Henry B. Wessel

CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy

We tested the efficacy and safety of glutamine (0.6gm/kg/day) and creatine (5gm/day) in 50 ambulant boys with Duchenne muscular dystrophy in a 6‐month, double‐blind, placebo‐controlled clinical trial. Drug efficacy was tested by measuring muscle strength manually (34 muscle groups) and quantitatively (10 muscle groups). Timed functional tests, functional parameters, and pulmonary function tests were secondary outcome measures. Although there was no statistically significant effect of either therapy based on manual and quantitative measurements of muscle strength, a disease‐modifying effect of creatine in older Duchenne muscular dystrophy and creatine and glutamine in younger Duchenne muscular dystrophy cannot be excluded. Creatine and glutamine were well tolerated. Ann Neurol 2005;58:151–155

Thoracic outlet syndrome.

&NA; Much controversy exists regarding the pathogenesis, diagnosis, and management of thoracic outlet syndrome. The authors review the embryology of several fibroosseous anomalies at the superior thoracic aperture and relate normal and morbid anatomy of this region and the putative roles of anthropomorphic, postural, and dynamic factors to the genesis of neurovascular symptoms. The salient clinical features of this syndrome are described, with emphasis on the peculiar pattern of motor weakness and the physiology of painful symptoms. Diagnostic methods are critiqued. The various surgical approaches for this syndrome are evaluated according to their facility for wide exposure, their potential morbidity, and their beneficial results. (Neurosurgery 22:105‐121, 1988)

Calpain III mutation analysis of a heterogeneous limb–girdle muscular dystrophy population

Objective: To determine the frequency of calpain III mutations in a heterogeneous limb–girdle muscular dystrophy (LGMD) population. Background: Mutations of the calpain III gene have been shown to cause a subset of autosomal recessive LGMDs. Patient populations studied to date have been primarily of French and Spanish origin, in which calpain III may cause 30% of autosomal recessive MDs. The incidence of calpain III mutations in non–French/Spanish MD patients has not been studied thoroughly. No sensitive and specific biopsy screening methods for detecting patients with abnormal calpain III protein are available. Thus, detection of patients relies on direct detection of gene mutations. Methods: The authors studied the calpain III gene in 107 MD patient muscle biopsies exhibiting normal dystrophin. Muscle biopsy RNA was produced for each patient, and the entire calpain III complementary DNA was screened for mutations by reverse-transcriptase PCR/single-strand conformation polymorphism using three different conditions. Results: The authors identified nine patients (eight unrelated) with causative mutations. Six of the seven distinct mutations identified are novel mutations and have not been described previously. Conclusion: The results suggest that approximately 9.2% of patients in the heterogeneous population with an LGMD diagnosis will show mutations of the calpain III gene. Interestingly, two patients were heterozygous for a single mutation at the DNA level, whereas only the mutant allele was observed at the RNA level. This suggests that there are undetectable, nondeletion mutations that ablate expression of the calpain III gene.

Dystrophin: A clinical perspective

Dystrophin, the protein product of the gene related to Duchenne and Becker muscular dystrophies, is a large cytoskeletal protein associated with the muscle fiber membrane. Recently identified dystrophin-related myopathies affecting animals can serve as experimental models for human disease. Immunologic detection of dystrophin in clinical muscle biopsies provides a direct biochemical test for both Duchenne and Becker muscular dystrophies. Applications of dystrophin testing include improved diagnostic accuracy, carrier detection, fetal diagnosis, and evaluation of asymptomatic male infants identified as a result of neonatal screening for increased serum creatine kinase levels. Identification of dystrophin has brought us to the point of addressing rational therapies.

Diagnosis of dystrophinopathies: Review for the clinician

The dystrophinopathies are muscle disorders due to an abnormality of an Xp21-linked gene which produces the dystrophin protein. The most common of these disorders are the Duchenne and Becker muscular dystrophies. Modern molecular genetic techniques enable reliable diagnosis and prognosis in many patients, but there are occasional pitfalls. Furthermore, the clinical spectrum of the dystrophinopathies are now such that the clinician needs to be aware of a broader range of clinical disorders that require analysis of the dystrophin gene and its product, not just those that mirror a classic Duchenne or Becker muscular dystrophy picture. This spectrum ranges from a severe form presenting at birth to asymptomatic elevation of CK. Females may be manifesting carriers or present as a severe phenotype when the abnormal gene is expressed as an X-autosome translocation or monosomy X. Laboratory diagnosis and prognosis can be made most accurately by using both DNA analysis at the dystrophin gene and immuno-analysis of muscle with antibodies directed against different regions of the protein product. This review describes some exemplary patients, suggests a clinical classification for dystrophinopathies, and outlines a diagnostic approach.

