Original article
Phenotypic and genotypic variability in Alpers syndrome

https://doi.org/10.1016/j.ejpn.2011.12.006Get rights and content

Abstract

Background

Alpers syndrome is one of the most common phenotypes of mitochondrial disorders in early childhood and has been associated with pathogenic mutations in POLG1.

Aims

To investigate the phenotypic–genotypic correlations in Alpers syndrome and to identify potential differences among patients with Alpers syndrome with or without pathogenic POLG1 mutations.

Methods

Patients with the phenotype of Alpers syndrome who were referred to our pediatric hospital during 1984–2007 and were diagnosed with mitochondrial encephalomyopathy underwent further biochemical, morphological and genetic investigations.

Results

A total of 19 patients were included in the study, of whom six had pathogenic POLG1 mutations including a novel mutation (c.907 G > A, p.Gly303Arg). Complete mtDNA sequencing in the subgroup without POLG1 mutations showed 5 novel and 5 very rare mtDNA variants considered as rare polymorphisms. Compared to POLG1(−) patients, the POLG1(+) patients more frequently had seizures at onset, which often became refractory. Ataxia and stroke-like episodes were much more common, while microcephaly and spasticity were encountered almost solely in the POLG1(−) group. Hepatic and ophthalmological involvement developed in 79% and 88% of patients, respectively. Most of the patients in both groups had predominant deficiency of complex I. In addition to the major degenerative changes in the cerebral cortex, the basal ganglia, thalamus and white matter were also involved to variable extent.

Conclusion

Alpers syndrome is a heterogeneous syndrome that should be considered in patients with early-onset progressive cortical encephalopathy regardless of liver involvement. The phenotype is different depending on the presence or absence of POLG1 mutations.

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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