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A cerebrohepatopathy and a rare and severe form of mitochondrial DNA (mtDNA) depletion syndrome characterized by the triad of progressive developmental regression, intractable seizures, and hepatic failure.
ORPHA:726Classification level: Disorder
- Alpers progressive sclerosing poliodystrophy
- Alpers syndrome
- Progressive neuronal degeneration of childhood with liver disease
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal recessive
- Age of onset: Infancy, Childhood, Adolescent, Adult
- ICD-10: G31.8
- OMIM: 203700
- UMLS: C0205710
- MeSH: D002549
- GARD: 5783
- MedDRA: 10062943
The incidence of AHS is estimated to be between 1/100,000 and 1/250,000.
Development is usually normal until disease onset and presentations are highly variable. The most common age of onset is between 2-4 years (ranges from 3 months to 36 years). Seizures (mainly partial, secondary generalized tonic-clonic, or myoclonic) are often the presenting feature, evolving into focal status epilepticus, epilepsia partialis continua, and/or multifocal myoclonic epilepsy. Seizures may respond to treatment initially but usually become intractable. Headaches, visual disturbances and movement disorders (e.g. myoclonus and choreoathetosis) are also common. Cerebellar ataxia develops in most patients. Peripheral neuropathy develops in many and becomes increasingly common in older children and young adults. Loss of cognitive function progresses with varying rates (rapid regression seen during infectious diseases) with manifestations including somnolence, irritability, loss of concentration, loss of language skills and memory deficits, ending in dementia and visual loss. Gastrointestinal involvement (i.e. swallowing dysfunction, intestinal dysmotility) is also noted. Liver disease may be indolent for years before the first acute exacerbation, but may be the first presenting symptom in some children. The clinical course of both brain and liver abnormalities is often episodic with acute exacerbations followed by periods of partial recovery.
AHS is due to mutations in the polymerase gamma (POLG) gene (15q24). This gene encodes DNA polymerase subunit gamma-1, which is involved in the replication and repair of mtDNA. Ecogenetic and epigenetic stressors, including incidental infections and drugs like valproic acid, can accelerate the onset of symptoms and modify how the phenotype unfolds.
Diagnosis is based on clinical and laboratory findings. Electroencephalogram findings include explosive seizures with asymmetric occipital lobe predominance of epileptiform discharges, evolving into epilepsia partialis continua or status epilepticus. Neuroimaging may show neuronal loss/gliosis and generalized brain atrophy. Mitochondrial respiratory chain deficiencies and low levels of mtDNA are noted in the liver and muscle as the disease progresses. Molecular genetic testing revealing a POLG mutation confirms diagnosis.
Differential diagnoses are numerous with some examples being disease phenocopies caused by mutations in the C10ORF2 gene (10q24), which can cause autosomal dominant progressive external ophthalmoplegia (adPEO) as well as recessive mutations that can lead to other phenotypes that may overlap with AHS. Others disorders include infantile neuronal ceroid-lipofuscinosis, late-infantile neuronal ceroid lipofuscinosis, MERRF and MELAS. Other POLG-related disorders include recessive mitochondrial ataxia syndrome (MIRAS), ataxia neuropathy spectrum (ANS), and autosomal recessive PEO.
Prenatal diagnosis is possible in families with a known disease-causing mutation.
AHS is inherited in an autosomal recessive manner. Genetic counseling is possible.
Management and treatment
There is no cure for AHS and treatment is symptomatic and palliative. Anticonvulsive therapy is prescribed for the management of epileptic seizures but is not always successful. As valproic acid may trigger or worsen liver disease, it is contraindicated. Occupational, physical, and/or speech therapy may be offered to maintain neurologic function as long as possible. Tracheostomy placement, artificial ventilation and placement of a gastric feeding tube may all be necessary as the disease progresses.
The prognosis is severe with life-expectancy in patients ranging from 3 months to 12 years, after disease onset.
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