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Mitochondrial myopathies belong to a larger group of systemic diseases caused by morphological or biochemical abnormalities of mitochondria. Mitochondrial disorders can be caused by mutations in either the mitochondrial or nuclear genome. Only 5 % of all mitochondrial disorders are autosomal dominant. We analyzed DNA from members of the previously reported Puerto Rican kindred with an autosomal dominant mitochondrial myopathy (Heimann-Patterson et al. 1997). Linkage analysis suggested a putative locus on the pericentric region of the long arm of chromosome 22 (22q11). Using the tools of integrative genomics, we established chromosome 22 open reading frame 16 (C22orf16) (later designated as CHCHD10) as the only high-scoring mitochondrial candidate gene in our minimal candidate region. Sequence analysis revealed a double-missense mutation (R15S and G58R) in cis in CHCHD10 which encodes a coiled coil-helix-coiled coil-helix protein of unknown function. These two mutations completely co-segregated with the disease phenotype and were absent in 1,481 Caucasian and 80 Hispanic (including 32 Puerto Rican) controls. Expression profiling showed that CHCHD10 is enriched in skeletal muscle. Mitochondrial localization of the CHCHD10 protein was confirmed using immunofluorescence in cells expressing either wild-type or mutant CHCHD10. We found that the expression of the G58R, but not the R15S, mutation induced mitochondrial fragmentation. Our findings identify a novel gene causing mitochondrial myopathy, thereby expanding the spectrum of mitochondrial myopathies caused by nuclear genes. Our findings also suggest a role for CHCHD10 in the morphologic remodeling of the mitochondria.

OBJECTIVE Patients with complex regional pain syndrome type I (CRPSD1) may have thermal allodynia after application of a non-noxious thermal stimulus to the affected limb. We measured the warm, cold, heat-evoked pain threshold and the cold-evoked pain threshold in the affected area of 16 control patients and patients with complex regional pain syndrome type 1/RSD to test the hypothesis that allodynia results from an abnormality in sensory physiology. SETTING A contact thermode was used to apply a constant 1 degrees C/second increasing (warm and heat-evoked pain) or decreasing (cold and cold-evoked pain) thermal stimulus until the patient pressed the response button to show that a temperature change was felt by the patient. Student t test was used to compare thresholds in patients and control patients. RESULTS The cold-evoked pain threshold in patients with CRPSD1/RSD (p

Paramyotonia congenita (PC) is an autosomal-dominant disorder due to a point mutation in the adult skeletal muscle Na channel gene. Muscle fibers from PC patients have normal membrane properties at 32 degrees C. At 27 degrees C, they are inexcitable, have increased Na conductance, and have a reduced resting membrane potential of -40 mV. To define the biophysical basis for the muscle membrane abnormalities, we performed patch clamp whole-cell and outside-out single Na channel studies at 22 degrees C on cultured human muscle cells from 4 control patients and 2 sisters with PC and the thr1313met mutant Na channel. The whole-cell studies showed no difference in window currents. Unlike cells transfected with the thr1313met mutant Na channel, the inactivation time constant, tau(h), for PC cells was similar to control cells. For PC recordings containing long-duration single Na channel openings, mean open time was prolonged at -60, -40, and -20 mV. The long-duration Na channel openings occurred randomly with no evidence of modal gating. The number of channel openings, occurrence of late openings, and the prolonged mean open time resulted in a sustained inward Na current at -40 mV. We suggest that the biophysical marker of the thr1313met mutant Na channel is a voltage- and temperature-dependent abnormality in mutant single Na channel behavior.

We present a family with severe exercise intolerance, progressive proximal weakness, and lactic acidemia. Fifteen of 24 family members in five generations were affected. Since the affected males do not have offspring at this time, the family pedigree is consistent with either maternal or autosomal dominant inheritance. Muscle histochemistry showed ragged-red fibers and electron microscopy showed globular mitochondrial inclusions. Biochemical analysis showed reduced muscle activities of mitochondrial NADH-cytochrome c reductase (1 of 2 patients), succinate-cytochrome c reductase (2 patients), and cytochrome c oxidase (2 patients). For 1 patient, sequence analysis of 44% of the muscle mitochondrial DNA including all 22 transfer RNA regions showed no point mutation with pathogenic significance. Southern blot analysis showed no deletion. Six affected members of the family were treated with methylprednisolone (0.25 mg/kg) for 3 months. Muscle strength, serum lactate, and energy metabolism at rest (measured by 31P magnetic resonance spectroscopy) significantly improved with treatment. © 1997 John Wiley & Sons, Inc. Muscle Nerve20: 1219–1224, 1997

