Polymyositis: an overdiagnosed entity.
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Biopsy↗
Biomedical subjects
Z Argov
Publications and source records attributed to Z Argov.
Hereditary inclusion body myopathy: the Middle Eastern genetic cluster.
BACKGROUND: Recessively inherited hereditary inclusion body myopathy (HIBM) with quadriceps sparing was initially described only in Jews originating from the region of Persia. The recent identification of the gene responsible for this myopathy and the common "Persian Jewish mutation" (M712T) enabled the re-evaluation of atypical phenotypes and the epidemiology of HIBM in various communities in the Middle East. OBJECTIVE: To test for the M712T mutation in the DNA from HIBM patients in the Middle East. METHODS: DNA from all suspected HIBM patients was tested for the M712T mutation. Unaffected members of families with genetically proven HIBM were studied too. In the majority of families, haplotype construction with markers spanning the 700-kb region of the HIBM gene was performed. RESULTS: One hundred twenty-nine HIBM patients of 55 families (Middle Eastern Jews, Karaites, and Arab Muslims of Palestinian and Bedouin origin) were homozygous for the M712T mutation, and all carried the same haplotype. Five clinically unaffected subjects were also homozygous for the common mutation and haplotype, including two older adults (ages 50 and 68 years). Atypical features with this same mutation were marked quadriceps weakness in five patients, proximal weakness only in two patients, facial weakness in three patients, and a muscle biopsy showing perivascular inflammation in one patient. CONCLUSIONS: The phenotypic spectrum of recessive HIBM is wider than previously described, and the diagnostic criteria for this myopathy must be changed. The Middle Eastern cluster is the result of a founder mutation, with incomplete penetrance, that is approximately 1,300 years old and is not limited to Jews.
Adolescent↗
Establishment of the genomic structure and identification of thirteen single-nucleotide polymorphisms in the human RECK gene.
The human RECK gene, mapped at 9p13-->p12, is known as a tumor suppressor gene and as a key regulator of extracellular matrix integrity and angiogenesis. We have established the entire genomic structure of this gene, which spans more than 87 kb and consists of 21 exons and 20 introns, and identified thirteen single nucleotide polymorphisms (SNPs). Four SNPs were identified in the coding region of the gene (exons 1, 9, 13 and 15), and the remaining nine in introns 5, 8, 10, 12, 15 and 17. The availability of the genomic organization of the RECK gene and the identification of polymorphisms throughout its entire genome will facilitate the evaluation of its role in several disorders and also contribute to the assignment of genes to the several diseases mapped to this chromosomal region.
Base Sequence↗
Modeling in vivo recovery of intracellular pH in muscle to provide a novel index of proton handling: application to the diagnosis of mitochondrial myopathy.
Post-exercise recovery of intracellular pH (pH(i)) assessed using phosphorus magnetic resonance spectroscopy has not been previously evaluated in its entirety due to its complex time-course and missing data points resulting from a transient loss of inorganic phosphate signal. By considering the transition from exercise to recovery as a step function input, pH(i) recovery was modeled based on the creatine-kinase equilibrium, and the entire pH(i) recovery was characterized by calculating the time required for pH(i) recovery (t(pHrec)). Applying this methodology, normal subjects showed a strong linear correlation between phosphocreatine (PCr) half-time and t(pHrec) (r = 0.90, P < 0.001). In mitochondrial myopathy (MM) patients with weakness in the limb examined, 9/10 had faster pH(i) recovery relative to PCr recovery; wide normal ranges from a control group which included deconditioned subjects resulted in 7 of those 10 patients having otherwise normal recovery indices. Therefore, modeling pH(i) recovery allows characterization of the entire pH(i) recovery and detects altered proton handling in MM patients, including those with otherwise normal recovery indices.
Adult↗
The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy.
Hereditary inclusion body myopathy (HIBM; OMIM 600737) is a unique group of neuromuscular disorders characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. The autosomal recessive form described in Jews of Persian descent is the HIBM prototype. This myopathy affects mainly leg muscles, but with an unusual distribution that spares the quadriceps. This particular pattern of weakness distribution, termed quadriceps-sparing myopathy (QSM), was later found in Jews originating from other Middle Eastern countries as well as in non-Jews. We previously localized the gene causing HIBM in Middle Eastern Jews on chromosome 9p12-13 (ref. 5) within a genomic interval of about 700 kb (ref. 6). Haplotype analysis around the HIBM gene region of 104 affected people from 47 Middle Eastern families indicates one unique ancestral founder chromosome in this community. By contrast, single non-Jewish families from India, Georgia (USA) and the Bahamas, with QSM and linkage to the same 9p12-13 region, show three distinct haplotypes. After excluding other potential candidate genes, we eventually identified mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene in the HIBM families: all patients from Middle Eastern descent shared a single homozygous missense mutation, whereas distinct compound heterozygotes were identified in affected individuals of families of other ethnic origins. Our findings indicate that GNE is the gene responsible for recessive HIBM.
