Jerry Mendell

Charcot-Marie-Tooth (CMT) neuropathies represent a heterogeneous group of peripheral nerve disorders affecting 1 in 2,500 persons. One variant, CMT1A, is a primary Schwann cell (SC) disorder, and represents the single most common variant. In previous studies, we showed that neurotrophin-3 (NT-3) improved the trembler(J) (Tr(J)) mouse and also showed efficacy in CMT1A patients. Long-term treatment with NT-3 was not possible related to its short half-life and lack of availability. This led to considerations of NT-3 gene therapy via adenoassociated virus (AAV) delivery to muscle, acting as secretory organ for widespread distribution of this neurotrophic agent. In the Tr(J) model of demyelinating CMT, rAAV1.NT-3 therapy resulted in measurable NT-3 secretion levels in blood sufficient to provide improvement in motor function, histopathology, and electrophysiology of peripheral nerves. Furthermore, we showed that the compound muscle action potential amplitude can be used as surrogate for ...

The pathogenesis of Duchenne muscular dystrophy starts before birth. Despite this, clinical trials exclude young boys because traditional outcome measures rely on cooperation. We recently used the Bayley-III Scales of Infant and Toddler Development to study 24 infants and boys with Duchenne muscular dystrophy. Clinical evaluators at six centers were trained and certified to perform the Bayley-III. Here, we report 6- and 12-month follow-up of two subsets of these boys. Nineteen boys (1.9 ± 0.8 years) were assessed at baseline and 6 months. Twelve boys (1.5 ± 0.8 years) were assessed at baseline, 6, and 12 months. Gross motor scores were lower at baseline compared with published controls (6.2 ± 1.7; normal 10 ± 3; P < 0.0001) and revealed a further declining trend to 5.7 ± 1.7 (P = 0.20) at 6 months. Repeated measures analysis of the 12 boys monitored for 12 months revealed that gross motor scores, again low at baseline (6.6 ± 1.7; P < 0.0001), declined at 6 months (5.9 ± 1.8) and further at 12 months (5.3 ± 2.0) (P = 0.11). Cognitive and language scores were lower at baseline compared with normal children (range, P = 0.002-<0.0001) and did not change significantly at 6 or 12 months (range, P = 0.89-0.09). Fine motor skills, also low at baseline, improved >1 year (P = 0.05). Development can reliably be measured in infants and young boys with Duchenne muscular dystrophy across time using the Bayley-III. Power calculations using these data reveal that motor development may be used as an outcome measure.

Limb-girdle muscular dystrophy type 2C (LGMD2C) is considered one of the severe forms of childhood-onset muscular dystrophy. The geographical distribution of founder mutations in the SGCG gene has a prominent effect on the prevalence of LGMD2C in certain populations. The aim of this study was to confirm the hypothesis that the c.787G>A (p.E263K) mutation in the SGCG gene is a founder mutation among Puerto Rican Hispanics and to characterize the associated clinical and immunohistochemical phenotype. Genotyping of six polymorphic microsatellite markers internal to (D13S232) and flanking (D13S175, D13S292, D13S787, D13S1243, D13S283) the SGCG gene was performed on four unrelated Puerto Rican patients with LGMD2C. Preserved ambulation to the second decade of life was observed in at least two subjects. Immunostaining of skeletal muscle demonstrated absence of γ-sarcoglycan in all affected subjects. Two markers, D13S232 and D13S292, were highly informative and confirmed that all four families share the haplotype of the mutant allele. Our findings confirm that the E263K missense mutation in the SGCG gene is a founder mutation in Puerto Rican Hispanics. A slowly progressive disease course with prolonged preservation of ambulation can be seen in association with this mutation, providing evidence for phenotypic variability.

... It was with great anticipation that I began reading Evaluation and Treatment of Myopathies by Drs Griggs, Mendell, and Miller ... It reviews newer techniques now widely applied to the genetic disorders of muscle including: Southern blot analysis and PCR techniques in a way that is ...

