Systematic screening for mutations in the promoter and the coding region of the 5-HT1A gene.

In the present study we sought to identify genetic variation in the 5-HT1A receptor gene which through alteration of protein function or level of expression might contribute to the genetic predisposition to neuropsychiatric diseases. Genomic DNA samples from 159 unrelated subjects (including 45 schizophrenic, 46 bipolar affective, and 43 patients with Tourette's syndrome, as well as 25 healthy controls) were investigated by single-strand conformation analysis. Overlapping PCR (polymerase chain reaction) fragments covered the whole coding sequence as well as the 5' untranslated region of the 5-HT1A gene. The region upstream to the coding sequence we investigated contains a functional promoter. We found two rare nucleotide sequence variants. Both mutations are located in the coding region of the gene: a coding mutation (A-->G) in nucleotide position 82 which leads to an amino acid exchange (Ile-->Val) in position 28 of the receptor protein and a silent mutation (C-->T) in nucleotide position 549. The occurrence of the Ile-28-Val substitution was studied in an extended sample of patients (n = 352) and controls (n = 210) but was found in similar frequencies in all groups. Thus, this mutation is unlikely to play a significant role in the genetic predisposition to the diseases investigated. In conclusion, our study does not provide evidence that the 5-HT1A gene plays either a major or a minor role in the genetic predisposition to schizophrenia, bipolar affective disorder, or Tourette's syndrome.

Direct molecular genetic diagnosis and heterozygote identification in X-linked Emery-Dreifuss muscular dystrophy by heteroduplex analysis.

X-linked Emery-Dreifuss muscular dystrophy (EMD) is a very rare, relatively benign muscle disorder. The disease is associated with potentially lethal cardiac arrhythmias in affected males and some heterozygous females. X-linked EMD can be genetically distinguished from phenotypically similar autosomal EMD. Heterogenic mutations are identified as the cause of X-linked EMD. We introduced heteroduplex analysis to follow the segregation of heterogenic emerin gene mutations in the families of six unrelated EMD patients. Heteroduplex analysis was proved to be a simple, fast and reliable tool for direct molecular genetic diagnosis of EMD in male patients and identification of heterozygotes even in families where affected males are not available as index cases.

[Noninvasive ventilation of a 4-year-old boy with severe central late onset hypoventilation syndrome]. / Nichtinvasive Beatmung bei einem vierjährigen Jungen mit schwerem zentralen "late onset"-Hypoventilationssyndrom.

BACKGROUND: In the literature we found only five reports about noninvasive ventilation in cases with central hypoventilation syndrome. PATIENT AND METHOD: We report about a 4-year-old boy with severe late onset hypoventilation syndrome. During an interval of 3 months with nasal mask ventilation during sleep he showed an excellent cognitive and statomotoric development. After this time, he needed a noninvasive ventilation with a negative pressure system. RESULTS AND DISCUSSION: In our opinion, noninvasive nasal mask ventilation is a modern method in the treatment of patients with central hypoventilation syndrome. Tracheotomy is only necessary during the first year of life.

[Noninvasive nocturnal nasal mask ventilation (NIPPV) in childhood and adolescence. Dresden experiences with 11 patients]. / Nichtinvasive nächtliche nasale Maskenbeatmung (NIPPV) im Kindes- und Jugendalter. Dresdener Erfahrungen mit elf Patienten.

BACKGROUND: There are only small experiences with mechanical ventilation via nasal mask in childhood. PATIENTS AND METHODS: Eleven patients using NIPPV (9 patients aged 4 to 18 years and 2 patients with cystic fibrosis aged 20 and 25 years). RESULTS: NIPPV was effective in all 11 patients. Seven patients needed supplemental oxygen. Theophyllin, Almitrin and Salbutamol could support the nasal ventilation in special conditions. CONCLUSION: Intermittent ventilation via nasal mask is a noninvasive and effective treatment of chronic respiratory failure in childhood. Monitoring with continuous pulse-oximetry is necessary.

Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype.

BACKGROUND: P426L and I179S are the two most frequent mutations in juvenile and adult metachromatic leukodystrophy (late-onset MLD), which, in contrast to infantile MLD, show marked phenotypic heterogeneity. OBJECTIVE: To search for genotype-phenotype correlations in late-onset MLD. METHODS: The authors reviewed the clinical course of 22 patients homozygous for mutation P426L vs 20 patients heterozygous for mutation I179S, in which the second arylsulfatase A (ASA) mutation had also been determined. RESULTS: P426L homozygotes principally presented with progressive gait disturbance caused by spastic paraparesis or cerebellar ataxia; mental disturbance was absent or insignificant at the onset of disease but became more apparent as the disease evolved. In contrast, compound heterozygotes for I179S presented with schizophrenia-like behavioral abnormalities, social dysfunction, and mental decline, but motor deficits were scarce. Reduced peripheral nerve conduction velocities and less residual ASA activity were present in P426L homozygotes vs I179S heterozygotes. CONCLUSION: The characteristic clinical differences between homozygous P426L and compound heterozygous I179S patients establish a distinct genotype-phenotype correlation in late-onset metachromatic leukodystrophy.

[Is there a "temporal psychosyndrome (Landolt)"?]. / Gibt es das "temporale Psychosyndrom (Landolt)"?

With reference to features of two cases of grave traumatic temporal cerebral injury, where a "temporal psychosyndrome" as defined by Landolt was not ascertainable, the question is raised whether, apart from temporal-lobe epilepsy, such a syndrome really exists. Computed tomography offers an enhanced objective basis for an investigation embracing an extensive patient population.

[Psychopathology and criminal personality changes in patients with frontal lobe injuries]. / Beitrag zu Psychopathologie und kriminogener Persönlichkeitsveränderung Stirnhirnverletzter.

