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S Shanske

Publications and source records attributed to S Shanske.

At least 109 records · Page 6Linked to original sources
PubMed1994

Identification of three novel mutations in non-Ashkenazi Italian patients with muscle phosphofructokinase deficiency.

We have identified three novel mutations in four non-Ashkenazi Italian patients with muscle phosphofructokinase (PFK-M) deficiency (Tarui disease). Patient 1 was homozygous for an A-to-C substitution at the 3' end of intron 6 of the PFK-M gene, changing the consensus splice-junction sequence AG to CG. The mutation leads to activation of two cryptic splice sites in exon 7, resulting in one 5 bp- and one 12 bp-deleted transcript. An affected brother was also homozygous, and both parents were heterozygous, for the splice-junction mutation. Patient 2 was homozygous for a G-to-C substitution at codon 39, changing an encoded arginine (CGA) to proline (CCA). Patient 3 was heterozygous for an A-to-C substitution at codon 543, changing an encoded aspartate (GAC) to alanine (GCC); the PFK-M gene on the other allele was not expressed, but sequencing of the reported regulatory region of the gene did not reveal any mutation.

Adolescent↗
PubMed1994

Three new mutations in patients with myophosphorylase deficiency (McArdle disease).

We report three new mutations in patients with myophosphorylase deficiency (McArdle disease). A splice-junction mutation (G-to-A transition at the 5' end of intron 14) and a missense mutation (CTG to CCG at codon 291, changing an encoded leucine to a proline) were identified in Caucasian patients who were heterozygous for a common mutation reported elsewhere (CGA [Arg] to TGA [stop]) at codon 49. The splice-junction mutation destroyed the consensus sequence at the 5' splice site, and a cryptic splice site 67 bp upstream was recognized instead. As a result, there was a 67-bp deletion in the 3'-terminal region of exon 14 in the transcript, resulting in a frameshift with premature translation termination. A deletion of a single codon, 708/709 (TTC, specifying phenylalanine) was identified in Japanese patients. Two affected siblings were homozygotes, and their parents were heterozygotes. A third, unrelated patient was heterozygous for the same mutation, while the myophosphorylase gene on the other allele was only faintly expressed.

Adolescent↗
PubMed1993

Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle's disease).

BACKGROUND AND METHODS: Myophosphorylase deficiency (McArdle's disease) is one of the most common causes of exercise intolerance, muscle cramps, and recurrent myoglobinuria. The myophosphorylase gene has been sequenced and assigned to chromosome 11, but the molecular basis of McArdle's disease is not known. We sequenced complementary DNA in 4 patients and studied genomic DNA by restriction-endonuclease analysis in 40 patients with McArdle's disease. RESULTS: Sequence analysis revealed three distinct point mutations: the substitution of thymine for cytosine at codon 49 in exon 1, changing an encoded arginine to a stop codon; the substitution of adenine for guanine at codon 204 in exon 5, changing glycine to serine; and the substitution of cytosine for adenine at codon 542 in exon 14, changing lysine to threonine. Analysis of restriction-fragment-length polymorphisms of appropriate fragments of genomic DNA after amplification with the polymerase chain reaction showed that 18 patients were homozygous for the stop-codon mutation, 6 had different mutations in the two alleles (compound heterozygotes), and 11 were presumed to be compound heterozygotes for a known mutation and an unknown one; only 5 patients had none of the three mutations. All three mutations were present in various combinations in five members of a family in which transmission appeared to be autosomal dominant. CONCLUSIONS: McArdle's disease is genetically heterogeneous, but the most common mutation is the substitution of thymine for cytosine at codon 49. These results suggest that in about 90 percent of patients the diagnosis of McArdle's disease can be made from a patient's leukocytes, thus avoiding the need for muscle biopsy.

Adolescent↗
PubMed1993

The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes presenting without stroke.

