Cynthia A. Carel

Association of anorexia nervosa with the high activity allele of the COMT gene: a family-based study in Israeli patients.

Anorexia nervosa (AN) is a common, severe and disabling psychiatric disorder, characterized by profound weight loss and body image disturbance.1 Family and twin studies indicate a significant genetic contribution2,3 and pharmacological data suggest possible dysfunction of the serotonergic4,5 and dopaminergic6–9pathways. Catechol-O-methyltransferase (COMT) is a candidate gene for mediating susceptibility to AN since it is involved in the dopamine catabolism10 and because its functional polymorphism (Val/Met 158) determines high (H) and low (L) enzymatic activity alleles.11 Fifty-one Israeli AN patients and their parents were genotyped with the COMT polymorphism. Using the haplotype relative risk (HRR) method it was found that the frequency of the H allele among alleles transmitted to AN patients from their parents was significantly higher than in those not transmitted (68% vs 51% χ2 = 5.20, df = 1, P = 0.023, odds ratio: 2.01). Transmission disequilibrium test (TDT) revealed that out of 49 heterozygote parents the H allele was transmitted to AN patients 33 times while the L allele was transmitted only 16 (McNemars χ2 = 5.90, df = 1, P = 0.015). Our study suggests that the COMT gene is associated with genetic susceptibility to AN, and that individuals homozygous for the high activity allele (HH) have a two-fold increased risk for development of the disorder.

Effect of Growth Hormone Treatment on Quality of Life of Short-Stature Children

While enhanced growth velocity is a well-established benefit following the initiation of growth hormone treatment (GHT), the potential benefit of GHT on quality of life (QOL) of short-stature children has not yet been documented. We compare QOL of two groups of short-stature children who attended the Endocrine Unit (EU) and were 2 SD or more below the average for age and gender. The first group included 96 patients of whom 65 were without any underlying disease, 15 had classical GH deficiency and 16 had Turner syndrome or renal disease. These patients were on GHT for at least 2 years. The other group included 33 patients. Owing to lack of resources to include these 33 patients in a clinical trial, they did not get GHT. They were normal variant of short stature, and their height was similar to the height of the 65 children included in the first group. QOL was assessed using self-administered questionnaires, which were filled out by the patients on their regular visit to the EU. QOL was defined in terms of school achievements, leisure activities, emotional and physical self-esteem, relationships with peers and family members. No significant differences were found between the two groups. The mean scores for the different domains of QOL ranged between 2.6 and 3.8 on a scale ranging from 1 (very pessimistic view) to 4 (very optimistic view).

High-affinity 3H-imipramine binding in platelets of children and adolescents with major affective disorders

High-affinity 3H-imipramine binding to platelet membranes was evaluated in 12 untreated children and adolescents aged 11-17 years who met the DSM-III criteria for major affective disorders. The affective patients were compared to 13 nonaffective subjects and 15 normal controls of similar ages. No significant difference in the maximal binding of 3H-imipramine (Bmax) and Kd values could be found among the three groups. 3H-Imipramine binding values failed to discriminate between patients with major depression and those with bipolar disorder, depressed type. No association between a positive family history of major affective disorders and 3H-imipramine binding values was detected.

Coping and satisfaction with growth hormone treatment among short-stature children

The ability of children to cope with a chronic medical problem requiring prolonged treatment has an effect on the quality of life of these children and of their parents and serves as an index of the quality of treatment. This study deals with coping ability and satisfaction with treatment of children whose stature was two or more SD below the average for age and gender. The study population included 96 patients, 53 of whom were male, who were on growth hormone (GH) treatment for at least 1 year. 65 patients were without any underlying disease, 15 had classical GH deficiency and 16 had Turner syndrome or renal disease. All patients were treated with daily injections at home from 12 to 66 months. Using a self-administered questionnaire, the ability to cope and the degree of satisfaction and compliance with treatment were assessed. No significant differences were found with respect to gender, the presence of an underlying disease, age at which treatment commenced or duration of treatment. Despite the fact that the outcome of GH treatment on final height has yet to be established, satisfaction and compliance were high.

Haplotype analysis of the COMT-ARVCF gene region in israeli anorexia nervosa family trios

