- The Food and Drug Administration (FDA, 2017) states that Depakene (valoproate) and Depakote ER (divalproex sodium) are contraindicated for patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder:
- “Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents.”
- “POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders.”
- Although not specific to genetic testing for POLG, the Mitochondrial Medicine Society (2015) developed consensus recommendations for the diagnosis and management of mitochondrial disease. Testing strategies, including strategies for genetic testing, were discussed.
- Recommendations for DNA testing include the following:
- “When considering nuclear gene testing in patients with likely primary mitochondrial disease, NGS methodologies providing complete coverage of known mitochondrial disease gene is preferred. Single-gene testing should usually be avoided because mutations in different genes can produce the same phenotype. If no mutation is identified via known NGS panels, then whole exome sequencing should be considered.”
- The European Federation of Neurological Sciences/European Neurological Society (EFNS/ENS) 2014 consensus guidelines on the diagnosis and management of chronic ataxias in adulthood recommend POLG testing in the following evaluation of individuals with autosomal recessive cerebellar ataxia:
- “Step 1: mutation analysis of the FRDA gene for Friedreich’s ataxia (although one can refrain from this in the case of severe cerebellar atrophy), and biochemical testing that includes cholestanol, vitamin E, cholesterol, albumin, creatine kinase (CK) and a-fetoprotein. Also consider doing nerve conduction studies/EMG (presence versus absence of peripheral neuropathy, axonal versus demyelinating) and referral to an ophthalmologist (retinitis pigmentosa, cataract, cherry red spot etc.) (Table S2) (good practice point).”
- “Step 2: mutation analysis of the SACS, POLG, Aprataxin (APTX) and SPG7 genes (taking into account specific phenotypes, as given in Table S2), and biochemical testing for white cell enzymes, phytanic acid and long chain fatty acids (good practice point).”
- “Step 3: referral to a specialized centre, e.g. for skin or muscle biopsy targeted at diagnoses such as Niemann-Pick type C, recessive ataxia with coenzyme Q deficiency [aarF domain containing kinase 3 (ADCK3)/autosomal recessive spinocerebellar ataxia 9 (SCAR9)] and mitochondrial disorders, or for extended genetic screening using gene panel diagnostics (good practice point).”
- A 2014 expert-authored review suggests the following testing strategy for those with a known or suspected diagnosis of a POLG related disorder:
- “Standard clinical investigations can identify findings that, in the context of an appropriate family history, can suggest one of the POLG-related phenotypes.”
- “Confirmation of the diagnosis of a POLG-related disorder requires identification of POLG pathogenic variants by molecular genetic testing.”
- “One of the following two approaches can be used:”
- “Direct sequencing of POLG”
- “Two tiered analysis: targeted analysis for the common POLG pathogenic variants p.Ala467Thr, p.Trp748Ser, and p.Gly848Ser, followed by sequence analysis of the entire coding region if no pathogenic variants or only one pathogenic variant is found.”
- “In persons meeting the diagnostic criteria of an autosomal recessive POLG related disorder but in whom sequence analysis identifies only one disease causing “POLG” allele, further testing may be considered to search for a second pathogenic variant in regulatory regions (e.g., the POLG promoter) or in relate mitochondrial DNA replication genes such as C10orf2 (formerly PEO1; (encodes the twinkle helicase) and POLG2 to investigate the possibility of digenic inheritance. ”
- “Digenic inheritance has been reported in arPEO in a simplex case with pathogenic variants in POLG and C10orf2.”
- “Oligonucleotide array should be strongly considered as microdeletions involving intragenic regions of POLG are reported and therefore relevant in a symptomatic individual with a single heterozygous pathogenic variant.”
- “An alternative genetic testing strategy is use of a multi-gene panel that includes POLG and other genes of interest.”
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