuria (dark urine) after exercise is noted in around 50% of patients, potentially leading to acute kidney failure. A 'second wind' phenomenon with relief of myalgia and fatigue after a few minutes of rest is observed in many patients. The clinical presentation is usually very classical, but some patients may have very moderate forms. In a few cases, onset very early in life with hypotonia, generalized muscle weakness and progressive respiratory failure has been described.
Etiology
The condition is caused by mutations in the PYGM gene (11q13), leading to muscle phosphorylase deficiency. Mutation p.R50X may account for 40% to 50% of the alleles in Caucasian populations.
Diagnostic methods
The diagnosis is based on biological findings revealing a lack of lactate elevation in blood during ischemic forearm test, excess glycogen, and deficient phosphorylase activity in the muscle biopsy.
Differential diagnosis
The differential diagnosis should include GSD type 7 (see this term).
Genetic counseling
The condition is autosomal recessive.
Management and treatment
Treatment is based on controlled physical training in order to develop mitochondrial oxidation capacities in muscles, and programmed glucose intake according to exercising periods. Diets with high protein intake have yielded variable results.
Prognosis
Prognosis is favorable when severe rhabdomyolysis is avoided. However, myoglobinuria may lead to potentially life-threatening renal failure.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr Roseline FROISSART


Glycogen storage disease due to muscle phosphofructokinase deficiency

Muscle phosphofructokinase (PFK) deficiency (Tarui's disease), or glycogen storage disease type 7 (GSD7), is a rare form of glycogen storage disease characterized by exertional fatigue and muscular exercise intolerance. It occurs in childhood.

Summary:
Epidemiology
About 100 cases have been reported worldwide.
Clinical description
Clinical signs are muscular exercise intolerance (more severe than in type 5; see this term). Compensated hemolysis (increased bilirubin and reticulocytes) and hyperuricemia are associated. A rapidly fatal infant form has also been observed in 6 families.
Etiology
The condition is caused by mutations in the PFKM gene (12q13) encoding the muscular isoenzyme of PFK, a key enzyme in the regulation of anaerobic glycolysis which has 3 isoenzymes (for the muscle, liver, and platelets).
Diagnostic methods
The diagnosis is based on biological findings, revealing increased amounts of abnormal glycogen and enzyme deficiency (1 to 33% residual activity) in a muscle biopsy, whereas activity in erythrocytes is over 50%.
Differential diagnosis
Differential diagnoses include the other forms of glycogen storage disease (see these terms).
Genetic counseling
The condition is autosomal recessive, although a few cases with pseudodominance or symptomatic heterozygous individuals have been found.
Management and treatment
The only treatment is to avoid intensive exercise. It should be noted that carbohydrates induce lower muscular performance (due to the decreased amounts of free fatty acids and ketone bodies).
Prognosis
Myoglobinuria may lead to renal failure.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr Roseline FROISSART


Glycogen storage disease due to muscle phosphorylase kinase deficiency

Glycogen storage disease due to muscle phosphorylase kinase (PhK) deficiency is a benign inborn error of glycogen metabolism characterized by exercise intolerance.

Summary:
Epidemiology
The disease is very rare with less than 30 patients reported in the literature.
Clinical description
The disease starts generally in adolescence or adulthood. Patients may present with exercise intolerance with myalgia, cramps, fatigue, and sometimes myoglobinuria. In some cases, patients may present with progressive muscle weakness. Symptoms are usually mild, and myopathy may be asymptomatic. A neonatal form with generalized muscular hypotonia and respiratory insufficiency has also been described.
Etiology
Phosphorylase kinase (PhK) is an enzyme which plays a key role in the regulation of glycogenolysis as it is required for glycogen phosphorylase activation. It consists of four copies of each four subunits (alpha, beta, gamma and calmoduline) encoded by different genes on different chromosomes and differentially expressed in various tissues. Muscle-specific isoforms of the alpha and gamma subunits are encoded by the PHKA1 gene and the PHKG1 gene respectively, but until now mutations have been only identified in the PHKA1 gene and the transmission is X-linked.
Diagnostic methods
Biochemical diagnosis of the muscle form can be made by measuring phosphorylase kinase activity in a muscle biopsy. Genetic testing is useful to confirm or establish the diagnosis.
Differential diagnosis
Differential diagnoses include GSD due to myophosphorylase deficiency (GSD type V), and other GSDs affecting the muscle (GSD types XI, XII, XIII and XIV) (see these terms).
Management and treatment
Most patients do not require any specific treatment.
Prognosis
Prognosis is generally good.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Roseline FROISSART  - Pr Philippe LABRUNE  - Pr Pascal LAFORET


Glycogen storage disease due to phosphoglycerate kinase 1 deficiency

A rare inborn errors of metabolism characterized by variable combinations of non-spherocytic hemolytic anemia, myopathy, and various central nervous system abnormalities.

