Search

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: To redefine the utility of CSF-ACE as a selective indicator of probable CNS neurosarcoidosis., Methods: 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., Results: The M +/- SD for CSF-ACE activity was significantly higher (p < 0.05) 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., Conclusions: CSF-ACE activity is a useful biochemical marker of probable CNS neurosarcoidosis when brain and/or spinal cord MRI show diffuse enhancing lesions.

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 <0.001) was significantly decreased when compared with the thresholds in control patients (i.e., 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 CRPS1/RSD was (p <0.05) decreased significantly when compared with thresholds in control patients. The warm- and cold-detection thresholds in patients with CRPS1/RSD were similar to the thresholds in control patients., Conclusions: This study suggests that thermal allodynia in patients with CRPS1/RSD results from decreased cold-evoked and heat-evoked pain thresholds. The thermal pain thresholds are reset (decreased) so that non-noxious thermal stimuli are perceived to be pain (allodynia).

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., (Copyright 2000 John Wiley & Sons, Inc.)

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.

Patients with diabetic amyotrophy may have an inflammatory vasculopathy and may obtain reversal of neurological deficits with immunosuppression. We present a patient with NIDDM, subacute onset of painful asymmetric polyradiculopathy, and unilateral enhancement of lumbar nerve roots on MRI. Clinical improvement and resolution of nerve root enhancement occurred with immunosuppression. We suggest, therefore, that nerve biopsy and gadolinum-enhanced lumbosacral MRI be performed in all patients presenting with diabetic amyotrophy. If nerve root enhancement is present or if nerve biopsy shows perivascular infiltrates, we recommend a trial of immunosuppression.

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.

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, P<0.01). 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 (P>0.05) to surgical outcome.

Purpose: To determine the appearance of reflex sympathetic dystrophy (RSD) at magnetic resonance (MR) imaging., Materials and Methods: Fifty-one patients with suspected RSD were prospectively evaluated at MR imaging with T1- and T2-weighted sequences and T1-weighted sequences with fat suppression before and after the intravenous administration of contrast material., Results: RSD was confirmed in 45 patients. In 35 patients with stage 1 RSD, skin thickening (31 patients), tissue enhancement with contrast material (31 patients), and soft-tissue edema (six patients) were demonstrated. In five patients with stage 2 RSD, skin thickening (two patients), skin thinning (two patients), and infrequent contrast material enhancement (one patient) were demonstrated. There was no edema in this group of patients. In five patients with stage 3 RSD, inconsistent skin changes were also demonstrated; however, muscle atrophy (four patients) was demonstrated in this stage only., Conclusion: MR imaging was beneficial in the demonstration of soft-tissue abnormalities in patients with RSD. MR imaging may also help stage RSD, particularly stages 1 and 3.

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.

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.

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.

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.

Since the relationships between traditional assessments in ALS patients have not been defined, three clinical and four electrophysiological assessments were performed in a cross-sectional study of 87 ALS patients. The clinical assessments produced Norris ALS scores, muscle strength scores and illness durations (DUR). The electrophysiological assessments produced scores for motor unit interference pattern, denervation potentials, compound muscle action potential, and fasciculations. The individual muscle scores were averaged to produce mean scores, and Spearman rank correlations were performed on the mean scores. The association between Norris ALS and mean muscle strength (MMS) scores is significant (p less than .001, rs = 0.84), and these scores are significantly correlated with mean interference pattern (0.77, 0.82), mean denervation potential (-0.63, -0.70), and mean compound muscle action potential scores (0.55, 0.60), respectively. Correlations between IP and DP scores (-0.71), IP and CMAP scores (0.62), and DP and CMAP (-0.56) scores are also significant. Scatterplots of the data and regression lines suggest linear relationships between each of these assessments. Illness duration and fasciculation scores are not strongly correlated (rs less than 0.55) with any of the other clinical or electrophysiological assessments.

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."

Electrophysiologic studies were performed on aneurally cultured human muscle cells from seven patients with myotonic muscular atrophy and seven controls. There was no significant difference in resting membrane potential. When the cells were hyperpolarized to -80 mV, there was no significant difference in effective membrane resistance, effective membrane capacitance, normalized membrane conductance, membrane threshold, action potential amplitude, or maximum rate of rise of the action potential. Repetitive discharges were elicited by anodal-break excitation in a few cells from each group. We found no evidence that cultured myotonic atrophy muscle cells are electrically different from control cells.

Previous studies in cat, rat, and swine have implicated fiber type as influencing the halothane and caffeine contracture test used to diagnose malignant hyperthermia (MH). The authors performed fiber type analysis using myosin ATPase stains on 31 fascicles of skeletal muscle from nine patients following contracture testing. There was no significant difference in fiber type composition between fascicles from MH negative (n = 5) and MH positive (n = 4) patients. Furthermore, examining each of the 31 fascicles, the authors found no correlation (P greater than .05) of contracture magnitude with percentage of either Type I or Type II fibers using the Pearson Product-Moment correlation calculation. The authors conclude that fiber type composition does not influence contracture test results in human biopsies.