A polyneuropathy affecting a large number of workers was recently observed at a plant producing plastic-coated and color-printed fabrics. Epidemiological data suggested strongly that methyl N-butyl ketone (MBK) was responsible for the outbreak. This hypothesis is now supported by the development of a peripheral neuropathy in chickens, rats, and cats exposed to MBK at atmospheric concentrations of 200 to 600 parts per million, 24 hours per day, 7 days per week. Although the animals were exposed continuously and the affected workers were exposed intermittently, the averages of the total number of hours of exposure for development of the peripheral neutropathy in the animals and workers were remarkably close.

The pathogenesis of the peripheral neuropathy induced by vincristine is poorly understood, but interference of vinca alkaloids with microtubule assembly suggests that microtubule changes could be important. This possibility was studied by directly exposing the rat sciatic nerve to graded concentrations of vincristine sulfate. Microtubule length histograms prepared from randomly selected axons showed a unimodal distribution in vincristine and control axons. In vincristine-exposed axons, however, there was a shift to shorter length microtubules, and the mean measured length of microtubules (0.42 +/- 0.37 micron) was significantly (P less than 0.001) shorter than controls (0.67 +/- 0.55 micron). On cross-sections, the vincristine-exposed axons showed a decrease in the number of microtubules per square micrometer of axonal area compared to controls. These findings fit best with a loss of portion(s) of each microtubule and support the possibility that microtubules changes were associated with malorientation of microtubules and neurofilaments, accompanied by free vesicle accumulation and fragmentation of the smooth endoplasmic reticulum. These structural alterations would account for the previously observed abnormalities in axoplasmic transport and would also provide insight into the commonly observed peripheral neuropathy induced by vincristine treatment.

The spontaneous autoimmune peripheral polyneuropathy (SAPP) model in B7-2 knockout nonobese diabetic mice mimics a progressive and unremitting course of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In this study, bone marrow-derived dendritic cells (DCs) were transduced to express vasoactive intestinal polypeptide (VIP) using a lentiviral vector (LV-VIP). These transduced DCs (LV-VIP-DCs) were then injected intravenously (i.v.) into 16-week-old (before disease onset) and 21-week-old (after disease onset) SAPP mice in order to prevent or attenuate the disease. Outcome measures included behavioral tests, clinical and histological scoring, electrophysiology, real-time PCR, flow cytometry analyses, and enzyme-linked immunosorbent assay. LV-VIP-DCs were recruited to the inflamed sciatic nerve and reduced the expression of inflammatory cytokines. A single injection of LV-VIP-DC delayed the onset of disease, stabilized, and attenuated clinical signs correlating with ameliorated behavioral functions, reduced nerve demyelination, and improved nerve conduction. This proof-of-principle study is an important step potentially leading to a clinical translational study using DCs expressing VIP in cases of CIDP refractory to standard immunosuppressive therapy.

Excessive accumulation of intracellular calcium in Duchenne muscular dystrophy (DMD) may be a necessary step in the process that causes muscle damage in this disease. Because of this possibility, a controlled trial of the calcium channel blocking agent nifedipine was undertaken. One hundred and five patients were randomized and treated in a double-blind manner for 18 months. Muscle strength, contractures, functional ability, cardiopulmonary changes, and laboratory data were monitored. The dose of nifedipine was 0.75-1 mg/kg/day in the first 6 months and 1.5-2 mg/kg/day for the next 12 months. Satisfactory blood levels of nifedipine were attained. The study had a power greater than 0.99 to detect a slowing of the illness to 25% of its original rate of progression. No significant improvement was demonstrated in the treated group. One or more of the frequent mild side effects of flushing, dizziness, and leg edema, often associated with the use of nifedipine in adults, occurred transiently in approximately one-half of the patients in the nifedipine group and in 21% of the placebo group. Four patients died, two on nifedipine and two on placebo. This study demonstrates that nifedipine is safe to administer in children, but that it is without beneficial effect on the course of DMD.