Mitochondrial disease mimicking Charcot-Marie Tooth disease.
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Adult↗
Biomedical subjects
C M Sue
Publications and source records attributed to C M Sue.
Measurement of ATP production in mitochondrial disorders.
Mitochondrial diseases are a heterogeneous group of disorders caused by mutations in both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Mitochondrial disease leads to impaired respiratory chain function and reduced ATP production. The aim of this study was to compare disturbances in mitochondrial function by measuring ATP synthesis in fibroblasts derived from patients with nDNA and mtDNA defects. Skin fibroblasts derived from 22 patients with either nDNA-related disorders (n = 8) or mtDNA-related disorders (n = 14) were analysed. ATP synthesis was markedly decreased in fibroblasts derived from patients with nDNA-related disorders but only variably so in patients with mtDNA mutations. In fibroblasts with the MELAS 3243A > G mutation, ATP synthesis correlated with mutant load. We believe that the observed differences in ATP production between cell lines derived from patients with nDNA-related disorders and mtDNA-related disorders may help in the assessment of patients with undiagnosed mitochondrial disease. The clinical comparisons observed in patients with nDNA- and mtDNA-related disorders may be explained by differences in the disturbance of ATP synthesis measured in the two conditions.
Adenosine Triphosphate↗
Prevalence of mitochondrial DNA haplogroups in an Australian population.
Mitochondrial DNA (mtDNA) haplogroups are 'neutral polymorphisms' in the mtDNA genome, which have accumulated and persisted along maternal lineages as the human population has migrated worldwide. Three ethnically distinct lineages of human mtDNA populations have been identified: European, characterized by nine haplogroups H, I, J, K, T, U, V, W and X; African, characterized by superhaplogroup L and Asian, characterized by superhaplogroup M. We studied the prevalence of mtDNA haplogroups in participants of the Blue Mountains Eye Study, a large population-based survey of vision conducted between 1991 and 2000 of non-institutionalized permanent residents aged 49 years or older from two suburban postcode areas, west of Sydney, Australia. Total DNA isolated from either hair follicles or blood was available for 3377 of the 3509 participants (96.2%) to determine mtDNA haplogroups by polymerase chain reaction/restriction fragment length polymorphism analysis. Approximately 94.2% of samples could be assigned to one of the nine major European haplogroups, whereas a further 1.2% included the African (L) and Asian (M) superhaplogroups. The five principal haplogroups represented were H (42.9%), U (14.1%), J (10.7%), T (9.2%) and K (8.1%), which together included 85% of this population.
DNA, Mitochondrial↗
A5814G mutation in mitochondrial DNA can cause mitochondrial myopathy and cardiomyopathy.
We describe a 5-year-old child with hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis. Mitochondrial DNA analysis showed a heteroplasmic A5814G point mutation in the tRNA(Cys) gene. The mutational load was extremely high (>95%) in muscle, fibroblasts, and blood. This report expands the clinical heterogeneity of the A5814G mutation, which should be considered in the differential diagnosis of hypertrophic cardiomyopathy in childhood.
Acidosis, Lactic↗
Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA.
OBJECTIVE: To elucidate the molecular basis of a mitochondrial myopathy associated with recurrent myoglobinuria and cytochrome c oxidase (COX) deficiency in muscle. BACKGROUND: Recurrent myoglobinuria is typically seen in patients with inborn errors of carbohydrate or lipid metabolism, the main sources of energy for muscle contraction. Relatively little attention has been directed to defects of the mitochondrial respiratory chain in patients with otherwise unexplained recurrent myoglobinuria. METHODS: Having documented COX deficiency histochemically and biochemically in the muscle biopsy from a patient with exercise-induced recurrent myoglobinuria, the authors sequenced the three mitochondrial DNA (mtDNA)-encoded COX genes, and performed restriction fragment length polymorphism analysis and single-fiber PCR. RESULTS: The authors identified a nonsense mutation (G5920A) in the COX I gene in muscle mtDNA. The mutation was heteroplasmic and abundantly present in COX-negative fibers, but less abundant or absent in COX-positive fibers; it was not found in blood or fibroblasts from the patient or in blood samples from the patient's asymptomatic mother and sister. CONCLUSIONS: The G5920A mutation caused COX deficiency in muscle, explaining the exercise intolerance and the low muscle capacity for oxidative phosphorylation documented by cycle ergometry. The sporadic occurrence of this mutation in muscle alone suggests that it arose de novo in myogenic stem cells after germ-layer differentiation. Mutations in mtDNA-encoded COX genes should be considered in patients with recurrent myoglobinuria.
