Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease.

Hereditary rippling muscle disease (RMD) is an autosomal dominant human disorder characterized by mechanically triggered contractions of skeletal muscle. Genome-wide linkage analysis has identified an RMD locus on chromosome 3p25. We found missense mutations in positional candidate CAV3 (encoding caveolin 3; ref. 5) in all five families analyzed. Mutations in CAV3 have also been described in limb-girdle muscular dystrophy type 1C (LGMD1C; refs. 6,7), demonstrating the allelism of dystrophic and non-dystrophic muscle diseases.

Myotonia congenita and myotonic dystrophy in the same family: coexistence of a CLCN1 mutation and expansion in the CNBP (ZNF9) gene.

Myotonia is characterized by hyperexcitability of the muscle cell membrane. Myotonic disorders are divided into two main categories: non-dystrophic and dystrophic myotonias. The non-dystrophic myotonias involve solely the muscle system, whereas the dystrophic myotonias are characterized by multisystem involvement and additional muscle weakness. Each category is further subdivided into different groups according to additional clinical features or/and underlying genetic defects. However, the phenotypes and the pathological mechanisms of these myotonic disorders are still not entirely understood. Currently, four genes are identified to be involved in myotonia: the muscle voltage-gated sodium and chloride channel genes SCN4A and CLCN1, the myotonic dystrophy protein kinase (DMPK) gene, and the CCHC-type zinc finger, nucleic acid binding protein gene CNBP. Additional gene(s) and/or modifying factor(s) remain to be identified. In this study, we investigated a large Norwegian family with clinically different presentations of myotonic disorders. Molecular analysis revealed CCTG repeat expansions in the CNBP gene in all affected members, confirming that they have myotonic dystrophy type 2. However, a CLCN1 mutation c.1238C>G, causing p.Phe413Cys, was also identified in several affected family members. Heterozygosity for p.Phe413Cys seems to exaggerate the severity of myotonia and thereby, to some degree, contributing to the pronounced variability in the myotonic phenotype in this family.

Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia.

Myotonia congenita is a non-dystrophic muscle disorder affecting the excitability of the skeletal muscle membrane. It can be inherited either as an autosomal dominant (Thomsen's myotonia) or an autosomal recessive (Becker's myotonia) trait. Both types are characterised by myotonia (muscle stiffness) and muscular hypertrophy, and are caused by mutations in the muscle chloride channel gene, CLCN1. At least 50 different CLCN1 mutations have been described worldwide, but in many studies only about half of the patients showed mutations in CLCN1. Limitations in the mutation detection methods and genetic heterogeneity might be explanations. In the current study, we sequenced the entire CLCN1 gene in 15 Northern Norwegian and three Northern Swedish MC families. Our data show a high prevalence of myotonia congenita in Northern Norway similar to Northern Finland, but with a much higher degree of mutation heterogeneity. In total, eight different mutations and three polymorphisms (T87T, D718D, and P727L) were detected. Three mutations (F287S, A331T, and 2284+5C>T) were novel while the others (IVS1+3A>T, 979G>A, F413C, A531V, and R894X) have been reported previously. The mutations F413C, A531V, and R894X predominated in our patient material. Compound heterozygosity for A531V/R894X was the predominant genotype. In two probands, three mutations cosegregated with myotonia. No CLCN1 mutations were identified in two families. Our data support the presence of genetic heterogeneity and additional modifying factors in myotonia congenita.

Cerebral computed tomography and electroencephalography compared with neuropsychological findings in systemic lupus erythematosus.

Central nervous system involvement was evaluated in 36 patients with systemic lupus erythematosus (SLE) using cerebral computed tomography (CT), electroencephalography (EEG), and a neuropsychological test battery. The purpose was to investigate whether brain dysfunction as assessed by comprehensive neuropsychological investigation is associated with findings of routine investigation methods such as CT and EEG which are available in most hospitals. Abnormal EEG was found in 19%, and CT revealed cerebral atrophy in 47% of SLE patients. Few neuropsychological functions were affected by the presence of abnormal EEG, cerebral atrophy, or infarcts. Significant associations were found only between cortical atrophy and impairment of tactile spatial problem-solving and motor dexterity, and between cortical infarcts and motor dexterity in the dominant hand. The value of conventional EEG in assessing cerebral SLE is negligible, except for identifying epileptic activity and focal pathology. Cerebral CT has little relevance in predicting brain dysfunction as established by neuropsychological assessment in SLE, except for detecting cortical atrophy and infarcts.