Summary:
Epidemiology
Phosphoglycerate kinase (PGK) deficiency prevalence is unknown but about 30 unrelated affected families have been reported so far.
Clinical description
The majority of patients present with chronic hemolytic anemia, which may be severe in some cases. Myopathy is a common finding and is characterized by exercise-intolerance, muscle weakness, cramping, myalgia and episodes of myoglobinuria. Rhabdomyolysis has also been reported in a few patients. Intellectual deficit is frequent, and other central nervous system manifestations may be also present including hemiplegic migraines, epilepsy, ataxia and tremor. Only a few patients show all three cardinal features of the disorder (hemolytic anemia, central nervous system abnormalities and myopathy), and several cases of PGK deficiency with myopathy in the absence of hemolytic anemia have been reported. Only one asymptomatic patient has been described with mild PGK deficiency.
Etiology
PGK deficiency is caused by mutations in the PGK1 gene (Xq13.3) and around 20 different disease-causing variants have been identified so far in affected families. PGK is a key enzyme in the glycolytic pathway catalyzing the conversion of 1,3-bisphosphoglycerate into 3-phosphoglycerate and generating ATP. PGK is a ubiquitous enzyme expressed in all tissues except the testes.
Diagnostic methods
Diagnosis is made on the basis of the clinical picture, together with biochemical studies revealing low erythrocyte and muscle PGK enzyme activity (below 23% and 25% of normal respectively), and identification of PGK1 gene mutations by molecular analysis.
Differential diagnosis
The differential diagnosis should include other causes of hereditary non-spherocytic hemolytic anemia.
Antenatal diagnosis
Molecular prenatal diagnosis is feasible for families of an index case.
Genetic counseling
PGK deficiency is inherited as an X-linked trait and most of the reported patients were hemizygous males. However, heterozygous females may have a variable degree of hemolytic anemia. All women born to affected men will be carriers (mild manifesting or not) with no male to male transmission. Female carriers have a 50 % risk of an affected male or female carrier with each pregnancy.
Management and treatment
In patients with severe chronic anemia, regular blood transfusions are required. Splenectomy has been shown to be beneficial in some cases.
Prognosis
The prognosis is variable, depending on the severity of the anemia and on the presence of the other manifestations.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Pr Mark TARNOPOLSKY


A rare glycogen storage disease characterized by susceptibility to rhabdomyolysis complicated by episodes of exercise-induced muscle pain, cramping, and myoglobinuria. Tubular aggregates may be present on muscle biopsy.

Summary:
Epidemiology
The prevalence of this disease is still unknown. Fewer than 50 cases were reported worldwide. About half of the identified cases are related to the p.W78X variant (most common in patients with African American ancestry) with the remaining cases coming from other ethnic groups in the United States, Europe, and the Middle East.
Clinical description
Glycogen storage disease due to phosphoglycerate mutase deficiency (also known as GSD type X) is characterized by exercise intolerance leading to rhabdomyolysis which manifests through muscle cramps and pain accompanied by acute renal symptoms such as myoglobinuria. In the majority of cases, intense physical exercise is accompanied by abnormal elevation of creatine kinase, which persists between exertional episodes. Some patients present with glycogen accumulation and tubular aggregates within the skeletal muscle cells on muscle biopsy. Due to low specificity of the symptoms, many patients remain undiagnosed.
Etiology
The disease is caused by homozygous or compound heterozygous variants of the PGAM2 gene which encodes the muscle isoenzyme of phosphoglycerate mutase (PGAM2), a terminal glycolysis enzyme. PGAM2 reversibly catalyzes the conversion reaction of 3-phosphoglycerate (3-PGA) to 2-phosphoglycerate (2-PGA), which is then further metabolized to produce pyruvate. During exercise, insufficient residual PGAM2 activity results in the inability to catabolize enough glucose to meet the increased energy needs of the muscle cells. This leads to a decrease in intracellular ATP levels and an increase in intracellular calcium levels which cause the breakdown of skeletal muscle (rhabdomyolysis), resulting in symptoms of muscle soreness, cramping, and dark urine.
Diagnostic methods
A patient presenting with exercise intolerance with episodes of rhabdomyolysis characterized by abnormal creatine kinase levels persisting after exercise, abnormally elevated aspartate aminotransferase and alanine aminotransferase levels (which are secondarily elevated in the setting of hyperCKemia), and detection of myoglobinuria, should raise suspicion of a metabolic myopathy. Forearm ischemic exercise test (FIET) will produce an abnormally low increase of lactate concentration. Skeletal muscle biopsy reveals tubular aggregates and may show glycogen accumulation. To establish the final diagnosis, the most reliable method is sequencing of PGAM2 for biallelic pathogenic or likely pathogenic variants.
Differential diagnosis
The differential diagnosis is based on a clinical picture of myalgia and includes beta-oxidation defects, mitochondrial diseases, and other glycogen storage diseases (GSD), particularly GSD type V and GSD type VII which share features of sensitivity to rhabdomyolysis with GSD type X, as well as a lesser increase in lactate production compared to the norm following exercise. Tubular aggregates visible on muscle biopsy are specific to GSD type X.
Genetic counseling
The transmission is autosomal recessive. Genetic counseling can be offered to at-risk couples to inform them of the 25% risk of transmission to offsprings.
Management and treatment
The management of the disease is adapted to the patient's symptoms. Patients should be informed that strenuous exercises can trigger episodes of rhabdomyolysis and myoglobinuria. Limitation of simple carbohydrates in the diet is of theoretical benefit; dietary therapy has not been systemically studied in GSD type X. Regular, low-intensity exercise under optimal hydration conditions may reduce the intensity of muscle symptoms. To date, there is no treatment that replaces or restores PGAM2 activity.
Prognosis
GSD type X is not thought to impact the longevity of affected individuals. It is important to recognize and treat episodes of rhabdomyolysis promptly should they occur, as rhabdomyolysis can lead to significant morbidity and mortality, including multiorgan failure, if left untreated.

                            Last update:
                            September 2023

                            - Expert reviewer(s):
                            Dr Benjamin COCANOUGHER  - Dr Priya KISHNANI  - Dr Rebecca KOCH


Glycogen storage disease due to phosphorylase kinase deficiency

Glycogen storage disease (GSD) due to phosphorylase kinase deficiency is a group of inborn errors of glycogen metabolism that is clinically and genetically heterogeneous. This group comprises GSD due to liver phosphorylase kinase (PhK) deficiency, GSD due to muscle PhK deficiency and GSD due to liver and muscle PhK deficiency (see these terms).

