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We ascertained a nuclear family in which three of four siblings were affected with an unclassified autosomal recessive myopathy characterized by severe weakness, respiratory impairment, scoliosis, joint contractures, and an unusual combination of dystrophic and myopathic features on muscle biopsy. Whole genome sequence from one affected subject was filtered using linkage data and variant databases. A single gene, MEGF10, contained nonsynonymous mutations that co-segregated with the phenotype. Affected subjects were compound heterozygous for missense mutations c.976T > C (p.C326R) and c.2320T > C (p.C774R). Screening the MEGF10 open reading frame in 190 patients with genetically unexplained myopathies revealed a heterozygous mutation, c.211C > T (p.R71W), in one additional subject with a similar clinical and histological presentation as the discovery family. All three mutations were absent from at least 645 genotyped unaffected control subjects. MEGF10 contains 17 atypical epidermal growth factor-like domains, each of which contains eight cysteine residues that likely form disulfide bonds. Both the p.C326R and p.C774R mutations alter one of these residues, which are completely conserved in vertebrates. Previous work showed that murine Megf10 is required for preserving the undifferentiated, proliferative potential of satellite cells, myogenic precursors that regenerate skeletal muscle in response to injury or disease. Here, knockdown of megf10 in zebrafish by four different morpholinos resulted in abnormal phenotypes including unhatched eggs, curved tails, impaired motility, and disorganized muscle tissue, corroborating the pathogenicity of the human mutations. Our data establish the importance of MEGF10 in human skeletal muscle and suggest satellite cell dysfunction as a novel myopathic mechanism. Electronic supplementary material The online version of this article (doi:10.1007/s10048-012-0315-z) contains supplementary material, which is available to authorized users.

The autosomal recessive neuromuscular disorder proximal spinal muscular atrophy (SMA) is caused by the loss or mutation of the survival motor neuron (SMN) gene, which exists in two nearly identical copies, telomeric SMN (telSMN) and centromeric SMN (cenSMN). Exon 7 of the telSMN gene is homozygously absent in approximately 95% of SMA patients, whereas loss of cenSMN does not cause SMA. We searched for other telSMN mutations among 23 SMA compound heterozygotes, using heteroduplex analysis. We identified telSMN mutations in 11 of these unrelated SMA-like individuals who carry a single copy of telSMN: these include two frameshift mutations (800ins11 and 542delGT) and three missense mutations (A2G, S262I, and T274I). The telSMN mutations identified to date cluster at the 3' end, in a region containing sites for SMN oligomerization and binding of Sm proteins. Interestingly, the novel A2G missense mutation occurs outside this conserved carboxy-terminal domain, closely upstream of an SIP1 (SMN-interacting protein 1) binding site. In three patients, the A2G mutation was found to be on the same allele as a rare polymorphism in the 5' UTR, providing evidence for a founder chromosome; Ag1-CA marker data also support evidence of an ancestral origin for the 800ins11 and 542delGT mutations. We note that telSMN missense mutations are associated with milder disease in our patients and that the severe type I SMA phenotype caused by frameshift mutations can be ameliorated by an increase in cenSMN gene copy number.

We evaluated 173 patients in the Clinical Investigation of Duchenne Dystrophy study to determine if patients from the same kindred were more alike clinically than patients within the study population as a whole. A high intrafamilial correlation was noted for age-adjusted muscle strength scores. While noninherited factors could, in part, explain the results, it seems likely that genetic heterogeneity may contribute to the observed similarity within Duchenne dystrophy kindreds.

Eight consecutive patients who underwent thymectomy for the treatment of myasthenia gravis were evaluated prospectively for the development of postoperative pericarditis. In four of the eight patients (50 percent) pericarditis developed within 48 hours after thymectomy. All four had a three-component pericardial friction rub, two of the four patients had a new postoperative pericardial effusion by echocardiography, and in two typical ECG diffuse concave ST segment elevation and evolutionary ST and T wave changes developed. In the four patients with postoperative pericarditis, a malignant thymoma adherent to the pericardium was found in two, while two patients had a normal thymus histology with no adherence to the pericardium. Thus, postoperative pericarditis was found in both of the patients with a thymoma and in two of six patients without a thymoma. This study demonstrates that a high incidence of pericarditis occurs following thymectomy for the treatment of myasthenia gravis.

