Coşkun Özdemir

Mutations in Kir2.1 Cause the Developmental and Episodic Electrical Phenotypes of Andersen's Syndrome

Andersens syndrome is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. We have mapped an Andersens locus to chromosome 17q23 near the inward rectifying potassium channel gene KCNJ2. A missense mutation in KCNJ2 (encoding D71V) was identified in the linked family. Eight additional mutations were identified in unrelated patients. Expression of two of these mutations in Xenopus oocytes revealed loss of function and a dominant negative effect in Kir2.1 current as assayed by voltage-clamp. We conclude that mutations in Kir2.1 cause Andersens syndrome. These findings suggest that Kir2.1 plays an important role in developmental signaling in addition to its previously recognized function in controlling cell excitability in skeletal muscle and heart.

THE RESULTS TO BE EXPECTED FROM ELECTRICAL TESTING IN THE DIAGNOSIS OF MYASTHENIA GRAVIS

The purpose of this study was to derive numerical data concerning the probability of diagnosing myasthenia gravis by electrical tests, employing repetitive stimulation of motor nerves. This was done by recording the compound muscle action potential (CMAP) from 80 patients with clear-cut myasthenia gravis, using a number of different, reportedly useful, testing techniques. In 95% of these patients, the diagnosis could be documented by the careful application of rather simple methods, providing several muscles, including a proximal one such as deltoid, were studied.

The dominant chloride channel mutant G200R causing fluctuating myotonia : Clinical findings, electrophysiology, and channel pathology

Clinical, electrophysiological, and molecular findings are reported for a family with dominant myotonia congenita in which all affected members have experienced long‐term fluctuations of the symptom of myotonia. In some patients myotonia is combined with myalgia. The myotonia‐causing mutation in this family is in the gene encoding the muscular chloride channel, hClC‐1, predicting the amino acid exchange G200R. We have constructed recombinant DNA vectors for expression of the mutant protein in tsA201 cells and investigation of the properties of the mutant channel. The most prominent alteration was a +100‐mV shift of the midpoint of the activation curve. Therefore, within the physiological range the open probability of the mutant channel is markedly smaller than in wild‐type. This shift is likely to be responsible for the myotonia in the patients. The fluctuating symptoms of this chloride channelopathy are discussed with respect to short‐term fluctuations of myotonia in the sodium channelopathy of potassium‐aggravated myotonia.

Transient weakness and compound muscle action potential decrement in myotonia congenita

Twenty‐five Turkish patients with recessive myotonia congenita (RMC), 16 of whom had genetic confirmation, were studied. Nineteen had transient weakness. In the upper extremities, onset age of transient weakness was usually in the early teens. All untreated RMC patients had a compound muscle action potential decrement of ⩾25%, usually above 50%, with repetitive nerve stimulation at 10/s for 5 s. Patients with other nondystrophic diseases with myotonia, except 1 patient with dominant myotonia congenita, had no transient weakness and a CMAP decrement below 25%.

Mapping of the second Friedreich's ataxia (FRDA2) locus to chromosome 9p23-p11: evidence for further locus heterogeneity

Abstract. Friedreichs ataxia (FRDA), the most-common form of autosomal recessive ataxia, is inherited in most cases by a large expansion of a GAA triplet repeat in the first intron of the frataxin (X25) gene. Genetic heterogeneity in FRDA has been previously reported in typical FRDA families that do not link to the FRDA locus on chromosome 9q13. We report localization of a second FRDA locus (FRDAff2) to chromosome 9p23–9p11, and we provide evidence for further genetic heterogeneity of the disease, in a family with the classic FRDA phenotype.

ELECTRICAL MYOTONIA IN HETEROZYGOUS CARRIERS OF RECESSIVE MYOTONIA CONGENITA

We investigated electrophysiologically the unaffected parents of patients with recessive myotonia congenita. We studied 18 families, in nine of which the diagnosis was confirmed by molecular genetics. Brief myotonic discharges were present in at least one parent in 67% of the families. Fathers were more likely than mothers to show these discharges. The difficulty in distinguishing very mildly affected parents with dominant myotonia congenita from the heterozygous carriers of recessive myotonia congenita is stressed.

Segmental distribution of muscle weakness in SMA III: implications for deterioration in muscle strength with time1

We examined 26 spinal muscular atrophy type III (SMA III) patients with SMNt deletions, searching for possible segmental distribution of muscle weakness. In those with disease duration of < or = 11 years, the weakest muscles were upper lumbar innervated ones in the lower extremities. In the upper extremities, early involvement of triceps muscle suggested the possibility of lower cervical (C7) onset. Electrophysiologically, weaker muscles had a more severe reduction in the recruitment pattern, particularly in the lower extremities. However, severe reduction in recruitment was sometimes also observed in clinically strong muscles. In patients with disease duration of > or = 16 years and regardless of disease duration, in those with disease onset at < or = 3 years of age, weakness and severe electrophysiological changes were more widespread. These findings may suggest a progression in muscle weakness with time. When compared to 12 patients with Becker muscular dystrophy (BMD), early stage SMA III with weak iliopsoas-strong gluteus maximus stood in contrast to BMD with weak gluteus maximus-strong iliopsoas.

The use of botulinum toxin in localizing neuromyotonia to the terminal branches of the peripheral nerve.

In 2 patients with neuromyotonia, nerve blocks had no effect on the abnormal activity, while intramuscular injection of the botulinum toxin abolished the discharges in one and greatly diminished them in the other. Botulinum toxin thus helps to localize the origin of the neuromyotonic discharges to the terminal regions of the peripheral nerve in those cases where the more proximal portions cannot be held responsible.

Decrement pattern in Lambert–Eaton myasthenic syndrome is different from myasthenia gravis

The decrement pattern at low rates of repetitive nerve stimulation in myasthenia gravis (MG) is characterized by a decrease of compound muscle action potential size within the first 4-5 responses. With subsequent stimuli, compound muscle action potential size either increases or does not change. Following an observation that the pattern of decrement might be different in patients with Lambert-Eaton myasthenic syndrome (LEMS), we retrospectively studied traces from eight LEMS patients and 14 patients with seropositive generalized MG, calculating decrement percent from first to fourth and from first to ninth compound muscle action potential. In the LEMS patients, compound muscle action potential amplitude decreased progressively from first to ninth stimulus at 2, 3 or 5Hz in all traces but one. In contrast, MG patients demonstrated the expected improvement after the initial decrement in all traces except one. In the evaluation of patients suspected of having myasthenia gravis, the finding of progressive decrement pattern at low rates of repetitive nerve stimulation may alert the electromyographer to the possibility of Lambert-Eaton syndrome and prompt the performance of further electrodiagnostic tests.

DNA analysis in Turkish Duchenne/Becker muscular dystrophy families

SummaryThe molecular genetics of Duchenne/Becker muscular dystrophy was investigated in 81 affected Turkish families. Deletions were detected by multiplex polymerase chain reaction assays and cDNA Southern analyses. The distribution of the deletions along the gene and their correlation to clinical phenotype were different from the studies reported on other populations. Moreover, DNA polymorphisms in mothers were determined using 8 DNA probes and three CA repeat sequences, and a high degree of informativeness was observed.