Summary:
Epidemiology
The prevalence at birth is estimated at around 1/100,000.
Clinical description
GSD due to liver PhK deficiency is the most common sub-type and presents in early childhood with hepatomegaly, growth retardation, and mild delay in motor development. During adulthood, symptoms usually disappear. Patients with GSD due to liver and muscle PhK deficiency may have marked hepatomegaly and mild muscular hypotonia in childhood. GSD due to muscle PhK deficiency presents in adolescence or adulthood with exercise intolerance, myalgia, and sometimes myoglobinuria but symptoms are generally mild.
Etiology
Phosphorylase kinase (PhK) is an enzyme which plays a key role in the regulation of glycogenolysis as it is required for glycogen phosphorylase activation. It consists of four copies of each four subunits (alpha, beta, gamma and calmoduline) encoded by different genes on different chromosomes and differentially expressed in various tissues. GSD due to liver PhK deficiency is due to mutations in the PHKA2 or PHKG2 genes encoding the liver isoforms of the alpha and gamma subunits of PhK. Transmission is X-linked and autosomal recessive, respectively. GSD due to liver and muscle PhK deficiency is transmitted in an autosomal recessive manner and is due to mutations in the PHKB gene which encodes the beta subunit of PhK. The muscle-specific isoforms of the alpha and gamma subunits of PhK are encoded by the PHKA1 and PHKG1 genes respectively, but until now mutations have only been found in the PHKA1 gene in patients with GSD due to muscle PhK deficiency. Transmission is X-linked.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Roseline FROISSART  - Pr Philippe LABRUNE  - Pr Pascal LAFORET


Glycogen storage disease with severe cardiomyopathy due to glycogenin deficiency

A rare autosomal recessive glycogen storage disease characterized by severe cardiomyopathy and cardiac dilatation potentially progressing to heart failure requiring transplantation. Cardiomyocytes show large inclusions of storage material consistent with polyglucosan. Clinical evidence of skeletal muscle involvement is usually absent.


GM1 gangliosidosis type 1 is the severe infantile form of GM1 gangliosidosis (see this term) with variable neurological and systemic manifestations.

Summary:
Epidemiology
Type 1 is the most frequent form of GM1 gangliosidosis but the exact prevalence is not known. About 200 cases have been reported to date. Overall prevalence at birth of GM1 gangliosidosis is estimated to be approximately 1:100,000 to 200,000 live births.
Clinical description
The onset of this disorder may be in utero (non immune hydrops fetalis) or by the age of six months. Clinical signs are variable and include arrest/regression of neurological development, hypotonia, visceromegaly, macular cherry-red spots, dysostosis and coarse facial features. Cardiomyopathy may occur.
Etiology
GM1 gangliosidosis is caused by mutations in the GLB1 gene (3p22.3) coding for beta-galactosidase.
Diagnostic methods
Diagnosis is based on clinical signs although classic signs are not always present at diagnosis. Biochemical and/or molecular genetic tests confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes mucopolysaccharidoses, sphingolipidoses and oligosaccharidoses (see these terms).
Antenatal diagnosis
Prenatal diagnosis can be performed by analysis of beta-galactosidase activity and/or by GLB1 molecular analysis in either chorionic villus (CV) cells or amniotic fluid cells if mutations are found in an index case.
Genetic counseling
GM1 gangliosidosis is an autosomal recessive disease. Genetic counseling should be provided to affected families.
Management and treatment
Treatment for patients with GM1 gangliosidosis is symptomatic and supportive.
Prognosis
Prognosis is very poor with life-expectancy rarely exceeding 2 years. Causes of death include pneumonia due to recurrent aspiration and cardiopulmonary failure.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Anna CACIOTTI  - Dr Maria Alice DONATI  - Dr Amelia MORRONE


GM1 gangliosidosis type 2 is a clinically variable, infancy or childhood-onset form of GM1 gangliosidosis (see this term) characterized by normal early development and psychomotor regression between seven months and three years of age.

Summary:
Epidemiology
Type 2 is a less frequent form of GM1 gangliosidosis compared to infantile type 1 disease but the exact prevalence, although unknown, is likely to be underestimated. Fewer than 50 cases have been reported to date. Overall prevalence at birth of GM1 gangliosidosis is estimated to be approximately 1:100,000 to 200,000 live births.
Clinical description
Patients with the childhood form of this disorder develop signs and symptoms of intermediate severity including locomotor disturbances, strabismus, muscle weakness, seizures, lethargy and lung infections. Compared to type 1, visceromegaly and skeletal anomalies are milder or may be absent. Macular cherry-red spots are infrequent. The course of the disorder is characterized by slower progression. Facial coarsening develops over time.
Etiology
GM1 gangliosidosis is caused by mutations in the GLB1 gene (3p22.3) coding for beta-galactosidase.
Diagnostic methods
Diagnosis is suggested by clinical signs, such as psychomotor regression and facial coarsening. Biochemical and/or genetic tests confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes mucopolysaccharidoses, sphingolipidoses and oligosaccharidoses (see these terms).
Antenatal diagnosis
Prenatal diagnosis can be performed by analysis of beta-galactosidase activity and/or by GLB1 molecular analysis in either chorionic villus (CV) cells or amniotic fluid cells if mutations are identified in an index case.
Genetic counseling
GM1 gangliosidosis is an autosomal recessive disease. Genetic counseling should be provided to affected families.
Management and treatment
Treatment for patients with GM1 gangliosidosis is symptomatic and supportive.
Prognosis
Prognosis is poor with survival into mid-childhood or early adulthood.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Anna CACIOTTI  - Dr Maria Alice DONATI  - Dr Amelia MORRONE


GM1 gangliosidosis type 3 is a mild, chronic, adult form of GM1 gangliosidosis (see this term) characterized by onset generally during childhood or adolescence and by cerebellar dysfunction.