• Eighteen patients with chronic inflammatory demyelinating polyneuropathy were studied with evoked potentials to assess for evidence of central nervous system demyelination. Both visual and brain-stem auditory evoked responses were obtained, and the results were compared with magnetic resonance imaging (MRI). An evoked potential was abnormal in nine of 18 patients, five of whom had central nervous system evidence of demyelination by MRI. Evoked potentials identified four patients with probable anterior optic pathway involvement that was not demonstrable by MRI. These findings continue to support that chronic inflammatory demyelinating polyneuropathy is associated with a central demyelinating disorder and more importantly emphasize the possibility of a common pathogenic mechanism in central and peripheral nerve demyelination.

Several studies have raised the question of abnormal biogenic amine metabolism in Duchenne muscular dystrophy (DMD). A small group of DMD patients and controls were screened for abnormalities in systemic biogenic amine metabolism in a carefully controlled clinical environment The mean 24-hour urinary excretion levels of norepinephrine, epinephrine, and 5-hydroxyindoleacetic acid (5-HIAA) were identical in the group of DMD patients compared to their normal sibling controls. In the cerebrospinal fluid (CSF), 5-HIAA and homovanillic acid (HVA) levels were similar in DMD patients and controls, and no 5-hydroxytryptamine (5-HT) was detected in the CSF of either group. This study suggests that the characteristic lesions of DMD do not result from a simple excess of circulating amines.

We examined the role of the complement system in the pathogenesis of dermatomyositis. Using an antibody against the neoantigens of the terminal C5b-9 membrane attack complex, we performed immunocytochemical studies that localized this complex to the intramuscular microvasculature (arterioles and capillaries) of muscle biopsy specimens from 10 of 12 patients (83 percent) with childhood dermatomyositis and 5 of 19 patients (26 percent) with adult dermatomyositis. Fifty-two control specimens, including 14 from patients with polymyositis and 12 from patients with denervation atrophy (a condition known to be associated with necrotic capillaries), showed no deposition of membrane attack complex in the microvasculature. These findings indicate that the complement system is deposited, bound, and activated to completion within the intramuscular microvasculature of patients with dermatomyositis. In addition to providing further evidence for the presence of vasculopathy in dermatomyositis, these findings suggest a primary role for complement in mediating vessel injury in the disease, particularly in its childhood form.

A controlled-randomized trial of plasma exchange combined with prednisone was compared to supportive care alone in patients with acute inflammatory polyradiculoneuropathy (AIP). The design of this study differs from other reported trials of plasma exchange in AIP because prednisone was used in the treatment group to prevent the possibility of antibody rebound. Furthermore, in this study, detailed muscle strength testing formed the principal basis for assessment of therapeutic efficacy while in the British, North American, and French studies, a functional assessment scale was used. Analysis of our data revealed no significant improvement in the treated group over the controls. The sample size, albeit small (12 treated and 13 controls), had the power (95% chance) to detect a change of two British Medical Research Council grades of strength between the groups. The difference in our results versus others (North American and French studies) probably reflects the adverse effects of prednisone on recovery in AIP. An additional consideration is that plasma exchange may have an overall modest effect on the course of AIP, less appreciated when individual muscles are tested compared to assessment by large functional categories.

Axoplasmic transport studies were done in rats with a zinc pyridinethione-induced dying-back neuropathy characterized by the accumulation of branched interconnected tubulovesicular profiles in the motor nerve terminals. Fast anterograde transport studies in sensory and motor systems were significantly reduced compared to controls but there was a wide variation in results and a lack of correlation with clinical involvement. Retrograde transport studies showed a delay in the time of onset and a reduction in the amount of retrograde transported materials. Analysis of the integrals of retrograde transport indicated that the defect was related to a failure in the turn-around process in the distal axon as opposed to a decreased rate of retrograde transport. Similar changes were not present in the proximal morphologically normal portion of the axon where retrograde transport was provoked with a crush injury.

