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Two siblings with Lafora disease (LD) are described: one with epilepsy, myoclonus, EEG abnormalities, severe dementia and many Lafora bodies (LBs) in muscle and skin tissue; the other with myoclonus, epilepsy, EEG abnormalities and LBs in muscle and in skin tissue, without dementia. The findings suggest that the diagnosis of LD by skin and muscular biopsy is possible in the early stage of the disease, when there are myoclonic epilepsy and EEG abnormalities, before the onset of dementia.

We report a patient with a progressive, predominantly sensory neuropathy and a IgM kappa M-protein that binds to Schmidt-Lantermann incisures. A sural nerve biopsy showed primary axonal damage and IgM deposits at Schmidt-Lantermann incisures were seen by direct immunoperoxidase. Serum from the patient injected into rat sciatic nerve reacts with the incisures as with those in the patient's nerve. The IgM kappa M-protein reacts with chondroitin sulfate C and binds to a broad nerve protein band with a mobility of between 170 and 118 kDa. Peripheral neuropathy may be related to the M-protein, which had immunocytochemical reactivity not previously described for patients with polyneuropathy and IgM monoclonal gammopathy.

We report a patient (S.T.) with multiple congenital anomalies and developmental delay associated with an interstitial deletion of 1q23-1q25. Molecular analysis of the deletion was performed using DNA markers that map to 1q. Five DNA markers, MLAJ-1 (D1S61), CRI-L1054 (D1S42), HBI40 (D1S66), OS-6 (D1S75), and BH516 (D1S110), were demonstrated to be deleted. Informative polymorphisms demonstrated this to be a de novo deletion of the maternally derived chromosome. Deletion status was determined using restriction fragment length polymorphism (RFLP) analysis supplemented with densitometry in the experiments where RFLP analysis was not fully informative. Deletions were confirmed by Southern analysis using genomic DNA from a somatic cell hybrid retaining the del(1)(q23-q25) chromosome that was constructed from patient S.T. Flow karyotyping confirmed the deletion and estimated that the deletion encompassed 11,000-16,000 kb. The clinical and cytogenetic characteristics of S.T. are compared with those of ten previously described patients with monosomy 1q21-1q25.

Although anatomical abnormalities of the upper airway have been recorded in some patients with obstructive sleep apnoea (OSA), a muscle tone dysregulation also seems to have an important role in this disorder. Since habitual snoring is the initial stage of OSA, the structural characteristics of upper airway muscles (medium pharyngeal constrictor muscle [MPCM]) from 13 men (9 non-snorers and 4 habitual snorers) were studied. MPCM fibre structure in non-snorers was broadly similar to that in normal limb muscles, with the exception that fibre diameters were smaller for all fibre types. Compared with limb muscles, MPCM had a smaller proportion of type IIb fibres and a higher proportion of types I and IIa fibres. MPCM in habitual snorers had an abnormal distribution of fibre types (low percentage of type I and type IIb fibres and high percentage of type IIa fibres) compared with non-snorers (p less than 0.001) and the type IIa fibres were hypertrophic. No myopathic or neurogenic changes were seen. Two possible hypotheses explain the abnormal distribution of fibre types in snorers. First, a constitutionally determined reduction of slow alpha-motor neurons induces an adaptive transformation of type IIb to type IIa fibres and a hypertrophy of type IIa fibres; or, second, motor neurons change their patterns of discharge and, hence, of activation, and modify fibre-type distribution of MPCM as an adaptation to the anatomical characteristic of upper airway and habitual snoring.

A child developed severe, generalized muscle weakness which persisted for 6 weeks, after receiving muscle relaxants for 1 week while requiring ventilator support. Electrodiagnostic studies indicated a presynaptic disorder of the neuromuscular junction which improved with high-frequency stimulation, similar to findings in Lambert-Eaton syndrome. Muscle specimens exhibited neurogenic targetoid fiber atrophy. Ultrastructure of the neuromuscular junction indicated terminal axon degeneration and atrophy with depletion of the secretory vesicles. Most reported patients with post-ventilator paresis have received steroids and muscle relaxants; muscle weakness commonly has been brief and attributed to steroids. We believe that this reversible myasthenic syndrome probably represents neurotoxicity due to high doses of steroidal nondepolarizing blocking agents; however, available data are insufficient to resolve this controversy.