Summary:
Epidemiology
Type 3 is a less frequent form of GM1 gangliosidosis compared to infantile type 1 disease but the exact prevalence, although unknown, is likely to be underestimated. About 70 cases have been reported to date. Overall prevalence at birth of GM1 gangliosidosis is estimated to be approximately 1:100,000 to 200,000 live births. Most reported cases are in patients of Japanese origin.
Clinical description
Marked variability of clinical signs and age of onset has been reported. Patients generally show slowly progressive dementia, dysarthria, dystonia, short stature, mild vertebral anomalies and ataxia. Eye movements are normal.
Etiology
GM1 gangliosidosis is caused by mutations in the GLB1gene (3p22.3) coding for beta-galactosidase.
Diagnostic methods
Diagnosis is clinically suggested by dystonia and slurred speech, usually detected at school age. Biochemical and/or molecular genetic tests confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes mucopolysaccharidoses, sphingolipidoses and oligosaccharidoses (see these terms).
Antenatal diagnosis
Prenatal diagnosis can be performed by analysis of beta-galactosidase activity and/or by GLB1 molecular analysis in either chorionic villus (CV) cells or amniotic fluid cells if mutations are identified in an index case.
Genetic counseling
GM1 gangliosidosis is an autosomal recessive disease. Genetic counseling should be provided to affected families.
Management and treatment
Treatment for patients with GM1 gangliosidosis is symptomatic and supportive.
Prognosis
Prognosis is variable.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Anna CACIOTTI  - Dr Maria Alice DONATI  - Dr Amelia MORRONE


GM1 gangliosidosis is a rare lysosomal storage disorder characterized biochemically by deficient beta-galactosidase activity and clinically by a wide range of variable neurovisceral, ophthalmological and dysmorphic features.

Summary:
Epidemiology
The disorder is panethnic but worldwide prevalence is not known. Prevalence at birth is estimated to be approximately 1:100,000 to 200,000 live births. High prevalence has been found in Malta and Brazil, and in the Cypriot and Roma populations.
Clinical description
There are three types of GM1 gangliosidosis based on the age of onset: a severe rapidly progressive infantile form with onset before six months of age (type 1 GM1 gangliosidosis), a late infantile or juvenile form with onset between seven months and 3 years of age with delayed motor and cognitive development (type 2 GM1 gangliosidosis), and an adult, chronic form with late onset between 3 and 30 years of age (type 3 GM1 gangliosidosis) characterized primarily by generalized dystonia (see these terms). Disease severity appears to be related to the level of beta-galactosidase activity.
Etiology
The disorder is caused by mutations in the GLB1gene (3p22.3) coding for beta-galactosidase. To date, more than 165 mutations have been identified. Deficient enzyme activity leads to toxic accumulation of gangliosides in body tissues, and particularly in the central nervous system (CNS).
Diagnostic methods
Diagnosis may be difficult due to the wide clinical spectrum of the disease. Clinical suspicion is based on signs of storage such as facial coarsening, hypertrophic gums, cherry-red macula, visceromegaly, dysostosis and psychomotor delay. Peripheral blood smear (testing vacuolated lymphocytes) and urine oligosaccharides are good orientation tests. Gaucher-like foam cells have been reported on bone marrow examination. Diagnosis is confirmed by biochemical assay of beta-galactosidase activity and/or by molecular genetic testing. A secondary combined defect of both GLB1 and neuraminidase (NEU1) (causing galactosialidosis; see this term) has to be excluded.
Differential diagnosis
Differential diagnosis includes mucopolysaccharidoses, sphingolipidoses and oligosaccharidoses (see these terms).
Antenatal diagnosis
Prenatal diagnosis can be performed by analysis of beta-galactosidase activity and/or by GLB1 molecular analysis in either chorionic villus (CV) cells or amniotic fluid cells, if mutations are identified in an index case.
Genetic counseling
GM1 gangliosidosis is an autosomal recessive disease. Genetic counseling should be provided to affected families.
Management and treatment
Treatment for patients with GM1 gangliosidosis is symptomatic and supportive. Substrate reduction therapy is a potential approach for clinical trials in late-onset forms.
Prognosis
Prognosis depends on the type of GM1 gangliosidosis and is extremely poor in the severe infantile form and variable in the chronic adult form of the disease.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Anna CACIOTTI  - Dr Maria Alice DONATI  - Dr Amelia MORRONE


GM2 gangliosidosis, AB variant is an extremely rare, severe genetic disorder characterized by progressive neurological decline due to ganglioside activator deficiency.


GM3 synthase deficiency is a rare congenital disorder of glycosylation due to impaired synthesis of complex ganglioside species initially characterized by irritability, poor feeding, failure to thrive and early-onset refractory epilepsy, followed by postnatal growth impairment, severe developmental delay or developmental regression, profound intellectual disability, deafness and abnormalities of skin pigmentation (mostly freckle-like hyperpigmented and depigmented macules). Visual impairment due to cortical atrophy (visible on magnetic resonance imaging), choreoathetosis and hypotonic tetraparesis usually appear gradually. Dysmorphic facial features may be associated.


GMPPB-related limb-girdle muscular dystrophy R19

A form of limb-girdle muscular dystrophy, that can present from birth to early childhood, characterized by hypotonia, microcephaly, mild proximal muscle weakness (leading to delayed walking and difficulty climbing stairs), mild intellectual disability and epilepsy. Additional manifestations reported in some patients include cataracts, nystagmus, cardiomyopathy, and respiratory insufficiency.


GMS syndrome describes an extremely rare syndrome involving goniodysgenesis, intellectual disability and short stature in addition to microcephaly, short nose, small hands and ears, and that has been seen in one family to date. There have been no further descriptions in the literature since 1992.


GNAO1-related developmental delay-seizures-movement disorder spectrum

A rare genetic neurological disorder characterized by a phenotypic spectrum of mild to severe developmental delay and hypotonia, variably associated with intellectual disability, early-onset seizures, and movement disorders, such as dystonia, ataxia, chorea, and dyskinesia. Brain imaging may show delayed myelination, thin corpus callosum, or cerebral atrophy.