Delayed relaxation of muscle following voluntary contraction was an unusual feature of a mild chronic sesorimotor peripheral neuropathy in an adult. This abnormality resulted from rapid repetitive discharges in motor nerves occurring only in response to passing impulses; there was no spontaneous nerve discharge. Voluntary contraction of affected muscles generated involuntary high-frequency discharges of motor unit potentials, which persisted briefly after attempted relaxation. Nerve blocks localized independent zones of hyperexcitability in distal and proximal sections of nerve from which such repetitive discharges could be triggered. Intravenous administration of phenytoin diminished the discharge. Examination of intramuscular nerve bundles revealed loss of myelinated nerve fibers with numberous sprouting and remyelinating axons. These findings, along with muscle biopsy changes of neurogenic atrophy and type grouping, strongly favor an axonal neuropathy. An explanation for the repetitive nerve discharge is slow waning of heightened excitability of a motor nerve after passage of an impulse.

Ninety-six patients with Duchenne muscular dystrophy (DMD) were randomized and placed either on placebo or oral leucine at a dose of 0.2 g per kg per day. Patients were evaluated using a protocol that measured muscle strength, joint contracture, functional grade and activity, and pulmonary function tests. After 1 month there was a transient but significant difference in the strength of the two groups, the treated group being stronger than the placebo group. At 6 months there was also a transient difference in joint contracture measurements. Analysis of the data showed that the difference between the groups for both these measurements could not be ascribed to a therapeutic effect of leucine but rather to an unexpected drop in the placebo group. This was recognized only because the slope of deterioration for these functions had been well documented during the natural history phase of the study. These results indicate that oral leucine failed to produce a therapeutic response over a 1-year double-blind, controlled trial.

Attention has recently been directed toward patients having a polyneuropathy and a monoclonal IgM anti-myelin-associated glycoprotein (anti-MAG) antibody. The possibility of a pathogenetic role for the anti-MAG antibody in the evolution of the polyneuropathy and in the development of central nervous system signs, including tremor and ataxia, remains unresolved. In 5 patients with this syndrome whose clinical courses were followed closely, in 1 of whom a complete postmortem examination of the nervous system was performed, we made the following observations: the anti-MAG antibody did not localize to the compact layer of the myelin sheath in affected nerves, but did localize to areas of myelin splitting; anti-MAG antibody present in the sural nerve of an affected individual for 7 years was not associated with progressive pathology; anti-MAG antibody was not deposited in the central nervous system of an affected individual, although the antibody did bind to these same tissues in vitro; deposition of anti-MAG antibody observed at postmortem examination did not correlate with the degree of pathological change; and study of the peripheral nervous system favored a primary axonal neuropathy with secondary demyelination.

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.

Some patients with peripheral neuropathy and gammopathy have IgM monoclonal antibodies that react with the myelin-associated glycoprotein (MAG), some 20–26 kDa glycoproteins present only in the peripheral nervous system (PNS), and some acidic glycolipids that are also PNS-specific. This communication describes an investigation of 18 patients with IgM paraproteinemia and neuropathy to test for the presence of antibodies that react with each of these components. Eleven patients had IgM that reacted with MAG, and in all cases the IgM also reacted with the lower Mr glycoproteins and the acidic glycolipids that are specific for the PNS. With respect to the other 7 patients that did not react with MAG, in no instance did immune-staining of electroblots reveal the presence of reactivity with the 20–26 kDa glycoproteins of the PNS or with any other protein antigen in the PNS or central nervous system (CNS). However, these 7 patients fell into 3 categories with regard to reactivity with acidic glycolipids: (1) three reacted with the acidic glycolipid fraction of both PNS and CNS tissue; (2) two reacted with the acidic glycolipid fraction of the PNS but not the CNS; and (3) two showed no reactivity with the acidic glycolipids from either PNS or CNS.

The peripheral neuropathy seen with necrotizing angiopathy is said to begin classically as a mononeuritis multiplex, usually associated with polyarteritis nodosa, rheumatoid arthritis, or systemic lupus erythematosus. Our experience, however, suggests that a large number of these patients do not have a well-defined collagen vascular disease or the typical clinical pattern. In 350 consecutive nerve biopsies (sural or superficial radial), 16 patients showed a necrotizing angiopathy in the epineurial blood vessels. Six of these 16 patients had a distal symmetrical sensorimotor poly-neuropathy. The remaining 10 had a mononeuritis multiplex, although in 8 overlapping nerve involvement somewhat obscured the picture of mononeuritis. In 12 patients, no specific underlying collagen vascular disease could be diagnosed by accepted criteria despite extensive clinical, radiological, and serological evaluations. The peripheral neuropathy was the only objective evidence of vasculitis in 7 of these 12 patients. Our findings suggest that patients with a peripheral neuropathy secondary to necrotizing angiopathy often do not have a definable collagen vascular disease. In fact, peripheral neuropathy may be the sole manifestation of vasculitis. Furthermore, the neuropathy was found to be a distal symmetrical sensorimotor neuropathy in a higher proportion of cases than has been documented previously.

