William S. Hall Psychiatric Institute

Along with antioxidant properties, carnitine is an important regulator of lipid metabolism in humans. While beneficial effects of carnitine have been demonstrated in animal models of Huntington's disease (HD), metabolism of carnitine has not been studied in humans with this illness. In this retrospective database review from 23 patients admitted to a HD-specialized nursing home unit, we found a relatively high prevalence of hypocarnitinemia (6 cases, 26%). Our review suggests that catabolism and chronic valproate use predisposed our patients to develop hypocarnitinemia. The patients with low serum carnitine levels who received levocarnitine supplementation, during a mean period of 7.3 months, showed improvement in motor, cognitive and behavioral measures. We hypothesize that observed improvement related to the resolution of reversible metabolic encephalopathy and myopathy associated with secondary carnitine deficiency. In conclusion, notwithstanding its limitations, this is the first study to report measurements of carnitine levels in HD patients, revealing relatively high prevalence of hypocarnitinemia in our population. Our findings suggest that HD patients with hypocarnitinemia may benefit from low-dose levocarnitine supplementation. Further studies of carnitine metabolism and supplementation in HD patients are warranted.

BackgroundAge at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; however, several studies have indicated that other genetic factors also contribute to the variability in HD age at onset. To identify modifier genes, we recently reported a whole-genome scan in a sample of 629 affected sibling pairs from 295 pedigrees, in which six genomic regions provided suggestive evidence for quantitative trait loci (QTL), modifying age at onset in HD.MethodsIn order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs.ResultsSuggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87, p = 0.002) increased to genome-wide significance for linkage in the combined sample (LOD = 4.05, p = 0.00001), while suggestive evidence for linkage was observed at 18q22, in both the follow-up sample (LOD = 0.79, p = 0.03) and the combined sample (LOD = 1.78, p = 0.002). Epistatic analysis indicated that there is no interaction between 6q23-24 and other loci.ConclusionIn this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.

Autistic disorder is a pervasive neurodevelopmental disorder characterized by deficits in language and social communication, as well as stereotyped patterns of behavior. Peak LOD scores from several genomic screening efforts indicate the presence of an autistic disorder susceptibility locus within the distal long arm of human chromosome 7 (7q31-q35). Wassink et al. [2001: Am J Med Genet 105:406-413] reported that WNT2, located at 7q31, influences genetic risk in autistic disorder. These findings were enhanced when examined in a subset of families with severe language impairment. WNT genes encode secreted growth factor-like proteins that participate in growth regulation, differentiation, and tumorigenesis. We tested for genetic association of two WNT2 variants in an independent data set of 135 singleton and 82 multiplex families. No significant association was found between autistic disorder and the WNT2 genotypes in either the overall data set or in the language-impaired subset of families. However, differences in allele frequencies of the 3' UTR single nucleotide polymorphism between the present population and that of Wassink et al. may account for the inability to detect association between WNT2 and autistic disorder in the present data set. We also screened the two reported autistic disorder mutations previously detected by Wassink et al. We did not identify any activating mutation in the coding region of the WNT2 gene. Thus, we conclude that activating mutations of the WNT2 gene are not a major contributor to the development of autistic disorder in these data.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting via the GABAA receptors. The GABAA receptors are comprised of several different homologous subunits, forming a group of receptors that are both structurally and functionally diverse. Three of the GABAA receptor subunit genes (GABRB3, GABRA5 and GABRG3) form a cluster on chromosome 15q11-q13, in a region that has been genetically associated with autistic disorder (AutD). Based on these data, we examined 16 single nucleotide polymorphisms (SNPs) located within GABRB3, GABRA5 and GABRG3 for linkage disequilibrium (LD) in 226 AutD families (AutD patients and parents). Genotyping was performed using either OLA (oligonucleotide ligation assay), or SSCP (single strand conformation polymorphism) followed by DNA sequencing. We tested for LD using the Pedigree Disequilibrium Test (PDT). PDT results gave significant evidence that AutD is associated with two SNPs located within the GABRG3 gene (exon5_539T/C, p = 0.02 and intron5_687T/C, p = 0.03), suggesting that the GABRG3 gene or a gene nearby contributes to genetic risk in AutD.

Attention Deficit Hyperactivity Disorder (ADHD) and Post-Traumatic Stress Disorder (PTSD) show a high degree of comorbidity in traumatized children. Two hypotheses may help explain this relationship: children with ADHD are at higher risk for trauma due to their impulsivity, dangerous behaviors, and parents who may have a genetic predisposition for impairment of their own impulse control; and hyperarousal induced by severe trauma and manifested by hypervigilance and poor concentration may impair attention to create an ADHD-like syndrome. Four illustrative cases are presented, and implications for treatment are discussed.

Conventional theories about stressors severe enough to lead to PTSD have focused on external events. Historically, however, psychosis has been considered one of the most severe stressors to which one can be subjected. The impact of psychosis, in the case of schizophrenia, may be mistaken for the psychosis itself. The possibility of a comorbid, psychosis-induced PTSD should be considered in persons who have experienced a psychotic illness. Recognition of the syndrome may lead to more effective and emphathic clinical treatment of persons with severe mental illness.

Our study was done to determine whether patients with schizophrenia and a coexisting physical disorder could adequately discuss the physical illness with a physician. We defined the minimal standard of adequate communication as the ability to acknowledge and name a physical problem during an index hospitalization. Of the 110 patients studied, 38 had a total of 54 medical illnesses (diabetes mellitus, hyponatremia, thyroid disorder, urinary tract infection, bladder dysfunction, hypertension, anemia, liver disorder, and seizure disorder). After two years of follow-up, 28 of these 38 patients agreed to participate in the second part of the study. Upon interview, 24 patients were unable to name at least one of their physical problems. This study reproduces the previous findings of psychiatric patients' difficulty in communicating about physical illness. It suggests that the communication difficulty is constant and not lessened in the nonacute situation.