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Biomedical subjects

R C Griggs

Publications and source records attributed to R C Griggs.

At least 73 records · Page 4Linked to original sources

Myotonic dystrophy with no trinucleotide repeat expansion.

We report 3 patients from 2 families with myotonic dystrophy who do not show an abnormal expansion of CTG trinucleotide repeats within the myotonic dystrophy gene. Characteristic features of myotonic dystrophy in these patients were frontal balding, cataracts, cardiac conduction abnormalities, and testicular atrophy with myotonia and muscle weakness. Results of muscle histopathology were consistent with myotonic dystrophy. Genetic analysis of leukocyte and muscle DNA showed a normal number of CTG repeats. The demonstration of normal CTG repeat number for the myotonic dystrophy gene does not exclude the diagnosis of myotonic dystrophy.

Adult↗

Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features.

Andersen's syndrome is a clinically distinct form of potassium-sensitive periodic paralysis associated with cardiac dysrhythmias. The subtle nature of the cardiac and dysmorphic features may delay the recognition of this syndrome and its potentially lethal cardiac dysrhythmias. The genetic defect in Andersen's syndrome is not genetically linked to other forms of potassium-sensitive periodic paralysis and is probably distinct from the long QT syndrome locus.

Abnormalities, Multiple↗

Ekbom's syndrome: lipomas, ataxia, and neuropathy with MERRF.

A 66-year-old woman with hereditary deafness and multiple symmetric lipomas presented with ataxia, slight myopathy, and neuropathy. Molecular genetic analysis of mitochondrial DNA revealed the adenine to guanine transition at position 8344 in the tRNA gene for lysine that has been associated with the myoclonic epilepsy and ragged red fiber (MERRF) syndrome. The deafness was transmitted by the patient's father and may have been an unrelated autosomal defect rather than a paternally transmitted mitochondrial point mutation.

Aged↗

Facioscapulohumeral muscular dystrophy (FSHD): design of natural history study and results of baseline testing. FSH-DY Group.

Faciscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder with a characteristic distribution of weakness and variable severity. Prospective, longitudinal data on FSHD are essential for the design of therapeutic trials and in assessment of genetic heterogeneity. We enrolled 32 well-defined FSHD patients and 32 normal subjects in a natural history study of FSHD. All subjects underwent baseline quantitative muscle testing (QMT), manual muscle testing (MMT), and functional testing. QMT demonstrated substantial weakness in muscles usually spared in FSHD. Major right/left side-to-side differences in strength were documented but, unexpectedly, were not related to handedness. Using the QMT data on normal subjects, we developed regression models relating strength to age, gender, and height and used these models to standardize QMT measurements in FSHD patients, expressing them as the number of SDs from average normal performance. This model-based strategy should facilitate the construction of composite scores to describe the natural history of FSHD and could be useful for constructing sensitive measures of progression in other neuromuscular diseases.

Adult↗

Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis.

Hyperkalemic periodic paralysis (hyperKPP) and paramyotonia congenita (PC) are genetic muscle disorders sharing the common features of myotonia and episodic weakness. In hyperKPP, patient symptoms and signs are worsened by elevated serum potassium, whereas in PC, muscle cooling exacerbates the condition. There are patients in whom features of both hyperKPP and PC are present. These diseases result from molecular alterations in the adult skeletal muscle sodium channel. This report summarizes our sodium channel mutation analysis in 25 families with hyperKPP and PC. We also report the putative disease-causing mutation in acetazolamide-responsive myotonia congenita, a related disease in which myotonia is worsened by potassium but in which episodic weakness does not occur. This missense mutation (I1160V) occurs at a very highly conserved position in the sodium channel, cosegregates with the disease, and was not present in any of a large panel of normal DNAs. Electrophysiologic characterization of specific mutations will lead to better understanding of the biophysics of this voltage-gated ion channel.

Acetazolamide↗

Genetics of facioscapulohumeral muscular dystrophy: new mutations in sporadic cases.

A gene for facioscapulohumeral muscular dystrophy (FSHD) has been linked to chromosome 4q35 in families with the disease. We have used recently characterized p13E-11/D4S809 probes that map near or within the FSHD gene to investigate eight sporadic cases of FSHD whose parents showed no signs of disease. Probe p13E-11/D4S809 detected novel DNA fragments in seven of the eight sporadic FSHD individuals and not in the parents, substantiating the clinical diagnosis. Two sisters with FSHD whose parents were clinically normal had a novel DNA fragment suggestive of germline mosaicism. Probe p13E-11/D4S809 is potentially helpful in genetic counseling. However, because this probe may also detect a locus unlinked to chromosome 4, because of possible genetic heterogeneity in FSHD, and because of the presence of recombinants in autosomal dominantly inherited families, closer markers or gene definition will be needed for accurate genetic counseling in other situations.

Blotting, Southern↗

Intranuclear rods in severe congenital nemaline myopathy.

We compared the muscle pathology and clinical course in eight patients with congenital nemaline myopathy. An abundance of large intranuclear rods was present in the muscle fibers of one patient with a rapid, fatal course. Intranuclear rods were not present in the muscles of seven patients with a benign course. The large intranuclear rods and the smaller sarcoplasmic rods were similar ultrastructurally and exhibited positive immunoperoxidase staining with anti-alpha-actinin antibodies. The accumulation of alpha-actinin within myonuclei may reflect a severe disturbance of normal intracellular processes regulating myofibrillar synthesis. Since two previously reported infants with intranuclear nemaline rods also had a fatal outcome, the presence of intranuclear rods may represent a marker for a severe form of congenital nemaline myopathy.