Fourteen patients were identified with (1) pain and sensory changes in a brachial plexus distribution, (2) aggravation of pain with use of the affected extremity, and (3) pain on palpation over the brachial plexus. All patients had minimal or no intrinsic hand muscle atrophy. Only one patient had cervical ribs. Nerve conduction studies were normal, and electromyography (EMG) showed mild chronic neuropathic changes in 2 patients. None of the patients responded to conservative therapy over a prolonged period (7-12 months). A compressive brachial plexopathy from abnormally attached or enlarged scalene muscles that affected both upper and lower trunks of the brachial plexus was found at surgery in all patients. In 13 patients, at least one fibrous band compressed the lower trunk of the brachial plexus. Therefore, neurogenic thoracic outlet syndrome can occur from cervical bands and scalene muscle anomalies without intrinsic hand muscle atrophy, cervical ribs, enlarged C7 transverse processes, or EMG abnormalities.

IgM M-proteins in some motor neuron disease (MND) patients bind immunologically to shared determinants on gangliosides GM1 and GD1b. Since patients with these M-proteins have improved with immunotherapy the antibodies may be important in the pathogenesis of MND. To study how the M-proteins might damage motor neurons, we established co-cultures of human neurons from spinal cord explants and human myotubes. Antibodies from patient but not control serum bound to the cultured neurons. Neurons in co-cultures degenerated after incubation with patient but not control serum. These results demonstrate that anti-GM1 antibodies can bind to and destroy spinal cord neurons that are cultured with muscle. Nerve-muscle co-cultures can serve as a system to examine effects of anti-GM1/GD1b M-proteins on motor neurons.

Although swallowing difficulties (dysphagia) frequently occur in acute brainstem infarction, physiological studies of dysphagia (videofluoroscopy, manometry) are rarely reported. We present a patient with ipsilateral Horner's syndrome, palatal and laryngeal weakness, aphagia, and ipsilateral face and contralateral extremity pin and temperature loss due to lateral medullary infarction confined to the rostral dorsolateral medulla (RDM). Videofluoroscopy showed that the patient was unable to initiate a swallow. Manometry showed a markedly reduced peak pharyngeal pressure and weak pharyngeal contractions. Within 20 months, the patient's neurological deficits resolved, videofluoroscopy showed a normal swallow, and manometry showed normal peak pharyngeal pressure. Correlation of the clinical, physiological, and imaging evaluations shows that aphagia and severe bilateral pharyngeal paresis can result from unilateral RDM infarction. We suggest that, in man, the bilateral medullary swallowing centers function as one integrated center, and that infarction of a portion of this center is sufficient to cause complete loss of swallowing.

To redefine the utility of CSF-ACE as a selective indicator of probable CNS neurosarcoidosis.The diagnosis of probable CNS neurosarcoidosis required: (a) biopsy evidence of systemic sarcoidosis, (b) cortical, brainstem, and/or spinal cord deficits, (c) enhancing lesions on brain and/or spinal cord MRI, and (d) exclusion of other etiologies which could account for the neurological deficits. Radioassay measurement of CSF-ACE activity was performed in 11 patients who met our criteria for probable CNS neurosarcoidosis and 207 control patients.The M +/- SD for CSF-ACE activity was significantly higher (p0.05) for the 11 probable CNS neurosarcoidosis patients (9.5 +/- 6.9 nmol/mL/min) than for the control patients (2.9 +/- 2.7 nmol/mL/min). The optimal CSF-ACE activity discriminator value was 8 nmol/mL/min. At this value, the sensitivity and specificity of CSF-ACE activity was 55% and 94%, respectively.CSF-ACE activity is a useful biochemical marker of probable CNS neurosarcoidosis when brain and/or spinal cord MRI show diffuse enhancing lesions.