The association of malignant hyperthermia (MH) with neuromuscular disorders has been recognized since 1970. These disorders include central core disease, Duchenne muscular dystrophy, myotonia congenita, myotonic dystrophy, nonspecific myopathies, and King-Denborough syndrome. In order to assess the anesthetic risk of MH in the neuromuscular population, we performed halothane and caffeine contracture testing for MH susceptibility on biopsied muscle removed from 25 consecutive neuromuscular patients during diagnostic evaluation. Positive contracture tests were found in 7 of 18 patients with myopathic disorders and 3 of 7 patients with neurogenic disorders. Two of our patients had anesthetic events suggesting MH. These findings suggest that myopathic and neuropathic disorders share pathogenic mechanisms with MH, resulting in positive contracture tests and possibly leading to clinical events during anesthesia. Although there is controversy regarding the interpretation of a positive contracture test, contracture testing remains the most widely accepted test for MH susceptibility. Thus, a variety of neuromuscular disorders may be associated with MH susceptibility, and caution should be exercised during anesthesia in this group of patients.

1. Step torque perturbations were applied to flex or extend the wrists of normal human subjects who were instructed to restore the joint to its initial position as quickly as possible. The resulting electromyographic (EMG) activity was recorded from the flexor carpi radialis, flexor carpi ulnaris, and extensor carpi radialis. Experiments were performed under control and three altered conditions of the limb: 1) ischemia, 2) vibration, and 3) local ulnar nerve anesthesia. The effects of the procedures on the EMG responses in four poststimulus intervals--the myotatic (30-60 ms), late myotatic (60-120 ms), postmyotatic (120-200 ms), and stabilizing (200-400 ms)--were studied. 2. Ischemia was induced in the forearm by means of a sphygmomanometer cuff inflated to 150 mm of mercury around the upper arm. After about 20 min of ischemia the stretch-evoked EMG activity over the 30-60-ms and 60-120-ms intervals were abolished, while the longer latency responses persisted. 3. Vibration at frequencies between 50 and 120 Hz was applied to the tendon of the stretched muscle. Vibration consistently reduced the EMG activity only in the 30-60-ms interval. 4. The ulnar nerve was blocked near the elbow joint by local anesthetic. Varying degrees of block were obtained, from a mild sensory impairment to a complete block. At intermediate degrees of block, EMG activity in the 30-60-ms and 60-120-ms intervals were attenuated with little alteration in later responses. 5. The data are used to differentiate functionally the myoelectric responses evoked in four poststimulus time segments in the stretched muscle by step torque perturbations.

Application of external torque to cause joint rotation evokes electromyogram (EMG) activity in the stretched muscles. These responses were studied in the tibialis anterior (TA) and flexor carpi ulnaris (FCU) muscles of normal human subjects in conjunction with a nerve block procedure by a local anesthetic agent. In both muscles, differences were observed between the myotatic and postmyotatic portions of the evoked EMG response. During recovery from a complete nerve block, the late components of the EMG (postmyotatic and stabilizing responses) recovered to the preblock magnitude faster than the early components (myotatic and late myotatic responses). Following partial nerve block, the late EMG components were diminished to a lesser extent and recovered faster than the early EMG components. This study suggests that peripheral afferent inputs are obligatory for the myotatic and late myotatic EMG responses. The effects of peripheral afferent inputs on postmyotatic responses are to modulate these later responses. However, the absence of peripheral afferent inputs will not prevent or even delay postmyotatic responses.

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.

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.

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.

In this report, the following criteria were used for the diagnosis of causalgia: (a) the presence of continuous, burning pain distal to a site of injury; (b) hyperalgesia and allodynia in the painful area; and (c) a traumatic event occurring proximal in the painful area and within weeks prior to the onset of pain. The McGill pain questionnaire was used to test the selected pain population for homogeneity. The scores were similar among the patients and different from the scores in other pain syndromes. It is concluded that the above criteria are sufficient to make the diagnosis of causalgia. In addition, it appears that a central nervous system abnormality best accounts for the clinical features of causalgia.

To test the hypothesis that causalgia is a reflex sympathetic dystrophy with focal sympathetic hyperactivity in the painful area, we studied skin conductance, temperature, and a radiometric index of blood flow in 10 patients and 10 controls. Skin conductance was significantly higher, and both skin temperature and blood flow index were significantly lower in the patient extremities. When the affected and homologous, non-affected extremity values were compared, asymmetries were more common and of larger magnitude in the patient group. There was no consistent pattern of asymmetry. These results do not support the hypothesis that causalgia is a reflex sympathetic dystrophy.

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.

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.

Laser Doppler measurements of skeletal muscle blood flow were performed in 12 patients with neuromuscular disorders and 6 controls. The mean resting blood flows and postocclusive reactive hyperemias were similar for the patients with neuropathic disorders and for controls. The patients with myopathic disorders had higher resting muscle blood flows and reactive hyperemias. Correlation of blood flow results and muscle biopsy characteristics suggested that muscle type grouping was not associated with a change in skeletal muscle blood flow, whereas muscle fiber degeneration was associated with an increased blood flow.