Adolescent↗

Extreme variability of expression in monozygotic twins with FSH muscular dystrophy.

We describe monozygotic twins who are either discordant or show extreme variability in the expression of facioscapulohumeral muscular dystrophy (FSHD). One twin was severely incapacitated by FSHD. The asymptomatic twin demonstrated equivocal facial weakness on physical examination, but no difference on quantitative myometry when compared with normal controls. High-resolution cytogenetic analysis showed no chromosomal abnormalities. Five polymorphic 4q35 markers known to be linked to FSHD showed identical RFLP patterns, indicating that submicroscopic chromosomal rearrangement is unlikely. We conclude that this set of twins represents an extreme case of variability in the expression of the FSHD gene.

Adult↗

Duchenne dystrophy: randomized, controlled trial of prednisone (18 months) and azathioprine (12 months)

Prednisone has been shown to improve strength in Duchenne dystrophy. Azathioprine often benefits corticosteroid-responsive diseases and can reduce the dose of prednisone needed. The present study reports a randomized, controlled trial of prednisone and azathioprine designed to assess the longer-term effects of prednisone and to determine whether azathioprine alone, or in combination with prednisone, improves strength. Ninety-nine boys (aged five to 15 years) with Duchenne dystrophy were randomized to one of three groups: (I) placebo; (II) prednisone 0.3 mg/kg/d; or (III) prednisone 0.75 mg/kg/d. After 6 months, azathioprine 2 to 2.5 mg/kg/d was added in groups I and II and placebo added in group III. The study showed that the beneficial effect of prednisone (0.75 mg/kg/d) is maintained for at least 18 months and is associated with a 36% increase in muscle mass. There was weight gain, growth retardation, and other side effects. Azathioprine did not have a beneficial effect. This study suggests that prednisone's beneficial effect is not due to immunosuppression.

Adolescent↗

Mononuclear cell analysis of muscle biopsies in prednisone- and azathioprine-treated Duchenne muscular dystrophy.

Prednisone improves strength and function in patients with Duchenne dystrophy. Although the mechanism of this effect is uncertain, prior studies suggested that the benefit might result from immunosuppressive effects on T lymphocytes invading muscle. A recent randomized, double-blind, controlled trial of prednisone and azathioprine demonstrated that azathioprine had no effect in Duchenne dystrophy, raising questions about the role of immunosuppression in mediating clinical improvement. The goal of this current study was to compare the effects of prednisone and azathioprine on mononuclear infiltrates from biopsies performed at the end of the controlled clinical trial (reported separately in the article by Griggs et al on page 520). We studied 14 patients from the prednisone group (0.75 mg/kg/d), 10 from the combination therapy group (prednisone 0.3 mg/kg/d and azathioprine 2.5 mg/kg/d), and 13 from the azathioprine group (2.5 mg/kg/d), and used monoclonal antibodies for cell typing. There were no significant differences between the groups for total T cells, T-cell subsets, B cells, natural killer cells, total mononuclear cells, necrotic muscle fibers, or fibers focally invaded by mononuclear cells. These data indicate that azathioprine decreases mononuclear subsets infiltrating muscle to a similar degree as does prednisone, although azathioprine-treated patients do not show a clinical improvement. This implies that immunosuppressive actions on cellular infiltrates in muscle are probably not the primary mechanism of prednisone-induced clinical improvement.

Adolescent↗

Acetazolamide-induced nephrolithiasis: implications for treatment of neuromuscular disorders.

Carbonic anhydrase inhibitors can cause nephrolithiasis. We studied 20 patients receiving long-term carbonic anhydrase inhibitor treatment for periodic paralysis and myotonia. Three patients on acetazolamide (15%) developed renal calculi. Extracorporeal lithotripsy successfully removed a renal calculus in one patient and surgery removed a staghorn calculus in another, permitting continued treatment. Renal function remained normal in all patients. Nephrolithiasis is a complication of acetazolamide but does not preclude its use.

Acetazolamide↗

The periodic paralyses.

These mysterious attacks of muscle weakness are difficult to treat because the different forms are hard to define, and potassium plays a different role in each one. New genetic probes should finally resolve these issues. In the meantime, attacks can be prevented in at least some patients. A multicenter study is now under way to determine the best treatment for each subtype.

Carbonic Anhydrase Inhibitors↗

Sequence of changes in body composition induced by testosterone and reversal of changes after drug is stopped.

OBJECTIVE: --To study the changes in body composition produced by large doses of testosterone and reversal of changes when the drug is discontinued. DESIGN: --Weekly injections of testosterone enanthate were given to young adult male volunteers for 12 weeks. Repeated assays of lean body mass (LBM) by potassium 40 counting were made during this period and at intervals during the ensuing 5 to 6 months. PARTICIPANTS AND SETTING: --Subjects who were living on their own, who were known to be free of significant disease, and who volunteered as controls for a study of patients with neuromuscular disease. Assays were done in the Clinical Research Center. MAIN OUTCOME MEASURES: --Changes in body weight, LBM, and (by subtraction) body fat. RESULTS: --Testosterone treatment produced a progressive increase in LBM and a progressive decrease in body fat. Body composition reverted slowly toward normal when the injections were stopped; thus, the effects of testosterone lingered for some time. The magnitude of the observed changes in LBM was in keeping with the change in urinary creatinine excretion reported for these same subjects. CONCLUSION: --Testosterone is a powerful anabolic agent that also serves to reduce body fat content.

Adipose Tissue↗