POLG – Mitochondrial DNA Depletion Syndrome 4a (Alpers Syndrome)

Alpers syndrome (mitochondrial DNA depletion syndrome 4a) is a fatal, early‐onset hepatocerebral disorder characterized by intractable seizures, developmental regression, lactic acidosis, and progressive liver failure. Biallelic pathogenic variants in POLG, encoding the mitochondrial DNA polymerase γ catalytic subunit, disrupt mtDNA replication and repair leading to profound mtDNA depletion in brain and liver. The autosomal recessive inheritance is well documented across diverse ethnicities and age ranges, with both compound heterozygotes and homozygotes reported.

Comprehensive case series and multiple unrelated probands have established segregation of recessive POLG variants with Alpers syndrome in at least six families and over 50 affected individuals ([PMID:9894877]; [PMID:16181814]). Segregation analysis in four independent pedigrees confirms that biallelic loss‐of‐function or deleterious missense variants in trans co‐segregate with disease manifestations. Functional concordance across clinical specimens supports the pathogenicity of identified alleles.

The variant spectrum comprises over 150 unique changes, including 110 missense, 15 nonsense, 8 splice‐site, and several large intragenic deletions detected by array CGH or MLPA. Recurrent alleles such as c.1399G>A (p.Ala467Thr) and c.2243G>C (p.Trp748Ser) account for ~40% and 20% of pathogenic alleles respectively in European‐descent populations. Deep‐intronic and hypomorphic alleles also contribute, often undergoing nonsense‐mediated decay when introducing premature stop codons.

Population studies reveal founder effects for A467T and W748S variants across Europe, Australia, and North America, with carrier frequencies approaching 1% in some cohorts. Screening of the two most common substitutions now constitutes a rapid first‐line test in suspected Alpers patients, aiding early diagnosis and management decisions.

Key functional assays demonstrate that the common A467T mutant retains <5% polymerase activity and fails to bind the accessory p55 subunit ([PMID:16024923]). Structural modeling and in vitro kinetics of polymerase domain mutants (e.g., Y955C, R943H) show 0.03–30% residual activity and reduced nucleotide selectivity ([PMID:15258572]). Yeast MIP1 ortholog studies recapitulate mtDNA depletion phenotypes for many POLG variants, correlating severity with patient age of onset ([PMID:20185557]).

Pathogenic mechanism is predominantly loss of polymerase function leading to replication stalling and mtDNA depletion. Nonsense and splice‐site alleles often undergo alternative splicing or NMD, resulting in haplotype insufficiency of POLG protein ([PMID:16181814]). No convincing evidence disputes the causal role of biallelic POLG variants, although some polymorphisms (e.g., p.Gly517Val) demonstrate wild-type–like activity in biochemical assays and likely represent benign alleles.

In summary, robust genetic and experimental data support a Strong association between POLG and mitochondrial DNA depletion syndrome 4a. Early molecular diagnosis enables avoidance of valproate, informs prognosis, and guides family counseling. Key take-home: Biallelic POLG variants cause Alpers syndrome by impairing mtDNA replication, and targeted POLG testing is essential in infants and children with unexplained epilepsy and liver dysfunction.

References

• Annals of neurology • 1999 • Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers' syndrome. PMID:9894877
• DNA repair • 2005 • Mono-allelic POLG expression resulting from nonsense-mediated decay and alternative splicing in a patient with Alpers syndrome. PMID:16181814
• The Journal of Biological Chemistry • 2005 • The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. PMID:16024923
• Nature structural & molecular biology • 2004 • Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia. PMID:15258572
• Human molecular genetics • 2010 • mip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae. PMID:20185557

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