GlyT1 encephalopathy: Characterization of presumably disease causing GlyT1 mutations.

Glycine constitutes a major inhibitory neurotransmitter predominantly in caudal regions of the CNS. The extracellular glycine concentration is regulated synergistically by two high affinity, large capacity transporters GlyT1 and GlyT2. Both proteins are encoded by single genes SLC6A9 and SLC6A5, respectively. Mutations within the SLC6A5 gene encoding for GlyT2 have been demonstrated to be causative for hyperekplexia (OMIM #614618), a complex neuromuscular disease, in humans. In contrast, mutations within the SLC6A9 gene encoding for GlyT1 have been associated with GlyT1 encephalopathy (OMIM #601019), a disease causing severe postnatal respiratory deficiency, muscular hypotonia and arthrogryposis. The consequences of the respective GlyT1 mutations on the function of the transporter protein, however, have not yet been analysed. In this study we present the functional characterisation of three previously published GlyT1 mutations, two mutations predicted to cause truncation of GlyT1 (GlyT1Q573* and GlyT1K310F+fs*31) and one predicted to cause an amino acid exchange within transmembrane domain 7 of the transporter (GlyT1S407G), that are associated with GlyT1 encephalopathy. Additionally, the characterization of a novel mutation predicted to cause an amino acid exchange within transmembrane domain 1 (GlyT1V118M) identified in two fetuses showing increased nuchal translucency and arthrogryposis in routine ultrasound scans is demonstrated. We show that in recombinant systems the two presumably truncating mutations resulted in an intracellular retained GlyT1 protein lacking the intracellular C-terminal domain. In both cases this truncated protein did not show any residual transport activity. The point mutations, hGlyT1S407G and hGlyT1V118M, were processed correctly, but showed severely diminished activity, thus constituting a functional knock-out in-vivo. Taken together our data demonstrate that all analysed mutations of GlyT1 that have been identified in GlyT1 encephalopathy patients cause severe impairment of transporter function. This is consistent with the idea that loss of GlyT1 function is indeed causal for the disease phenotype.

A complex chromosomal rearrangement with a translocation 4;10;14 in a fertile male carrier: ascertainment through an offspring with partial trisomy 14q13-->q24.1 and partial monosomy 4q27-->q28 [corrected].

Complex chromosomal rearrangements (CCRs) are usually associated with infertility or subfertility in male carriers. If fertility is maintained, there is a high risk of abnormal pregnancy outcome. Few male carriers have been identified by children presenting with mental retardation/congenital malformations (MR/CM) or by spontaneous abortions of the spouses. We report a de novo CCR with five breakpoints involving chromosomes 4, 10 and 14 in a male carrier who was ascertained through a son presenting with MR/CM due to an unbalanced karyotype with partial trisomy 14 and partial monosomy 4. The child has a healthy elder brother. In the family history no abortions were reported. No fertility treatment was necessary. Cytogenetic analysis from the affected son showed a reciprocal translocation t(4;10) with additional chromosomal material inserted between the translocation junctions in the derivative chromosome 10. The father showed the same derivative chromosome 10 but had additionally one aberrant chromosome 14. Further molecular cytogenetic analyses determined the inserted material in the aberrant chromosome 10 as derived from chromosome 14 and revealed a small translocation with material of chromosome 4 inserted into the derivative chromosome 14. Thus the phenotype of the son is supposed to be associated with a partial duplication 14q13-->q24.1 and a partial monosomy 4q27-->q28. Including our case we are aware of eleven CCR cases with fertile male carriers. In eight of these families normal offspring have been reported. We propose that exceptional CCRs in fertile male carriers might form comparatively simple pachytene configurations increasing the chance of healthy offspring.

Mental comorbidity of chronic insomnia in general practice attenders using DSM-III-R.

The major aim of this study was to investigate links between chronic insomnia and mental and personality disorders using the DSM-III-R classification. Of a sample of 2512 general practice attenders, 105 with a chronic insomnia complaint over a 4-month period were evaluated for mental and personality disorders. In addition, the significance of other factors such as personality traits, social functioning and the patient's own estimation of sleep quality was studied. Sixty-six patients got a diagnosis of a current insomnia using a structured interview for DSM-III-R. Fifty percent of them had at least one additional current Axis I or II diagnosis. Affective disorders were most common as principal psychiatric diagnosis followed by substance use disorders. The general practitioners were poor in recognizing their patients' chronic insomnia complaints and the high percentage of substance abusers among them. The important role of psychopathology in chronic insomnia sufferers was indicated by the high number of patients who displayed prominent personality traits. The predominant personality pattern was characterized by a pattern of internalization of problems combined with an anxious-depressive reaction style. In summary, strong associations between chronic insomnia, mental disorders and psychopathology were confirmed by this investigation.

Test-retest reliability and validity of the Structured Interview for Sleep Disorders According to DSM-III-R.

OBJECTIVE: The purpose of this study was to evaluate the reliability of sleep disorder diagnoses in DSM-III-R by using a newly developed interview, the Structured Interview for Sleep Disorders According to DSM-III-R (SIS-D) and to evaluate the concordance between these diagnoses and sleep laboratory data. In addition, the sources of disagreements between two interviewers in the diagnoses given to the same patient were determined. METHOD: Two different interviewers used the SIS-D to diagnose 68 patients with complaints of sleep disorders. The concordance between these interviewers' diagnoses and polysomnographic findings was investigated by using kappa statistics. RESULTS: There were excellent reliabilities for almost all current main diagnostic categories and good concordance between diagnoses made on the basis of the structured interview and polysomnographic data. The main source of disagreement between interviewers was found in the symptom information given by the patient. CONCLUSIONS: These findings provide support for the utility of DSM-III-R sleep disorder diagnoses and for their retention in DSM-IV. These findings also accord well with a recent literature review of the DSM-III-R diagnosis of primary insomnia by the DSM-IV Work Group on Sleep Disorders. The good concordance between interview diagnoses and polysomnographic data suggests that a structured interview such as the SIS-D may be a useful screening instrument. The authors discuss the implications of these findings for the polysomnographic evaluation of chronic insomnia.