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Alpers syndrome

ORPHA726
Synonym(s) Alpers progressive sclerosing poliodystrophy
Alpers-Huttenlocher syndrome
Progressive neuronal degeneration of childhood with liver disease
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
Age of onset Childhood
Adolescent
Adult
Infancy
Neonatal
ICD-10
  • G31.8
OMIM
UMLS
  • C0205710
MeSH
  • D002549
MedDRA
  • 10062943

Summary

Alpers syndrome is a cerebrohepatopathy and developmental, mitochondrial DNA depletion syndrome characterized by the clinical triad of psychomotor regression, seizures, and liver disease. The birth incidence is believed to be between 1/100 000 and 1/250 000. Most patients with Alpers syndrome are asymptomatic at birth and develop normally for weeks to years before the onset of symptoms. About 80% present in the first 2 years, and 20% present between 2 and 25 years of age. The first alerting symptoms can be: fasting hypoglycemia secondary to underlying liver disease, failure to thrive, infection-associated encephalopathy, spasticity, myoclonus, focal seizures, status epilepticus, or fulminant hepatic failure. Cortical blindness is seen with disease progression in about 25% of cases. Gastrointestinal dysmotility and cardiomyopathy may occur. Psychomotor regression is typically episodic and often associated with intercurrent infection. Seizures are mixed-type and difficult to control. They may include generalized, partial, and/or atonic components-often with focal characteristics, epilepsia partialis continua (EPC), and/or myoclonus. 'Alpers-like'' phenotypes without hepatopathy and with heterogeneous clinical course can also be observed. Transmission is autosomal recessive. Mutations in POLG, the gene for the mitochondrial DNA polymerase gamma account for approximately 90% of cases with the classical phenotype and fewer than 1/3 of patients with the 'Alpers-like'' phenotype. The full symptom cluster is rarely seen at first medical contact and the order of symptom onset is not diagnostic. This makes diagnosis difficult until the disease has progressed. Brain MRI is initially normal, but evolves to show cerebral volume loss. Diffusion weighted MR Imaging (DWI) may reveal asymmetric, patchy cortical, basal ganglial, thalamic, and cerebellar involvement. The occipital cortex is commonly involved. Brain proton MR spectroscopy (MRS) typically shows focal lactate elevations and reduced N-acetyl aspartate (NAA). Cerebrospinal fluid (CSF) chemistry consistently shows elevated protein. CSF and blood lactate levels may be transiently elevated. The hepatopathy is often mild initially. Chronic transaminase elevations of just 2-3 fold are common. This may progress to micronodular cirrhosis with regenerative nodules, bile ductular proliferation, and microvesicular steatosis. Other liver histologies also occur. Liver failure may result. The gold standard for confirming the clinical diagnosis of Alpers syndrome is now POLG DNA testing. Neither quantitative mitochondrial DNA (mtDNA) studies looking for mtDNA depletion, nor mitochondrial respiratory chain biochemistry is consistently abnormal early in the course of disease, and are therefore not useful for early diagnosis. Prenatal diagnosis is now available by POLG DNA testing in couples with a previously affected child and known genotypes. Treatment is symptomatic. Anticonvulsive therapy is prescribed for the management of epileptic seizures. Valproic acid may trigger or worsen liver disease and is contraindicated when Alpers syndrome in suspected. In case of liver failure, liver transplantation is contraindicated, as death typically follows liver transplant by progressive Alpers brain disease. The role of mitochondrial cofactor therapy with CoQ10, balanced B vitamin preparations, L-carnitine, and creatine is not yet known. Physiotherapy, avoidance of group settings that promote the spread of common seasonal, childhood respiratory infections, avoidance of fasting to prevent hypoglycemia, and attention to good nutrition can help to ease symptoms and reduce the frequency of neurodegenerative episodes, but are not proven to improve the overall severe prognosis. Death typically occurs within 2 months to 15 years of diagnosis.

Expert reviewer(s)

  • Pr Robert K. NAVIAUX

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Detailed information

Clinical practice guidelines
  • DE (2009)
Clinical genetics review
  • EN (2012)
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