OBJECTIVE: To study and describe a large family with the tRNA Leu(UUR) point mutation at position 3243 in mitochondrial DNA, which is associated with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes. DESIGN: Survey; case series. SETTING: University hospital inpatient and outpatient neurology department. PATIENTS: Twelve patients from three generations in a family carrying the tRNA Leu(UUR) point mutation at position 3243 were studied. INTERVENTIONS: Clinical evaluation, muscle biopsy, and mitochondrial DNA point mutation quantitation of the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes in muscle and blood. MAIN OUTCOME MEASURE: Correlation between clinical, pathologic, and genotypic features. RESULTS: Family members had various combinations of sensorineural hearing loss, retinal pigmentary degeneration, migraine, hypothalamic hypogonadism, and mild myopathy. Only one member had a strokelike episode at the age of 46 years. This patient had the highest point mutation percentage. CONCLUSION: This report suggests that this point mutation may not be associated with stroke in all families and that whether patients develop stroke may depend on the percentage of mutant mitochondrial DNA and its tissue distribution.

Adult↗
PubMed1993

Glycogen branching enzyme deficiency in adult polyglucosan body disease.

Branching enzyme activity was assayed in muscle, peripheral nerve, and leukocytes from 2 Ashkenazi-Jewish patients with adult polyglucosan body disease and 1 African-American and 3 Caucasian patients with the same clinical and pathological features. Branching enzyme activity was normal in the muscle specimens from both Jewish and non-Jewish patients. However, the activity was markedly decreased not only in the leukocytes from the 2 Jewish patients (confirming previous findings), but also in peripheral nerve specimens, whereas it was normal in nerve tissue and leukocytes from all non-Jewish patients. These data confirm a branching enzyme deficiency in a subgroup of patients with adult polyglucosan body disease, and show that the defect is tissue-specific, suggesting that adult polyglucosan body disease has more than one biochemical basis.

1,4-alpha-Glucan Branching Enzyme↗
PubMed1993

Phenotypic heterogeneity in families with the myoclonic epilepsy and ragged-red fiber disease point mutation in mitochondrial DNA.

Two families with a point mutation in mtDNA associated with myoclonic epilepsy and ragged-red fiber disease showed pronounced clinical heterogeneity. The mothers of the two families had adult-onset myopathy with ragged-red fibers, partial deficiency of cytochrome c oxidase, and sensory neuropathy. Members of the first family had variable clinical features of progressive ataxic-myoclonic encephalomyopathy and of the other family, primarily adult-onset myopathy. There was a point mutation from A to G at nucleotide pair 8344 located in the tRNALys gene of the mtDNA of all patients tested, three in Family 1, and the mother of Family 2. This clinical heterogeneity may reflect the effects of varying proportions of mutant and wild-type mtDNA in the different organ systems in each individual.

Adenine↗
PubMed1993

The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome.

Twelve patients with Leigh's syndrome from 10 families harbored a T > G point mutation at nt 8993 of mtDNA. This mutation, initially associated with neurogenic weakness, ataxia, and retinitis pigmentosa, was later found to result in the Leigh phenotype when present in a high percentage. In our patients, the mutation was heteroplasmic, maternally inherited, and appeared to segregate rapidly within the pedigrees. Quantitative analysis revealed a good correlation between percentage of mutant mitochondrial genomes and severity of the clinical phenotype. The mutation was not found in > 200 patients with other mitochondrial encephalomyopathies or in controls. Mitochondrial enzyme activities were normal in all but 1 patient, and there were no ragged-red fibers in the muscle biopsy. Lactic acidosis was present in 92% of patients. Our findings suggest that the mtDNA nt 8993 mutation is a relatively common cause of Leigh's syndrome.

Child↗
PubMed1993

Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA.

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is commonly associated with an A-->G transition at position 3243 of the mitochondrial DNA. To determine the diversity of clinical syndromes associated with this mutation, 91 patients with mitochondrial encephalomyopathies that did not conform to the MELAS phenotype were screened. Twenty one patients with the 3243 mutation, most of whom had progressive external ophthalmoplegia (PEO) were found. Clinical features did not distinguish PEO patients with the 3243 mutation from those with large-scale deletions of mtDNA. However, most cases with single large-scale mtDNA deletions were sporadic, whereas most patients with the 3243 mutation had affected maternal relatives. Histochemical studies of muscle showed that cytochrome c oxidase (COX) deficiency was more severe in patients with PEO than in patients with typical MELAS, even though PEO patients had a lower percentage of mutant genomes in muscle. These data imply that the 3243 mutation is a major cause of familial PEO, and suggests that the threshold number of mtDNAs harboring the 3243 mutation necessary to affect a particular tissue vary in different patients. The proportion of mutant genomes in combination with other, still undefined, tissue-specific modulating factors seem to determine the overall clinical syndrome.