Gnathodiaphyseal dysplasia (GDD) is a bone dysplasia characterized by bone fragility, frequent bone fractures at a young age, cemento-osseous lesions of the jaw bones, bowing of tubular bones (tibia and fibula) and diaphyseal sclerosis of long bones associated with generalized osteopenia. GD follows an autosomal dominant mode of transmission.


GNB5-related intellectual disability-cardiac arrhythmia syndrome

A rare genetic disease characterized by intellectual disability, developmental delay, language deficits, and cardiac arrhythmia (most commonly sick sinus syndrome). Additional reported features include epilepsy, hypotonia, retinal abnormalities, nystagmus, attention deficit hyperactivity disorder, autism, and gastroesophageal reflux. The severity of the phenotype is highly variable.


GNE myopathy is a rare autosomal recessive distal myopathy characterized by early adult-onset, slowly to moderately progressive distal muscle weakness that preferentially affects the tibialis anterior muscle and that usually spares the quadriceps femoris. Muscle biopsy reveals presence of rimmed vacuoles.

Summary:
Epidemiology
Worldwide prevalence is estimated at 1/1,000,000, however it is more frequent in populations of Persian Jewish and Japanese ethnicity.
Clinical description
The disease usually starts during the third decade of life (but the onset may range from the early teens to the 5th decade). Typically, distal weakness in the legs with foot drop is the first sign, followed by (usually) slow progression to the proximal muscles (thigh) and the upper limbs (hand muscles). Shoulder girdle muscles are subsequently involved, with relative sparing of the triceps. Neck flexor muscles are also commonly affected. A unique clinical pattern of this myopathy is sparing of quadriceps in spite of major involvement of other thigh muscles. Unusual patterns of onset in proximal lower limb musculature and even in the upper limbs have been observed. Ocular, pharyngeal, and cardiac muscles are usually spared. Respiratory muscles are generally not affected until the very late stages in wheelchair-bound patients. Occasionally, affected individuals may present facial weakness.
Etiology
GNE myopathy is caused by biallelic mutations in the GNE gene (9p13.3) which encodes a bi-functional enzyme involved in the sialic acid biosynthetic pathway. Mutations in this gene result in a 30-60% decrease in enzyme activity leading to a decreased sialylation of glycoproteins and glycolipids. Hyposialylation appears to be involved in disease pathogenesis, but the process by which a defect in GNE leads to muscle disease is still elusive. With increasing number of patients, genotype-phenotype correlations are currently emerging.
Diagnostic methods
Diagnosis is suspected in individuals with early-onset foot drop, negative dominant family history, sustained quadriceps sparing despite marked weakness of all other thigh muscles, modest elevation of serum creatine kinase (2-5x), muscle biopsy showing fiber size variation (with atrophy) and presence of rimmed vacuoles and congophilic protein aggregates. MRI reveals a characteristic pattern of muscle involvement with (from the early stages of the disease) severe fatty-fibrous replacement of the biceps femoris short head muscles, accompanied by less severe involvement of the gluteus minimus, tibialis anterior, extensor hallucis and digitorum longus, soleus and gastrocnemius medialis muscles. Genetic screening revealing pathogenic variants in GNE confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes other adult-onset distal myopathies with rimmed vacuolar pathology (i.e. distal myopathy, Welander type; tibial muscular dystrophy; adult-onset distal myopathy due to VCP mutation; and vocal cord and pharyngeal distal myopathy), myofibrillar myopathies, and Laing early-onset distal myopathy.
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
In the absence of a proven effective therapy, management remains mainly supportive. Metabolic supplementation with sialic acid or a precursor of sialic acid, as well as gene therapy, are under investigation.
Prognosis
Most patients become wheelchair-bound after 15-20 years of disease onset. About 5% of patients have atypical early involvement of the quadriceps muscle resulting in earlier non-ambulation.

                            Last update:
                            September 2018

                            - Expert reviewer(s):
                            Dr Johanna PALMIO  - Pr Bjarne UDD


Goblet cell carcinoma (GCC) is an aggressive type of endocrine tumor of the appendix (see this term) presenting equally in males and females in the fifth decade of life and manifesting with a palpable mass and abdominal pain or acute appendicitis. Metastasis to the ovaries, peritoneum or right colon has usually already occurred in half of patients at the time of diagnosis.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by Hirschsprung disease, facial dysmorphism (sloping forehead, high arched eyebrows, long eyelashes, telecanthus/hypertelorism, ptosis, prominent ears, thick earlobes, prominent nasal bridge, thick philtrum, everted lower lip vermillion and pointed chin), global developmental delay, intellectual disability and variable cerebral abnormalities (focal or generalized polymicrogyria, or hypoplastic corpus callosum).