A 1-month-old boy was admitted because of failure to thrive. He was floppy and had bilateral ptosis, diminished reflexes, and poor suck. He had aspiration pneumonia, developed seizures, and died at age 3 1 / 2 months. Laboratory data showed lactic acidosis, proteinuria, glycosuria and generalized aminoaciduria. He was an only child, and family history was negative. Muscle biopsy showed large clumps of granules positive with oxidative enzyme stains and increased lipid droplets. Ultrastructural studies showed large aggregates of mitochondria, many of which were greatly enlarged and contained disoriented or concentric whorls of cristae and paracrystalline inclusions. Cytochrome c oxidase was absent in fresh frozen sections by histochemical staining. By biochemical assay, cytochrome c oxidase (cytochrome aa3) was 6% of normal in muscle biopsy and undectectable in autopsy muscle; spectra and content of cytochromes showed lack of cytochrome aa3, decreased cytochrome b and normal cytochrome cc1. In kidney, cytochrome-c-oxidase activity was 38% of normal and spectra showed decreased cytochromes aa3 and b. The association of fatal infantile mitochondrial myopathy, lactic acidosis and renal dysfunction was previously reported by Van Biervliet et al and appears to be a distinct nosologic entity, one of the few biochemically defined mitochondrial myopathies.

In Duchenne's muscular dystrophy, functional impairment of smooth muscle in the gastrointestinal tract can cause acute gastric dilatation and intestinal pseudo-obstruction that may be fatal. We describe a patient with this syndrome who at autopsy had smooth-muscle degeneration of the stomach. To provide objective evidence of functional smooth-muscle impairment in Duchenne's dystrophy, we performed gastric-emptying studies in 11 patients and 11 normal controls, using technetium-99m radionuclide scintigraphy in a test meal of oatmeal. The patients with Duchenne's dystrophy had delayed gastric-emptying times (118.18 +/- 32.21 minutes [mean +/- SEM]) as compared with controls (42.5 +/- 3.4 minutes, P less than 0.01). The cause of the pathological and functional abnormalities we describe in smooth muscle is unknown but may be a deficiency of dystrophin, the recently identified gene product of the Duchenne's muscular dystrophy locus.

Therapeutic trials in muscular dystrophy have often been inconclusive. A protocol has been designed which selects patients with Duchenne muscular dystrophy and permits accurate measurement of their status. An integral part of the protocol is a system for checking on the consistency of the data obtained using a computer program.

Gangliosides were extracted, separated by thin layer chromatography, and quantitated in three cranial nerves of the garfish (Lepisosteus osseus): the completely unmyelinated olfactory nerve (OLF), and two nerves composed of both myelinated and unmyelinated fibers, viz., the main trunk of the maxillary nerve (MAX) and a branch of the maxillary nerve (BR-MAX). Morphological studies on each of these nerves were done to verify that the OLF had been excised free of any contamination from the accompanying myelinated BR-MAX, to aid in the interpretation of the biochemical findings, and to clarify the nature of the OLF supporting cell. The chief chemical findings were (1) documentation of the presence of gangliosides in nerves previously thought not to contain them, (2) demonstration that gangliosides can be associated with unmyelinated nerves, (3) demonstration of a greater proportion of one simple ganglioside (G-6) in the OLF but greater proportions of two complex gangliosides (G-2 and G-O) in the MAX and BR-MAX, and (4) that either GM4 or a variant of the GM3 is present in OLF. The morphological findings with respect to the difficulty of ascribing only peripheral nervous system characteristics to the OLF supporting cell are discussed in relation to the ganglioside band chromatographing slightly ahead of GM4 in the OLF.

Growth hormone (GH) and prolactin (PRL) secretion was evaluated in seven patients with Duchenne muscular dystrophy. GH and PRL levels following sleep and 24 h mean serum GH and PRL concentrations were normal in these subjects. Overnight GH and PRL concentrations were evaluated in four of these patients before and following administration of the serotonin inhibitor, parachlorophenylalanine (PCPA). Although PCPA produced a significant decrease in urinary 5HIAA concentrations, the treatment had no significant effect on GH and PRL levels. These findings raise the possibility that serotonin may not be involved in nocturnal GH and PRL secretion in these patients.

