Piraye Serdaroglu

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.

Behçet's disease and the nervous system.

Abstract Behçet’s disease is a multisystem inflammatory disorder with unknown aetiology. It is a disease of young adults with a more severe course in males subjects. Its prevalence is high in the Mediterranean basin and Japan and has been linked with human leucocyte antigen B5 (HLA-B5) in those countries. According to the diagnostic criteria formed by the International Study Group, recurrent oral ulceration is a prerequisite, with two more typical symptoms or signs. Neurological involvement is one of the most devastating manifestations of Behçet’s disease. The involvement is either caused by primary neural parenchymal lesions (neuro- Behçet) or secondary to major vascular involvement (vasculo Behçet). The course is relapsing-remitting, secondary progressive or primary progressive. The most commonly involved area is the brain stem, with additional symptoms or signs, hemispherical involvement with mental changes being the most common. Intracranial hypertension, usually owing to dural sinus thrombosis, has a special place in Behçet’s disease. The most common clinical findings are pyramidal signs. Sensory symptoms or signs are much less frequent, and hemianopia and higher cortical function disturbances as well as pure cerebellar syndrome are rare features. Cerebrospinal fluid usually has a high protein content and/or pleocytosis. Notably, in the acute period most patients have lesions shown by magnetic resonance imaging (MRI) extending from the brain-stem to diencephalic structures. Differential diagnosis from multiple sclerosis can be difficult in patients with hemispheric white matter MRI hyperintensities. Immunosuppressives are used in treatment.

Clinical comparison of anti-MuSK- vs anti-AChR-positive and seronegative myasthenia gravis

We compared 65 anti-acetylcholine receptor (AChR)-negative myasthenia gravis (MG) patients, including 32 anti-muscle-specific tyrosine kinase (MuSK)-positive (49%) and 33 anti-MuSK-negative (seronegative) (51%) patients, with 161 anti-AChR-positive MG patients. The anti-MuSK-positive group had a higher frequency of bulbar involvement and respiratory crises. The seronegative group was in between the anti-MuSK positive and the anti-AChR positive groups, being closer to the latter, with regard to the severity of the disease. At the end of follow-up, the outcome of the anti-MuSK-positive patients was not different from that of the anti-AChR-positive patients, although their maintenance corticosteroid dose was higher. The seronegative patients had better outcome than the other two groups.

Neuropsychological follow-up of 12 patients with neuro-Behçet disease.

Abstract We analyzed the data obtained from neuropsychological evaluations of 12 neuro-Behçet Disease (NBD) patients who had been followed up for 35.6 ± 23.7 months with successive neuropsychological testing by a comprehensive battery. Memory impairment, which seems to stem basically from a retrieval deficit, was the major finding in this series. The most severely affected memory process was delayed recall, being impaired in all of the patients in the verbal and/or visual modalities. This was followed closely by an impairment in the process of acquisition and storage. In addition to the memory impairment, a “clinical impression of personality change” toward either disinhibition or apathy was seen in 8 of the 12 patients. Attention deficit was of the third highest frequency and was present in 7 patients, followed by deficits of executive functions of frontal system which were present in 5. Other cognitive domains were rarely involved. Neuropsychological status deteriorated insidiously, regardless of the neurological attacks during the follow-up period in most of the patients. Furthermore, our observations also showed the presence of cognitive decline prior to detectable lesions on CT or MRI, emphasizing the need for neuropsychological testing in NBD patients. The late stages of the disease seem to be reflected in MRI as an enlargement of the third ventricle and atrophy of the upper brainstem, which could be compatible with memory loss. Our series, a rather selected group, suggests that NBD can be associated with a special pattern of cognitive deficit, especially memory loss and personality change. The designation of any specific neurobehavioral syndrome for NBD, however, awaits further study.

Masked assessment of MRI findings: is it possible to differentiate neuro-Behçet's disease from other central nervous system