A rare form of painful nondystrophic myotonia.

OBJECTIVE: In this paper we report a painful nondystrophic myotonia which has not been previously described. Pain is a rare symptom in myotonia. We report a myotonic disorder in a 34-year-old woman and her 14-year-old daughter. Painful cramps occur during and after exercise in the mother, and both patients can demonstrate unusual contractions in the tongue. In the present study we try to evaluate the mechanisms behind the unique finding of trains of high amplitude of positive waves, not seen in the earlier known myotonic conditions. METHODS: Clinical investigations and electromyography with single and dual channel recordings and muscle morphometry were performed. RESULTS: The electromyographic recordings reveal positive waves, fibrillation potentials and myotonic discharges. In addition, extraordinary findings were made of trains of high frequency positive potentials with very high amplitudes and with conduction block along the muscle fibres. CONCLUSIONS: In this new form of myotonia with likely dominant heredity, the specific finding of trains of high amplitude positive waves indicates ephaptic transmission within bundles of neighbouring muscle fibres.

Quantitative magnetic resonance imaging and the electrophysiology of the carpal tunnel region in floor cleaners.

OBJECTIVES: The purpose of this study was to evaluate possible structural changes of the wrist and subclinical damage in the median nerves of healthy floor cleaners. METHODS: Twenty-four cleaners and 19 referents (noncleaners), all women, underwent bilateral magnetic resonance (MR) wrist examination and nerve conduction studies. They were all randomly selected from an occupational health service. From MR images the volumes of the wrist, carpal tunnel, and thenar and hypothenar muscles were calculated, as well as the signal intensity of the median nerve, bilaterally. RESULTS: No significant difference in the volume of the carpal tunnel was found in the two groups. The relative signal intensity of the median nerve was 0.55 for the cleaners and 0.48 for the referents (P = 0.05). The mean nerve conduction velocity values were 55.2 m.s-1 for the right median nerve of the cleaners and 57.4 m.s-1 for the right median nerve of the referents (P = 0.03). The median nerve of the cleaners had a mean sensory amplitude of 128.2 microV compared with 162.8 microV for the referents (P = 0.01). There was a tendency towards a longer distal latency of the median nerve in the cleaner group. CONCLUSIONS: This study revealed subclinical intrinsic damage to the median nerve, as demonstrated by MR, and poorer electrophysiological nerve function among workers at high risk (cleaners) compared with workers at lower risk (noncleaners).

Non-convulsive status epilepticus in the adult mentally retarded. Classification and role of benzodiazepines.

Non-convulsive status epilepticus (NCS) is rarely encountered and may appear with a psychiatric mask. As clouding of consciousness is the major ictal manifestation, the condition may easily be overlooked in the mentally retarded. We have studied 11 mentally retarded patients with NCS. Since NCS with a focal onset may have a generalized ictal EEG pattern, a classification of NCS solely based on the seizure classification may be misleading. In some patients, it is impossible, both clinically and on the basis of EEG recordings, to distinguish between continuous complex partial seizures and atypical absences. We therefore propose a revised classification of NCS based on the ictal EEG pattern and the epilepsy syndrome diagnosis (I) NCS in generalized epilepsy syndromes, (II) NCS in localization-related epilepsy, (a) with localized EEG features, (b) with generalized EEG features, and (c) with transitional EEG features, and (III) undetermined NCS. Four of our patients were classified as Group I, two as Group IIa, one as Group IIb, one as Group IIc, and three as Group III. Benzodiazepines at small or standard doses may be ineffective in terminating NCS, particularly in the Lennox-Gastaut Syndrome. The identification of trigger factors is essential. Drugs seemed to be the most important precipitants in our patients; in three, NCS was induced by recurrent rectal diazepam over-administration. This complication of rectal diazepam treatment in epilepsy has not been addressed previously.

Bilateral fast MR imaging of the rheumatoid wrist.