A controlled randomized trial of plasma exchange combined with prednisone was compared with supportive care alone in patients with Guillain-Barre syndrome (GBS). There was no significant improvement in the treated group over the controls. The sample size, albeit small (12 treated and 13 controls), had the power (95% chance) to detect a change of 2 British Medical Research Council grades of strength between the groups. The difference in our results and others that indicated a beneficial effect of plasma exchange may reflect an adverse effect of prednisone on recovery in GBS. Failure to find a benefit of plasma exchange in our patients also raises the possibility that GBS may be a heterogeneous disorder with humoral factors playing a role in some but not all patients.

Peripheral neuropathy as a cause for the scapuloperoneal syndrome continues to be controversial. This report provides further evidence in support of a scapuloperoneal neuropathy as a separate nosologic entity. Three men had a slowly progressive disorder of 5-17 years duration with prominent weakness and atrophy of scapular stabilizer, shoulder girdle and distal lower extremity muscles accompanied by a distal pan-modality sensory loss. Electrodiagnostic studies and sural nerve biopsies indicated a primary axonal neuropathy with secondary demyelination and remyelination.

Cases of a toxic distal polyneuropathy have been studied in a plant producing plastic-coated and color-printed fabrics. After the screening of 1,157 employees, a total of 86 verified cases were detected. Of these, 11 were moderate to severe in intensity and usually with motor and sensory involvement; 38 were mild, with sensory signs prevailing; and 37 were minimal, but with characteristic electrodiagnostic abnormalities. Muscle weakness and electromyographic abnormalities were predominantly distal. Reflex loss was minimal. Sensory deficits were distal and limited to pain, touch, and temperature discrimination with occasional loss of vibration sense. The distribution of involvement, severity of the disorder, and temporal course of the outbreak correlated with exposure with methyl n-butyl ketone. After elimination of this agent, improvement was noted in the majority of cases.

We performed a randomized, double-blind, controlled six-month trial of prednisone in 103 boys with Duchenne's muscular dystrophy (age, 5 to 15 years). The patients were assigned to one of three regimens: prednisone, 0.75 mg per kilogram of body weight per day (n = 33); prednisone, 1.5 mg per kilogram per day (n = 34); or placebo (n = 36). The groups were initially comparable in all measures of muscle function. Both prednisone groups had significant improvement of similar degree in the summary scores of muscle strength and function. Improvement began as early as one month and peaked by three months. At six months the high-dose prednisone group, as compared with the placebo group, had improvement in the time needed to rise from a supine to a standing position (3.4 vs. 6.2 seconds), to walk 9 m (7.0 vs. 9.7 seconds), and to climb four stairs (4.0 vs. 7.1 seconds), in lifting a weight (2.1 vs. 1.2 kg), and in forced vital capacity (1.7 vs. 1.5 liters) (P less than 0.001 for all comparisons). There was an increase in urinary creatinine excretion (261 vs. 190 mg per 24 hours), which suggested an increase in total muscle mass. However, the prednisone-treated patients who had required long-leg braces (n = 5) or wheelchairs (n = 11) continued to require them. The most frequent side effects were weight gain, cushingoid appearance, and excessive hair growth. We conclude from this six-month study that prednisone improves the strength and function of patients with Duchenne's muscular dystrophy. However, further research is required to identify the mechanisms responsible for these improvements and to determine whether prolonged treatment with corticosteroids may be warranted despite their side effects.

• Between 1979 and 1987 we documented the natural history of Duchenne muscular dystrophy in 170 patients, aged from 3 to 23 years, by making serial measurements in over 5000 individual evaluations. This database makes it possible to design and conduct therapeutic trials using natural history controls. Such trials do not replace the need for randomized placebo-controlled trials of promising agents but they do require fewer patients, are cost-effective, and permit the use of high-risk therapy where toxicity monitoring may be important. Natural history-controlled trials, therefore, may serve as a screening method for new therapeutic agents. Drugs showing a significant benefit can then be evaluated in a randomized controlled trial.

