RESUMEN
Cytochrome c oxidase (COX) deficiency is a phenotypically diverse group of diseases caused by variants in over 30 genes. Biallelic pathogenic variants in COX6B1 have been described in four patients to date with varying disease manifestations. We describe the clinical features and follow-up of a patient with a novel homozygous pathogenic variant in COX6B1 who presented acutely with severe encephalomyopathy associated with an infection. New findings include ophthalmological evaluation and follow-up of neuroradiological investigations. The novel p.Trp31Arg variant was predicted to be pathogenic in silico, and further functional analyses with biochemical analysis of mitochondrial function showed isolated COX deficiency. Muscle biopsy showed a specific lack of COX6B1 protein together with complex IV deficiency on western blot, enzyme histochemistry, and immuno-histochemistry.
RESUMEN
BACKGROUND AND PURPOSE: Most mitochondrial disorders with onset in early childhood are progressive and involve multiple organs. The m.3250T>C mutation in MTTL1 has previously been described in a few individuals with a possibly riboflavin-responsive myopathy and an association with sudden infant death syndrome was suspected. We describe a large family with this mutation and evaluate the effect of riboflavin treatment. METHODS: Medical data were collected with the help of a standardized data collection form. Sanger sequencing was used to screen for variants in mitochondrial DNA and the proportion of the mutation was analyzed in different tissues. Biochemical and muscle morphological investigations of muscle tissue were performed in two individuals. The effect of riboflavin treatment was evaluated in two individuals. RESULTS: Thirteen family members experienced exercise intolerance with fatigue and weakness. Inheritance was maternal with 100% penetrance. The course was either static or showed improvement over time. There was no evidence of other organ involvement except for a possible mild transient cardiac enlargement in one child. Muscle investigations showed isolated complex I deficiency and mitochondrial proliferation. The level of m.3250T>C was apparently 100%, i.e. homoplasmic, in all examined tissues. Riboflavin treatment showed no effect in any treated family member and there have been no cases of sudden infant death in this family. CONCLUSIONS: This study illustrates the importance of considering mitochondrial disorders in the work-up of individuals with exercise intolerance and provides a better understanding of the phenotype associated with the m.3250T>C mutation in MTTL1.
Asunto(s)
ADN Mitocondrial/genética , Tolerancia al Ejercicio/genética , Miopatías Mitocondriales/genética , Mutación , ARN de Transferencia/genética , Adulto , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mitocondrias/genética , Miopatías Mitocondriales/tratamiento farmacológico , Linaje , Fenotipo , Riboflavina/uso terapéutico , Complejo Vitamínico B/uso terapéutico , Adulto JovenRESUMEN
In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.
Asunto(s)
Ácido Fólico/uso terapéutico , Leucovorina/uso terapéutico , Metilenotetrahidrofolato Deshidrogenasa (NADP)/deficiencia , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Anemia Megaloblástica/tratamiento farmacológico , Anemia Megaloblástica/genética , Anemia Megaloblástica/patología , Células Cultivadas , Resultado Fatal , Femenino , Deficiencia de Ácido Fólico/tratamiento farmacológico , Deficiencia de Ácido Fólico/genética , Deficiencia de Ácido Fólico/patología , Humanos , Hiperhomocisteinemia/tratamiento farmacológico , Hiperhomocisteinemia/genética , Hiperhomocisteinemia/patología , Lactante , Recién Nacido , Masculino , Antígenos de Histocompatibilidad Menor , Inmunodeficiencia Combinada Grave/tratamiento farmacológico , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/patología , Adulto JovenRESUMEN
We describe a second patient with the 583G>A mutation in the tRNA(phe) gene of mitochondrial DNA (mtDNA). This 17-year-old girl had a mitochondrial myopathy with exercise intolerance and an asymptomatic retinopathy. Muscle investigations showed occasional ragged red fibers, 30% cytochrome c oxidase (COX)-negative fibers, and reduced activities of complex I+IV in the respiratory chain. The mutation was heteroplasmic (79%) in muscle but undetectable in other tissues. Analysis of single muscle fibers revealed a significantly higher level of mutated mtDNA in COX-negative fibers. Our study indicates that the 583G>A mutation is pathogenic and expands the clinical spectrum of this mutation.
Asunto(s)
Miopatías Mitocondriales/genética , Mutación/genética , ARN de Transferencia de Fenilalanina/genética , ARN/genética , Enfermedades de la Retina/genética , Adolescente , Análisis Mutacional de ADN , Transporte de Electrón/genética , Complejo IV de Transporte de Electrones/metabolismo , Tolerancia al Ejercicio/genética , Femenino , Humanos , Miopatías Mitocondriales/complicaciones , Miopatías Mitocondriales/fisiopatología , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Debilidad Muscular/genética , Debilidad Muscular/fisiopatología , ARN Mitocondrial , Retina/patología , Retina/fisiopatología , Arteria Retiniana/patología , Arteria Retiniana/fisiopatología , Enfermedades de la Retina/complicaciones , Enfermedades de la Retina/fisiopatologíaRESUMEN
Mitochondrial changes are frequently encountered in sporadic inclusion-body myositis (s-IBM). Cytochrome c oxidase (COX)-deficient muscle fibers and large-scale mitochondrial DNA (mtDNA) deletions are more frequent in s-IBM than in age-matched controls. COX deficient muscle fibers are due to clonal expansion of mtDNA deletions and point mutations in segments of muscle fibers. Such segments range from 75 microm to more than 1,000 microm in length. Clonal expansion of the 4977 bp "common deletion" is a frequent cause of COX deficient muscle fiber segments, but many other deletions also occur. The deletion breakpoints cluster in a few regions that are similar to what is found in human mtDNA deletions in general. Analysis in s-IBM patients of three nuclear genes associated with multiple mtDNA deletions, POLG1, ANT1 and C10orf2, failed to demonstrate any mutations. In s-IBM patients with high number of COX-deficient fibers, the impaired mitochondrial function probably contribute to muscle weakness and wasting. Treatment that has positive effects in mitochondrial myopathies may be tried also in s-IBM.
Asunto(s)
Mitocondrias Musculares/patología , Miositis por Cuerpos de Inclusión/patología , Envejecimiento/genética , Secuencia de Bases , ADN Mitocondrial/genética , Complejo IV de Transporte de Electrones/análisis , Humanos , Mitocondrias Musculares/enzimología , Mitocondrias Musculares/fisiología , Miopatías Mitocondriales/genética , Datos de Secuencia Molecular , Fibras Musculares Esqueléticas/enzimología , Fibras Musculares Esqueléticas/patología , Mutación , Miositis por Cuerpos de Inclusión/metabolismo , Fosforilación Oxidativa , ARN de Transferencia/genética , Eliminación de SecuenciaRESUMEN
We report a novel heteroplasmic T-->C mutation at nt position 582 within the mitochondrial tRNA(Phe) gene of a 70-year-old woman with mitochondrial myopathy. No other family members were affected, suggesting that our patient was a sporadic case. The muscle showed frequent ragged red fibers and 43% cytochrome c oxidase deficient fibers. The mutation alters a conserved base pairing in the aminoacyl acceptor stem. The mutation load was 70% in muscle homogenate and varied from 0 to 95% in individual muscle fiber segments. Cytochrome c oxidase-negative fibers showed significantly higher levels of mutated mtDNA (>75%) than Cytochrome c oxidase-positive fibers (<55%). This mutation adds to the previously described four pathogenic mutations in the tRNA(Phe) gene.