Alpers-Huttenlocher Syndrome Fact Sheet

Clinical FeaturesAlpers-Huttenlocher syndrome is notable for the triad of progressive encephalopathy with intractable seizures, neuropathy and liver failure. Headaches and movement disorders are also common. Some individuals have variable degrees of developmental delay. Episodic psychomotor regression is sometimes present, and cognitive function declines over time. Onset is usually in infancy. The disease is progressive, and most patients die by age 3 years due to liver failure. However, presentation, onset and progression are variable, and prognosis cannot be determined based on genotype.

DiagnosisClinical criteria for AHS has been suggested to include (1) refractory, mixed type seizures, (2) psychomotor regression, and (3) hepatopathy (Nguyen et al. 2006). A molecular confirmation requires identification of a deleterious variant in both copies of the POLG1 gene.

GeneticsAHS is caused by variants in the POLG1 gene. This is a nuclear gene that is involved in production of mitochondria. Alterations in POLG1 can lead to depletion of mitochondria over time. Variants in POLG1 are also associated with several other diseases, with broad and overlapping features. AHS is the most severe manifestation of POLG1 variants.

InheritanceAHS is an autosomal recessive disorder. Parents who carry a single POLG1 variant associated with AHS are typically asymptomatic. When both parents carry a single POLG1 variant, the chance for offspring to have AHS is 1 in 4, or 25%.

Clinical testingGene sequencing will identify 95% of deleterious mutations in POLG1. Another 5% of POLG1 mutations are detected by deletion and duplication studies.

Note that the differential diagnoses for mitochondrial disease is broad, and because expression varies, a patient’s findings may be non-specific. When mitochondrial disease is generally suspected, mitochondrial depletion studies can narrow the list of candidate genes. However, this requires invasive liver or muscle biopsy. For families opposed to this strategy, it is reasonable to begin testing with POLG1 because it is a common cause of mitochondrial disease, and has immediate implications for management.

ManagementManagement is primarily supportive. The healthcare team and family should options relating to the balance between quality of life and intensity of treatment. Interventions may include physical, occupational and speech therapies, feeding tube, assisted and artificial ventilation, seizure control, pain management, and treatment for liver failure. Infection and other metabolic stressors should be avoided to reduce complications and slow progression of disease.

Individuals with POLG1 mutations should avoid valproic acid and sodium divalproate, which can trigger or exacerbate liver dysfunction. Alternative management of seizures should be sought, and liver enzymes monitored closely when medications metabolized by liver enzymes cannot be avoided.

Published October 2013© NCHPEGAll rights reserved

ReferencesGeneReviews: POLG-related disorders at www.ncbi.nlm.nih.gov/books/NBK26471/ Genetics Home Reference: Alpers-Huttenlocher syndrome at www. ghr.nlm.nih.gov/condition/alpers-huttenlocher-syndrome Stumpf JD, Saneto RP, Copeland WC. 2013. Clinical and molecular features of POLG -related mitochondrial disease . Cold Spring Harb Perspect Biol 5(4):a011395.Nguyen KV, Sharief FS, Chan SSL, Copeland WC, Naviaux RK. 2006. Molecular analysis of Alpers syndrome. J Hepatol 45:108-16.

Published June 2013© NCHPEGAll rights reserved