Alterations in the membraneous organelles were studied in two experimental neuropathies: 2,5-hexanedione (2,5- HD) and s,s′-iminodiproprionitrile (IDPN), both of which exhibit massive neurofilamentous accumulation. The membranous organelles were stained using the diaminobenzidine potassium ferrocyanide (DPF) method. In 2,5-HD, where there is a progressive impairement of fast axoplasmic transport, studies of the smooth endoplasmic reticulum (SER) revealed a fragmentation and disruption of the continuity of the longitudinally oriented interconnecting tubules and a significant increase in the number of free vesicles. In IDPN, where studies of fast transport have been normal, the longitudinal orientation of the smooth SER tubules was not disturbed although channels of longitudinally oriented tubules of SER were clustered with microtubules and mitochondria. This study suggests that in 2,5-HD the accumulation of vesicles in association with fragmentation and disorganization of the SER is one of the morphologic correlates of the impaired fast anterograde transport system.

A generalized toxic polyneuropathy was identified in a 23-year-old woman after excessive intentional inhalation of compressed N2O delivery from cartridges through a whipped-cream dispenser. The chronology of the patient's N2O abuse correlated clearly with two episodes of recurrent polyneuropathy. The toxic effects were limited to the nervous system, primarily involving the peripheral nerves, although some signs suggested a possible effect on the cerebellum or its connections. The findings on sural nerve biopsy were nonspecific, characterized principally by axonal degeneration. Gas chromatographic analysis of the N2O cartridges dispensed through the whipped-cream canister revealed an exposure to N2O and 26 other compounds. Three of these, trichloroethylene, toluene, and phenol, are known neurotoxins.

N 1918, Hoffman described a method of eliciting, in man, an easily identified monosynaptic response, the H reflex2 Classically, the H reflex is initiated by electrical stimulation of a mixed nerve, such as the posterior tibial nerve in the popliteal fossa. The H reflex is recorded from the gastroc-soleus muscles by needle or overlying surface electrodes. While the posterior tibial nerve is the conventional site of stimulation, other stimulus sites are applicable. We have also used the femoral and ulnar nerves to obtain monosynaptic responses from the muscles they innervate. In interpretation of the oscilloscope recordings (Fig. 1) evoked by stimulation of the posterior tibial nerve, it must be remembered that the stimulus affects both sensory and motor fibers. With low intensity stimulation, the large afferent fibers are the first to respond. This afferent impulse courses to the spinal cord and synapses directly with the large alpha motor neuron of the anterior horn. A monosynaptic response is evoked, and the H reflex appears in the calf following a 30-msec delay. The H reflex amplitude increases with increments in the stimulus shock. When stimulation is of sufficient magnitude, smaller fibers of higher threshold respond, producing the M wave, which results from direct stimulation of motor fibers and appears in the calf 6 msec after posterior tibial nerve stimulation. As the stimulus increases in intensity, the amplitude of the M wave increases, and that of the H reflex decreases. This decrease in the H reflex is presumably a result of antidromic bloekade.~,7, 9

The highly characteristic early and midstage histological lesions of Duchenne dystrophy were reproduced experimentally in the rat by the combination of a vascular abnormality, aortic ligation, which does not affect the structure of the intramuscular blood vessels, and the humoral vasoactive substance 5-hydroxytryptamine. Neither ligation nor injection of 5-hydroxytryptamine alone causes changes in the muscle fibers. This result establishes the possibility of a similar combined mechanism for a nonstructural ischemia pathogenesis in Duchenne dystrophy. The proposed pathogenesis is contrary to the generally held idea that the cause is an intrinsic abnormality of muscle fiber metabolism.

Background: Periodic paralyses and paramyotonia congenita are rare disorders causing disabling weakness and myotonia. Mutations in sodium, calcium, and potassium channels have been recognized as causing disease. Objective: To analyze the clinical phenotype of patients with and without discernible genotype and to identify other mutations in ion channel genes associated with disease. Methods: The authors have reviewed clinical data in patients with a diagnosis of hypokalemic periodic paralysis (56 kindreds, 71 patients), hyperkalemic periodic paralysis (47 kindreds, 99 patients), and paramyotonia congenita (24 kindreds, 56 patients). For those patients without one of the classically known mutations, the authors analyzed the entire coding region of the SCN4A , KCNE3 , and KCNJ2 genes and portions of the coding region of the CACNA1S gene in order to identify new mutations. Results: Mutations were identified in approximately two thirds of kindreds with periodic paralysis or paramyotonia congenita. The authors found differences between the disorders and between those with and without identified mutations in terms of age at onset, frequency of attacks, duration of attacks, fixed proximal weakness, precipitants of attacks, myotonia, electrophysiologic studies, serum potassium levels, muscle biopsy, response to potassium administration, and response to treatment with acetazolamide. Conclusions: Hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and paramyotonia congenita may be distinguished based on clinical data. This series of 226 patients (127 kindreds) confirms some clinical features of this disorder with notable exceptions: In this series, patients without mutations had a less typical clinical presentation including an older age at onset, no changes in diet as a precipitant, and absence of vacuolar myopathy on muscle biopsy.