We performed a retrospective study of 29 patients with CRPS1 (RSD) who were initially examined between 1983 and 1993, and had either transthoracic (lower third of stellate ganglia to T3) or lumbar (L2-L4) sympathectomy. The patients were followed from 24 to 108 months after surgery. Patients with unsuccessful surgical outcomes had significantly longer duration of symptoms before surgery (median, 36 months) than those with successful outcomes (median, 16 months) by Wilcoxon rank sum test (chi2=8.69, df=1, P0.01). All seven patients (100%) who had sympathectomy within 12 months of injury, nine of 13 patients (69.2%) who had sympathectomy within 24 months of injury, and only four of nine patients (44.4%) who had sympathectomy after 24 months of injury obtained permanent (greater than 24 months) symptom relief. Patient age, sex, occupation, site of injury, type of injury, presence of trophic changes, and duration of follow-up were not significantly related (P0.05) to surgical outcome.

Mutations of the skeletal muscle sodium (Na) channel have been reported in families with paramyotonia congenita (PC), an autosomal dominant disorder with cold and/or exercise induced stiffness and myotonia. Functional consequences of specific Na channel mutations responsible for PC have not been described. Patch clamp recording of single Na channels were made in cultured myotubes at 22 and 34 degrees C from a PC patient with the thr1313met mutation. Cell-attached and outside-out recordings of mutant PC channels contained long duration and late openings. The mean open time was increased and the ensemble average showed a prolonged inward Na current. This membrane depolarization could cause repetitive action potentials and the clinical syndrome.

Background: Reflex sympathetic dystrophy (RSD) is a poorly understood syndrome of post-traumatic pain, autonomic dysfunction, and progressive tissue atrophy, Classical descriptions of the cutaneous manifestations of RSD are usually limited to skin atrophy, vascular instability, and hyperhidrosis. Objective: Our objective was to further delineate the cutaneous changes in RSD. Methods: We have observed RSD-related inflammatory and bullous lesions in nine patients with active RSD. Results: Eight patients had significant edema of involved skin, two patients had evidence of a pigmented purpura-like inflammatory dermatitis, and two other patients had bullae on involved skin, Ultrastructural studies on a biopsy specimen from one patient with recurrent bullae revealed a disrupted basement membrane and abnormal anchoring fibrils. Conclusion: Skin disease in RSD is more diverse than commonly appreciated and includes severe edema, inflammatory lesions, and a nonimmune bullous eruption.

In 1989, the Centers for Disease Control recognized the existence of an epidemic illness characterized by myalgia and eosinophilia in individuals taking preparations containing L-tryptophan. We evaluated 3 patients with eosinophilia-myalgia syndrome who presented with subacute progressive neuropathies. The neuropathies were predominantly motor and maximal in the lower extremities. Two patients were confined to a wheelchair and one was ventilator-dependent and bedridden. Sensory loss predominantly involved small fiber modalities. Electrophysiological studies showed multifocal marked conduction slowing and conduction block indicating segmental demyelination, with associated axonal degeneration that was accentuated distally. Examination of sural nerve biopsy specimens demonstrated axonal degeneration in all 3 patients and perivascular infiltrates in 2. Levels of quinolinic acid, a neurotoxic metabolite of L-tryptophan, were elevated in the cerebrospinal fluid in the 2 patients in whom it was measured. The cause of the neuropathy is unknown but may include immune mechanisms or toxicity of eosinophils, L-tryptophan, its metabolic products, or contaminants within L-tryptophan preparations.

We followed a patient with a lower motor neuron form of motor neuron disease whose neurologic disorder improved following immunotherapy. The patient did not have an M protein but did have IgM antibodies to ganglioside GM1 detectable at serum titers of 1:2,000 by ELISA. These antibodies were found only in the IgM fraction with lambda light chains and immunoreacted with GD1b and Gal (beta 1-3) GalNAc.