Abstract Two neuroradiologists reviewed MRI studies of 34 patients with neuro-Behçets disease (NBD), 22 with multiple sclerosis (MS) and 7 with systemic lupus erythematosus (SLE) with central nervous system involvement, masked to the clinical diagnosis, age and sex of the patients. Of the patients with NBD 12 were in an acute attack; the others had chronic disease. MRI was assessed using a set of criteria, looking at atrophy, the site of discrete parenchymal lesions, regions of predominant involvement and the extent of the lesion(s). The observers also made a guess at the clinical diagnosis. The brain stem and/or basal ganglia were the most predominantly involved sites in all patients with acute NBD; 75 % of these lesions were large and confluent, mainly extending from the brain stem to the diencephalon and basal ganglia. However, in chronic cases, the predominant involvement was in the brain stem and/or basal ganglia in only 36 %, and in cerebral hemisphere white matter in another 36 %; 27 % of these patients showed no parenchymal lesion. Hemisphere white-matter lesions were equally distributed between periventricular and other areas in NBD, while in MS more were periventricular, and in SLE more were nonperiventricular. Brain-stem atrophy was seen in 21 % of patients with NBD, with a specificity of 96.5 %. In the absence of cortical atrophy, its specificity was 100 %. The attempt at making a radiological diagnosis was successful in all cases of acute NBD and 95.5 % of patients with MS, but in only 40 % of patients with chronic NBD. Most of this latter groups MRI studies were interpreted as MS. An extensive lesion involving the brain stem and basal ganglia seemed to be diagnostic of acute NBD. However, hemisphere white-matter lesions could not be differentiated from those in MS.

Cytokines and chemokines in neuro-Behçet's disease compared to multiple sclerosis and other neurological diseases

Cytokines and chemokines in cerebrospinal fluid (CSF) can have implications on the pathogenesis of neuro-Behçets disease (NB). CSF and serum samples from 33 patients with NB, 25 with multiple sclerosis (MS), 20 patients with infectious and/or inflammatory neurological diseases (IN) and 14 with other noninflammatory neurological diseases (NIN) were investigated by ELISA. In the CSF, CXCL10 levels were significantly higher in NB and IN than NIN and MS, whereas CXCL8 was increased in NB compared to NIN. CCL2 levels in MS CSF and sera were lower, whereas CXCL8 in MS sera was higher than the other groups. IL-12 was elevated in CSF of IN compared to NB and NIN and also in the CSF of MS compared to NIN. No difference was detected for IL-10 and IL-17. These results reflect that NB has a mediator pattern in resemblance with non-specific inflammations such as neuro-infections compared to autoimmune disorders such as multiple sclerosis, suggesting that a currently unknown infection might be the trigger of a vasculitic process in the central nervous system (CNS).

Clinical characteristics and course of spinal cord involvement in Behçet's disease

Parenchymal neurological involvement in Behçets disease (p‐NBD) usually presents with a brainstem syndrome; occasionally spinal cord may also be involved. Files of patients with Behçets disease and spinal cord involvement were reviewed retrospectively, in comparison with other types of p‐NBD. Amongst 216 patients with p‐NBD, 24 had spinal cord involvement (11%). Most commonly patients presented with sensory‐motor symptoms, sphincter and/or sexual dysfunction evolving over days. Four of 10 patients showed single or multiple cervical and/or dorsal lesions on spinal MRIs and one showed dorsal atrophy. Although the clinical picture was variable, it tended to be severe; seven cases had primary progressive course, 11 cases had a secondary progressive course after initial attack(s), four had attacks with severe residual sequela and two had improvement after attacks. After a median follow‐up period of 67 months, eight were independent and 14 were dead or dependent, whereas amongst the remaining patients with p‐NBD, 113 patients were independent and 56 patients were dead or dependent (P < 0.05). Our study suggests that spinal cord involvement has even worse prognosis compared with other types of p‐NBD. Therefore, recognition of spinal cord involvement in Behçets patients should prompt early vigorous treatment.

Anti-αB-crystallin immunoreactivity in inflammatory nervous system diseases

AbstractαB-Crystallin, a small heat shock protein, is an immuno-dominant antigen with increased tissue expression in demyelination. To investigate the humoral response against αB-crystallin, the sera and CSF samples of patients with multiple sclerosis (MS), Guillain-Barré syndrome (GBS), neuro-Behçets disease (NBD) and other non-inflammatory neurological disease (NIND) were screened by enzyme-linked immunosorbent assay for anti-αB-crystallin IgG and IgM antibodies. Serum and CSF IgG antibody responses to αB-crystallin were significantly elevated only in NBD patients (serum IgG, NBD 1.29±0.49 vs NIND 0.95±0.39, p=0.01; CSF IgG, NBD 1.22±0.64 vs. NIND 0.81±0.35, P=0.01). Similarly, high serum IgM antibody titres were also detected in NBD (1.83±0.72 vs. 1.16±0.49, P=0.0005) and in MS (1.57±1.07, P=0.046), whereas elevated CSF IgM responses were observed to be high only in GBS (2.09±1.09 vs. 1.41±0.7, P=0.007). Humoral responses against αB-crystallin are increased in NBD and GBS, which may implicate this central nervous system antigen in the causation and pathogenesis of these inflammatory nervous system disorders.

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%.