The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations

Abstract

PurposeMutations in POLG, the most common single-gene cause of inherited mitochondrial disease, are diagnostically challenging owing to clinical heterogeneity and overlap between syndromes. We aimed to improve the clinical recognition of POLG-related disorders in the pediatric population.MethodsWe performed a multinational, phenotype: genotype study using patients from three centers, two Norwegian and one from the United Kingdom. Patients with age at onset <12 years and confirmed pathogenic biallelic POLG mutations were considered eligible.ResultsA total of 27 patients were identified with a median age at onset of 11 months (range 0.6-80.4). The majority presented with global developmental delay (n=24/24, 100%), hypotonia (n=22/23, 96%) and faltering growth (n=24/27, 89%). Epilepsy was common, but notably absent in patients with the myocerebrohepatopathy spectrum phenotype. We identified two novel POLG gene mutations.ConclusionOur data suggest that POLG-related disease should be suspected in any child presenting with diffuse neurological symptoms. Full POLG sequencing is recommended since targeted screening may miss mutations. Finally, we simplify the classification of POLG-related disease in children using epilepsy as the crucial defining element; we show that Alpers and myocerebrohepatopathy spectrum follow different outcomes and that they manifest different degrees of respiratory chain dysfunction.

Mitochondrial diseases and status epilepticus

“…22 The disorder is caused by biallelic mutations in POLG, encoding the catalytic subunit of DNA polymerase gamma (the enzyme responsible for replicating mtDNA), which leads to progressive depletion of the mtDNA. 22 Eighty-nine percent of cases had therapy-resistant epilepsy. 22 Eighty-nine percent of cases had therapy-resistant epilepsy.…”

Elevated cerebrospinal fluid protein in POLG‐related epilepsy: Diagnostic and prognostic implications

“…Epilepsy is particularly common in the early childhood and juvenile groups; focal seizures, commonly evolving into bilateral convulsive seizures, are the most common seizure types in both adult and pediatric patients, with epileptiform discharges predominantly occurring over the occipital regions . The majority of the patients develop therapy‐resistant epilepsy …”

“…2 Mutations in POLG cause disease that varies in severity from devastating infantile phenotypes such as Alpers syndrome and myocerebrohepatopathy spectrum (MCHS) to juvenile syndromes comprising epilepsy and ataxia [3][4][5] and to late onset myopathies with progressive external ophthalmoplegia (PEO). 6,7 Epilepsy is particularly common in the early childhood and juvenile groups 3,4,[8][9][10] ; focal seizures, commonly evolving into bilateral convulsive seizures, 11,12 are the most common seizure types in both adult and pediatric patients, with epileptiform discharges predominantly occurring over the occipital regions. 13 The majority of the patients develop therapy-resistant epilepsy.…”

“…13 The majority of the patients develop therapy-resistant epilepsy. 9,10 The blood-brain barrier (BBB) is formed by a continuous layer of cerebral endothelial cells held together by tight junctions (Figure 1), separating the blood components from the brain microenvironment and regulating the entry and exit of ions, nutrients, macromolecules, and energy metabolites. The BBB is a part of the neurovascular unit that includes blood vessels, neurons, astrocytes, pericytes, and microglia, and that is divided into several compartments: the BBB, the blood-cerebrospinal fluid (CSF) barrier, the arachnoid barrier, neuroependyma (the fetal-CSF brain barrier), and adult ependyma (free exchange).…”

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.…”