This study measured the warm, cold, heat-evoked pain threshold and the cold-evoked pain threshold in the affected area of 16 control patients and patients with complex regional pain syndrome type 1/RSD (CRPSD1) to test the hypothesis that allodynia results from an abnormality in sensory physiology. The cold-evoked pain threshold in patients with CRPSD1/RSD was significantly decreased when compared with the thresholds in control patients (ie, a smaller decrease in temperature was necessary to elicit cold-pain in patients with CRPSD1/RSD than in control patients). The heat-evoked pain threshold in patients with CRPSD1/RSD was decreased significantly when compared with thresholds in control patients. The warm-detection and cold-detection thresholds in patients with CRPS1/RSD were similar to the thresholds in control patients. Conclude that the study suggests that thermal allodynia in patients with CRPS1/RSD resulted from decreased cold-evoked and heat-evoked pain thresholds. The thermal pain thresholds are reset so that non-noxious thermal stimuli are perceived to be pain (allodynia).

We report nine patients with muscle aching, cramps, stiffness, exercise intolerance, and peripheral nerve hyperexcitability. Neurologic examination showed calf fasciculations in seven, quadriceps myokymia in two, and deltoid myokymia in one patient. Two patients had mild increase in serum creatine kinase. Muscle biopsy showed either no abnormality (three patients) or mild neurogenic changes (four patients). Fasciculations were the only abnormality on routine electrodiagnostic studies. Supramaximal stimulation of the median, ulnar, peroneal, and posterior tibial nerves at frequencies of 0.5, 1, 2, and 5 Hz produced showers of electrical potentials following the M response in at least one nerve. In three patients, the fasciculations and evoked electrical potentials were abolished by regional application of curare but not nerve block. Carbamazepine therapy caused moderate-to-marked reduction of symptoms and nerve hyperexcitability. We designate this hyperexcitable peripheral nerve disorder as the "cramp-fasciculation syndrome."

A reflective transducer which combines a gallium arsenide infrared emitting diode and silicon phototransistor has been adapted for use us a photoelectric plethysmograph. This device is inexpensive, compact, and easily applied to the skin surface. The phototransistor responds in a linear fashion to the range of light intensities generally obtained from normal subjects, and the phototransistor output is relatively independent of both temperature and prior light exposure. The light source possesses a narrow spectral distribution in the infrared region. These characteristics suggest that the LKD-transistor photoplethysmograph is superior to the miniature tungsten lump-photoconductive cell combination generally employed in photoplethysmography.

To evaluate malignant hyperthermia (MH) susceptibility in X-linked muscular dystrophies, halothane and caffeine contracture tests were performed on muscle fiber bundles from five patients with Duchenne muscular dystrophy (DMD) and two patients with Becker muscular dystrophy (BMD). Two DMD patients and one BMD patient had positive contracture tests. Since a positive contracture test is currently the best indicator of anesthetic susceptibility in the MH population, and episodes of MH in dystrophic patients have been reported, patients with DMD and BMD may be at risk for developing similar anesthetic complications. Awareness of this potential anesthetic risk is of importance because orthopedic interventions are increasingly more common in these patients.

The King-Denborough syndrome (KDS) is characterized by dysmorphic features, myopathy, and malignant hyperthermia (MH). Physiologic contracture testing for MH susceptibility has not been reported in KDS. A young boy with KDS underwent muscle biopsy evaluation at age 3 years that documented an abnormal contracture response to halothane, indicating MH susceptibility. Histopathology demonstrated small type II fibers associated with type I hypertrophy. Contracture testing of muscle obtained from the patient's mother was positive, while a sibling's test was negative. This case is the first to demonstrate susceptibility to MH with KDS by using physiologic contracture testing. The presence of positive MH results in both the patient and his mother suggest one of the following: (1) KDS may be part of the spectrum of autosomal dominantly inherited MH; (2) the locus for MH and for KDS may be linked closely and inherited concurrently, or; (3) the association of MH and KDS may be coincidental.

A commercial transducer combining a gallium arsenide infrared emitting diode and silicon phototransistor has been adapted for use as a photoelectric plethysmograph. This device is superior to the tungsten lamp-photoconductive cell plethysmograph generally available.

Anti-MAG IgM antibodies were detected by ELISA in a patient with slowly progressive peripheral neuropathy. Serum IgM content was normal, and no M-protein was detected by serum protein electrophoresis, immunoelectrophoresis, or immunostaining. By immunoblot analysis, the anti-MAG antibodies were IgMk; they reacted with human and bovine MAG but not with mouse MAG. The data suggest that there was an anti-MAG IgM M-protein in concentration too low to be detected by conventional techniques. Tests for anti-MAG antibodies should be done in patients with slowly progressive neuropathy of unknown etiology, even in the absence of detectable serum M-protein.

