Walter G. Bradley

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.

A clinical trial of creatine in ALS

Background: Mitochondrial dysfunction occurs early in the course of ALS, and the mitochondria may be an important site for therapeutic intervention. Creatine stabilizes the mitochondrial transition pore, and is important in mitochondrial ATP production. In a transgenic mouse model of ALS, administration of creatine prolongs survival and preserves motor function and motor neurons. Methods: The authors conducted a randomized double-blind, placebo controlled trial on 104 patients with ALS from 14 sites to evaluate the efficacy of creatine supplementation in ALS. The primary outcome measure was maximum voluntary isometric contraction of eight upper extremity muscles, with secondary outcomes including grip strength, ALS Functional Rating Scale–Revised, and motor unit number estimates. Patients were treated for 6 months, and evaluated monthly. Results: Creatine was tolerated well, but no benefit of creatine could be demonstrated in any outcome measure. CI analysis showed that the study, although powered to detect a 50% or greater change in rate of decline of muscle strength, actually made an effect size of greater than 23% unlikely. It was also demonstrated that motor unit number estimation was performed with acceptable reproducibility and tolerability, and may be a useful outcome measure in future clinical trials. Conclusion: Any beneficial effect of creatine at 5 g per day in ALS must be small. Other agents should be considered in future studies of therapeutic agents to address mitochondrial dysfunction in ALS. In addition, motor unit number estimation may be a useful outcome measure for future clinical trials in ALS.

Abnormalities of peripheral nerves in murine muscular dystrophy

Mice of the Bar Harbor 129 Re dydy strain suffer from a progressive degeneration of the skeletal muscles similar in pathological characteristics to that of human Duchenne muscular dystrophy. Previously the nervous system of these animals has been described as being without abnormality. This report details striking abnormalities of the dorsal and ventral roots and proximal parts of the sciatic nerves of these animals. The abnormalities consist of non-myelinated axons of up to 6 μ diameter, without surrounding Schwann cell cytoplasm, collected into extensive areas between a few relatively normal myelinated axons. These areas are surrounded by sheets of Schwann cells, which show the morphological counterparts of active metabolism, and some of which show attempted myelination of axons. These abnormalities are equally extensive in older and in younger animals, though the appearance is very similar to that of foetal developing nerve. Minor evidence of axonal degeneration is present. The changes are interpreted as indicating a developmental abnormality of myelination by Schwann cells, perhaps as a result of the impaired mitotic division of these cells. They offer an experimental model for the investigation of a number of problems of nerve physiology. Preliminary studies of peripheral nerve and nerve roots from human cases of Duchenne muscular dystrophy and from dystrophic hamsters have not revealed a similar abnormality. The change is therefore likely to be a phenomenon confined to the dystrophic mouse, and one which is unrelated to the coexisting skeletal muscle degeneration.

Stroke in young adults.

Strokes in young adults are uncommon and often a diagnostic challenge. A retrospective study of strokes due to intracerebral hemorrhage, subarachnoid hemorrhage, or cerebral infarction was undertaken. We reviewed the medical records of 113 young patients aged 15-45 years who were admitted to the Medical Center Hospital of Vermont with a diagnosis of stroke between 1982 and 1987. This group comprised 8.5% of patients of all ages admitted for stroke, 2.3 times the proportion observed in the National Survey of Stroke. Nontraumatic intracerebral hemorrhage was diagnosed in 46 young patients (41%); the main causes included aneurysms, arteriovenous malformations, hypertension, and tumors. Subarachnoid hemorrhage was found in 19 young patients (17%); the majority were due to aneurysms. The remaining 48 young patients (42%) had cerebral infarction, the majority due to cardiogenic emboli and premature atherosclerosis. Mitral valve prolapse, the use of oral contraceptives, alcohol drinking, and migraine were infrequent sole causes of cerebral infarction in the absence of other risk factors. The case-fatality rate for this group of young patients with stroke was 20.4% compared with 23.9% for the National Survey of Stroke. Young adults with stroke deserve an extensive but tailored evaluation, which should include angiography and echocardiography.

Cyanobacterial neurotoxin BMAA in ALS and Alzheimer's disease.

Objective –  The aim of this study was to screen for and quantify the neurotoxic amino acid β‐N‐methylamino‐l‐alanine (BMAA) in a cohort of autopsy specimens taken from Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and non‐neurological controls. BMAA is produced by cyanobacteria found in a variety of freshwater, marine, and terrestrial habitats. The possibility of geographically broad human exposure to BMAA had been suggested by the discovery of BMAA in brain tissues of Chamorro patients with ALS/Parkinsonism dementia complex from Guam and more recently in AD patients from North America. These observations warranted an independent study of possible BMAA exposures outside of the Guam ecosystem.