We present three instances in which cytoplasmic bodies in muscle fibers were associated with Werdnig-Hoffmann disease. The children presented within the first 6 weeks of life with clinical symptoms and laboratory studies indicative of infantile spinomuscular atrophy (ISMA). Initial muscle biopsies in each case revealed signs of muscle immaturity and cytoplasmic bodies but lacked features of denervation. Follow-up biopsies in 2 cases revealed changes typical of ISMA, but cytoplasmic bodies were no longer present. A follow-up biopsy was not available in the third child who also had a clinical course consistent with ISMA. We discuss the pathogenesis of cytoplasmic bodies and their significance in association with Werdnig-Hoffmann disease.

In order to characterize the mechanism(s) causing vitamin E deficiency during chronic childhood cholestasis, we studied 6 vitamin E-deficient cholestatic children with clinical evidence of neurologic dysfunction (group A), 4 vitamin E-sufficient cholestatic children and young adults with normal neurologic status (group B), and 6 vitamin E-sufficient noncholestatic children (group C). Intestinal absorption of dl-alpha-tocopherol (assessed by an oral tolerance test) was markedly impaired (p less than 0.001) in group A compared with groups B and C, which did not differ from each other. Intraluminal total bile acid concentrations were markedly depressed in group A compared with age-matched controls (0.50 vs. 7.00 mM, p less than 0.001), whereas concentrations were low normal in group B. Intramuscular dl-alpha-tocopherol was well absorbed in 4 group A subjects and corrected abnormal hydrogen peroxide hemolysis. Our data suggest that low intraluminal bile acid concentrations result in malabsorption and deficiency of vitamin E in children with prolonged, severe cholestasis. Intact plasma transport and tissue uptake of vitamin E during cholestasis suggest that intramuscular vitamin E should be utilized for prevention and therapy of the neurologic abnormalities caused by vitamin E deficiency.

We studied the effect of long-term correction of vitamin E deficiency on neurologic function in 14 children with chronic cholestasis. Vitamin E repletion was achieved in all, either by large oral doses (up to 120 IU per kilogram of body weight per day) or by intramuscular administration of dl-alpha-tocopherol (0.8 to 2.0 IU per kilogram per day). With early institution of therapy, neurologic function remained normal in two asymptomatic children below the age of three years after 15 and 18 months of therapy. Neurologic function became normal in three symptomatic children below age three after 18 to 32 months of therapy. Restitution of neurologic function was more limited in nine symptomatic children 5 to 17 1/2 years old after 18 to 48 months of therapy. We conclude that vitamin E repletion therapy should be initiated at an early age in children with chronic cholestasis complicated by vitamin E deficiency, to prevent irreversible neurologic injury.

Vitamin E malabsorption and deficiency during chronic childhood cholestasis has been associated with a progressive ataxic neurologic syndrome. Hyporeflexia, the first sign of neurologic dysfunction, may begin prior to age 2 years, but severe symptoms do not develop until age 5 to 10 years. To establish the age of onset of neuropathologic lesions, we prospectively evaluated four young children with severe cholestasis. Malabsorption and deficiency of vitamin E were documented by low serum vitamin E concentrations, low serum vitamin E to total serum lipids ratios, elevated hydrogen peroxide hemolysis, and impaired absorption of a pharmacologic dose of alpha-tocopherol. Abnormal neurologic findings in two patients were limited to areflexia, ptosis, mild truncal ataxia, and hypotonia; two patients had minimal signs of neurologic dysfunction. Sural nerve histology at age 6 to 25 months revealed a degenerative axonopathy involving large-caliber myelinated fibers, but without quantitative axonal loss. Muscle histology and histochemistry tests yielded normal results. Our study suggests that neurologic injury may occur during the first two years of life in vitamin E-deficient children with cholestatic hepatobiliary disease, obligating aggressive attempts at correcting this deficiency state at a very young age.

Three term infants had severe hypotonia, a maturation defect of type 1 muscle fibers, and extramedullary hematopoiesis (EMH) in quadriceps muscle specimens obtained within one month of birth. Although predominantly myelopoietic, signs of inflammatory myopathy were absent. One patient had congenital myopathy with maturation arrest of type 1 fibers, another had transient maturation delay of type 1 fibers, and the third patient was subsequently classified as having spinomuscular atrophy. Extramedullary hematopoiesis was demonstrated in normal muscle obtained from young fetuses, but not in muscle obtained at autopsy from infants representing the third trimester and first postnatal month, or in muscle biopsy specimens from 15 other hypotonic infants with type 1 fiber size disproportion. We conclude that EMH in muscle of hypotonic infants is an abnormal persistence of a fetal state that is associated with delayed muscle maturation with diverse origins. Extramedullary hematopoiesis in muscle may indicate hypoxia, but signs of perinatal asphyxia in these babies were inconclusive. Low blood flow due to inactivity or an unidentified product of immature muscle may promote intramuscular EMH, but there is no evidence to suggest that myelopoiesis is injurious to muscle fibers. Intramuscular EMH should be distinguished from inflammation.