Adult↗
Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease).
"Lysosomal glycogen storage disease with normal acid maltase" which was originally described by Danon et al., is characterized clinically by cardiomyopathy, myopathy and variable mental retardation. The pathological hallmark of the disease is intracytoplasmic vacuoles containing autophagic material and glycogen in skeletal and cardiac muscle cells. Sarcolemmal proteins and basal lamina are associated with the vacuolar membranes. Here we report ten unrelated patients, including one of the patients from the original case report, who have primary deficiencies of LAMP-2, a principal lysosomal membrane protein. From these results and the finding that LAMP-2-deficient mice manifest a similar vacuolar cardioskeletal myopathy, we conclude that primary LAMP-2 deficiency is the cause of Danon disease. To our knowledge this is the first example of human cardiopathy-myopathy that is caused by mutations in a lysosomal structural protein rather than an enzymatic protein.
Antigens, CD↗
Paroxysmal word deafness secondary to focal epilepsy.
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Auditory Perceptual Disorders↗
Mitochondrial respiratory chain diseases and mutations in nuclear DNA: a promising start?
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Cell Nucleus↗
G8363A mutation in the mitochondrial DNA transfer ribonucleic acidLys gene: another cause of Leigh syndrome.
We identified a G-->A transition at nt-8363 in the mitochondrial DNA transfer ribonucleic acidLys gene in blood and muscle from a 13-month-old girl who had clinical and neuroradiologic evidence of Leigh syndrome and died at age 27 months. The mutation was less abundant in the same tissues from the patient's mother, who developed myoclonus epilepsy with ragged red fibers (MERRF) in her late 20s. In both mother and daughter, muscle histochemistry showed ragged red and cytochrome c oxidase-negative fibers and biochemical analysis showed partial defects of multiple respiratory-chain enzymes. A maternal half-sister of the proband had died at 2.5 years of age from neuropathologically proven Leigh syndrome. The G8363A mutation, which previously had been associated with cardiomyopathy and hearing loss, MERRF, and multiple lipomas, also should be included in the differential diagnosis of maternally inherited Leigh syndrome.
Adult↗
Differential features of patients with mutations in two COX assembly genes, SURF-1 and SCO2.
We screened 41 patients with undiagnosed encephalomyopathies and cytochrome c oxidase (COX) deficiency for mutations in two COX assembly genes, SURF-1 and SCO2; 6 patients had mutations in SURF-1 and 3 had mutations in SCO2. All of the mutations in SURF-1 were small-scale rearrangements (deletions/insertions); 3 patients were homozygotes and the other 3 were compound heterozygotes. All patients with SCO2 mutations were compound heterozygotes for nonsense or missense mutations. All of the patients with mutations in SURF-1 had Leigh syndrome, whereas the 3 patients with SCO2 mutations had a combination of encephalopathy and hypertrophic cardiomyopathy, and the neuropathology did not show the typical features of Leigh syndrome. In patients with SCO2 mutations, onset was earlier and the clinical course and progression to death more rapid than in patients with SURF-1 mutations. In addition, biochemical and morphological studies showed that the COX deficiency was more severe in patients with SCO2 mutations. Immunohistochemical studies suggested that SURF-1 mutations result in similarly reduced levels of mitochondrial-encoded and nuclear-encoded COX subunits, whereas SCO2 mutations affected mitochondrial-encoded subunits to a greater degree. We conclude that patients with mutations in SURF-1 and SCO2 genes have distinct phenotypes despite the common biochemical defect of COX activity.