To evaluate the structural changes in the carpal tunnel and possible intrinsic median nerve damages in RA patients, quantitative bilateral magnetic resonance imaging (MRI) of the wrists was performed by means of a fast imaging sequence. Thirty-three women with RA and 42 controls were examined. The length of the carpal tunnel, the carpal tunnel volume/wrist volume (CTV/WV) ratio and the signal intensity of the nerve were calculated in both groups, bilaterally. The CTV/WV ratio was 0.12 in the patients and 0.11 in the control group (p = 0.007). A negative association was found between disease duration and carpal tunnel volume/wrist volume ratio (p = 0.049). Mean distal latency in the right motor median nerve was 3.0 +/- 0.4 msec (patients) and 3.4 +/- 0.6 msec (controls) (p = 0.002). Mean values in the right sensory branch were 1.2 +/- 0.1 msec (patients) and 1.4 +/- 0.3 (controls) (p = 0.01). The lack of association between the size of the carpal canal and neurophysiological parameters found in this study may suggest a possible protection of the median nerve by the increased canal size in patients with RA.

The rheumatoid wrist: bilateral MR analysis of the distribution of rheumatoid lesions in axial plan in a female population.

In this case-control study, we analyzed 146 wrists: a) to search for the distribution pattern of the rheumatoid lesions and, b) to correlate the distribution pattern of these lesions with the clinical parameters. Thirty-one patients with rheumatoid arthritis (RA) and 42 controls-all women-were examined by means of a bilateral MR fast field echo (FFE) sequence, in axial plan. The wrist was divided into three regions: metacarpal (level I), carpal (level II) and radioulnar (level III). Erosions were present in thirty (97%) patients and in six (14%) controls. They were asymmetrically distributed at all levels, mainly at level II. Marrow infiltration and bone destruction were seen in 35% of the patients in an asymmetrical pattern at level I and II, respectively. These lesions were absent in the control group. Subchondral cysts were asymmetrically present in both groups-in 48% of the patients at levels II and III, and in 11% of the controls at level II. In the patient group, this asymmetrical pattern of the lesions correlated with the disease duration at levels I and II (p = 0.011 and p = 0.013, respectively). Most lesions were found at the radial force-bearing column of the wrist, more in the right side. Synovial hypertrophy and hyperintense median nerve were evident in 96% and 70% of the patients, respectively. We concluded that contrary to common belief rheumatoid damages to the carpal bones become rather asymmetrical as the disease progresses. The line of force along the radial side of the wrist possibly influences the distribution pattern of the rheumatoid lesions.

Increased risk of median nerve dysfunction in floor cleaners: a controlled clinical and neurophysiological study.

We studied median nerve involvement in a group of asymptomatic handworkers at risk for carpal tunnel syndrome, and we evaluated damage to thin and thick nerve fibres in the distribution area of the median nerve. Considering floor cleaners as workers at high risk of developing cumulative traumatic disorders in the wrist, we included 42 cleaners and 41 controls. We assessed nerve conduction studies, vibration threshold, and temperature and pain thresholds of the median nerve. The cleaners had significantly impaired motor nerve conduction velocity (p = 0.006), longer sensory distal latency (p = 0.01), lower sensory amplitude (p = 0.0005), and increased difference in heat and cold threshold of the median nerve (p = 0.0002). Increased temperature threshold was associated with prolonged sensory distal latency of the median nerve in the cleaners. In conclusion, impaired neurophysiological variables in the median nerve in floor cleaners compared with controls confirm the hypothesis that those workers are at risk of developing median nerve dysfunction. Sensory nerves seem to be more susceptible to injury than motor branches.

Combined testing of autonomic and sensory dysfunction in patients with unilateral facial flushing and sweating during exercise.

AIMS OF THE STUDY: Patients with unilateral facial flushing are occasionally referred to clinical neurophysiological evaluation with the question of the site of lesion. These patients may have a mixture of autonomic and sensory symptoms. We wanted to study to which extent a combined autonomic and sensory clinical neurophysiological testing before and after exercise may help in the diagnostic evaluation of the patients. PATIENTS AND METHODS: Five patients were investigated at rest with quantitative sensory thresholds (QST, measurement of thermal thresholds) and quantitative sudomotor axon reflex test (QSART) in all extremities. Sweet volumes (QSWEAT) and skin temperatures were then measured after 30 to 60 minutes of exercise. RESULTS: Marked side-to-side differences were observed for QST and QSART at rest as well as for QSWEAT and skin temperatures following exercise, in accordance with the patients' symptoms. However, asymptomatic abnormal findings were also demonstrated in the feet of four patients, following both crossed and non-crossed distributions. EMG/neurography and MRI-findings were normal in all patients and no aetiological explanations were found. CONCLUSION: Combined autonomic and sensory testing including the legs provided evidence of unexpectedly more widespread abnormalities, including asymptomatic findings. Although the patients presented with seemingly similar symptoms, there was a striking heterogeneity in their results, suggesting different sites of dysfunction. An extracranial lesion was considered likely in one or maybe two patients, while the possibility of a central lesion had to be considered in the three other patients.