We studied serum vitamin E levels and the ratio of serum vitamin E to serum lipid levels in 11 children with chronic cholestasis complicated by vitamin E deficiency, as defined by characteristic neurologic signs or sural-nerve histopathology in addition to impaired intestinal absorption of vitamin E. Eight of the children had low levels of serum vitamin E, as well as low ratios of serum vitamin E to total lipids and to cholesterol. However, three patients had normal serum vitamin E levels but low ratios of serum vitamin E to total lipids (two of the three had normal ratios of vitamin E to cholesterol). In four patients who were not vitamin E-deficient, all three values were normal. We conclude that vitamin E deficiency may exist in a child with a normal serum vitamin E concentration and that the ratio of serum vitamin E to total serum lipids is the most reliable biochemical index of vitamin E status during chronic childhood cholestasis.

Seven children with neuromuscular disease were placed on mechanical ventilation before the age of 2 years. The outcome for these patients was variable and did not correlate with primary diagnosis. There appeared to be a high correlation between the incidence of electrocardiogram changes and death. Our experience demonstrates that there was a high mortality rate (57%) in neuromuscular patients supported by mechanical ventilation before the age of 2 years.

We studied cultures of human skeletal muscle in vitro and established standards for biochemical markers of cellular differentiation. DNA synthesis ceased at the time of fusion, implying the absence of fibroblasts. Myosin heavy-chain synthesis, creatine and pyruvate kinase activities, and isoenzymes of creatine kinase were measured serially over 36 days. Filamin and fibronectin proteins were identified in these cultures. Compared to chick muscle in culture, human skeletal muscle cells remained relatively immature. These data provide a basis for the study of diseased human muscle cells in culture.

Insulin-induced hyperpolarization of up to 9 mV has been described in isolated frog [J. Physiol. Lond. 252: 43-58, 1975; Am. J. Physiol. 251 (Cell Physiol. 4): C249-C254, 1979] and mammalian (Molecular Basis of Insulin Action, New York: Plenum, 1985, p. 451-463; Am. J. Physiol. 197: 524-526, 1959; Am. J. Physiol. 198: 1066-1070, 1960) skeletal muscle. We have shown that a similar hyperpolarization occurs in situ after administration of insulin in anesthetized rats. In streptozotocin (STZ)-treated rats, insulin produced approximately 66-70% of the hyperpolarization observed in normal rat skeletal muscle in situ. Administration of ouabain in situ blocked the insulin-induced hyperpolarization in the normal group of rats and significantly blunted the effect in the STZ group. These results suggest that insulin-induced hyperpolarization in skeletal muscle results from direct activation of the Na+-K+-ATPase pump. In isolated skeletal muscle from normal and STZ rats, there was no difference in the amount of the insulin-induced hyperpolarization. There was an additive, but small, hyperpolarizing effect of insulin and isoproterenol when administered in combination, suggesting that the greater magnitude of the insulin-induced hyperpolarization observed in situ in normal rats may be due to an additive effect of injected insulin and endogenous release of epinephrine. Alternatively, STZ treatment may directly alter the Na+-K+ pump so that its response to insulin is lessened.

To determine the frequency of biochemical vitamin E deficiency and of the clinical signs of the vitamin E deficiency neurologic syndrome in children with prolonged neonatal cholestatic disorders, we studied 46 children (aged 1 month to 17.0 years) with chronic forms of intrahepatic neonatal cholestasis and 47 children (aged 4 months to 8.0 years) with extrahepatic biliary atresia. Based on serum vitamin E concentrations and the ratios of serum vitamin E concentration to total serum lipid concentration, 64% of the intrahepatic and 77% of the extrahepatic cholestasis groups were vitamin E deficient. Prior to age 1 year, neurologic function was normal in all children. Between ages 1 and 3 years, neurologic abnormalities were present in approximately 50% of the vitamin E-deficient children; after age 3 years, neurologic abnormalities were present in all vitamin E-deficient children. Areflexia was the first abnormality to develop between ages 1 and 4 years; truncal and limb ataxia, peripheral neuropathy, and ophthalmoplegia developed between ages 3 and 6 years. Neurologic dysfunction progressed to a disabling combination of findings by ages 8 to 10 years in the majority of vitamin E-deficient children. Neurologic function was normal in the vitamin E-sufficient children. We conclude that vitamin E status should be evaluated in infants in whom cholestasis is diagnosed, and effective therapy should be initiated to prevent or treat vitamin E deficiency at an early age.