Adolescent↗
PubMed1993

MELAS point mutation with unusual clinical presentation.

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a multisystemic mitochondrial disorder (Pavlakis et al. Advances in Contemporary Neurology. Philadelphia: Davis, 1988: 95-133) and most patients with the typical MELAS phenotype have a point mutation in mitochondrial DNA, an A to G transition at nucleotide 3243 (Goto et al. Nature 1990; 348; 651-653; Koboyashi et al. Biochem Biophys Res Commun 1990; 173: 816-822; Ciafaloni et al. Ann Neurol 1992; 31: 391-398). A 9-yr-old boy presenting with chronic asthma and depression was found to have abnormal mitochondria, partial defects of respiratory chain enzymes, and the MELAS point mutation.

Acid-Base Imbalance↗
PubMed1993

Maternally inherited Leigh syndrome.

A 6 1/2-year-old girl had developmental regression, and Leigh syndrome was diagnosed. A second girl born to the same mother after heterologous artificial insemination also lost acquired skills and died at 2 1/2 years of age; neuropathologic examination confirmed the diagnosis of Leigh syndrome. Tissues from both children and from the mother had a point mutation at nucleotide 8993 in the adenosinetriphosphatase 6-gene of mitochondrial DNA. This family illustrates that Leigh syndrome can be transmitted by maternal inheritance.

Adenosine Triphosphatases↗
PubMed1993

Phosphoglycerate kinase deficiency: biochemical and molecular genetic studies in a new myopathic variant (PGK Alberta)

Biochemical analysis of muscle in a 37-year-old man with exercise intolerance, myalgia, recurrent myoglobinuria, and retinitis pigmentosa showed phosphoglycerate kinase (PGK) deficiency. Kinetic and physical characteristics of the mutant enzyme differed from those of two previously reported cases, suggesting a distinct mutation. Southern blot analysis showed similar bands in patient and control, but Northern blot analysis of muscle mRNA showed an abnormally large message. These data demonstrate that PGK deficiency is clinically, biochemically, and genetically heterogeneous.

Adult↗
PubMed1993

Clinical features associated with the A-->G transition at nucleotide 8344 of mtDNA ("MERRF mutation").

We looked for the A-->G transition at position 8344 of mtDNA in 150 patients, most of them with diagnosed or suspected mitochondrial disease, to assess the specificity of this mutation for the MERRF phenotype, to define the clinical spectrum associated with the mutation, and to study the relationship between percentage of mutation in muscle and clinical severity. Our results confirm the high correlation between the A-->G transition at position 8344 and the MERRF syndrome, but they also show that this mutation can be associated with other phenotypes, including Leigh's syndrome, myoclonus or myopathy with truncal lipomas, and proximal myopathy. The absence of the mutation in four typical MERRF patients suggests that other mutations in the tRNA(Lys) gene, or elsewhere in the mitochondrial DNA, can produce the same phenotype.

Adult↗
PubMed1993

The molecular genetic basis of muscle phosphoglycerate mutase (PGAM) deficiency.

The glycolytic enzyme phosphoglycerate mutase (PGAM) is a dimer, and mature human skeletal muscle contains almost exclusively the MM form of the enzyme, PGAM-M. In 1981, we identified a patient with PGAM-M deficiency, and three additional patients have since been described. All presented with exercise intolerance, cramps, and myoglobinuria. We report two new patients with PGAM-M deficiency and describe the molecular lesions in five patients--four African-Americans and one Caucasian. Three patients were homozygous for an identical G-to-A transition converting an encoded Trp to an in-frame stop codon (codon 78). A fourth patient was heterozygous for this mutation and also carried an A-to-C mutation converting Glu to Ala (codon 89). The fifth patient, the only Caucasian, was homozygous for a different point mutation, a C-to-T mutation, converting Arg to Trp (codon 90).

Adolescent↗
PubMed1992

MELAS: clinical features, biochemistry, and molecular genetics.