Effects of glycerol and hyperosmolality on intracranial pressure

Glycerol has been used in cerebral edema for hyperosmolar dehydration of brain tissue, but only empirical relationships govern this use. Since the efficacy of treatment with glycerol would likely increase with data on the relationship between drug blood levels and intracranial pressure (ICP), we examined the clinical pharmacology of the drug. Plasma samples were assayed for glycerol by a new method using gas chromatography with a flame ionization detector. Data were collected from 12 children who were in Childrens Hospital of Pittsburgh (CHP) and who had cerebral edema of differing etiology that was treated with glycerol; they were monitored by intraventricular catheter. Glycerol was infused according to CHP guidelines. ICP reduction correlated with glycerol concentration and plasma concentrations of 1 to 3 mg/ml (10 to 30 mOsm/ml) were necessary to maintain an ICP below 20 torr. The relationship between osmolality and plasma glycerol level was also examined; there was good correlation between the idiogenic osmolality and drug concentration. Our studies support the clinical observations that relatively high doses of glycerol (0.2 to 1.0 gm/kg/hr), leading to plasma concentrations of 10 to 30 mOsm/l, are necessary to control ICP in patients with cerebral edema. Glycerol blood levels may be estimated from serum osmolality.

Myasthenia gravis associated with human T-cell lymphotropic virus type III infection

A 15-year-old boy is described with myasthenia gravis, hemophilia A, positive HTLV-III serology, antithyroglobulin and antimicrosomal antibodies, and laboratory evidence of altered cell-mediated immunity. Treatment with pyridostigmine produced dramatic clinical improvement. The results of this patient raise the possibility of myasthenia gravis as the sole or presenting clinical manifestation of infection with HTLV-III.

Inability to induce fragile sites at CTG repeats in congenital myotonic dystrophy

Myotonic dystrophy (DM) is a trinucleotide repeat syndrome which can contain 50 to over 2,000 CTG repeats in affected individuals, but does not express a fragile site. Although one prior study [Jalal et al., Am J Med Genet 46:441-443, 1993] did not find evidence of fragility at 19q13.3 in six individuals affected with DM using induction protocols for folate sensitive fragile sites, other chemicals may induce fragile site expression at this site. In an attempt to induce fragile sites at 19q13.3, blood cultures from four congenital DM cases and four control individuals treated with fluorodeoxyuridine (folate-sensitive rare fragile sites), bromodeoxyurdine (rare and common fragile sites), aphidicolin (common fragile sites), and 5-azacytidine (common fragile sites) were harvested using routine cytogenetic technique. Slides were solid stained and 100 cells were examined for fragile site expression, particularly on F group chromosomes. The latter were photographed prior to destaining and G-banded to verify chromosome and band location of breakage. No culture conditions induced a fragile site at band 19q13.3 at > 1% expression in patients with congenital DM. Our results suggest that CTG repeats, even when present in > 1,000 copies, may behave differently from other large expansions which are associated with fragile sites. The CTG repeats in DM are not associated with a methylated CpG island, as are folate-sensitive fragile sites, which most likely plays a role in the expression of fragile sites at the trinucleotide repetitive site.

Congenital alopecia, seizures, and psychomotor retardation in three siblings

Three siblings, devoid of hair at birth, had an unusual autosomal recessive disorder characterized by universal congenital alopecia, microcephaly, seizures, psychomotor retardation, and severe growth failure. Metabolic and chromosome studies were normal. Skin biopsies disclosed immature hair follicles, some of which were filled with keratotic material but had no hair shafts. Neuropathologic features included cerebral cortical hypoplasia, neuronal depletion, and microcalcifications. The familial occurrence of universal congenital alopecia conjoined with nonprogressive central nervous system abnormalities in this and other kindreds defines a nosologic group of neurocutaneous disorders in which congenital alopecia is the solitary cutaneous manifestation.