Peripheral neuropathy caused by severe hypothermia.

OBJECTIVE: To report follow-up data in the evaluation of peripheral neuropathy in a 29-year old female after accidental deep hypothermia (13.7°C) in 1999. METHODS: Nerve conduction studies (NCS) and electromyography (EMG) were performed 20 days after the accident and again after 5 months and 1, 3, 5 and 11 years. Macro EMG was performed after 3, 5 and 11 years. To evaluate small fiber function, RR-interval, sympathetic skin response, quantitative sensory testing and skin biopsy for quantification of intra-epidermal nerve fiber density were performed in 2009. RESULTS: In the intensive care unit sensory and motor responses were absent except for the tibial nerves, and EMG showed profuse denervation. Improvement of amplitudes and conduction velocities was seen during the first 5 years. Muscular atrophy of hand muscles persisted. Large fibers were involved more extensively than small fibers. CONCLUSIONS: A severe axonal sensorimotor polyneuropathy developed in the intensive care unit following severe hypothermia. The mechanism was most likely cold injury to peripheral nerves. SIGNIFICANCE: The clinical picture and the laboratory findings indicate that even multi-organ dysfunction and, of specific interest in this study, a severe axonal degeneration may come to a good restitution after long time.

A family with dominant hereditary myotonia, muscular hypertrophy, and increased muscular irritability, distinct from myotonia congenita thomsen.

Myotonia is a symptom, which occurs in a series of hereditary diseases, and it is also seen in less frequently occurring syndromes. A summary is given of conditions with myotonia. Five cases are reported from a family with a dominant hereditary disease presenting myotonia, muscular hypertrophy and increased muscle irritability as the only symptoms. In the most affected patient, some unusual rolling muscle contractions are seen. Apart from a moderate increase of creatin kinase, supplementary examinations are normal. The clinical picture resembles myotonia congenita Thomsen, but differs from this in significant respects. Other diagnostic possibilities are also considered. It is concluded that the clinical picture is different from all previously described conditions.

Unusual response to extradural analgesia in the presence of an intradural spinal tumour.

A patient is presented in whom indications of the presence of an intradural, extramedullary tumour became apparent during the induction of an extradural block. It is suggested that a combination of signs should arouse suspicions of such a tumour close to the puncture site. Pain within an area covered by an extradural block does not indicate necessarily a supraspinal cause for the pain.

Audiologic findings in a family with mitochondrial disorder.

Mitochondrial disorder is an inborn error of metabolism affecting the cellular respiratory chain. Defective energy production leads to a wide variety of clinical manifestations (ataxia, epilepsy, dementia, myopathy, polyneuropathy, retinal pigment anomalies, and cardiomyopathy with conduction anomalies). Hearing loss is a regular feature and is often the first clinical symptom. Audiologic data from 26 members of a family in three generations is presented. One of these patients was examined for the biochemical error. Respiratory study of muscle biopsy revealed a mild defect in the NADH-ubiquinone oxidoreductase step of the oxidative phosphorylation (complex I). The content of cytochrome aa3 (complex IV) was also reduced. Adult onset sensorineural hearing loss starting in the high frequency region progresses with a fairly constant speed in this family. A cochlear type of hearing loss is found in the less pronounced cases. Advanced cases present features of retrocochlear affection with decreasing speech recognition, elevated acoustic reflex thresholds, and increased ABR latency with derangement of potentials. Caloric sensitivity was unaffected.

Epilepsy in a mitochondrial disorder.

