Alpers syndrome (progressive infantile poliodystrophy)
Incidence
Alpers’ Syndrome is a recessive genetic disease with a frequency of about 1:250,000 live births. Many cases die before an accurate diagnosis is made, so the true frequency is still an estimate. Alpers is caused by inheriting two copies of the POLG gene that are dysfunctional. These are called mutant copies. The function of the POLG gene is to copy mitochondrial DNA. In Alpers’ Syndrome, POLG is defective, so after a period of time, the amount of mitochondrial DNA in the cell falls below a critical threshold of about 35% of normal. When this happens, the mitochondria become sick, and begin to misfire. This leads to the brain and liver disease of classical Alpers’ Syndrome.
Clinical Characteristics
Alpers syndrome is a fatal disorder due to mutations in the POLG gene encoding the catalytic subunit of mitochondrial DNA polymerase gamma (Pol gamma) involved in mitochondrial DNA (mtDNA) replication. It is a rapidly progressive encephalopathy with intractable seizures and diffuse neuronal degeneration. It may occur with liver involvement (Alpers-Huttenlocher syndrome) and without it. Pts are normal at birth. In 2/3 of pts. symptoms start before age 1 year, in 1/4 on the second year, and in 10% in late childhood or adolescence. Seizures start after a period of slow motor and mental development, with FTT and occasional vomiting. Usually seizures start abruptly and become intractable with frequent status epilepticus, with rapid neurological deterioration and cortical blindness. Evidence of liver disease is usually present (A-H syndrome) but not always. Hepatomegaly and jaundice occur late but liver biochemical dysfunction is usually present early, sometimes before seizure start. EEG shows very slow waves of high voltage with low voltage polyspikes. VER slowly dissapear. ERG is normal. CT scan show progressive cerebral atrophy with low density lesions in medial aspects of occipital lobes. Liver biopsy is abnormal, fatty infiltration, fibrosis, cirrhosis, etc. Almost 70% die before age 3 years. There is severe neuronal loss in the brain, with spongy appearence similar to J-K disease. When liver is not involved, seizures tend to be mostly myoclonic and the occipital lobes are not predominantly involved. No treatment is available. The white matter tend to be spared in successive imaging studies. There is no evidence of retinal degeneration.
Precipitants
Often infections.
Provocation Tests
no
Diagnostic Procedures
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. Some times brain biopsy may be done, but it is no specific.