Fifty-nine percent of 49 patients with motor neuron disease and 25% of 91 control subjects had IgM antibodies to ganglioside GM1 but usually not to GD1b at titers less than 1:80. This suggests that antibodies to GM1 may be part of the normal human antibody repertoire. However, given the higher incidence of antibodies to GM1 in patients with motor neuron disease, there may be specific epitopes important in antiganglioside antibodies associated with motor neuron disease.

We report a family in which two sisters with myotonia congenita (MyC) were referred for malignant hyperthermia (MH) evaluation after each developed muscle rigidity with anesthesia. Halothane contracture testing of skeletal muscle in both was consistent with MH susceptibility. A third sister without clinical evidence of MyC was negative on contracture testing. These results suggest an association between MyC and MH susceptibility.

An in vitro model system was designed to permit simultaneous measurements of blood flow, blood pressure, and the pulsatile radiometric signal during flow studies with Ringer's solution and blood of hematocrit 32,41, and 51. When the in vitro system contained a cat carotid artery, increases in blood flow were associated with increases in the pulsatile radiometric signal. Changes in the pulsatile radiometric signal were linearly related to changes in mean flow and highly correlated with changes in the pulsatile flow, mean pressure, and pulsatile pressure. Results from the regression analyses suggest that the pulsatile radiometric signal may be attributed to reflection from the artery wall. When the in vitro system contained a glass cell, increases in blood flow were associated with decreases in the pulsatile radiometric signal. There was an inverse linear relationship between the pulsatile radiometric signal and mean flow, and changes in the pulsatile radiometric signal were highly and inversely correlated with changes in pulsatile flow and pulsatile pressure. These results suggest that when recording over the cutaneous microcirculation, the pulsatile radiometric signal is in part due to changes in the red blood cell scattering and absorption coefficients.

The electroencephalogram, electromyogram, and electro-oculogram were recorded during wakefulness and sleep from two patients with palatal myoclonus. The myoclonus of branchial muscles was persistently present and irregularly varied around a fixed frequency. Its amplitude varied directly with the amplitude of background EMG activity both during wakefulness and in sleep. The complex abnormal ocular movements occurred at the same frequency as the branchial myoclonus. They disappeared during sleep to return during desynchronized sleep following a rapid eye movement. Voluntary extremity movements provoked in them a rhythmical myoclonus of identical frequency to the simultaneously recorded branchial myoclonus. These observations suggest that voluntary or involuntary muscle activity is necessary for the expression of palatal myoclonus and that the abnormal branchial muscle, ocular, and extremity movements are caused by a common pathophysiologic mechanism.

• Electrophysiological studies were performed on aneurally cultured muscle cells from one patient with adult-onset acid maltase deficiency (AAMD) and from controls. The cells from the patient with AAMD had a higher mean resting membrane potential, a lower input resistance, and a higher incidence of action potentials at resting membrane potential than the control cells. Therefore, sarcolemma maturation was not adversely affected. The AAMD cells had membrane thresholds and action potential amplitudes similar to those of the control cells, and rarely produced repetitive action potentials. Therefore, the membrane instability noted in adult muscle fibers from the patient with AAMD was not present in cultured cells. This study does not support the suggestion that the biochemical and morphological abnormalities present in muscle fibers of patients with AAMD are sufficient to cause the electrical abnormalities.

• Hartnup disease is a rare genetic disorder of amino acid transport associated with variable and intermittent clinical abnormalities. A family is described in which three siblings had an intermittently progressive neurological disease and two of the affected siblings had the Hartnup-pattern aminoaciduria. Neuropathological examination of one case showed severe diffuse atrophy, generalized neuronal loss in the cortex, and Purkinje cell loss in the cerebellum. In vivo and in vitro studies of intestinal amino acid transport in the surviving sibling indicated a partial defect in the transport of several neutral amino acids (tryptophan, alanine, serine, and methionine) with normal transport of other neutral amino acids (threonine, phenylalanine, histidine, tyrosine, and isoleucine). Transport of glycine, proline, hydroxyproline, and the basic amino acids appeared normal.