Biomedical subjects

S Shanske

Publications and source records attributed to S Shanske.

At least 37 records · Page 2Linked to original sources

PubMed1999

Molecular characterization of McArdle's disease in two large Finnish families.

We have studied two large unrelated Finnish families with myophosphorylase deficiency (McArdle's disease). In one, we identified a new nonsense mutation at codon 540 in exon 14 of the myophosphorylase gene, changing an encoded glutamic acid to a stop codon (E540X). The second family carried a splice-junction mutation at the 5' splice site of intron 14 (1844+G-->A), previously reported in one Caucasian patient and in a consanguineous Druze family. These data further enlarge the list of mutations associated with McArdle's disease and establish that McArdle's disease is genetically heterogeneous also within the Finnish population.

Adult↗

PubMed1999

A new mitochondrial DNA mutation (A3288G) in the tRNA(Leu(UUR)) gene associated with familial myopathy.

We describe a family with a maternally inherited mitochondrial myopathy and an A3288G mutation in the tRNA(Leu(UUR)) gene. The proband had muscle cramping and mild weakness while her brother had long-standing limb and respiratory muscle weakness and her daughter had elevated serum CK. The mutation, which was nearly homoplasmic in muscle and heteroplasmic in blood, affects the TpsiC loop at a conserved site and was not found in 107 controls. This report confirms the frequent association of tRNA(Leu(UUR)) mutations with respiratory muscle involvement and bolsters the concept that tRNA(Leu(UUR)) is a hotspot for mtDNA mutations.

Adult↗

PubMed1999

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↗

PubMed1999

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↗

PubMed1999

Polymorphic variants in the human mitochondrial cytochrome b gene.

We report the polymorphic variants of the human cytochrome b gene based on sequence analysis in 32 Caucasian individuals. We found 27 variants (12 synonymous changes and 15 amino acid replacements). Of these, 15 (8 silent changes and 7 amino acid replacements) have not been previously reported. Based on restriction length polymorphism analysis of patients and their maternal relatives, we conclude that these new amino acid replacements represent maternally inherited polymorphisms. Comparative analysis of the data suggests that four different genotypes can be defined for the human cytochrome b gene.

Cytochrome b Group↗

PubMed1999

The mitochondrial DNA C3303T mutation can cause cardiomyopathy and/or skeletal myopathy.

OBJECTIVE: Several mutations in mitochondrial DNA have been associated with infantile cardiomyopathy, including a C3303T mutation in the mitochondrial transfer RNA(Leu(UUR)) gene. Although this mutation satisfied generally accepted criteria for pathogenicity, its causative role remained to be confirmed in more families. Our objective was to establish the frequency of the C3303T mutation and to define its clinical presentation. STUDY DESIGN: Families with cardiomyopathy and maternal inheritance were studied by polymerase chain reaction/restriction fragment length polymorphism analysis looking for the C3303T mutation. RESULTS: We found the C3303T mutation in 8 patients from 4 unrelated families. In one, the clinical presentation was infantile cardiomyopathy; in the second family, proximal limb and neck weakness dominated the clinical picture for the first 10 years of life, when cardiac dysfunction became apparent; in the third family, 2 individuals presented with isolated skeletal myopathy and 2 others with skeletal myopathy and cardiomyopathy; in the fourth family, one patient had fatal infantile cardiomyopathy and the other had a combination of skeletal myopathy and cardiomyopathy. CONCLUSIONS: Our findings confirm the pathogenicity of the C3303T mutation and suggest that this mutation may not be rare. The C3303T mutation should be considered in the differential diagnosis of skeletal myopathies and cardiomyopathy, especially when onset is in infancy.

Adolescent↗

PubMed1999

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↗

PubMed1999

A nonsense mutation in the myophosphorylase gene in a Japanese family with McArdle's disease.

We identified a new mutation in the myophosphorylase gene in a Japanese family with McArdle's disease. This point mutation results in the replacement of a tryptophan at amino acid position 361 with a stop codon, the third nonsense mutation in this disorder. Our findings further expand the already wide spectrum of genetic lesions associated with McArdle's disease, and establish that molecular genetic heterogeneity is also present in the Japanese population.

Aged↗

PubMed1999

A new mutation in the myophosphorylase gene (Asn684Tyr) in a Spanish patient with McArdle's disease.