Three unrelated school teachers taught in the same school classroom for 2-5 years and subsequently developed amyotrophic lateral sclerosis (ALS) over an 18-year period. This clustering was not accompanied by an increased death rate for ALS in the county where the teachers lived and worked. Statistical analysis revealed that ALS as the cause of death for three teachers from the same school would be highly improbable as a random event. These findings suggest that the patient's shared school environment may have been a source of exposure to an agent pathogenetically significant in the development of their disease.

✓ The relationship between brain tumor location and thromboembolism was studied by a retrospective review of autopsy and clinical material. Patients with suprasellar tumors had a higher incidence of thromboembolic complications than those with tumors in other locations. An associated derangement of hypothalamic function is suggested as predisposing to thromboembolism.

Five patients had a neurological syndrome develop beginning three to ten days after Hymenoptera insect stings. Three had typical acute inflammatory polyradiculoneuropathy (Guillain-Barre syndrome). A fourth was similar, except that seizures developed, and the fifth patient showed only cranial nerve involvement and hyporeflexia. The timing of these neurological manifestations following insect stings suggests the possibility of a direct or indirect cause-and-effect relationship. ( JAMA 1982;247:1443-1445)

It is unclear whether sporadic reports of concurrent multiple sclerosis (MS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) represent coincidence or whether these two demyelinating disorders are pathogenically related. We utilized the sensitivity of magnetic resonance imaging (MRI) in detecting central nervous system (CNS) lesions to investigate 16 patients with CIDP. Six of the 16 had periventricular, subcortical, and brainstem white matter lesions indistinguishable from those seen in MS. Three of these patients had definite clinical and laboratory evidence of MS; three others with abnormal MRIs had no findings indicative of CNS disease. Previous reports have indicated that a significant number of MS patients have peripheral nerve demyelination. Our study suggests that many CIDP patients have concurrent CNS demyelination. Taken together, these observations support the existence of a central-peripheral inflammatory demyelinating syndrome. Whether this combined demyelinating syndrome lies on a spectrum between MS and CIDP or is a separate pathogenic entity will require further investigation.

816 USE OF GENETIC LINKAGE COMBINED WITH SERUM CREATINE KINASE AND PYRUVATE KINASE FOR CARRIER DETECTION IN DUCHENNE DYSTROPHY

Excerpt Cyclosporine is an immunosuppressant used primarily in transplantation (1) and more recently in the therapy of autoimmune disease (2, 3). Nephrotoxicity is a well-recognized complication of...

Azathioprine toxicity was examined in 64 consecutively treated patients with various neuromuscular diseases. Reversible leukopenia was seen in 14 patients (22%). Hepatotoxicity developed in six patients (9%), and a systemic reaction characterized by fever, abdominal pain, nausea, vomiting, and anorexia occurred in eight patients (12%). Toxic effects limited the dose of azathioprine in 27 patients (42%) and led to discontinuation of therapy in 13 (20%). Macrocytosis developed in 20% of patients, but did not require an adjustment in the dose. Two patients received allopurinol and azathioprine; both developed reversible leukopenia and macrocytosis. Patients with hematologic and hepatic toxicity, but not those with systemic toxicity, successfully tolerated retreatment with azathioprine. Toxicity was delayed as long as 56 weeks after starting azathioprine in some patients.