Specimens of the quadriceps femoris muscle from four infants with neonatal myotonic dystrophy had features of muscle fiber immaturity. Delayed establishment of major fiber subtypes and persistent myotubes, seen in the youngest infant, resolved in a repeated specimen obtained at the age of 4 months. Prominence of satellite cells, central nuclei, acid phosphatase activity sites, and Golgi zones diminished with age at biopsy. All four infants had type 1 fiber-size disproportion. These results substantiate the concept of delayed muscle fiber maturation in myotonic dystrophy.

A male infant had sensory and autonomic dysfunction, and his identical twin had a similar clinical finding. One twin was extensively studied, utilizing sural nerve, skin, and conjunctival biopsy specimens, to evaluate the status of peripheral sensory axons. The results support an antenatal neurodevelopmental disturbance in axonal growth that affects sensory neurons and limits their distal extension. Neuropathologic studies of this patient closely resemble findings in hereditary sensory neuropathy type II; clinically, however, this patient resembles patients with congenital autonomic dysfunction and universal pain loss. Investigation of proximal and distal sural nerve, skin, and/or conjunctival biopsy specimens is recommended in patients with sensory and autonomic dysfunction to help differentiate these patients to assist in genetic counselling, treatment, and prognosis. It is possible that clinical overlap in such patients may result from a common neuropathic process, but with varying degrees of involvement.

Cylindrical spirals are unique membranous structures that were detected in skeletal muscle of a mother and one of her two children; all three have percussion myotonia but no evidence of weak or wasted skeletal muscles. Muscle cramps, stiffness, posteffort muscle tightness, myotonic lid lag, and the cylinders appear or progress with age, but the disorder is asymptomatic in the children and only mildly incapacitating in the mother. The cylinders are 8 mu long and 1 mu wide, are composed of spiraling double-laminate membrane resembling myelin, and are derived from abnormal subsarcolemmal tubulovesicular structures that are interpreted as pathological T-tubes.

We used an indirect immunoperoxidase technique (Avidin-Biotin system) to study the sera of patients with "clinically probable" Alzheimer's disease (AD) and with Down's Syndrome (DS), compared with age-matched controls. Diluted sera were incubated with paraffin sections of hippocampus, frontal, temporal, and parieto-occipital lobes from normal human brains. Biotinylated anti-human goat gamma-globulins were used as secondary antisera. A significantly greater percentage of neurons were immunostained in all the brain regions (frontal, temporal, and parieto-occipital lobes and hippocampus) incubated with sera of AD patients than with sera of DS patients or of controls. This indicates that AD patients have an excess of circulating neuron-binding antibodies (NBAs), mainly reacting with cytoplasmic structures. NBAs could be either the cause or the result of the cerebral lesion found in AD. This study is not able to answer this question, but some previous data from our own and other laboratories suggest that NBAs have a role in the pathogenesis of AD lesions. Since we found no increase of NBAs in DS patients, the brain lesions in DS appear to have a different pathogenesis.

In an attempt to confirm prior reports of vitamin E deficiency in Werdnig-Hoffmann disease, we assessed vitamin E nutritional status in 11 children and 6 adults with spinal muscular atrophy (SMA). Serum vitamin E levels (10.6 +/- 3.3 micrograms/ml for those less than 12 years old, 13.2 +/- 4.5 for those older than 12) and the ratio of serum vitamin E to total serum lipids were normal in all patients. Vitamin E nutritional status appears to be normal in SMA, and vitamin E therapy is not indicated.

