Rapidly Progressive Neurological Deterioration in a Child with Alpers Syndrome Exhibiting a Previously Unremarkable Brain MRI

Abstract

Alpers syndrome is a fatal disorder due to mutations in the POLG gene encoding the catalytic subunit of mitochondrial DNA polymerase γ (Pol γ) involved in mitochondrial DNA (mtDNA) replication. We describe a case of Alpers syndrome due to POLG mutations, with rapidly progressive course, a fatal outcome, and an essentially normal brain MRI in the early oligo-symptomatic phase. Our observation suggests that Alpers syndrome should be considered even in patients with an initially unremarkable brain MRI. The patient was found to harbor the p.Q497H, p.W748S and p.E1143G mutations in cis on one allele, and a fourth mutation, the p.G848S on the other allele. Although the individual mutations detected in the presented case have been previously reported, the specific genotype formed by the particular combination of these is novel.

Key words

POLG - Alpers syndrome - mitochondrial DNA depletion - DNA polymerase gamma

References

• 1 Bernier FP, Boneh A, Dennett X. et al . Diagnostic criteria for respira-tory chain disorders in adults and children.  Neurology. 2002;  59 1406-1411
• 2 Blackwood W, Buxton PH, Cumings JN. et al . Diffuse cerebral degeneration in infancy (Alpers’ disease).  Arch Dis Child. 1963;  38 193-204
• 3 Chan SS, Longley MJ, Copeland WC. Modulation of the W748S mutation in DNA polymerase gamma by the E1143G polymorphismin mitochondrial disorders.  Hum Mol Genet. 2006;  15 3473-3483
• 4 Davidzon G, Greene P, Mancuso M. et al . Early-onset familial parkinsonism due to POLG mutations.  Ann Neurol. 2006;  59 859-862
• 5 Davidzon G, Mancuso M, Ferraris S. et al . POLG mutations and Alpers syndrome.  Ann Neurol. 2005;  57 921-923
• 6 Laveaucoupet J de, Roffi F, Audibert F. et al . Progressive neuronal degeneration of childhood: prenatal diagnosis by MRI.  Prenat Diagn. 2005;  25 307-310
• 7 Vries MC de, Rodenburg RJ, Morava E. et al . Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations.  Eur J Pediatr. 2007;  166 229-234
• 8 Ferrari G, Lamantea E, Donati A. et al . Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA.  Brain. 2005;  128 723-731
• 9 Hakonen AH, Davidzon G, Salemi R. et al . Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders.  Eur J Hum Genet. 2007;  15 779-783
• 10 Horvath R, Hudson G, Ferrari G. et al . Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene.  Brain. 2006;  129 1674-1684
• 11 Huttenlocher PR, Solitare GB, Adams G. Infantile diffuse cerebral degeneration with hepatic cirrhosis.  Arch Neurol. 1976;  33 186-192
• 12 Lamantea E, Tiranti V, Bordoni A. et al . Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia.  Ann Neurol. 2002;  52 211-219
• 13 Naviaux RK, Nguyen KV. POLG mutations associated with Alpers’ syndrome and mitochondrial DNA depletion.  Ann Neurol. 2004;  55 706-712
• 14 Nguyen KV, Ostergaard E, Ravn SH. et al . POLG mutations in Alpers syndrome.  Neurology. 2005;  65 1493-1495
• 15 Rovio AT, Marchington DR, Donat S. et al . Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility.  Nat Genet. 2001;  29 261-262
• 16 Taylor RW, Turnbull DM. Laboratory diagnosis of mitochondrial disease. London, Chapman & Hall Medical 1997
• 17 Van Goethen G, Dermaut B, Lofgren A. et al . Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions.  Nat Genet. 2001;  28 211-212
• 18 Van Goethen G, Martin JJ, Dermaut B. et al . Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia.  Neuromuscul Disord. 2003;  13 133-142
• 19 Van Goethen G, Schwartz M, Lofgren A. et al . Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy.  Eur J Hum Genet. 2003;  11 547-549
• 20 Winterthun S, Ferrari G, He L. et al . Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations.  Neurology. 2005;  64 1204-1208

1 These two authors contributed equally.

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