Biomedical subjects

J R Mendell

Publications and source records attributed to J R Mendell.

At least 91 records · Page 5Linked to original sources

PubMed1994

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↗

PubMed1994

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↗

PubMed1994

Respiratory dysfunction in muscular dystrophy and other myopathies.

Respiratory muscle weakness occurs in a wide spectrum of acute and chronic myopathic disorders, and may cause a restrictive ventilatory defect and life-threatening ventilatory failure. Therapeutic intervention is based on a thorough knowledge of the course of each disease and meticulous monitoring of respiratory function. Comprehensive management of patients with myopathic disorders requires an understanding of the pathophysiology and specific manifestations of respiratory involvement in each disease.

Humans↗

PubMed1994

Three new mutations in patients with myophosphorylase deficiency (McArdle disease).

We report three new mutations in patients with myophosphorylase deficiency (McArdle disease). A splice-junction mutation (G-to-A transition at the 5' end of intron 14) and a missense mutation (CTG to CCG at codon 291, changing an encoded leucine to a proline) were identified in Caucasian patients who were heterozygous for a common mutation reported elsewhere (CGA [Arg] to TGA [stop]) at codon 49. The splice-junction mutation destroyed the consensus sequence at the 5' splice site, and a cryptic splice site 67 bp upstream was recognized instead. As a result, there was a 67-bp deletion in the 3'-terminal region of exon 14 in the transcript, resulting in a frameshift with premature translation termination. A deletion of a single codon, 708/709 (TTC, specifying phenylalanine) was identified in Japanese patients. Two affected siblings were homozygotes, and their parents were heterozygotes. A third, unrelated patient was heterozygous for the same mutation, while the myophosphorylase gene on the other allele was only faintly expressed.

Adolescent↗

PubMed1993

Gene delivery to spinal motor neurons.

This study demonstrates the direct delivery of plasmid gene constructs into spinal motor neurons utilizing retrograde axoplasmic transport. The plasmid vectors contained the Lac Z gene under the control of both the Rous sarcoma virus (RSV) and Simian virus (SV)40 promoters. beta-Galactosidase expression was observed in alpha and gamma motor neurons by histochemical staining following direct injection into the sciatic nerve or gastrocnemius muscle. The presence of LacZ gene constructs was confirmed by the polymerase chain reaction (PCR). The ability to introduce gene constructs into motor neurons allows for the study of gene regulation and permits the development of gene therapy strategies for motor neuron diseases including the spinal muscular atrophies (SMA) and amyotrophic lateral sclerosis (ALS).

Animals↗

PubMed1993

Acute renal failure resulting from intravenous immunoglobulin therapy.

In idiopathic thrombocytopenic purpura, a known immune-mediated disorder, intravenous IgG is the treatment of choice. Success and the lack of side effects of intravenous IgG in the treatment of idiopathic thrombocytopenic purpura have encouraged consideration of its use in the treatment of neurologic disorders of presumed autoimmune pathogenesis. In this report, we describe two patients who developed acute renal failure following intravenous IgG treatment. The first patient had chronic inflammatory demyelinating polyneuropathy and was treated with intravenous IgG instead of prednisone because of preexisting diabetes. The second patient had idiopathic thrombocytopenic purpura and received intravenous IgG treatment as part of standard care. The patient with idiopathic thrombocytopenic purpura had unrelated bilateral high-grade renal artery stenosis. Both patients had a creatinine level of 140 mumol/L (1.6 mg/dL) prior to treatment. Renal biopsies performed during acute renal failure in each patient demonstrated marked swelling and vacuolization of the proximal tubular epithelial cytoplasm typical of high-solute-load-induced damage (similar to that associated with the use of mannitol). This report draws attention to the importance of screening for impaired renal function before intravenous IgG therapy is initiated. The patients we describe received standard doses of intravenous IgG at the recommended infusion rate yet developed oliguric renal failure. Awareness of serious side effects and recognition of predisposing factors provide means of avoiding known life-threatening complications of intravenous IgG therapy.