The neuromyopathy of vincristine in man. Clinical, electrophysiological and pathological studies

Abstract This report details the neuromyopathy caused by vincristine in a group of patients receiving the drug for the treatment of malignant intracranial gliomata. Weekly intravenous injections of the drug (0.05 mg/kg body weight) were given for up to 20 months to 37 patients, 23 adults and 14 children. All adults receiving vincristine for more than 2 months developed a mixed sensorimotor peripheral neuropathy of varying severity. The subjective complaints were mainly sensory, while the objective deficit was mainly motor. In 3 patients the neuropathy was painful; 3 developed external ophthalmoplegia, and 2 vocal cord paralysis. Proximal muscle pain with weakness and wasting developed in many adults. Children appeared less sensitive to the toxic effects of vincristine. Motor and sensory nerve conduction velocities were measured at intervals during the treatment of 2 adults and 3 children with vincristine for periods of up to 10 months. The distal sensory and motor latency increased during treatment, and complete conduction block developed in several of the nerves studied. Apart from this conduction block, significant slowing of motor nerve conduction in the main nerve trunks did not occur. Biopsies from proximal limb muscles were obtained from 3 patients at the time of the myalgia. A few areas of segmental necrosis and phagocytosis were seen with the light microscope. Under the electron microscope many fibres showed myofibrillary disruption, with the accumulation of occasional fibrillary subsarcolemmal masses. A sural nerve biopsy from a patient with a sensorimotor neuropathy contained both myelinated and non-myelinated fibres undergoing axonal degeneration, with phagocytosis of myelin debris. In addition to the changes seen in the biopsies, autopsy material from 5 of these patients showed denervation atrophy of the distal muscles. There was no abnormality of dorsal root ganglia, or of the spinal cord or brain attributable to the vincristine, though the ultrastructure of these regions was not studied. The significance and mechanism of the toxic damage produced in nerve and muscle by vincristine is discussed.

Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: A randomized trial

Background: Patients with ALS commonly exhibit pseudobulbar affect. Methods: The authors conducted a multicenter, randomized, double-blind, controlled, parallel, three-arm study to test a defined combination of dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) (AVP-923) for the treatment of pseudobulbar affect in ALS. Q inhibits the rapid first-pass metabolism of DM. The effects of AVP-923 (30 mg of DM plus 30 mg of Q) given twice daily for 28 days were compared with those of its components. Patients were evaluated on days 1, 15, and 29. The primary efficacy variable was the change from baseline in the Center for Neurologic Study Lability Scale (CNS-LS) score. Secondary efficacy variables were laughing/crying episode rates and changes in Visual Analog Scales for Quality of Life (QOL) and Relationships (QOR). Efficacy was evaluated in intention-to-treat subjects who were not poor metabolizers of DM (n = 65 for AVP-923, n = 30 for DM, and n = 34 for Q). Safety was assessed in all randomized subjects (n = 140). Results: AVP-923 patients experienced 3.3-point greater improvements in CNS-LS than DM patients (p = 0.001) and 3.7-point greater improvements than Q patients (p < 0.001). AVP-923 patients exhibited lower overall episode rates, improved QOL scores, and improved QOR scores (p < 0.01 for all endpoints). Adverse effects were mostly mild or moderate; treatment-related discontinuation was 24% for AVP-923, 6% for DM, and 8% for Q. Conclusions: AVP-923 palliates pseudobulbar affect in ALS. Overall benefits of treatment are reflected in fewer episodes of crying and laughing and improvements in overall quality of life and quality of relationships.

A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis

Objective: To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS. Methods: A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival. Results: Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis). Conclusions: At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.

The spectrum of chronic inflammatory demyelinating polyneuropathy

Research criteria for the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) were proposed by an Ad Hoc Subcommittee of the American Academy of Neurology (AAN) in 1991, and since then these criteria have been widely used in clinical studies. We have been impressed by the frequent finding of electrophysiological changes of a demyelinating neuropathy in patients whose clinical presentation does not conform to the usually accepted clinical phenotype of CIDP. To determine the clinical spectrum of CIDP, we conducted a retrospective review of patients of the peripheral electrophysiology laboratory of the University of Miami-Jackson Memorial Medical Center. Diagnostic criteria for acquired demyelination of an individual nerve were adapted from the AAN research criteria for the diagnosis of CIDP (1991). Patients were accepted for inclusion when such evidence was demonstrated in at least one motor nerve or at least two sensory nerves. We then reviewed the clinical phenotype and the underlying etiology of the neuropathy in these cases. Eighty-seven patients, 63 male and 24 female, age of onset 4-84 (mean 49.3) years, met these inclusion criteria. Forty-seven patients (54%) had distinct features outside the usual clinical presentation of CIDP. Of these, 15 (17%) had predominantly distal features, 13 (15%) had exclusively sensory polyneuropathy; seven (8%) had markedly asymmetric disease, seven (8%) had associated CNS demyelination, four (5%) had predominant cranial nerve involvement, and one (1%) had only the restless legs syndrome. An associated medical condition that may have been responsible for the acquired demyelinating neuropathy was present in 60% of the patients. We conclude that spectrum of CIDP is broader than would be indicated by the strict application of the AAN research criteria, and that many of the cases meeting more liberal criteria frequently respond to immunosuppressive therapy.

Duration of synthesis phase in neurilemma cells in mouse sciatic nerve during degeneration

Abstract Synthesis phase of proliferating neurilemma cells in adult mouse sciatic nerve was studied during Wallerian degeneration. Its duration was found to be relatively constant (8.6–10.3 hours) and independent of variations in the neurilemma cell labeling index (0.8–15.5%). By the same technique, the duration of the synthesis phase in proliferating neurilemma cells in 2-day-old mouse sciatic nerve (10.5 hours) was roughly comparable to that during peripheral nerve degeneration in the adult mouse.