Two novel compound heterozygous mutations in OPA3 in two siblings with OPA3-related 3-methylglutaconic aciduria

Christina Lam,Linda K Gallo,Richard Dineen,Carla Ciccone,Heidi Dorward,George E Hoganson,Lynne Wolfe,William A Gahl,Marjan Huizing

doi:10.1016/j.ymgmr.2014.02.003

Abstract

OPA3-related 3-methylglutaconic aciduria, or Costeff Optic Atrophy syndrome, is a neuro-ophthalmologic syndrome of early-onset bilateral optic atrophy and later-onset spasticity, and extrapyramidal dysfunction. Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is markedly increased. OPA3-related 3-methylglutaconic aciduria is due to mutations in the OPA3 gene located at 19q13.2–13.3. Here we describe two siblings with novel compound heterozygous variants in OPA3: c.1A>G (p.1M>V) in the translation initiation codon in exon 1 and a second variant, c.142+5G>C in intron 1. On cDNA sequencing the c.1A>G appeared homozygous, indicating that the allele without the c.1A>G variant is degraded. This is likely due to an intronic variant; possibly the IVS1+5 splice site variant. The older female sibling initially presented with motor developmental delay and vertical nystagmus during her first year of life and was diagnosed subsequently with optic atrophy. Her brother presented with mildly increased hip muscle tone followed by vertical nystagmus within the first 6months of life, and was found to have elevated urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid, and optic atrophy by 1.5years of age. Currently, ages 16 and 7, both children exhibit ataxic gaits and dysarthric speech. Immunofluorescence studies on patient's cells showed fragmented mitochondrial morphology. Thus, though the exact function of OPA3 remains unknown, our experimental results and clinical summary provide evidence for the pathogenicity of the identified OPA3 variants and provide further evidence for a mitochondrial pathology in this disease.

Highlights

The branched-chain organic acids 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGR) are excreted only in trace amounts in the urine of healthy individuals [1]
Increased urinary excretion of 3-MGA and 3-MGR (20–40 mmol/mol creatinine) is a relatively common finding in metabolic disorders, especially in disorders with mitochondrial dysfunction, and is often accompanied by increased excretion of other metabolites. 3-Methylglutaconic acidurias (3-MGA-urias) represent a group of disorders with significantly and consistently increased urinary 3-MGA and 3-MGR (40–1000 mmol/mol creatinine), where these increased metabolites are a hallmark of the phenotype and the key to diagnosis of the disorder [2,3]
We previously described that the OPA3 gene contains three exons encoding two transcripts formed by alternative splicing (Fig. 1) [8], which were recently annotated into GenBank

Summary

Introduction

The branched-chain organic acids 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGR) are excreted only in trace amounts in the urine of healthy individuals (less than ~6 mmol/mol creatinine) [1]. Increased urinary excretion of 3-MGA and 3-MGR (20–40 mmol/mol creatinine) is a relatively common finding in metabolic disorders, especially in disorders with mitochondrial dysfunction, and is often accompanied by increased excretion of other (disease specific) metabolites. Variant 2 (exons 1+2) is expressed and conserved from fungi to primates, while variant 1 is uniquely found in mammals

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Results

Conclusion