Acute Kidney Injury↗

PubMed1993

Acute paralytic syndrome in three American men. Comparison with Chinese cases.

OBJECTIVE: To define clinically an unusual acute paralytic syndrome with features distinctive from those of the Guillain-Barré syndrome and similar to those described in Chinese children and young adults. DESIGN: Case series. SETTING: University medical centers. PATIENTS: Three North American men (mean age, 29 years) who presented with acute symmetric weakness and muscle cramps after a preceding gastrointestinal tract illness. These patients had no sensory symptoms, developed no respiratory insufficiency or facial weakness, and had normal to brisk muscle stretch reflexes. RESULTS: Results of serial nerve conduction studies were normal except for low-amplitude motor potentials. Needle electromyography revealed diffuse denervation potentials. Cerebrospinal fluid showed an elevated protein level and, in one case, a mild pleocytosis. A sural nerve biopsy specimen in one patient was normal; muscle biopsy specimens showed denervation atrophy. CONCLUSION: These cases resemble those described in Chinese children and young adults and may represent a postviral monophasic process affecting the anterior horn cell or distal motor nerve terminal. Further pathologic correlation will be required to identify the exact site of the lesion. Differentiation is important when considering modes of treatment.

Action Potentials↗

PubMed1993

Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis.

Clinical and electrophysiological data have outlined a spectrum of similar yet distinct periodic paralyses, including potassium-sensitive (hyperkalemic periodic paralysis [HYPP]) and temperature-sensitive (paramyotonia congenita [PC]) forms. Recent work has revealed that these disorders result from allelic defects in the alpha-subunit of the adult, human skeletal muscle sodium channel. We report an additional mutation, a leucine-->arginine substitution in the S3 segment of domain 4 (L1433R), that results in the PC phenotype. Five other HYPP and PC families have been ascertained, and previously reported sodium channel mutations have been identified in each. Characterization of these mutations and phenotypic variations in such families will contribute to the understanding of sodium channel structure and function relationships, as well as channel malfunction in the periodic paralyses.

Adult↗

PubMed1993

Exon 44 nonsense mutation in two-Duchenne muscular dystrophy brothers detected by heteroduplex analysis.

Utilizing a heteroduplex method, we screened the dystrophin exon 43-45 region for point mutations, including small deletions and insertions. The method depends upon the formation of a heteroduplex between wild-type and mutant DNA PCR products. DNA specimens from one hundred and four DMD patients without detected deletions or duplications were multiplexed amplified for exons 43, 44, and 45. The PCR products were mixed with the PCR products from nonaffected controls, electrophoresed, and examined for the presence of altered mobility heteroduplex bands. An exon 44 nonsense mutation in two DMD brothers and a common intron 44 polymorphism were identified using this approach. Although the exon 44-45 region is a hotspot for deletion breakpoints, it does not appear to be prone to point mutations. The technique is extremely useful for screening several exons simultaneously and it allowed us to screen a large number of patients.

Base Sequence↗

PubMed1993

Mapping the facioscapulohumeral muscular dystrophy gene is complicated by chromsome 4q35 recombination events.

A gene responsible for facioscapulohumeral muscular dystrophy (FSHD) has been linked to polymorphisms on chromosome 4q35. Multipoint linkage analyses have placed this gene distal to all reported genetic markers on the chromosome. By using as a probe a clone isolated from a cosmid containing sequences related to a homeobox domain, de novo DNA rearrangements were reported in sporadic and familial cases of FSHD. Linkage analysis of an EcoRI polymorphism detected by this clone in twenty-four multigenerational FSHD families revealed recombinants between this marker and the disease with a recombination fraction of 0.05. Two families with apparent germline mosaicism were also identified.

Blotting, Southern↗

PubMed1993

A missense mutation in the dystrophin gene in a Duchenne muscular dystrophy patient.