Over a 10-year period, we followed up 60 patients (35 men and 25 women) with chronic inflammatory demyelinating polyradiculoneuropathy. Diagnosis was based on previously outlined criteria. Patients were treated in a uniform manner and the overwhelming majority, 56 (94.9%) of 59 treated patients, initially responded to immunosuppressive therapy. The time for initial improvement was 1.9 +/- 3.6 months while the time to reach a clinical plateau was 6.6 +/- 5.4 months. The course was monophasic in 32 patients (53.3%) and relapsing in 28 (46.6%). Despite the initial responsiveness, only 24 (40%) of 60 patients are in partial or complete remission, receiving no medication. Two patients died. We were unable to identify specific clinical or laboratory features at the time of diagnosis that predicted outcome. Our data analysis, along with previous reports, suggests that chronic inflammatory demyelinating polyradiculoneuropathy may be more heterogeneous than previously emphasized. In this light, we have proposed diagnostic criteria that allow for the heterogeneity but at the same time provide for a more consistent approach to better establish the natural history of this condition.

• We investigated the effect of highdose prednisone therapy in 33 boys with Duchenne muscular dystrophy. The drug was given daily in doses of 1.5 mg/kg of body weight (to a maximum of 80 mg) for six months. Muscle strength, joint contractures, timed functional tests, functional ability, and pulmonary function were measured at the beginning and end of the treatment period. The trial was designed using natural history controls, and the power of the study was 0.80 to detect a slowing of 50% in the rate of progression. During the period of the trial, muscle strength, functional grades, timed functional tests, and pulmonary function improved. Contractures followed the expected natural history of the illness.

We elected to use cyclosporin A (CsA) in a woman debilitated by refractory chronic inflammatory demyelinating polyradiculoneuropathy. Although strength improved coincident with CsA therapy, after 21 months she developed congestive heart failure and had a precipitous loss of renal function with chronic renal failure requiring hemodialysis. While most CsA-induced nephrotoxicity is dose related and reversible, the kidney biopsy in our patient showed chronic nephropathy, a complication previously unreported in the native kidney of a nontransplant patient. A slow rise in blood pressure preceded serum creatinine changes and was an early indicator of impending irreversible nephrotoxicity.

Study of creatine phosphokinase (CPK) isoenzymes using a quantitative column chromatographic technique showed that there was a significant difference in serum MB isoenzyme activity between patients with Duchenne muscular dystrophy (42 mU per milliter) and those with other kinds of neuromuscular diseases (8 mU per milliter). In the Duchenne patients, the serum MB isoenzyme activity did not correlate with clinical cardiac disease. Furthermore, skeletal muscle damage produced in the rat by aortic ligation and 5-hydroxytryptamine resulted in significant elevations of plasma MB isoenzyme activty. These studies suggest that the serum MB isoenzyme activity in the Duchenne muscular dystrophy patients is probably arising from skeletal, not cardiac muscle and may reflect a distinct pathogenesis from other kinds of neuromuscular disorders.

A third case of phosphoglycerate mutase (PGAM) deficiency, a metabolic myopathy involving terminal glycolysis, was identified in a 24-year-old black man with episodic, exercise-induced myoglobinuria since age 13. To better understand the physiologic consequences of PGAM deficiency, incremental exercise testing was performed. Results were compared with those of two patients having myophosphorylase deficiency and five normals. In contrast to the patients with phosphorylase deficiency, the PGAM-deficient patient achieved near-normal levels of maximal exercise and produced a normal peak lactate after exercise. The mechanisms underlying the asymptomatic performance of such strenuous exercise in this case are uncertain, but the data suggest that unidentified factors are operative in precipitating attacks of myoglobinuria in patients with some metabolic myopathies. Despite similar clinical histories, patients with different glycolytic enzyme deficiencies can have striking differences in exercise tolerance.

• Open-biopsy electromyography (EMG) of two muscles of a 29-year-old man with slowly progressive proximal weakness demonstrated a striking pattern of excessively recruited, pathologically small motor unit potentials. This pattern is usually equated with myopathy. Histologic study of tissue enclosing the recording sites, however, yielded evidence of neurogenic disease alone. In muscle, this included isolated and small groups of atrophic type I, IIA, and IIB fibers, and in intramuscular nerve a loss of myelinated fibers with connective tissue and Schwann cell proliferation. The EMG pattern is considered to reflect a reduced number of activated muscle fibers within motor units due to random neurogenic involvement of terminal axons.

A double blind study of the effects of dexamethasone on acute stroke was conducted at the Neurological Institute of New York. At the end of the study, it was found that 17 patients had been treated with placebo and 14 patients had been treated with dexamethasone. The dose of steroid was 16 mg daily for 10 days followed by tapering doses from 12 mg to zero over the ensuing 7 days.