Amino Acid Sequence↗
Physical and transcriptional map of the hereditary inclusion body myopathy locus on chromosome 9p12-p13.
Hereditary inclusion body myopathy (HIBM) is a group of neuromuscular disorders characterised by adult-onset, slowly progressive distal and proximal muscle weakness and typical muscle pathology. Previously, we have mapped the gene responsible for a recessive form of HIBM to chromosome 9p1 and narrowed the interval to one single YAC clone of 1 Mb in size. As a further step towards the identification of the HIBM gene, we have constructed a detailed physical and transcriptional map of this region. A high resolution BAC contig that includes the HIBM critical region, flanked by marker 327GT4 and D9S1859, was constructed. This contig allowed the precise localisation of 25 genes and ESTs to the proximal region of chromosome 9. The expression pattern of those mapped genes and ESTs was established by Northern blot analysis. In the process of refining the HIBM interval, 13 new polymorphic markers were identified, of which 11 are CA-repeats, and two are single nucleotide polymorphisms. Certainly, this map provides an important integration of physical and transcriptional information corresponding to chromosome 9p12-p13, which is expected to facilitate the cloning and identification not only of the HIBM gene, but also other disease genes which map to this region.
Chromosomes, Artificial, Bacterial↗
Splicing mutation in dysferlin produces limb-girdle muscular dystrophy with inflammation.
Mutations in dysferlin were recently described in patients with Miyoshi myopathy, a disorder that preferentially affects the distal musculature, and in patients with Limb-Girdle Muscular Dystrophy 2B, a disorder that affects the proximal musculature. Despite the phenotypic differences, the types of mutations associated with Miyoshi myopathy and Limb-Girdle Muscular Dystrophy 2B do not differ significantly. Thus, the etiology of the phenotypic variability associated with dysferlin mutations remains unknown. Using genetic linkage and mutation analysis, we identified a large inbred pedigree of Yemenite Jewish descent with limb-girdle muscular dystrophy. The phenotype in these patients included slowly progressive, proximal, and distal muscular weakness in the lower limbs with markedly elevated serum creatine kinase (CK) levels. These patients had normal development and muscle strength and function in early life. Muscle biopsies from 4 affected patients showed a typical dystrophic pattern but interestingly, in 2, an inflammatory process was seen. The inflammatory infiltrates included primarily CD3 positive lymphocytes. Associated with this phenotype, we identified a previously undescribed frameshift mutation at nucleotide 5711 of dysferlin. This mutation produced an absence of normal dysferlin mRNA synthesis by affecting an acceptor site and cryptic splicing. Thus, splice site mutations that disrupt dysferlin may produce a phenotype associated with inflammation.
Alternative Splicing↗
Muscle phosphorus magnetic resonance spectroscopy oxidative indices correlate with physical activity.
The purpose of this study was to assess the effect of physical deconditioning on skeletal muscle's oxidative metabolism as evaluated by phosphorus-31 magnetic resonance spectroscopy ((31)P MRS). Twenty-seven subjects without muscle disease, representing a wide range of fitness levels, were evaluated with (31)P MRS. Spectra were obtained at rest and during recovery from in-magnet exercise. The data show a significant correlation between maximum resting metabolic equivalent (MET) score and the following (31)P MRS recovery indices: adenosine diphosphate and phosphocreatine recovery half-time; initial phosphocreatine resynthesis rate; calculated estimation of mitochondrial capacity; pH at end of exercise; and phosphocreatine depletion. In addition, significant differences between the deconditioned and conditioned group were found for all of the aforementioned recovery indices. At rest, only the inorganic phosphate concentration was significantly different between the two groups. These data indicate that physical activity level should be taken into account when assessing patients' oxidative metabolism with (31)P MRS.
Adenosine Diphosphate↗
Gabapentin may be hazardous in myasthenia gravis.
