Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Abstract

We performed a systematic review of the clinical, molecular, and biochemical features of polymerase gamma (POLG)-related epilepsy and current evidence on seizure management. Patients were identified from a combined electronic search of articles using Ovid Medline and Scopus databases, published from January 2000 to January 2015. Only patients with a confirmed genetic diagnosis of POLG mutations were considered. Seventy-two articles were included for analysis. We identified 128 pathogenic variants in 372 patients who had POLG-related epilepsy. Among these, 84% of the cases harbored at least one of these pathogenic variants: p.Ala467Thr, p.Trp748Ser, and p.Gly848Ser. A bimodal distribution of disease onset was present in early childhood (<5 years) and adolescence; female patients had a later presentation than male patients (median age 4.00 vs. 1.83 years, p-value = 0.041). Focal-onset seizure including convulsive, myoclonus, and occipital seizures was common at the outset and was refractory to pharmacotherapy. We confirmed that homozygous pathogenic variants located in the linker region of POLG were associated with later age of onset and longer survival compared to compound heterozygous variants. In addition, biochemical and molecular heterogeneities in different tissues were frequently observed. POLG-related epilepsy is clinically heterogeneous, and the prognosis is, in part, influenced by the location of the variants in the gene and the presence of hepatic involvement. Normal muscle and fibroblast studies do no exclude the diagnosis of POLG-related mitochondrial disease and direct sequencing of the POLG gene should be the gold standard when investigating suspected cases.

Mitochondrial diseases and status epilepticus

“…Similar findings were obtained in a systematic review of 229 patients with POLG-related epilepsy in whom seizure semiology had been reported; 49% had generalized status epilepticus, whereas 34% had focal motor status. 24…”

Dissecting the neuronal vulnerability underpinning Alpers’ syndrome: a clinical and neuropathological study

“…Mutations in POLG cause a spectrum of clinical phenotypes, including myoclonic epilepsy myopathy and sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS) and both dominant and recessive chronic progressive external ophthalmoplegia (CPEO) . POLG defects result in either mtDNA depletion or accumulation of mtDNA deletions, and in Alpers’ syndrome it is depletion of mtDNA which is responsible for the development of severe mitochondrial respiratory chain impairments, and consequent cellular dysfunction and cell death in brain and liver . Recent whole exome sequencing has identified other molecular genetic causes of Alpers’ syndrome, including pathogenic mutations in FARS2 which encodes phenylalanyl‐tRNA synthetase , NARS2 which encodes asparaginyl‐tRNA synthetase and PARS2 which encodes prolyl‐tRNA synthetase .…”

Synaptic energy metabolism and neuronal excitability, in sickness and health

“…POLG‐related syndromes comprise a continuum of overlapping diseases, ranging from severe phenotypes, such as Alpers‐Huttenlocher syndrome, to milder forms, including progressive external ophthalmoplegia. These syndromes characteristically present with epilepsy (50%‐80% at disease onset) . Alpers‐Huttenlocher syndrome is associated with infantile‐onset refractory, focal or generalized epilepsy.…”

“…These syndromes characteristically present with epilepsy (50%-80% at disease onset). 198,199 Alpers-Huttenlocher syndrome is associated with infantile-onset refractory, focal or generalized epilepsy. Seizures are predominantly occipital, as in mitochondrial spinocerebellar ataxia and epilepsy caused by POLG mutations, and are characterized by ictal visual loss, nystagmus, visual hallucinations of flickering colored light, and dysmorphopsia.…”