We have identified a novel missense mutation, an A-T transition at codon 684 in exon 17, changing an encoded asparagine to a tyrosine (Asn684Tyr) in a Spanish patient with typical McArdle's disease. The patient was a compound heterozygote, with a previously-described mutation (Gly204Ser) on the other allele. This report expands the molecular genetic heterogeneity in McArdle's disease, emphasizes the presence of private mutations in specific ethnic groups, and indicates that geographic origin must be considered before undertaking DNA analysis for diagnosis.

Adult↗

PubMed1999

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↗

PubMed1999

A novel missense mutation in the glycogen branching enzyme gene in a child with myopathy and hepatopathy.

We have identified a novel missense mutation in the gene for glycogen branching enzyme (GBE 1) in a 16-month-old infant with a combination of hepatic and muscular features, an atypical clinical presentation of glycogenosis type IV (GSD IV). The patient was heterozygous for a G-to-A substitution at codon 524 (R524Q), changing an encoded arginine (CGA) to glutamine (CAA), while the GBE1 gene on the other allele was not expressed. This case broadens the spectrum of mutations in patients with GSD IV and confirms the clinical and molecular heterogeneity of this disease.

1,4-alpha-Glucan Branching Enzyme↗

PubMed1999

Mitochondrial DNA mutations at nucleotide 8993 show a lack of tissue- or age-related variation.

Two pathogenic mitochondrial DNA mutations, a T-to-G substitution (8993T > G) and a T-to-C substitution (8993T > C), at nucleotide 8993 have been reported. We describe 13 pedigrees with mitochondrial DNA mutations at nucleotide 8993; 10 pedigrees with the 8993T > G mutation and three with the 8993T > C mutation. Prenatal diagnosis of the nucleotide 8993 mutations is technically possible. However, there are three major concerns: (i) that there is variation in mutant loads among tissues; (ii) that the mutant load in a tissue may change over time; and (iii) that the genotype-phenotype correlation is not clearly understood. We have used the 13 pedigrees to determine specifically the extent of tissue- and age-related variation of the two mutations at nucleotide 8993 in the mitochondrial DNA. The tissue variation was investigated by analysing two or more different tissues from a total of 18 individuals. The age-related variation of the mutation was investigated by comparing the amount of both mutations in blood taken at birth and at a later age. No substantial tissue variation was found, nor was there any substantial change in the proportion of either mutation over periods of 8-23 years in the four individuals studied. In addition, we noted that two features were remarkably common in families with nucleotide 8993 mutations, namely (i) unexplained infant death (8 cases in 13 pedigrees); and (ii) de novo mutations (5 of the 10 8993T > G pedigrees).

Aging↗

PubMed1999

Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene.

Mammalian cytochrome c oxidase (COX) catalyses the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. Mitochondrial DNA (mtDNA) encodes three COX subunits (I-III) and nuclear DNA (nDNA) encodes ten. In addition, ancillary proteins are required for the correct assembly and function of COX (refs 2, 3, 4, 5, 6). Although pathogenic mutations in mtDNA-encoded COX subunits have been described, no mutations in the nDNA-encoded subunits have been uncovered in any mendelian-inherited COX deficiency disorder. In yeast, two related COX assembly genes, SCO1 and SCO2 (for synthesis of cytochrome c oxidase), enable subunits I and II to be incorporated into the holoprotein. Here we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency. Immunohistochemical studies implied that the enzymatic deficiency, which was most severe in cardiac and skeletal muscle, was due to the loss of mtDNA-encoded COX subunits. The clinical phenotype caused by mutations in human SCO2 differs from that caused by mutations in SURF1, the only other known COX assembly gene associated with a human disease, Leigh syndrome.

Amino Acid Sequence↗

PubMed1999

Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993.

Mitochondrial genetics is complicated by heteroplasmy, or mutant load, which may be from 1%-99%, and thus may produce a gene dosage-type effect. Limited data are available for genotype/phenotype correlations in disorders caused by mtDNA mutations; therefore, prenatal diagnosis for mtDNA mutations has been hindered by an inability to predict accurately the clinical severity expected from a mutant load measured in fetal tissue. After reviewing 44 published and 12 unpublished pedigrees, we considered the possibility of prenatal diagnosis for two common mtDNA mutations at nucleotide 8993. We related the severity of symptoms to the mutant load and predicted the clinical outcome of a given mutant load. We also used the available data to generate empirical recurrence risks for genetic counseling, which may be used in conjunction with prenatal diagnosis.

Adenosine Triphosphatases↗

PubMed1999

A stop-codon mutation in the human mtDNA cytochrome c oxidase I gene disrupts the functional structure of complex IV.