A patient with painful neuropathy developed ocular, facial, and masticatory weakness and fatigue after 3 months of gabapentin (GBP) treatment (400 mg/day). An elevated level of serum acetylcholine receptor antibodies (AChR-Ab) was detected. The patient recovered following pyridostigmine therapy and withdrawal of GBP and, 2 years later, is practically asymptomatic despite positive AChR-Ab. Because of this clinical observation, we gave 150 mg/kg GBP to rats with experimental autoimmune myasthenia gravis (EAMG). Repetitive nerve stimulation at 3-Hz was performed, and the 5th/1st amplitude ratio was used to calculate the decremental response. In all EAMG rats, GBP induced a transient, abnormal decrement (7-20%) 90 to 240 min after administration. No decrement was induced by GBP in normal rats. Thus, GBP aggravates the decrement in EAMG. The mechanism involved in the hitherto unreported possible unmasking of myasthenia gravis (MG) by GBP is unknown. Gabapentin should be used with caution in this disease.
Acetates↗
Insights into muscle diseases gained by phosphorus magnetic resonance spectroscopy.
Phosphorus magnetic resonance spectroscopy (P-MRS) has now been used in the investigation of muscle energy metabolism in health and disease for over 15 years. The present review describes the basics of the metabolic observations made by P-MRS including the assumptions and problems associated with the use of this technique. Extramuscular factors, which may affect the P-MRS results, are detailed. The important P-MRS observations in patients with mitochondrial myopathies, including the monitoring of experimental therapies, are emphasized. The findings in other metabolic myopathies (those associated with glycolytic defects or endocrine disturbances) and in the destructive myopathies (the dystrophies and the inflammatory myopathies) are also described. Observations made in normal and abnormal fatigue, fibromyalgia, and malignant hyperthermia are considered. Finally, a summary of the possible diagnostic use of P-MRS in exercise intolerance is provided.
Energy Metabolism↗
MR spectroscopy and imaging in metabolic myopathies.
Magnetic resonance spectroscopy and imaging of muscle and brain offers new possibilities for noninvasive diagnosis of metabolic myopathies. These functional techniques allow assessment of the pathophysiology of these disorders and also can be used for monitoring disease evolution and response to therapy. In this article, the authors review the magnetic resonance spectroscopy and imaging features of mitochondrial encephalomyopathies, glycolytic disorders, and hypothyroidism.
Adenosine Triphosphate↗
Secondary reduction in calpain 3 expression in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy (primary dysferlinopathies).
Dysferlin is the protein product of the gene (DYSF) that is defective in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy. Calpain 3 is the muscle-specific member of the calcium activated neutral protease family and primary mutations in the CAPN3 gene cause limb girdle muscular dystrophy type 2A. The functions of both proteins remain speculative. Here we report a secondary reduction in calpain 3 expression in eight out of 16 patients with a primary dysferlinopathy and clinical features characteristic of limb girdle muscular dystrophy type 2B or Miyoshi myopathy. Previously CAPN3 analysis had been undertaken in three of these patients and two showed seemingly innocuous missense mutations, changing calpain 3 amino acids to those present in the sequences of calpains 1 and 2. These results suggest that there may be an association between dysferlin and calpain 3, and further analysis of both genes may elucidate a novel functional interaction. In addition, an association was found between prominent expression of smaller forms of the 80 kDa fragment of laminin alpha 2 chain (merosin) and dysferlin-deficiency.
Calpain↗
Muscular dystrophy due to dysferlin deficiency in Libyan Jews. Clinical and genetic features.
The cluster in Jews of Libyan origin of limb-girdle muscular dystrophy type 2B due to a dysferlin 1624delG mutation is described. The carrier frequency of this mutation is calculated to be approximately 10% in this population, in which the disease prevalence is at least 1 per 1300 adults. Twenty-nine patients from 12 families were all homozygous for the same mutation. However, clinical features were heterogeneous even within the same family: in half of the patients onset was in the distal muscles of the legs, which is similar to Miyoshi myopathy, while in others onset was in the proximal musculature, which is similar to other forms of limb-girdle dystrophies. Age at onset varied from 12 to 28 years (mean 20.3 +/- 5.5 years). One patient was presymptomatic at age 28 years. Progression was slow regardless of age of onset, patients remaining ambulatory until at least 33 years. Five patients described subacute, painful enlarged calves as an early, unusual feature. The variable features in this ethnic cluster contribute to the definition of the clinical spectrum of dysferlinopathies in general. The cause of the observed heterogeneity remains unclear.
Adult↗
Drug-induced myopathies.