Proceeding from H. Cosack (1937), and in view of the fact that since then no further casuistic contributions relating to the crimogenic aspect of the psychopathological frontal brain syndrome or to the forensic psychiatry of persons with frontal brain damage have appeared, we take up the discussion with five of our own cases. Since modern procedures have made it possible to localise exactly the consequences of brain damage, a new round of investigations might be expected to resolve the problems still left open.

Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel.

KCNQ2 and KCNQ3 are two homologous K(+) channel subunits that can combine to form heterotetrameric channels with properties of neuronal M channels. Loss-of-function mutations in either subunit can lead to benign familial neonatal convulsions (BFNC), a generalized, idiopathic epilepsy of the newborn. We now describe a syndrome in which BFNC is followed later in life by myokymia, involuntary contractions of skeletal muscles. All affected members of the myokymia/BFNC family carried a mutation (R207W) that neutralized a charged amino acid in the S4 voltage-sensor segment of KCNQ2. This substitution led to a shift of voltage-dependent activation of KCNQ2 and a dramatic slowing of activation upon depolarization. Myokymia is thought to result from hyperexcitability of the lower motoneuron, and indeed both KCNQ2 and KCNQ3 mRNAs were detected in the anterior horn of the spinal cord where the cells of the lower motoneurons arise. We propose that a difference in firing patterns between motoneurons and central neurons, combined with the drastically slowed voltage activation of the R207W mutant, explains why this particular KCNQ2 mutant causes myokymia in addition to BFNC.

Early recognition of hereditary motor and sensory neuropathy type 1 can avoid life-threatening vincristine neurotoxicity.

Hereditary motor and sensory neuropathy type 1 (HMSN-1) is an autosomal dominant disorder, which is usually not associated with neoplastic diseases. The disease predisposes to severe vincristine neurotoxicity. We report a 31-year-old women with recurrent Hodgkin's lymphoma and unrecognized HMSN-1 who developed severe motor neuropathy 3 weeks after the first cycle of treatment including 2 mg of vincristine. HMSN is diagnosed in most cases retrospectively, usually suggested by the observation of foot abnormalities or family history. Recognizing early signs of HMSN, such as areflexia and pes cavus deformity, can prevent severe neurotoxicity of polychemotherapy by avoiding vincristine.

The Kleine-Levin syndrome - effects of treatment with lithium -.

Kleine-Levin syndrome (KLS) is a rare disorder which affects mainly adolescents. Periods of extreme somnolence alternate with megaphagia, psychomental changes and behavioural symptoms. The cause and pathogenesis of KLS remains unknown. Several treatments have been tried and recently lithium has been proposed for a prophylactic use in single cases. In view of the rarity of KLS, long-term results of lithium therapy have not been described yet. We report the clinical course of five adolescents with KLS who were treated with lithium. All patients showed significant EEG and polysomnographic changes during the episodes and had normal results in the interval. All patients had relapses while being treated with lithium. But episodes of hypersomnia under lithium therapy were shorter and monosymptomatic with lack of behavioural symptoms. Statistical modelling showed that the risk for a relapsing episode under maintenance of lithium drops per months of therapy from 100 % to 93 %, and furthermore that the maintenance of lithium shortens the mean duration of episodes to 19 %. No severe side effects were observed. In conclusion, in KLS with a high frequency of episodes and severe behavioural changes lithium may become a treatment option.

Familial ALS in Germany: origin of the R115G SOD1 mutation by a founder effect.

Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) account for approximately 20% of patients with familial amyotrophic lateral sclerosis (FALS). In this study, sequence analysis of exons 1-5 of SOD1 in a large German cohort with FALS was performed. Among 75 affected patients, who were not obviously related probands with a positive family history, nine had missense mutations in SOD1. Four of the nine probands carry the same R115G mutation in exon 4 of the SOD1 gene. Genotyping with markers from the SOD1 locus revealed a common haplotype and shared allelic characteristics in these patients. These findings suggest that the R115G mutation in the German population originates from a common founder.

Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (i.e., 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease. In conclusion, the high proportion of de novo mutations together with the large spectrum of both LMNA mutations and the expression of the disease should now prompt screening for LMNA in familial and sporadic cases of both EDMD and dilated cardiomyopathy associated with conduction system disease.

A genome screen for genes predisposing to bipolar affective disorder detects a new susceptibility locus on 8q.

Bipolar affective disorder (BPAD), also known as manic depressive illness, is a severe psychiatric disorder characterized by episodes of mania and depression. It has a lifetime prevalence of approximately 1% in all human populations. In order to identify chromosomal regions containing genes that play a role in determining susceptibility to this psychiatric condition, we have conducted a complete genome screen with 382 markers (average marker spacing of 9.3 cM) in a sample of 75 BPAD families which were recruited through an explicit ascertainment scheme. Pedigrees were of German, Israeli and Italian origin, respectively. Parametric and non-parametric linkage analysis was performed. The highest two-point LOD score was obtained on 8q24 (D8S514; LOD score = 3.62), in a region that has not attracted much attention in previous linkage studies of BPAD. The second best finding was seen on 10q25-q26 (D10S217; LOD score = 2.86) and has been reported in independent studies of BPAD. Other regions showing 'suggestive' evidence for linkage localized to 1p33-p36, 2q21-q33, 3p14, 3q26-q27, 6q21-q22, 8p21, 13q11 and 14q12-q13. In addition, we aimed at detecting possible susceptibility loci underlying genomic imprinting by analyzing the autosomal genotype data with the recently developed extension of the GENEHUNTER program, GENEHUNTER-IMPRINTING. Putative paternally imprinted loci were identified in chromosomal regions 2p24-p21 and 2q31-q32. Maternally imprinted susceptibility genes may be located on 14q32 and 16q21-q23.