Adult↗
Maternally inherited hearing loss in a large kindred with a novel T7511C mutation in the mitochondrial DNA tRNA(Ser(UCN)) gene.
Thirty-six of 43 maternally related members of a large African American family experienced hearing loss. A muscle biopsy specimen from the proband showed cytochrome c oxidase (COX)-deficient fibers but no ragged-red fibers; biochemical analysis showed marked reduction of COX activity. A novel T7511C point mutation in the tRNA(Ser(UCN)) gene was present in almost homoplasmic levels (>95%) in the blood of 18 of 20 family members, and was also found in lower abundance in the other two. Single-fiber PCR showed that the mutational load was greater in COX-deficient muscle fibers. The tRNA(ser(UCN)) gene may be a "hot spot" for mutations associated with maternally transmitted hearing loss.
Adult↗
Maternally inherited nonsyndromic hearing loss.
In this study we characterized clinically and evaluated molecularly a large family with maternally inherited hearing impairment. Relatives were evaluated audiologically and clinically, the most likely pattern of inheritance was deduced, and molecular DNA analysis for the known mitochondrial mutations associated with hearing impairment was performed. Clinical examination of several relatives showed a normal general state of health, but in 14 of the members tested variable degrees of sensorineural hearing loss were noted. The pedigree was established and demonstrated a clear pattern of maternal inheritance, with 34 of 38 offspring of deaf mothers being hearing impaired, but none of 22 offspring of deaf fathers having any hearing impairment. Since by far the most likely explanation of such a maternal inheritance pattern is a mitochondrial mutation, molecular testing for the three known mitochondrial mutations, A1555G, A7445G, and Cins7472, was performed on 27 of the relatives. All of the individuals tested had the normal sequence at the sites tested. This family with nonsyndromic sensorineural hearing loss has an inheritance pattern strongly suggestive of a mitochondrial mutation. However, molecular testing for the three known mitochondrial mutations associated with nonsyndromic hearing impairment was negative, implying that additional molecular defects can lead to the same phenotype. The search for this novel molecular defect is underway.
Audiometry↗
A nonsense mutation (G15059A) in the cytochrome b gene in a patient with exercise intolerance and myoglobinuria.
We describe a new mitochondrial DNA mutation in the cytochrome b gene in a patient presenting with progressive exercise intolerance and myoglobinuria associated with complex III deficiency in muscle. The point mutation results in the replacement of a glycine at amino acid position 190 with a stop codon. This change predicts premature termination of translation, leading to a truncated protein missing 244 amino acids at the C-terminus of cytochrome b. The mutation fulfills all the accepted criteria for pathogenicity, suggesting that this is the primary cause of the myopathy in the patient.
Adult↗
Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene.
We report the first molecular defect in an NADH-dehydrogenase gene presenting as isolated myopathy. The proband had lifelong exercise intolerance but no weakness. A muscle biopsy showed cytochrome c oxidase (COX)-positive ragged-red fibers (RRFs), and analysis of the mitochondrial enzymes revealed complex I deficiency. Sequence analysis of the mitochondrial genes encoding the seven NADH-dehydrogenase subunits showed a G-to-A transition at nucleotide 11832 in the subunit 4 (ND4) gene, which changed an encoded tryptophan to a stop codon. The mutation was heteroplasmic (54%) in muscle DNA. Defects in mitochondrially encoded complex I subunits should be added to the differential diagnosis of mitochondrial myopathies.
Adult↗
Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM.