Two major entities continue to be controversial in the field of clinical myotoxicity: the various myopathies that are induced by the cholesterol-lowering agents and the acute quadriplegic myopathy of intensive care. Both conditions are relatively common, but their pathogenesis is unclear. The problematic issues related to these disorders are presented, with suggested topics for future research.
Acute Disease↗
Effects of cholinergic blockers on auditory brain-stem evoked potentials in rats.
The pharmacology of auditory brain-stem evoked potentials (ABEP) pathways is poorly understood. There are anecdotal reports on the involvement of various neurotransmitters but they were not investigated systematically. The aim of this study was to investigate the effects on ABEP of muscarinic and nicotinic blockers, administered into the cerebral ventricles. Atropine sulfate, d-Tubocurarine and saline were injected stereotactically into the lateral cerebral ventricle of anesthetized male rats. Auditory clicks were given at a rate of 20 s(-1). ABEP recording was performed before and 30 min after injection. Pre- and post-injection peak latencies and peak-to-peak amplitudes of positive waves were compared for each animal. Atropine reduced the amplitudes of waves P1, P3 and P4 and increased mildly the brain stem transmission time. d-Tubocurarine reduced the amplitudes of P1 and P4 with no significant effect on the peak latencies. Saline injection had no effect on any of the parameters. These results show that both cholinergic systems are involved in ABEP generation or transmission. Mechanism of action could be either direct inhibition of afferent pathways or indirect effect, via modulating efferent pathways.
Animals↗
Fine-structure mapping of the hereditary inclusion body myopathy locus.
The gene responsible for a recessive form of hereditary inclusion body myopathy (HIBM) has previously been mapped to a 10-cM interval on chromosome 9p1-q1. We report the results of further mapping studies using two-point linkage analyses and linkage disequilibrium analyses with 20 HIBM families. We demonstrate that the HIBM gene (HGMW-approved symbol IBM2) lies between loci D9S1791 and D9S50, which are about 1 Mb apart. Genetic analyses in 56 affected individuals of Persian, Afghani, and Iraqi Jewish descent demonstrated a common haplotype at these loci, indicating that a founding mutation accounts for disease in these related ethnic groups. beta-Tropomyosin, an abundant skeletal muscle protein that maps within 1 cM of D9S1791, was excluded as the disease gene because an intragenic polymorphism did not exhibit linkage disequilibrium in HIBM probands. We conclude that the disease gene resides in a 1-Mb interval on chromosome 9 and speculate that a novel muscle protein encoded there is mutated in HIBM.
Chromosomes, Human, Pair 9↗
Short-term aerobic training response in chronic myopathies.
We have previously demonstrated that patients with mitochondrial myopathies can benefit from short-term aerobic exercise training. In this study, we compared the responses to short-term aerobic training of patients with mitochondrial myopathies, patients with nonmetabolic myopathies, and sedentary normal subjects. Training consisted of 8 weeks of treadmill exercise at 70% to 85% of estimated maximum heart rate reserve. All groups showed significant improvements in estimated aerobic capacity as well as heart rate and blood lactate at submaximal exercise intensities. The increase in estimated aerobic capacity was greater in the mitochondrial myopathy patients than in the other two groups. Phosphorus magnetic resonance spectroscopy demonstrated increased oxidative capacity of muscle in patients with mitochondrial myopathies in response to this training but not in patients with other, nonmetabolic myopathies or sedentary control subjects. A self-assessed measurement of functional status (SF-36) suggested improved quality of life associated with the training. This study demonstrates that short-term aerobic training at low intensity can benefit patients with nonmetabolic myopathies but to a lesser extent than patients with mitochondrial myopathies.
Adolescent↗
Fitting cytosolic ADP recovery after exercise with a step response function.
Phosphorus magnetic resonance (MR) spectroscopy was used to measure the recovery kinetics of calculated cytoplasmic metabolically active adenosine diphosphate (ADP) after exercise in normal subjects and patients with mitochondrial myopathies. These kinetics have previously been fitted with a single exponential function, despite a complex time-dependent undershoot in many subjects. By considering the transition from ischemic-exercise to perfused-recovery as a step function input, a second-order linear system was developed yielding a step response function to fit the ADP recovery. Using this method, an average improvement in fit of 23% resulted in a significant improvement in the characterization of ADP recovery for all normal subjects with substantial undershoot. The patient group had a comparable improvement in fit of 11%. Fitting the ADP recovery with a second-order step response function can provide significantly better characterization of muscle oxidative metabolism in vivo.
Adenosine Diphosphate↗