Summary:
Epidemiology
Worldwide prevalence is less than 1/1,000,000; to date 24 cases have been described in the scientific and medical literature.
Clinical description
Disease onset is typically in the neonatal period with microcephaly and Hirschsprung disease. The clinical spectrum of Hirschsprung disease is broad, ranging from chronic constipation to life-threatening intestinal obstruction in neonates. Facial dysmorphism is present at birth but becomes more evident later on. Additional dysmorphic features may include maxillary hypoplasia, hypodontia, high arched palate, short neck, small hands, brachydactyly, fifth finger clinodactyly, fetal finger pads and flatfoot. Hypotonia, severe global developmental delay (with greatest impairment in expressive language skills) and moderate to severe intellectual disability are constant features. Cerebral magnetic resonance imaging reveals abnormalities in half of patients and may include polymicrogyria, corpus callosum hypoplasia, or subarachnoid space enlargement. Other highly variable features include ocular abnormalities (e.g. hyperopia, bilateral megalocornea), congenital heart defects (such as ventricular septal defects, aortic valve incompetence), urogenital abnormalities (incl. cryptorchidism, vesicoureteral reflux, multicystic renal dysplasia), skeletal involvement (e.g. short stature, scoliosis, femoral neck anteversion), and recurrent respiratory infections.
Etiology
Disease is caused by bi-allelic mutations in KIF1BP (10q21.3-q22.1), encoding kinesin family member 1 binding protein. KIF1BP loss of function disrupts cytoskeletal homeostasis.
Diagnostic methods
Diagnosis is based on clinical presentation of the typical features and should be confirmed with genetic testing. Hirschsprung disease is confirmed by rectal biopsy with histological findings of aganglionosis of the submucosal plexus.
Differential diagnosis
Main differential diagnoses include Mowat-Wilson (MWS) and Baraitser-Winter syndromes. Different facial characteristics (thick, horizontal eyebrows and uplifted earlobes with a central depression), presence of seizures and hypospadias, and absence of polymicrogyria and oligodontia distinguish MWS. Key overlapping features with Baraitser-Winter syndrome include intellectual disability, microcephaly, congenital ptosis, high-arched eyebrows, ocular coloboma and short stature; however, Hirschsprung disease, congenital heart defects, and urogenital malformations have not been reported in this syndrome.
Antenatal diagnosis
Genetic prenatal diagnosis is possible if bi-allelic mutations have previously been identified in the family. In absence of a familial case, diagnostic antenatal ultrasound is challenging. Antenatal detection of brain developmental anomalies, microcephaly, growth retardation and/or hyperechogenic gut are suspicious for the disease but must be confirmed by genetic testing.
Genetic counseling
The pattern of inheritance is autosomal recessive. For parents of an affected child the sibling-recurrence risk is 25%.
Management and treatment
Multidisciplinary medical care and preventive actions, such as treatment of cardiac, ocular, urogenital and skeletal issues and Hirschsprung disease, are required. Developmental assessments are needed to tailor medical care to individual needs and to increase the individual's quality of life.
Prognosis
Little information is available about the long-term outlook for individuals with Goldberg-Shprintzen megacolon syndrome. Quality of life and life expectancy depend on the presence and severity of birth defects.

                            Last update:
                            March 2019

                            - Expert reviewer(s):
                            Dr Irina GIURGEA


Goldmann-Favre syndrome (GFS) is a vitreoretinal dystrophy characterized by early onset of night blindness, reduced bilateral visual acuity, and typical fundus findings (progressive pigmentary degenerative changes, macular edema, retinoschisis).

Summary:
Epidemiology
Less than 20 cases have been reported so far, some of them born to consanguineous families. Both sexes seem equally affected.
Clinical description
The onset is usually in childhood. GFS manifests with progressive loss of visual acuity and night blindness. Peripheral vision can be decreased. Cataract is a frequent complication. Optic atrophy has been occasionally reported. The vitreous changes are degenerative and may include microfibrillar strands, liquefaction and posterior vitreous detachment. The fundus features include annular pigmentary changes (clumped pigment deposits), central or peripheral retinoschisis, cystoid macular edema. The GFS features are usually bilateral and symmetrical. The electroretinogram (ERG) is abnormal: both rod and cone ERGs are markedly diminished and may be non-detectable. Patients may have an increased sensitivity to blue light due to increased S-cone sensitivity.
Etiology
Mutations in the NR2E3 gene (formerly called PNR) have been identified in some patients with GFS. NR2E3 (15q23) encodes a retinal nuclear receptor that is involved in the differentiation of photoreceptors. GFS, some forms of autosomal recessive and dominant retinitis pigmentosa and enhanced S-cone syndrome (ESCS) are caused by mutations in the NR2E3 gene.
Diagnostic methods
Diagnosis is based on clinical findings, ocular investigations including fundus autofluorescence, optical coherence tomography, electroretinogram and mutations in NR2E3.
Differential diagnosis
GFS should be distinguished from X-linked retinoschisis, retinitis pigmentosa and autosomal dominant hyaloideoretinal degeneration (Wagner disease) (see these terms).
Genetic counseling
GFS is inherited as an autosomal recessive trait.
Prognosis
GFS has a progressive course. In most cases, visual loss occurs in the first two decades of life. Some improvement of visual acuity has been reported after treatments with cyclosporin A and bromocriptine.

                            Last update:
                            July 2009

                            - Expert reviewer(s):
                            Pr Christian HAMEL


A rare congenital limb malformation characterized by bifid femur, absent or hypoplastic tibia and ulna with limb shortening, oligodactyly, and ectrodactyly.

Summary:
Epidemiology
Approximately 200 cases have been reported worldwide.
Clinical description
The malformation presents with congenital aplasia/hypoplasia of the tibia, bifurcation of the distal femur, more commonly unilateral, accompanied by pre-axial oligodactyly or monodactyly of the feet. There is oligodactyly and ectrodactyly, often associated with an abnormality of the ulna. The pattern is frequently asymmetric. Occasionally other abnormalities can be present, namely congenital heart defects, cleft lip and palate and tracheo-oesophageal fistula.
Etiology
The etiology remains unknown. In two Japanese patients, a duplication and a triplication of a 210 Kb chromosomal segment in 17p13.3, including BHLHA9, has been detected, and considered a susceptibility factor for the limb malformation.
Diagnostic methods
Diagnosis is based on clinical and radiological findings.
Differential diagnosis
Differential diagnoses includes hypoplastic tibiae-postaxial-polydactyly syndrome and split hand foot malformation syndromes.
Antenatal diagnosis
Prenatal diagnosis can be performed by ultrasound scans in the second trimester of pregnancy.
Genetic counseling
Whilst the pattern of inheritance is currently unknown, autosomal dominant and autosomal recessive inheritance models have been suggested.
Management and treatment
Patients should be offered orthopedic and reconstructive surgery (involving prosthetics) and regular monitoring.
Prognosis
Life expectancy is not reduced but, in the absence of treatment, the functional prognosis is poor.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Dr Francesca FORZANO


Gonadoblastoma is a rare benign neoplasm of mixed sex cord and germ cells, arising mostly in the dysgenic gonads of young women with a chromosome Y anomaly, presenting with abdominal enlargement, variable feminization or virilization or, in some cases, being asymptomatic. It is often associated with dysgerminoma.