We studied 23 patients with clinically defined mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), 25 oligosymptomatic or asymptomatic maternal relatives, and 50 mitochondrial disease control subjects for the presence of a previously reported heteroplasmic point mutation at nt 3,243 in the transfer RNA(Leu(UUR)) gene of mitochondrial DNA. We found a high concordance between clinical diagnosis of MELAS and transfer RNA(Leu(UUR)) mutation, which was present in 21 of the 23 patients with MELAS, all 11 oligosymptomatic and 12 of 14 asymptomatic relatives, but in only five of 50 patients without MELAS. The proportion of mutant genomes in muscle ranged from 56 to 95% and was significantly higher in the patients with MELAS than in their oligosymptomatic or asymptomatic relatives. In subjects in whom both muscle and blood were studied, the percentage of mutations was significantly lower in blood and was not detected in three of 12 asymptomatic relatives. The activities of complexes I + III, II + III, and IV were decreased in muscle biopsies harboring the mutation, but there was no clear correlation between percentage of mutant mitochondrial DNAs and severity of the biochemical defect.

Acidosis, Lactic↗
PubMed1992

Correlation between clinical and molecular features in two MELAS families.

We describe the clinical, morphological, biochemical presentation in two MELAS families, and correlate it with the distribution and proportion of mitochondrial DNA carrying the A to G transition at nt 3243. Family A was characterized by late onset MELAS in two members, CPEO in one, and mild CNS involvement in another. 20-61% of mtDNA of affected and unaffected individuals was mutated in muscle, 2-18% in blood. There was no obvious correlation between clinical picture and proportion of mutated mtDNA. In family B full MELAS syndrome appeared only in the third generation, but the mutation was also detected in muscle of asymptomatic individuals of the first and second generation. The proportion of mutated mtDNA in blood, and to a lesser extent in muscle, correlated with the severity of the clinical presentation. The MELAS mutation is consistently detected in all asymptomatic maternal relatives of MELAS patients. We conclude that different clinical presentations of mitochondrial encephalomyopathy may coexist in the same family, and correlation between clinical severity and molecular abnormality is not always recognizable. Presence of the MELAS mutation in muscle and blood is a necessary but not sufficient condition for the expression of the typical MELAS phenotype.

Adult↗
PubMed1992

Molecular analysis of the muscle pathology associated with mitochondrial DNA deletions.

Large-scale deletions of mitochondrial DNA (mtDNA) are associated with a subgroup of mitochondrial encephalomyopathies. We studied seven patients with Kearns-Sayre syndrome or isolated ocular myopathy who harboured a sub-population of partially-deleted mitochondrial genomes in skeletal muscle. Variable cytochrome c oxidase (COX) deficiencies and reduction of mitochondrially-encoded polypeptides were found in affected muscle fibres, but while many COX-deficient fibres had increased levels of mutant mtDNA, they almost invariably had reduced levels of normal mtDNA. Our results suggest that a specific ratio between mutant and wild-type mitochondrial genomes is the most important determinant of a focal respiratory chain deficiency, even though absolute copy numbers may vary widely.

Blotting, Southern↗
PubMed1992

Mitochondrial encephalomyopathies: defects of nuclear DNA.

The term "mitochondrial diseases" encompasses a heterogeneous group of disorders in which a primary mitochondrial dysfunction is suspected or proven by morphologic, genetic, or biochemical criteria. Clinically, these progressive disorders usually affect muscle, either alone (mitochondrial myopathies) or in combination with other systems, most often brain (encephalomyopathies). Mitochondria are unique among intracellular organelles in that mitochondrial proteins are encoded by two genomes, nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). The vast majority of mitochondrial proteins are encoded by the nuclear genome, whereas mtDNA (a circular, double stranded 16.5 kb molecule) encodes only 13 polypeptides, all of them subunits of respiratory chain complexes. In addition to structural genes, mtDNA also codes for 22 transfer RNAs and two ribosomal RNAs. Our understanding of mitochondrial diseases has grown at an impressive rate in the past few years, and most of the progress has been in the area of mtDNA genetics, where several mtDNA mutations have been associated with specific diseases (reviewed in this issue by Zeviani et al.). In comparison, our understanding of mitochondrial disorders due to nDNA lesions has lagged behind and, to date, molecular defects of nuclear genes have been documented in only a few patients. We will review which alterations in the nuclear genome can cause mitochondrial disorders and which criteria are useful in identifying such mutations. While several examples will be provided, this is not intended as a complete review of the subject.

Cell Nucleus↗