Alpers-Huttenlocher Syndrome, also known as Mitochondrial DNA Depletion Syndrome 4a, is a severe POLG-related (Mitochondrial Polymerase Gamma Catalytic Subunit- related) disorder. POLG-related disorders are a group of conditions caused by mutations in the POLG gene, characterized by cerebral and hepatic degeneration. Alpers Syndrome is clinically typified by intractable epilepsy, psychomotor regression, and liver disease. In addition, patients may also show other neurological signs, such as ataxia, neuropathy, hypotonia, myoclonus, choreoathetosis, and parkinsonism. The liver degeneration is usually mild at first, but progresses to micronodular cirrhosis, bile-ductular proliferation, and microvesicular steatosis. Most patients are asymptomatic at birth. The first signs and symptoms of the condition usually develop in the first two-years of life.
Apart from the overt signs and symptoms, diagnosis relies on results of brain MRI or MR spectroscopy (MRS). Cerebrospinal fluid (CSF) chemistry consistently shows elevated protein. CSF and blood lactate levels may be transiently elevated, while transaminase levels may be chronically elevated. However, the gold standard for confirming the clinical diagnosis of Alpers syndrome is POLG DNA testing.
At present, there exists no cure for Alpers' disease, neither is there a way to slow disease progression. Treatment is symptomatic and supportive and may include the use of anticonvulsants to treat the seizures, and physical therapy to relieve spasticity and maintain muscle tone. Liver transplantation is contraindicated, as it has been found to be usually followed by progressive brain disease. Death typically occurs within 2 months to 15 years of diagnosis.
Frydman et al. (1993) reported the cases of eight patients from two Arab families and all born to parents who are first cousins. Onset in the first family was prenatal; in the four patients who were examined, severe microcephaly, intrauterine growth retardation, and typical manifestations of fetal akinesia, including retrognathia, joint limitations, and chest deformity, were found. The second family presented with an early infantile form. All of the affected offspring had micrognathia and one had findings of fetal akinesia, comparable to those seen in the other family. Microcephaly was mild at birth and progressed with age. Refractory neonatal convulsions, swallowing difficulties, and pneumonia complicated the clinical course of patients in both families, and all of the infants died before age 20 months. Comprehensive biochemical and metabolic studies in both families yielded normal results, and the diagnosis was supported by demonstration of extensive progressive brain atrophy on computerized tomography and typical histologic findings; the parietal cortex showed spongy state with focally accentuated severe loss of neurons. The cerebellar cortex showed severe loss of almost all granular cells and persistent Purkinje cells. Anomalies of dendritic arborization were also seen.
Mohamed et al. (2011) were the first to report cases of Alpers Syndrome from the UAE. They described eight patients (five females) from five families in the country. The first patient was a female who presented with focal seizures at 5-months of age, hypotonia and developmental delay. She also had mildly elevated bilirubin and albumin. She died of hepatic failure without a definite diagnosis being made. Her brother, born 3-years later, presented with similar symptoms, although there was no sign of liver involvement. The other six patients also had more or less the same symptoms. However, interestingly, the male patients showed no hepatic involvement. On the other hand, all males showed clear focal changes in the basal ganglia, an observation not noted in the females who underwent brain MRI. Surviving patients remained with neurological disease and developmental delay. Mohamed et al. (2011) emphasized the fact that at least in males, presentation with encephalopathy or focal status, even in the absence of hepatic disease, ought to raise the possibility of Alpers Syndrome. All seven patients in whom mutation testing was performed were found to be homozygous for the c.3286 C>T mutation in the POLG gene.
Al-Shamsi et al. (2014) undertook a study to calculate the birth prevalence of IEMs among Emiratis in the UAE by taking into consideration all neonates born with an inherited metabolic condition at Tawam Hospital between 1995 and 2012. A total of 37 distinct IEMs were found in Emirati neonates in this study, providing an estimated IEM birth prevalence of 75.24 per 100,000 live births. Mitochondrial DNA Depletion Syndromes were found to have a birth prevalence of between 2.2 and 4.9 per 100,000. A single mutation in the DLD gene was identified in patient(s) affected by the Alpers form of the condition.