We reviewed clinical data and quantitative muscle biopsy data from infants with hypotonia and developmental delay who had relatively small type 1 muscle fibers (fiber size disproportion; FSD). Study material consisted of 49 thigh muscle specimens from 37 patients, 1 week to 11.5 years old, who had FSD diagnosed between 1971 and 1985. Beyond 2 months of age, FSD was greater than 12% in at least one biopsy from all but 2 patients. In sequential specimens obtained from 11 patients, we observed that FSD may resolve, persist unchanged, or intensify with age. In 6 patients, hypotonia regressed, and development tended to normalize during 1-4 years of observation; FSD resolved in 4 cases, but numerical predominance of type 1 fibers persisted in 3 of them. In a small group designated congenital myopathy with FSD only, the disproportion in fiber diameter persisted unchanged or intensified with time and was more severe after the age of 6 months than in the other subgroups. We classified FSD as definitely or probably myopathic (15 cases), definitely or probably neuropathic (17 cases), and benign maturation delay (5 cases). Six of 17 neuropathic cases had a history of perinatal asphyxia. In most cases, type 1 fibers were absolutely small and type 2 fibers were hypertrophied, independent of classification. FSD is a manifestation of muscle maturation delay of variable etiology. The prevalence of nervous system disorders in our series suggests that neuronal dysfunction plays an important role in pathogenesis. We were unable to define morphometric criteria that consistently distinguished congenital myopathy with FSD from definable neuropathic FSD or from benign maturation delay.

Muscle cells were cultured from six patients with Duchenne muscular dystrophy and nine normal subjects. Protein and myosin content and pyruvate kinase (PK) activity were similar in normal and Duchenne muscular dystrophy cultures. Creatine kinase (CK) activity was lower in Duchenne muscular dystrophy cultures and the isoenzyme distribution indicated MB-CK was significantly lower, while BB-CK was significantly higher in later Duchenne muscular dystrophy cultures. This abnormal isoenzyme pattern suggested aberrant or impaired maturation of Duchenne muscular dystrophy myotubes in vitro.

In a previous report we showed that leukocytes from a group of patients with childhood dermatomyositis (CDM) were not cytotoxic toward cultured normal human skeletal muscle cells. Blood products from 11 patients with CDM and 12 age- and sex-matched controls were tested for cytotoxicity toward human endothelium using a chromium 51 assay. Mixed lymphocytes, monocytes, and serum alone or in combination did not produce endothelial cell death. The combination of serum and leukocytes, however, did produce some cytotoxic effects in three of 11 patients with CDM. We conclude that those factors tested in vitro are not responsible for the endothelial cell death but together may produce cytotoxic changes in some patients.

From birth, an infant girl had repeated episodes of loss of consciousness, apnea and bradycardia, aphonia, and severe pharyngeal-esophageal discoordination. These functional deficits correlated with a gross and microscopic malformation of the medulla oblongata, which is characterized by profound deficits of motor and sensory nuclei and of the reticular formation. We have classified this as an example of Möbius syndrome. No etiology was suggested from the history. Histopathologic findings are compatible with an early massive insult to developing structures in the tegmentum of the medulla oblongata.

Two infants with progressive spinomuscular atrophy presented with severe diaphragmatic dysfunction, increasing to 9 the number of cases with this clinically distinctive variant of Werdnig-Hoffmann disease. The anterior horn cell lesion was generalized but was exceptionally severe in the cervical spinal cord of our cases. Fiber size disproportion in serial thigh muscle samples indicated that qualitative neuronal dysfunction preceded appearance of typical denervation. Shoulder girdle muscle biopsy may be more appropriate in these infants, whose prognosis appears to be universally poor.

Skeletal muscle explants from normal subjects were established from biopsy material on collagen. Cellular outgrowth appeared within 3-4 days, and fusion of myoblasts was observed in 5-10 days. Multinucleated myotubes were impaled under high optical magnification, at 37 degrees C, with conventional glass microelectrodes. The mean resting potential was -44.4 mV +/- 2.4 (n = 399); -33 +/- 2.3 mV at 9 days (n = 10) vs -48 +/- 2.5 mV (n = 15) at 27 days. The average input resistance (Rin) was 9.7 M omega (n = 83). Action potentials could be elicited by electrical stimulation and had a mean amplitude of 55.9 +/- 2.1 mV with a mean maximum rate of rise (Vmax) of 72.1 +/- 7.5 V/s. The mean overshoot was 13.9 +/- 2.3 mV, and the action potential duration determined at 50% of repolarization (APD50) was 8.0 msec (n = 7). The resting membrane potential showed a depolarization of 23 mV/decade for extracellular potassium ion concentration ([K]o) between 4.5-100 mM. Thus, we have established the normal resting potential and maximum rate of rise of the action potential for human myotubes in culture. We have shown that the values for these are less than those previously reported in cultured avian and rodent cells. In addition, we have shown that the response in our system of the resting potential to change in extracellular potassium concentration is blunted compared to studies using isolated muscle, suggesting an increase in ratio of sodium to potassium permeability. Cultured human muscle cells depolarized in the presence of ouabain.