Mutations in the brain specific P/Q type Ca2+ channel alpha1 subunit gene, CACNA1A, have been identified in three clinically distinct disorders, viz. episodic ataxia type 2 (EA-2), familial hemiplegic migraine (FHM) and spinocerebellar ataxia 6 (SCA6). For individuals with EA-2, the mutations described thus far are presumed to result in a truncated protein product. Several different missense mutations have been identified in patients with FHM. At least two of these mutations have been identified on two different chromosome 19p13 haplotypes and thus represent recurrent mutations. In the present study, we have screened several individuals for mutations in all 47 exons in the CACNA1A gene by single-strand conformation analysis. We have characterised a novel missense mutation, G5260A, in exon 32 in a family segregating for EA-2. The consequence of this mutation is an amino acid substitution at a highly conserved position within the CACNA1A gene. This represents the first point mutation not resulting in a proposed truncated protein. Furthermore, this mutation has been detected in a family member with mild clinical signs including only migraine. Additionally, a second previously identified recurrent muta tion, C2272T, in exon 16 has been discovered in a patient with FHM.
Amino Acid Sequence↗
Infantile encephalopathy associated with the MELAS A3243G mutation.
MELAS syndrome is typically characterized by normal early development and childhood-onset recurrent neurologic deficits (stroke-like episodes), seizures, short stature, lactic acidosis, and ragged red fibers on muscle biopsy specimens. It is usually, but not invariably, associated with the A3243G point mutation in the mitochondrial DNA tRNALeu(UUR) gene. We report 3 unrelated children with the A3243G mutation who presented with severe psychomotor delay in early infancy. One patient's clinical picture was more consistent with Leigh syndrome, with apneic episodes, ataxia, and bilateral striatal lesions on brain magnetic resonance imaging (MRI). The second patient had generalized seizures refractory to treatment and bilateral occipital lesions on brain MRI. The third child had atypical retinal pigmentary changes, seizures, areflexia, and cerebral atrophy on brain MRI. All patients had several atypical features in addition to early onset: absence of an acute or focal neurologic deficit, variable serum and cerebrospinal fluid lactate levels, lack of ragged red fibers in muscle biopsy specimens. The proportion of mutant mtDNA in available tissues was relatively low (range, 5% to 51% in muscle; 4% to 39% in blood). These observations further extend the phenotypic expression of the A3243G "MELAS" mutation. Our findings confirm previous observations that there is poor correlation between abundance of mutant mtDNA in peripheral tissues and neurologic phenotype. This suggests that other factors contribute to the phenotypic expression of this mutation.
Brain↗
Neonatal presentations of mitochondrial metabolic disorders.
Because of the high energy requirements of the growing neonate, disorders of mitochondrial metabolism caused by defects in fatty acid oxidation, pyruvate metabolism, and the respiratory chain may often present in the neonatal period. Common neonatal presentations are hypotonia, lethargy, feeding and respiratory difficulties, failure to thrive, psychomotor delay, seizures, and vomiting. Laboratory clues include alterations in the levels of lactate, pyruvate (and the lactate/pyruvate ratio), glucose, and ketone bodies. Diagnosis usually depends on specific enzyme assays or on molecular genetic analysis. Without treatment, most infants die in the first few days or months of life. In the last decade, there have been significant advances in the understanding of the molecular basis of these disorders. This review discusses the major subgroups of mitochondrial disorders, focusing on defects of pyruvate oxidation, the Krebs cycle, and the respiratory chain. Disorders caused by respiratory chain defects may involve nuclear DNA, mitochondrial DNA, or intergenomic signaling. Recognition and early diagnosis of these conditions are important in the genetic counseling of these families.
DNA, Mitochondrial↗
Manifesting heterozygotes in a Japanese family with a novel mutation in the muscle-specific phosphoglycerate mutase (PGAM-M) gene.
Muscle-specific phosphoglycerate mutase (PGAM-M) deficiency results in a metabolic myopathy (glycogenosis type X). Three mutations in the PGAM-M gene have been described thus far, two in African-American families and one in a Caucasian family. In two of them, manifesting heterozygotes were documented. We found a new PGAM-M mutation in a Japanese family with partial PGAM deficiency: a G-to-A transition at nucleotide position 209, resulting in the substitution of a highly conserved glycine at codon 97 with aspartic acid (G97D). Two heterozygous family members for the G97D mutation presented with exercise intolerance and muscle cramps. We describe the first PGAM-M mutation in the Japanese population and confirm that heterozygous individuals can be symptomatic.
Amino Acid Sequence↗