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Sensory neuronopathy in patients harbouring recessive polymerase ? mutations.

ABSTRACT: Defects in the mitochondrial DNA replication enzyme, polymerase ?, are an important cause of mitochondrial disease with ?25% of all adult diagnoses attributed to mutations in the POLG gene. Peripheral neuronopathy is often part of the clinical syndrome and can represent the most disabling feature. In spite of this, the molecular mechanisms underlying the neuronopathy remain to be elucidated and treatment strategies are limited. In the present study, we use a combined approach comprising clinical, electrophysiological, neuropathological and molecular genetic investigations to unravel the mechanisms underpinning peripheral neuronopathy in autosomal recessive polymerase ?-related disease. Electrophysiological assessments documented a dorsal root ganglionopathy in all 11 cases. Of the 11 cases, eight also showed changes consistent with motor fibre loss. Detailed neuropathological investigation of two patients confirmed the electrophysiological findings, revealing atrophy of posterior columns and striking neuronal cell loss from the dorsal root ganglia, which was accompanied by severe mitochondrial biochemical abnormalities involving respiratory chain complexes I and IV due to clonally-expanded mitochondrial DNA deletions and a significant reduction in mitochondrial DNA copy number in affected neurons. We propose that the respiratory chain defects, secondary to mitochondrial DNA deletion and depletion, are likely to be responsible for pathology observed in the dorsal root ganglion and the sensory ganglionopathy documented electrophysiologically.

SUBMITTER: Lax NZ

PROVIDER: S-EPMC3267986 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Sensory neuronopathy in patients harbouring recessive polymerase γ mutations.

Lax Nichola Z NZ Whittaker Roger G RG Hepplewhite Philippa D PD Reeve Amy K AK Blakely Emma L EL Jaros Evelyn E Ince Paul G PG Taylor Robert W RW Fawcett Peter R W PR Turnbull Doug M DM

Brain : a journal of neurology 20111220 Pt 1

Defects in the mitochondrial DNA replication enzyme, polymerase γ, are an important cause of mitochondrial disease with ∼25% of all adult diagnoses attributed to mutations in the POLG gene. Peripheral neuronopathy is often part of the clinical syndrome and can represent the most disabling feature. In spite of this, the molecular mechanisms underlying the neuronopathy remain to be elucidated and treatment strategies are limited. In the present study, we use a combined approach comprising clinical ...[more]

PMID: 22189570

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Project description:Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.

Project description:BackgroundLethal recessive genetic variants are maintained at relatively low frequencies in a population in the heterozygous state, but by definition are fatal and therefore unobserved in the homozygous state. Since haplotypes allow the tagging of rare and untyped genetic variants, they have potential for studying lethal recessive variants. In this study, we used a large commercial population to identify putative lethal recessive haplotypes that impact either the total number born (TNB) or the number born alive (NBA) as a proportion of the total number born (NBA/TNB). We also compared the use of haplotypes with a single nucleotide polymorphism (SNP)-by-SNP approach and examined the benefits of using additional haplotypes imputed from low-density genotype data for the detection of lethal recessive variants. Candidate haplotypes were identified using population-wide haplotype frequencies and within-family analyses. These candidate haplotypes were subsequently assessed for putative lethal recessive effects on TNB and NBA/TNB by comparing carrier-to-carrier matings with carrier-to-non-carrier matings.ResultsUsing both medium-density and imputed low-density genotype data six regions were identified as containing putative lethal recessive haplotypes that had an effect on TNB. It is likely that these regions were related to at least four putative lethal recessive variants, each located on a different chromosome. Evidence for putative lethal recessive effects on TNB was found on chromosomes 1, 6, 10 and 14 using haplotypes. Using haplotypes from individuals genotyped only at medium-density or a SNP-by-SNP approach did not detect any lethal recessive effects. No lethal recessive haplotypes or SNPs were detected that had an effect on NBA/TNB.ConclusionsWe show that the use of haplotypes from combining medium-density and imputed low-density genotype data is superior for the identification of lethal recessive variants compared to both a SNP-by-SNP approach and to the use of only medium-density data. We developed a formal statistical framework that provided sufficient power to detect lethal recessive variants in species, which produce large full-sib families, while reducing false positive or type I errors. Applying this framework results in improvements in reproductive performance by purging lethal recessive alleles from a population in a timely and cost-effective manner.

Dataset Information

Sensory neuronopathy in patients harbouring recessive polymerase ? mutations.

Publications

Sensory neuronopathy in patients harbouring recessive polymerase γ mutations.

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