About two thirds of Duchenne muscular dystrophy (DMD) patients have either gene deletions or duplications. The other DMD cases are most likely the result of point mutations that cannot be easily identified by current strategies. Utilizing a heteroduplex technique and direct sequencing of amplified products, we screened our nondeletion/duplication DMD population for point mutations. We now describe what we believe to be the first dystrophin missense mutation in a DMD patient. The mutation results in the substitution of an evolutionarily conserved leucine to arginine in the actin-binding domain. The patient makes a dystrophin protein which is properly localized and is present at a higher level than is observed in DMD patients. This suggests that an intact actin-binding domain is necessary for protein stability and essential for function.

Amino Acid Sequence↗

PubMed1993

Identification of two point mutations and a one base deletion in exon 19 of the dystrophin gene by heteroduplex formation.

Two thirds of the Duchenne muscular dystrophy population have either gene deletions or duplications. The nondeletion/duplication cases are most likely the result of point mutations or small deletions and duplications that cannot be easily identified by current strategies. The major obstacle in identifying small mutations is due to the large size of the dystrophin gene. We selectively screened 5 DMD exons containing CpG dinucleotides in 110 DMD patients without detectable deletions or duplications. Nonsenses mutations are frequently due to a C- to -T transition within a CG dinucleotide pair. To screen for the nonsense mutations, we used the heteroduplex method. Utilizing this approach, we identified 2 different nonsense mutations and a single base deletion all occurring in exon 19. This is the first report of a clustering of small mutations in the dystrophin gene.

Base Sequence↗

PubMed1993

Chronic inflammatory demyelinating polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) represents an important acquired condition characterized by progressive, symmetrical, proximal and distal weakness. Muscle stretch reflexes are depressed and sensory loss is variable. Patients may have mild to severe weakness and may require assisted ambulation or wheelchairs. Rarely do patients require respiratory support. Laboratory features include nerve conduction changes and nerve biopsy pathology indicative of demyelination. Cerebrospinal fluid protein is characteristically elevated without pleocytosis. The condition is responsive to immunosuppressive therapy, especially prednisone and plasmapheresis (plasma exchange). CIDP frequently follows a chronic or relapsing course.

Chronic Disease↗

PubMed1993

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↗

PubMed1993

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↗

PubMed1993

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↗

PubMed1993

Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene.

We confirmed a mutation of the androgen receptor gene as the cause for Kennedy's disease, also called "X-linked recessive spinal and bulbar muscular atrophy" or "bulbospinal neuronopathy." The mutation is characterized by an increased size of a polymorphic tandem CAG repeat within the first exon of the gene. The study population consisted of 17 patients from seven families (five distinct kinships and two isolated cases). Two patients were as yet asymptomatic and had normal examinations. Four carrier females showed the mutant as well as the normal allele; none showed clinical features of Kennedy's disease. There was no large expansion of the mutation observed in three generations of one family. Phenotypic expression between and within families was variable and not related to the size of the mutation. This contrasts with the gene mutations found in myotonic dystrophy and fragile X syndrome, where increased severity of disease correlates with the number of tandem triplet repeats. The findings reported here appear to explain the failure to find genetic anticipation in Kennedy's disease. The DNA test for Kennedy's disease can now be used for definitive diagnosis and carrier detection. In addition, mutation analysis allows early detection, which has implications for potential treatment.

Creatine Kinase↗

PubMed1993

Polyneuropathy complicating bone marrow and solid organ transplantation.

We report a generalized polyneuropathy coincident with the occurrence of graft-versus-host disease in four patients undergoing bone marrow transplantation and accompanying solid organ rejection (heart and kidney) in two patients. The neuropathy affected proximal and distal muscles, demonstrated hyporeflexia or areflexia, and usually had elevated CSF protein. Electrophysiologic studies did not meet strict criteria for demyelination. The signs of neuropathy improved after immunosuppressive treatment or simultaneous to the resolution of graft-versus-host disease or tissue rejection. Polyneuropathy must be considered as a potential complication of tissue transplantation.

Adult↗