Defects in mitochondrial translation may lead to combined respiratory chain deficiency and typically cause childhood-onset multisystem disease. Only recently, a homozygous missense mutation (c.467T > G, p.Leu156Arg) in MRPL44, encoding a protein of the large subunit of the mitochondrial ribosome, has been identified in two siblings with hypertrophic cardiomyopathy. Using exome sequencing, we identified two further unrelated patients harboring the previously reported mutation c.467T > G, p.Leu156Arg in MRPL44 in the homozygous state and compound heterozygous with a novel missense mutation c.233G > A, p.Arg78Gln, respectively. Both patients presented with childhood-onset hypertrophic cardiomyopathy, which seems to be the core clinical feature associated with MRPL44 deficiency. However, we observed several additional clinical signs and symptoms including pigmentary retinopathy, hemiplegic migraine, Leigh-like lesions on brain MRI, renal insufficiency, and hepatopathy. Our findings expand the clinical spectrum associated with MRPL44 mutations and indicate that MRPL44-associated mitochondrial dysfunction can also manifest as a progressive multisystem disease with central nervous system involvement. Of note, neurological and neuro-ophthalmological impairment seems to be a disease feature of the second and third decades of life, which should be taken into account in patient management and counseling.
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This study was supported by the German Bundesministerium fürBildung und Forschung (BMBF) through the German Network for mitochondrial disorders (mitoNET; 01GM1113A to TK, and 01GM1113C to TM and HP) and through the E-Rare project GENOMIT (01GM1207 for TM and HP). TH was supported by the BMBF through the Juniorverbund in der Systemmedizin “mitOmics” (FKZ 01ZX1405C). TM was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) within the framework of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy) as well as by the DZHK (German Centre for Cardiovascular Research) and the BMBF (German Ministry of Education and Research).
Visualization of mate pair reads of the exome sequencing experiment of patient 1 using the Integrated Genomics Viewer demonstrating that reads covering both positions show either allele 1 (brown) or 2 (green). This finding confirms a bi-allelic localization of the identified MRPL44 variants in patient 1. (GIF 372 kb)
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