Original articlePhenotypic and genotypic variability in Alpers syndrome
Introduction
Alpers syndrome refers to a neurological disorder of infancy and early childhood, characterized by diffuse progressive cerebral atrophy. This cerebral degeneration affects predominantly the cerebral cortex and to a lesser degree the cerebellar gray matter, thalamus and basal ganglia. Atrophy of the related white matter is typically less striking.1 Over the years, many patients have been described with this condition that has been designated a number of different names, such as diffuse progressive degeneration of the gray matter of the cerebrum,2 progressive (infantile) cerebral poliodystrophy,3 spongy glio-neuronal dystrophy,4 or progressive neuronal degeneration of childhood.5
Similar patients had already been described in the nineteenth century,6 but the first comprehensive pathological study was presented by Alpers in 1931, when he described a three-month-old girl with a rapidly progressive, lethal disorder characterized by developmental regression and intractable seizures. Neuropathological investigations of this patient revealed widespread degeneration of the gray matter of the cerebrum.2 The diagnosis of Alpers syndrome was initially questioned. In some of the reported patients that followed, the neurodegenerative process was attributed to extensive perinatal cortical damage due to anoxia in relation to a complicated delivery,7, 8 postepileptic atrophy,8 and even an inflammatory process preceding the onset of the disease.9 Other patients had a suspected autosomal recessive inheritance with normal perinatal history and psychomotor development, followed by rapid deterioration, thus suggesting a genetic cause.10
In 1976, Huttenlocher drew attention to children with Alpers syndrome that in addition had liver cirrhosis or subacute hepatitis.11 These children had clinical onset between one and three years of age of a neurological condition that was dominated by severe seizures, most commonly status epilepticus, but also myoclonias and stroke-like episodes. Clinical evidence of hepatic dysfunction occurred later in the disease course, if at all. It was not until the mid-80s that Alpers syndrome was associated with a disturbed oxidative phosphorylation (OXPHOS) metabolism in the mitochondria. An association was found not only with defects of complex I12, 13, 14 and complex IV,12, 15 but also with mitochondrial DNA (mtDNA) depletion,16 indicating a probable mitochondrial origin of the disease.
Mitochondrial diseases form a heterogeneous group of disorders characterized by impaired energy production. They are caused by mutations in either mitochondrial or nuclear genes, which directly or indirectly affect OXPHOS.17 Alpers syndrome has been identified as one of the most common clinical phenotypes in children with mitochondrial OXPHOS disorders.18 Recently, Alpers syndrome (MIM # 203700) with liver involvement has been associated with mutations in POLG1.19, 20 POLG1 (MIM# 174763) encodes the catalytic subunit of mitochondrial DNA polymerase γ (pol γ), which is considered to be the replicative polymerase for mtDNA.21 Mutations in POLG1 are a frequent cause of multiple mtDNA deletions and/or mtDNA depletion. Pathogenic POLG1 mutations give rise to a heterogeneous spectrum of clinical syndromes.22, 23, 24, 25, 26, 27
Genotype–phenotype correlation studies are important for early diagnosis and improved decision-making. The primary objective of the present study was to investigate the phenotypic spectrum of patients with Alpers syndrome and impaired OXPHOS, as well as to identify the presence of underlying genetic defects, including pathogenic POLG1 mutations. The secondary objective of the present study was to investigate the differences between the studied patients with and without pathogenic POLG1 mutations, with respect to their clinical characteristics, disease course, biochemical investigations as well as neuropathological and neuroimaging findings.
Section snippets
Study population
Patients who were considered eligible for inclusion in the present study were those who fulfilled both the following criteria (1) and (2):
- (1)
Patients who underwent diagnostic testing of suspected mitochondrial disease in our hospital between January 1st 1984 and December 31st 2007 and were found to meet the diagnostic criteria of mitochondrial encephalomyopathy, as described elsewhere (see Appendix).18
- (2)
Patients with early-onset diffuse progressive cerebral atrophy that predominantly affected the
Results
A total of 19 patients with Alpers syndrome were included in the study. Among them, four were non-twin sibling pairs to non-related parents.
Discussion
Alpers syndrome is a common clinical phenotype in children with mitochondrial OXPHOS disorders, with an incidence estimated at 1 in 51,000 live births.18 Mutations in POLG1 have recently been found to cause Alpers syndrome.19, 20 Our findings show that such mutations only explain the mitochondrial respiratory chain deficiency in some patients with Alpers syndrome while the cause of the disorder is still unknown in the majority. The novel identified POLG1 mutation in patient #4 is probably
Conflict of interests
None declared.
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