Anorexia nervosa (AN) is a severe and complex psychiatric disorder with a significant genetic contribution. Previously, we found an association between AN and the 158Val/Met polymorphism of the catechol‐O‐methyltransferase (COMT) gene in a family‐based study of 51 Israeli AN trios. In the present study, we extended the original sample to include 85 family trios [66 AN restricting (AN‐R) and 19 bingeing/purging (AN‐BP) subtype] and performed a family‐based transmission disequilibrium test (TDT) analysis for five SNPs in the COMT and two in the adjacent ARVCF gene. Association was found between AN‐R and several SNPs in the COMT‐ARVCF region including the 158Val/Met polymorphism. TDT analysis of 5‐SNP haplotypes in AN‐R trios revealed an overall statistically significant transmission disequilibrium (P < 0.001). Specifically, haplotype B [COMT‐186C‐408G‐472G(158Val)‐ARVCF‐659C(220Pro)‐524T(175Val)] was preferentially transmitted (P < 0.001) from parents of AN‐R patients to their affected daughters, while haplotype A [COMT‐186T‐408C‐472A(158Met)‐ARVCF‐659T(220Leu)‐524C(175Ala)] was preferentially (P = 0.01) not transmitted. Haplotype B was associated with increased risk (RR 3.38; 0.95CI 1.98–6.43) while haplotype A exhibited a protective effect (RR 0.40; 0.95CI 0.21–0.70) for AN‐R. Preferential transmission of the risk alleles and haplotypes from the parents was mostly contributed by the fathers. No significant transmission disequilibrium of alleles or haplotypes was found for AN‐BP trios. The risk and protective haplotypes may carry molecular variations in the COMT gene or its vicinity that are relevant to the pathophysiology of restrictive anorexia nervosa in the Israeli‐Jewish population.

CAG repeat polymorphism within the KCNN3 gene is a significant contributor to susceptibility to anorexia nervosa: A case-control study of female patients and several ethnic groups in the Israeli Jewish population

The human small‐conductance Ca2+‐activated potassium channel gene KCNN3 has been involved in mechanisms underlying neuronal function and plasticity. A multiallelic CAG repeat polymorphism within the KCNN3 has been associated with schizophrenia and bipolar disorder. We have previously reported in a family‐based study that longer CAG repeats are preferentially transmitted to patients with anorexia nervosa (AN). The present study extends the analysis of KCNN3 allele distribution to a larger series of AN female patients and control groups, incorporating information on ethnicity and co‐morbidities associated with AN. The data analysis is presented while considering separately the two alleles of each individual, namely a minor (shorter) and a major (longer) allele. This study has found that the KCNN3 allele distribution in the general Israeli population does not differ significantly in at least four Jewish ethnic groups of Ashkenazi, North African, Iraqi, and Yemenite origin. These have been used as control groups in a matched case‐control analysis that has demonstrated a significant over‐representation of KCNN3 alleles with longer CAG repeats among AN patients (P < 0.001 for the major allele and P = 0.035 for allele sum). Under dichotomization, a significantly higher prevalence of the L allele (>19 repeats) has been observed among AN patients (P < 0.001). While considering AN and co‐morbid phenotypes, a tendency towards longer (L) alleles has been observed in the subset of patients with obsessive‐compulsive disorder (OCD) co‐morbidity. These findings further implicate KCNN3 as a significant contributor to predisposition to AN.

Decreased high affinity 3H-imipramine binding in platelets of enuretic children and adolescents

High affinity 3H-imipramine binding sites have been demonstrated in human brain and platelet membranes. It has been suggested that these binding sites selectively label serotonin transporter or uptake sites. Since imipramine has a beneficial effect in the treatment of nocturnal enuresis, the present study was carried out to investigate a possible association between alteration in 3H-imipramine binding parameters in enuretics in comparison to nonenuretic control subjects. 3H-Imipramine binding to platelets was examined in 16 enuretic children and adolescents and compared to that in 22 healthy subjects of similar ages. A significant reduction was observed in the number of 3H-imipramine binding sites, while the dissociation constants (Kd) did not differ significantly in the platelets of enuretics as compared to controls. 3H-Imipramine binding values did not discriminate between familial and nonfamilial enuresis. These results may indicate that an alteration in the serotonin transporter in peripheral or central neuronal levels might be involved in the pathophysiology of nocturnal enuresis.

Is psychotherapy mandatory during the acute refeeding period in the treatment of anorexia nervosa

Forty-five adolescent and preadolescent patients (42 females, three males) with anorexia nervosa (AN) were treated in a pediatric day care unit of a large urban hospital by a multidisciplinary team. In our treatment model, the pediatrician has the responsibility for the initial evaluation and physical rehabilitation while the pediatric psychiatrist does the initial evaluation of the patient and family and is available for intervention in an emergency. Parents are actively involved in the treatment program. Family psychotherapy is recommended for each patient and his or her family. Among 45 patients, 24 did not enter psychotherapy during the first 2 months of the refeeding period, while the remaining 21 patients started psychotherapy (family and/or individual) during this period. Weight gain was higher in the group without formal psychotherapy during the initial period of refeeding (7.3 +/- 3.1 kg versus 5 +/- 2.5 kg; p less than 0.01). It is suggested that the initiation of structured psychotherapy is not mandatory and does not contribute to treatment effectiveness in the acute phase when emaciation and negativism may hinder the psychotherapeutic process. We believe a multidisciplinary team, together with the parents, is the treatment of choice during the acute phase of AN.