In a large family with maternally inherited mitochondrial disease, a mild defect in the NADH-ubiquinone oxidoreductase step (complex 1) in the respiratory chain was found. Epilepsy was seen in nine (22%) of the 37 family members. Five of them, belonging to one branch of the family, had myoclonus epilepsy and EEG abnormalities consistent with this. The remaining four patients, belonging to other branches of the family tree, had partial epilepsy. Neurological symptoms also varied in different parts of the family. Possible explanations for the differences in phenotypic expressions are discussed.

The 3243 MELAS mutation in a pedigree with MERRF.

A mutation at base pair (bp) 3243 in mitochondrial DNA has been associated with mitochondrial myopathy, encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). A mutation at bp 8344 has been described as the cause of myoclonic epilepsy and ragged-red fiber disease (MERRF). Mitochondrial DNA was analyzed in a family with symptoms and signs consistent with MERRF. The DNA regions flanking bp 3243 and bp 8344 were amplified using the polymerase chain reaction, and the products were digested with restriction enzymes. The MELAS mutation at bp 3243 was found, but not the mutation at bp 8344. This illustrates the diverse clinical manifestations of the MELAS mutation.

Pre-eclampsia--a mitochondrial disease?

Mitochondrial dysfunction is a newly found group of inborn errors of metabolism in which there is a failure in the aerobic energy production. Disorders of mitochondrial metabolism exhibit a wide range of clinical symptoms which are related to the nature, severity and tissue distribution of the metabolic defect. Most reported cases are published in the neurological literature. In this report we describe for the first time a family with mitochondrial dysfunction with a high incidence of pre-eclampsia/eclampsia. The diagnosis of a mitochondrial disorder is verified by electronmicroscopic, electromyographic, histochemical and biochemical examinations. During pregnancy, the energy demand is increased due to both fetal and maternal requirements. A mitochondrial dysfunction, clinically symptomless in the non-pregnant state, may therefore become manifest during pregnancy. Characteristic features of pre-eclampsia such as disturbed ion transport, disturbed prostaglandin synthesis, vasoconstriction, platelet aggregation and hyperuricemia may be explained by mitochondrial dysfunction.

Generator sites for spontaneous activity in neuromyotonia. An EMG study.

A 16-year-old female patient with symptoms and signs compatible with neuromyotonia was studied with various neurophysiological tests and with muscle biopsy. Nerve conduction studies revealed signs of axonal motor neuropathy. EMG showed denervation in distal muscles, and moderate neurogenic changes in other muscles. Abundant spontaneous motor unit activity was recorded in all muscles. This activity did not disappear upon proximal nerve blockade with local anaesthetics. Based on the shape of spontaneous discharges and their behaviour on nerve stimulation and during voluntary effort, the site of generation was suggested. This varied for different discharges, from proximally in the nerve, to various sites along the intramuscular nerve tree. In some axons there were signs of conduction block proximal to the generation site for the spontaneous discharges. Different axons showed various degrees of abnormality; local hyperexcitability triggering new impulses only after the passage of a preceding impulse, increased hyperexcitability generating spontaneous activity, total impulse blocking, and finally axonal degeneration. Treatment with dihydantoin reduced the spontaneous activity with concomitant clinical improvement.

Mutations in mitochondrial transfer ribonucleic acid genes in preeclampsia.

OBJECTIVE: We investigated whether maternally inherited mitochondrial deoxyribonucleic acid mutations could be associated with preeclampsia because mendelian models fail to explain all the aspects of inheritance in preeclampsia. STUDY DESIGN: In two families with a high occurrence of preeclampsia and eclampsia the 22 mitochondrial transfer ribonucleic acid genes were sequenced in eight and three women, respectively. RESULTS: An A-to-G mutation in transfer ribonucleic acidleu[UUR] at nucleotide 3243 was found in one family, and in the other there was an A-to-G mutation at nucleotide 12308 in transfer ribonucleic acidleu[CUN]. Mutations of mitochondrial transfer ribonucleic acid genes are generally considered to have systemic consequences, which might explain the multiorgan involvement seen in preeclampsia. CONCLUSION: We report for the first time mutations in mitochondrial transfer ribonucleic acid genes in two families with a high occurrence of preeclampsia and eclampsia. Mitochondrial dysfunction caused by point mutations of mitochondrial deoxyribonucleic acid is maternally inherited, but in the case of mutations of nuclear genes mitochondrial dysfunction can be inherited as an autosomal recessive or dominant trait.