A rare disorder of the anterior segment of the eye caused by Neisseria gonorrhoeae, characterized by a severe mucopurulent conjunctivitis associated with lid edema, often also with localized lymphadenopathy. It may be complicated by uveitis or keratitis which can eventually lead to corneal perforation. The disease most often occurs in teenagers and young adults with a male predominance, while infections are much less common in newborns, where they are typically bilateral.


Good syndrome, also known as thymoma-immunodeficiency, is a very rare acquired immunodeficiency syndrome characterized by the association of thymoma and combined B-cell and T-cell immunodeficiency of adult onset with increased susceptibility to infections.


Gordon syndrome, also known as distal arthrogryposis type 3, is an extremely rare multiple congenital malformation syndrome characterized by congenital contractures of hand and feet with variable degrees of severity of camptodactyly, clubfoot and, less frequently, cleft palate. Intelligence is normal but in some cases, additional abnormalities, such as short stature, kyphoscoliosis, ptosis, micrognathia, and cryptorchidism may also be present. Gordon syndrome, Marden-Walker syndrome and arthrogryposis with oculomotor limitation and electroretinal anomalies clinically and genetically overlap, and could represent variable expressions of the same condition.


Gorham-Stout disease (GSD) is a rare disease of massive osteolysis associated with proliferation and dilation of lymphatic vessels. GSD may affect any bone in the body and can be monostotic or polyostotic. Symptoms at presentation are dependent upon the location(s) of the disease; the most common symptom is localized pain. The disease may be discovered after a pathological fracture.

Summary:
Epidemiology
To date around 300 cases have been reported in the literature. GSD does not display a clear race, sex predilection (1.6:1; male: female ratio) or geographic distribution.
Clinical description
GSD can present at any age, but is commonly diagnosed in children and young adults (average 13 years). GSD may affect any bone in the body but most commonly affects the ribs, followed by the cranium, clavicle and cervical spine. Additional affected areas include maxillofacial bones (mostly the mandible), sternum, humerus, hand, femur, and foot. GSD can be monostotic or polyostotic and symptoms vary according to the body sites affected. The most common symptom is localized pain. Swelling, weakness and functional impairment of affected limbs are also noticed. In the dentoalveolar region, mobile teeth, malocclusion, mandibular deviation and bony deformity may be observed. Patients with thoracic involvement may present respiratory distress (caused by chylothorax). Severe neurological defects and paralysis, secondary to vertebral involvement, are also observed. Patients with cervical spine or base of skull disease can develop cerebrospinal fluid leak. GSD may be discovered after a bone fracture (spontaneous or following minor trauma).
Etiology
Etiology of GSD is still elusive. The pathological process is the benign vascular proliferation of endothelial channels adjacent to or within bone, leading to extreme thinning of bony trabecula, osteoclast-mediated resorption, and replacement of bone with fibrous tissue. Tissue samples test positive for lymphatic endothelial cell markers, suggesting that GSD is a disease involving disordered lymphangiogenesis.
Diagnostic methods
Diagnosis relies on radiographic findings revealing progressive osteolysis and cortical destruction. Magnetic resonance imaging shows complete resorption of bone and replacement with infiltrative soft tissue that is of low signal intensity on T1-weighted imaging and high signal intensity on T2, with intense enhancement on contrast imaging. Immunohistochemical markers of lymphatic endothelial cells (LYVE-1, podoplanin/D2-40) reveal presence of lymphatic vessels in medullary and cortical regions of bones, and in affected soft tissues. Rib lesions should not be biopsied, as this procedure may elicit a refractory chylous effusion.
Differential diagnosis
Differential diagnosis includes generalized lymphatic anomaly (the major distinguishing characteristic is the progressive osteolysis seen in GSD), acroosteolysis dominant type, multicentric carpo-tarsal osteolysis with or without nephropathy, autosomal recessive carpotarsal osteolysis, hereditary sensory and autonomic neuropathy type 2, Farber lipogranulomatosis, Torg-Winchester syndrome, and idiopathic phalangeal acro-osteolysis (see these terms). Other causes of osteolysis such as infection, cancer (primary or metastatic), inflammatory or endocrine disorders should also be considered.
Genetic counseling
GSD occurs sporadically.
Management and treatment
Treatment of GSD includes drugs (bisphosphonates and/or interferon alpha 2b, sirolimus is also being studied) to stabilize progressive disease, and supportive procedures that may reduce or halt chylothorax (pleurectomy, pleurodesis, thoracentesis, and thoracic duct embolization or ligation), or may stabilize affected regions of the skeleton. Radiotherapy may be used in combination with these therapies, but is generally reserved for refractory or rapidly progressive disease.
Prognosis
Prognosis depends on the extent and location of affected areas. Mild disease may remain stable for many years, while severe cases involving the craniofacial and/or thoracic areas may be fatal. Pulmonary involvement may herald a worsened prognosis.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Dr Gulraiz CHAUDRY  - Dr Cameron TRENOR


A rare hereditary disorder due to autosomal dominant transmission with hamartosis characterized by multiple early-onset basal cell carcinoma (BCC), multiple jaw keratocysts and skeletal abnormalities.