We have identified a novel stop-codon mutation in the mtDNA of a young woman with a multisystem mitochondrial disorder. Histochemical analysis of a muscle-biopsy sample showed virtually absent cytochrome c oxidase (COX) stain, and biochemical studies confirmed an isolated reduction of COX activity. Sequence analysis of the mitochondrial-encoded COX-subunit genes identified a heteroplasmic G-->A transition at nucleotide position 6930 in the gene for subunit I (COX I). The mutation changes a glycine codon to a stop codon, resulting in a predicted loss of the last 170 amino acids (33%) of the polypeptide. The mutation was present in the patient's muscle, myoblasts, and blood and was not detected in normal or disease controls. It was not detected in mtDNA from leukocytes of the patient's mother, sister, and four maternal aunts. We studied the genetic, biochemical, and morphological characteristics of transmitochondrial cybrid cell lines, obtained by fusing of platelets from the patient with human cells lacking endogenous mtDNA (rho0 cells). There was a direct relationship between the proportion of mutant mtDNA and the biochemical defect. We also observed that the threshold for the phenotypic expression of this mutation was lower than that reported in mutations involving tRNA genes. We suggest that the G6930A mutation causes a disruption in the assembly of the respiratory-chain complex IV.

Adult↗

PubMed1999

A novel mutation in the mitochondrial DNA transfer ribonucleic acidAsp gene in a child with myoclonic epilepsy and psychomotor regression.

A novel A7543G mutation was found in the mitochondrial DNA transfer ribonucleic acidAsp gene in an 11-year-old girl with myoclonic seizures, developmental delay, and severe behavioral problems. Muscle histochemistry failed to show any ragged red fibers or cytochrome c oxidase-negative fibers, and muscle biochemistry showed partial cytochrome c oxidase deficiency. The mutation was heteroplasmic in muscle, fibroblasts, and blood from the patient and in blood from other affected family members, and the proportion of mutant mitochondrial DNA correlated with the severity of symptoms.

Biopsy↗

PubMed1999

Microanalysis of cardiolipin in small biopsies including skeletal muscle from patients with mitochondrial disease.

Cardiolipin is a specific mitochondrial phospholipid that is present in mammalian tissues in low concentration. To measure cardiolipin in small biopsies from patients with mitochondrial disease, we developed a new technique that can detect subnanomolar levels of well-resolved molecular species, the most abundant of which are tetralinoleoyl-cardiolipin (L(4)) and trilinoleoyl-oleoyl-cardiolipin (L(3)O). To this end, a fluorescence-labeled derivative of cardiolipin (2-[naphthyl-1'-acetyl]-cardiolipin dimethyl ester) was formed and analyzed by high performance liquid chromatography. Cardiolipin was measured in skeletal muscle biopsies from 8 patients with mitochondrial disease and in 17 control subjects. In 5 patients with mitochondrial disease, cardiolipin content was higher than normal (2. 4;-7.0 vs. 0.4;-2.2 nmol/mg protein). In 3 patients with mitochondrial disease, the L(4)/L(3)O ratio was lower than normal (2;-4 vs. 4;-6). Cardiolipin was also measured in various rat and dog muscle tissues. The L(4)/L(3)O ratio was higher in condensed "muscle" type mitochondria (heart ventricle, skeletal muscle, ratios 4;-7) than in orthodox "liver" type mitochondria (liver, smooth muscle, heart auricular appendage, H9c2 myoblasts, ratios 0.4;-3), suggesting that the L(4)/L(3)O proportion is important for cristae membrane structure. We concluded that the L(4)/L(3)O ratio is a tissue-specific variable that may change in the presence of mitochondrial disease. The new method is suitable to measure cardiolipin in muscle biopsies in order to estimate concentration of mitochondria.

Adolescent↗

PubMed1999

Two cases of prenatal analysis for the pathogenic T to G substitution at nucleotide 8993 in mitochondrial DNA.

We report the outcome of two prenatal analyses for the T to G mutation at nucleotide 8993 in the mitochondrial DNA. This mutation is associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) and the neurodegenerative condition, Leigh syndrome. One prospective mother was the sister of a severely affected individual, and had previously had an unaffected child and a stillborn child. The second prospective mother had two unaffected children and two affected children. The mutation was not detected in the chorionic villus sample from one fetus nor in the amniocytes from the other fetus. Both pregnancies were continued, and the resulting children were healthy at two years and five years of age. Prenatal diagnosis of this mitochondrial DNA mutation is an option likely to be acceptable to some families to prevent the birth of a child at high risk for neurological disease.

Adult↗