Molecular diagnosis of Alpers syndrome
Introduction
Alpers syndrome (MIM 203700; sometimes called Alpers–Huttenlocher syndrome, Alpers hepatopathic poliodystrophy, or hepatocerebral degeneration of childhood) is one of the oldest recognized phenotypes associated with mitochondrial disease. It was first described by Bernard Alpers in 1931 [1], and recently found to be associated with mutations in the gene for the mitochondrial DNA polymerase (POLG) [2], [3], [4]. It is also the first reported disorder to result from a biochemical deficiency in any human DNA polymerase [5]. Alpers syndrome is inherited as a monogenic, autosomal recessive disorder. It affects children and young adults, and is characterized by the clinical triad of: (1) refractory seizures that include a focal component, (2) psychomotor regression that is often episodic, and (3) characteristic liver disease [6]. Children and teens with Alpers syndrome are asymptomatic at birth and develop normally over the first few weeks to years of life. Later, they develop the signs and symptoms of the disease in stepwise fashion, with few patients surviving beyond their teens [7].
The mitochondrial DNA polymerase (pol γ) is essential for mitochondrial DNA replication and repair [8], [9]. Pol γ is comprised of a 140 kDa catalytic (α) subunit that contains DNA polymerase, 3′–5′ exonuclease, and dRP lyase activities, and a 55 kDa accessory (β) subunit that functions as a processivity and DNA binding factor [10]. The holoenzyme appears to function as a αβ2 heterotrimer [11]. The catalytic subunit is encoded by the POLG (sometimes called the POLG1) locus, which includes 23 exons, and is located on chromosome 15q25 [12]. The accessory subunit is encoded by the POLG2 locus, which includes 8 exons, and is located on chromosome 17q23. POLG is arranged in three domains as illustrated in Fig. 2: exonuclease (codons 1–417), linker (codons 418–755), and polymerase domain (codons 756–1239).
Of 16 eukaryotic DNA polymerases discovered to date [13], only POLG and POLH (pol η) have been associated with inherited human disease [14]. Here, we show that all 20 of the Alpers syndrome patients with POLG mutations reported to date have had at least one copy of the A467T or W748S substitution. Screening for these 2 mutations in POLG now constitutes the most rapid and sensitive test available for confirming the clinical diagnosis of Alpers syndrome.
Section snippets
Diagnostic criteria for Alpers syndrome
We analyzed DNA samples for POLG mutations from 15 sequential, unrelated patients clinically diagnosed with Alpers syndrome [6]. The minimum diagnostic triad for inclusion of patients in this prospective series was: (1) refractory, mixed-type seizures that often included a focal component, (2) psychomotor regression that was often episodic and triggered by intercurrent infection, and (3) hepatopathy with or without acute liver failure. The hepatopathy was triggered by Valproic acid in some
New POLG mutations
We found 5 new compound heterozygous POLG mutations that were associated with Alpers syndrome: (1) A467T/F749S, (2) A467T/R852C, (3) A467T/T914P, (4) A467T/L966R, and (5) A467T/L1173fsX (Table 1). The role of the A467T allele in Alpers syndrome has been previously reported [2], [4]. The F749S substitution was caused by a c.2528T > C mutation, located in exon 13. The R852C substitution was caused by a c.2836C > T mutation, located in exon 16. The T914P substitution was caused by a c.3022A > C
Discussion
Over 60 mutations in POLG have been described [24] (NIEHSa in the Web Resources section). Different allelic combinations are associated with 4 partially-overlapping groups of disease. These are: (1) Progressive External Ophthalmoplegia (PEO, ±multisystem disorder) [25], [26], [27], [28], (2) Ataxia, Neuropathy Spectrum (ANS) disorders (±seizures, dementia, liver dysfunction, or sensitivity to valproic acid; includes SANDO and MIRAS) [20], [21], [29], (3) Myoclonus, Epilepsy, Myopathy Spectrum
Web resources
- 1.
National Library of Medicine Online Mendelian Inheritance in Man (OMIM), www.ncbi.nlm.nih.gov/entrez/query.fcgi?db = OMIM Entries no. 203700 and no. 174763. Date Accessed July 19, 2005.
- 2.
National Institute of Environmental Health Sciences (NIEHSa). Human DNA Polymerase Gamma Mutation Database. URL: http://dir-apps.niehs.nih.gov/polg/index.cfm Date Accessed: July 19, 2005.
- 3.
National Institute of Environmental Health Sciences (NIEHSb). GeneSNPs of POLG. URL: http://www.genome.utah.edu/genesnps Date
Acknowledgements
This work was supported by a generous gift from Mrs Dorothy R. Engs, and by grants from the UCSD Foundation Christini Fund, The Lored Foundation, and the William Wright Family Foundation to RKN, and by intramural support from the National Institute of Environmental Health Sciences to WCC. Conflict of Interest Statement: The authors declare they have no financial or non-financial conflicts of interest.
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2017, Genetics in MedicineCitation Excerpt :Regarding phenotypic classification, our data reinforced the current understanding of Alpers and MCHS as two separate entities with different age at onset and survival. We found, however, significant overlap in clinical features between the Alpers and MCHS subgroups and application of the previously described criteria for diagnosis12,23was challenging. Using the characteristic liver pathological findings to differentiate, as previously suggested,12was not possible as liver biopsy was only performed in three of our cases.