Summary:
Epidemiology
The prevalence of Gorlin syndrome (GS) is estimated to be 1/31,000-1/164,000 in Europe. Birth prevalence in the UK is reported to be 1/19,000. Males and females are equally affected.
Clinical description
GS is characterized by the early onset of mandibular odontogenic keratocysts (2nd decade of life) and/or multiple BCCs (most commonly seen on the face, back and chest - 3rd decade of life). Approximately 60% of individuals have a recognizable appearance with macrocephaly, frontal bossing, coarse facial features, and facial milia. Ectopic calcification, particularly in the falx, is present in more than 90% of affected individuals by age 20 years. Palmar or plantar pits (asymmetrical, 2-3 mm in diameter, 1-3 mm in depth and developing in the 2nd decade) and skeletal anomalies (fusion of vertebrae, wedge-shaped vertebrae, bifid or fused ribs, hemivertebra, kyphoscoliosis, pectus deformity, sprengel deformity, syndactyly, polydactylia) are also reported. Additional features include facial dysmorphism (cleft lip/palate, macrocephaly), eye anomalies (cataract, coloboma, microphthalmos) and lymphomesenteric cysts. A predisposition to malignant or benign tumors such as medulloblastoma, meningioma, papillary fibroelastoma of the heart, ovarian fibroma (commonly bilateral and calcified), fibrosarcoma, nephroblastoma is observed.
Etiology
GS is caused by loss of functions due to mutations in the tumor suppressor gene PTCH1 (9q22.1-q31), which encodes the receptor of the sonic hedgehog ligand. Environmental exposure and other modifier genes (SUFU; PTCH2) may contribute to the variable expressivity observed in the clinical presentation. Mutations in PTCH1 also account for the majority of features in monosomy 9q22.3.
Diagnostic methods
Diagnosis is based upon presence of two major criteria and one minor criterion or one major and three minor criteria. Physical examination, radiography, ophthalmologic evaluation, dentist or orthodontist examination, skin examination, ultrasound test and echocardiography are essential to identify the criteria leading the diagnosis. Identification of a heterozygous germline PTCH1 or SUFU pathogenic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.
Differential diagnosis
Differential diagnosis includes: Sotos syndrome, Brooke-Spiegler syndrome, Bazex syndrome, Rombo syndrome, Muir-Torre syndrome, Beckwith-Wiedemann syndrome, isolated hydrocephaly or megalencephaly, an autosomal dominant or X-linked syndrome of hypotrichosis.
Antenatal diagnosis
Antenatal diagnosis is possible with ultrasound scans and DNA analysis extracted from fetal cells after amniocentesis or chronic villus sampling. Preimplantation genetic diagnosis may be proposed to families in which the pathogenic variant has been identified.
Genetic counseling
Transmission is autosomal dominant, with high penetrance and variable expressivity. Genetic counselling, including testing family members to distinguish familial mutations from de novo pathogenic variants, and assessment of genetic cancer risk should be offered. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Management and treatment
The treatment of choice for multiple BCC consists of a combined approach including surgery supplemented by cryotherapy, laser, photodynamic therapy or topical treatments. Use of oral retinoids is also suggested. Oral vismodegib may reduce development of BCC but adverse events are common. Sonic hedgehog inhibitors may be particularly helpful with lesions around the eyes. Radiation therapy must be avoided as it can cause invasion of BCC years later. Photodynamic therapy is particularly suitable for thin lesions of <2 mm on ultrasound. Surgical treatment using Mohs' microsurgery appears particularly effective. Jaw keratocysts are often recurrent and demand repeated surgical excisions. Ovarian fibroma is usually managed with conservative surgery to preserve normal ovarian tissue.
Prognosis
Life expectancy in GS is not affected. Early diagnosis is important due to susceptibility to multiple neoplasms in early age. Ovarian tumors are usually benign with risk of recurrence. In young patients, mandibular odontogenic keratocysts can cause displacement of developing teeth and may be associated with unerupted teeth and cause root resorption.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Pr Lorenzo LO MUZIO


Gorlin-Chaudhry-Moss (GCM) syndrome is a multiple congenital anomaly syndrome characterized by craniofacial dysostosis, facial dysmorphism, conductive hearing loss, generalized hypertrichosis, and extremity, ocular and dental anomalies.

Summary:
Epidemiology
To date, 7 cases of GCM have been described in the world literature and all patients are female with no known parental consanguinity.
Clinical description
GCM is a congenital disorder in which patients present with a stocky body build, normal intelligence, coronal craniosynostosis, facial dysmorphism (brachy/turricephaly, low anterior and posterior hairline, coarse hair, synophrys, depressed supraorbital ridges, short and downslanted or upslanted palpebral fissures, ectropion of lower eyelid, underdeveloped ala nasi, prominent columella, midface hypoplasia, and underdeveloped small ears with increased posterior angulation), conductive hearing loss, ocular (coloboma of the eyelid (see this term), hyperopia, microphthalmia) and oro-dental (microdontia, irregularly shaped widely spaced teeth, oligodontia (see this term), narrow, and high arched narrow palate with medial cleft) anomalies and generalized hypertrichosis. Anomalies of the extremities (hypoplastic distal phalanges, small/aplastic nails, cutaneous syndactyly, absent flexion crease of the thumbs, single transverse palmar creases), umbilical hernia, and hypoplasia of labia majora are also observed. Other additional features that may be observed include congenital laryngomalacia and heart disease (patent arterial duct) (see these terms). Progeroid syndrome, Petty type and Saethre-Chotzen syndrome (see these terms) have overlapping features with GCM syndrome and should be considered in the differential diagnosis.
Etiology
The etiology is still unknown and, to date, no causative gene has been implicated in the physiopathology of GCM.
Genetic counseling
GCM is considered to be inherited in an autosomal recessive manner. However, the lack of consanguinity combined with the fact that all affected patients are female could suggest a de novo X-linked dominant disorder with male lethality.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Dr Rasim ROSTI