Martin Gencik

Increased frequency of migraine in narcoleptic patients: a confirmatory study

Previously we have reported an increased prevalence of migraine in narcoleptic patients. Because of the theoretical and clinical implications of this finding we recruited an independent new study sample of 100 patients with proven narcolepsy and conducted a structured 26-item interview based on the international diagnostic criteria for headache disorders, the Kiel Headache Questionnaire. Narcolepsy symptoms were measured by means of the Stanford Centre for Narcolepsy Sleep Inventory. Migraine prevalence was twofold to fourfold increased in the narcoleptic patients and amounted to 44.4% in women and 28.3% in men. The onset of narcolepsy symptoms was 12.3 ± 11.4 years before the onset of migraine symptoms. The results might be regarded as indicative of a common pathophysiological pathway relevant to both of the two disorders.

A prepro-orexin gene polymorphism is associated with narcolepsy

The orexin (hypocretin) neurotransmitter system was recently shown to be directly involved in the pathogenesis of narcolepsy in two animal models. Furthermore, decreased levels of orexin A in the CSF were shown in narcoleptic patients. To define any genetic contribution of orexin to the etiology of narcolepsy, the authors screened the entire prepro-orexin gene for mutations or polymorphisms in 133 patients suffering from narcolepsy. They report an association of a rare polymorphism in the prepro-orexin gene with narcolepsy in a cohort of 178 patients.

Immunogenetic risk factors for anti‐neutrophil cytoplasmic antibody (ANCA)‐associated systemic vasculitis

Wegeners granulomatosis (WG) and microscopic polyangiitis are systemic autoimmune diseases characterized by the presence of ANCA in the sera of patients. Little is known about the aetiologic factors and genetic predisposition as well as the pathogenesis of these disease entities. A slightly decreased representation of HLA‐DRB1*13 and HLA‐DQB1*0603 individuals was observed in our cohort of ANCA‐associated systemic vasculitis (AASV) patients compared with controls. In addition, HLA‐DRB1*04 individuals were over‐represented in a subgroup of patients with WG in end‐stage renal disease as a result of renal vasculitis. In order to identify other genes relevant for these diseases, we investigated highly polymorphic markers in the vicinity of several immunorelevant genes, i.e. tumour necrosis factor (TNF)α, IL‐2, IL‐5 receptor α (IL‐5RA), in a group of 102 patients with AASV and compared the representation with controls. Furthermore, functional polymorphisms were directly analysed in the promotor region of TNFα as well as in the coding region of the FcγIIRA genes. Polymorphisms of the TNFα promotor (TNF‐308) as well as in the FcγIIRA gene were excluded as risk factors for the disease in our cohort. No major phenotype distribution differences were observed between patients and controls for the IL‐2 and IL‐5RA microsatellites. Most importantly, several haplotypes on chromosome 6p appeared strongly associated with proteinase 3 (PR3)‐ANCA+ AASV. Thus, as in other autoimmune diseases, different predisposing factors play differential aetiopathogenic roles in various groups of AASV patients.

Isolated loss of γ-sarcoglycan : Diagnostic implications in autosomal recessive limb-girdle muscular dystrophies

Mutations in the sarcoglycan (SG) genes cause a subset of limb‐girdle muscular dystrophies (LGMD). We report a Spanish patient with progressive LGMD exhibiting an almost isolated loss of γ‐SG and a homozygous Δ521‐T mutation in the γ‐SG gene. These results suggest that isolated loss of γ‐SG might remain undetected using only the α‐SG antibody in routine muscle biopsy studies. Both α‐ and γ‐SG antibodies should be used in the diagnostic detection of patients with LGMD.

Polymorphisms of the tumor necrosis factor receptors: no association with narcolepsy in German patients

Narcolepsy is a debilitating sleep disorder characterized by daytime sleepiness and cataplexy. The strong association of narcolepsy with the HLA system suggests an autoimmune cause. Tumor necrosis factor is a cytokine involved in both regulation of immune mechanisms and sleep. Several studies were undertaken to determine a contribution of tumor necrosis factor and its receptors to the pathogenesis of narcolepsy. A significant increase in the 196R allele, a functionally relevant polymorphism in the TNFR2 gene, has been found in Japanese patients, indicating altered transduction of tumor necrosis factor signals. Here we explore polymorphisms in both tumor necrosis factor receptor genes as risk factors in a German population sample. Neither the polymorphism in the TNFR1 nor that in the TNFR2 gene was associated with narcolepsy. Our findings contrast to those previously published and thus provide evidence for genetic heterogeneity between different narcolepsy populations.

Transcriptional profiles from patients with dystrophinopathies and limb girdle muscular dystrophies as determined by qRT-PCR

Abstract.Mutations in genes coding for the dystrophin-glycoprotein complex (DGC) cause inherited muscular dystrophies (MD), including Morbus Duchenne (DMD) and M. Becker (BMB) as well as limb-girdle muscular dystrophies (LGMD). New insights into the pathophysiology of the dystrophic muscle, the identification of compensatory mechanisms and additional proteins interacting with dystrophin are essential for developing new treatments. In order to define molecular mechanisms induced by lack of dystrophin and the subsequent counter-regulatory transcriptional response of degenerating muscle fibres, we have investigated the mRNA expression of 19 functionally linked genes in biopsies of patients with MD by means of real time qRT-PCR. Our results define a uniform transcriptional profile of the dystrophic muscle characterized by degeneration and regeneration. Several genes encoding structural proteins appear remarkably highly expressed.

ApoE polymorphisms in narcolepsy

SummaryBackgroundNarcolepsy is a common neuropsychiatric disorder characterized by increased daytime sleepiness, cataplexy and hypnagogic hallucinations. Deficiency of the hypocretin neurotransmitter system was shown to be involved in the pathogenesis of narcolepsy in animals and men. There are several hints that neurodegeneration of hypocretin producing neurons in the hypothalamus is the pathological correlate of narcolepsy. The ApoE4 allele is a major contributing factor to early-onset neuronal degeneration in Alzheimer disease and other neurodegenerative diseases as well.MethodsTo clarify whether the ApoE4 phenotype predisposes to narcolepsy or associates with an earlier disease onset, we have genotyped the ApoE gene in 103 patients with narcolepsy and 101 healthy controls.ResultsThe frequency of the E4 allele of the ApoE gene was 11% in the patient and 15% in the control groups. Furthermore, the mean age of onset did not differ between the ApoE4+ and ApoE4- patient groups.ConclusionOur results exclude the ApoE4 allele as a major risk factor for narcolepsy.

Alpha-sarcoglycanopathy previously misdiagnosed as Duchenne muscular dystrophy: implications for current diagnostics and patient care

Differential diagnosis of limb-girdle muscular dystrophy, including alpha-sarcoglycanopathy and Duchenne muscular dystrophy, is impossible to acheive on clinical grounds alone; therefore immunohistology, Western blotting and molecular genetic analysis are manadatory for a correct diagnosis. The patients genotype with a hitherto unknown mutation (Tyr134STOP) in exon 5 adds to the growing spectrum of mutations in the alpha-sarcoglycan gene.