Syndrome Carriers Research Articles

MERRF/MELAS overlap syndrome: a double pathogenic mutation in mitochondrial tRNA genes

BackgroundMyoclonic epilepsy with ragged-red fibres (MERRF) and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) are established phenotypes of mitochondrial encephalomyopathy. The m.8356T>C transition in the mitochondrial tRNALys gene is...

Report From the Jerusalem Workshop on Lynch Syndrome-Hereditary Nonpolyposis Colorectal Cancer

A Workshop was held in Jerusalem, Israel, on October 26 and 27, 2009 to discuss the management of Lynch syndrome-hereditary nonpolyposis colorectal cancer (CRC), with the primary goal to develop consensus for the optimal management of this disease. A second goal was to identify areas of research with the potential to advance the clinical management of Lynch syndrome. The perspectives and recommendations from the workshop are meant to be a platform for discussion and deliberation. The Workshop was organized by Moshe Shike (Memorial Sloan Kettering Cancer Center, New York) and sponsored by The Colon Cancer Foundation. More details of each presentation are available in an on-line supplement.

Qualitative assessment of FMR1 (CGG)n triplet repeat status in normal, intermediate, premutation, full mutation, and mosaic carriers in both sexes: Implications for fragile X syndrome carrier and newborn screening

PurposeFragile X syndrome is caused by expansion and subsequent methylation of a CGG trinucleotide repeat in the FMR1 5′-untranslated region. Southern blot analysis is typically required to determine expansion size for triplet repeat lengths >200. We describe a triplet-primed polymerase chain reaction-based method using automated capillary electrophoresis detection for qualitative assessment of expanded CGG repeats. MethodsThe assay uses triplet-primed polymerase chain reaction in combination with GC-melting reagents and substitution of 7-deaza-2-deoxyGTP for dGTP. Amplicons are resolved by capillary electrophoresis. ResultsA distinctive pattern of tapering or “stutter” polymerase chain reaction amplification was evident on capillary electrophoresis in male and female patients harboring all expanded allele lengths examined (up to 2000 CGG repeats) and could be used to differentiate normal, intermediate, premutation, and full mutation alleles. Full mutation alleles exhibited an additional late-migrating amplicon on capillary electrophoresis. Mixing experiments demonstrated sensitivity as low as 1% for detection of the full mutation allele. In a 1275-sample concordance study against our existing polymerase chain reaction platform (with Southern blot analysis for repeat lengths ≥55), the triplet-primed polymerase chain reaction method exhibited 100% concordance for normal, intermediate, expanded, and full mutation alleles. This method also detected the full mutation alleles in DNA isolated from blood spots. ConclusionThis assay provides an accurate assessment of FMR1 repeat status and holds promise for use in carrier and newborn screening. The method distinguishes normal homozygous females from full mutation carrying females. Although the method is not useful for accurate sizing, it supplements the classic polymerase chain reaction method and results in significant reduction in the number of Southern blot analyses required to be performed in the laboratory to accurately assess the FMR1 genotype in all individuals.

“It's something I need to consider”: Decisions about carrier screening for fragile X syndrome in a population of non‐pregnant women

Population carrier screening for fragile X syndrome can provide women with information about their risk of having a child with fragile X syndrome and their risk of fragile X-associated primary ovarian insufficiency and fragile X-associated tremor ataxia syndrome. Few studies have explored women's decisions when offered carrier screening for fragile X syndrome. Interviews were conducted with 31 women who participated in a pilot study offering carrier screening to non-pregnant women. A qualitative approach was used to gain an in-depth understanding of women's experiences and examine their decision-making processes, including women who were tested and those who decided not to be tested. The decision-making process occurred in two phases. In the first phase, the participant's reproductive stage of life and experience with illness and disability were major factors influencing whether she would consider screening. In the second phase of decision-making, participants' perceptions of the value of knowing their carrier status was the most notable factor for influencing whether a woman actually had the carrier test. Some women appreciated having time for deliberation and those who were tested did not express regret about their decision. Our findings support offering carrier screening for fragile X syndrome to non-pregnant women and suggest that women from the general population will have specific informational and counseling needs when offered carrier testing. This study highlights the unique challenges encountered by women from the general population when making a decision about testing for fragile X syndrome carrier status and illustrates the importance of understanding how women make decisions.

Risk and Epidemiological Time Trends of Gastric Cancer in Lynch Syndrome Carriers in The Netherlands

Although gastric cancer forms part of the Lynch syndrome tumor spectrum, the risk of developing gastric cancer in Lynch syndrome families is unknown, resulting in a lack of clear guidelines for surveillance. The aim of this study was to evaluate incidence trends and risk of developing gastric cancer among Lynch syndrome mutation carriers in a Western population. Lynch syndrome mutation carriers were selected from the Dutch Hereditary Cancer Registry. The gastric cancer incidence in Lynch syndrome mutation carriers was compared to the gastric cancer incidence in the Dutch population between 1970 and 2003. Standardized incidence ratios were calculated by a Poisson model. Cumulative risks were calculated by Kaplan-Meier analysis. Overall, 2014 Lynch syndrome mutation carriers were identified. Gastric cancer was diagnosed in 32 (1.6%) subjects (male/female: 21/11), 22 (69%) of them had a negative family history of gastric cancer. The standardized incidence ratios of gastric cancer was 3.4 (95% confidence interval, 2.1-5.2) and showed a nonsignificant decline between 1970 and 2003 (P = .30). Absolute risk of developing gastric cancer also showed no significant change over time (P = .51). Lifetime risk of developing gastric cancer was 8.0% in males vs 5.3% in females (P = .02), and 4.8% and 9% for MLH1 and MSH2 carriers, respectively. None of the 378 MSH6 carriers developed gastric cancer (P = .002 vs MLH1 and MSH2 combined lifetime risk). Lynch syndrome mutation carriers have a substantial risk for gastric cancer, in particular patients with an MLH1 or MSH2 mutation. Family history for gastric cancer is a poor indicator for individual risk. Surveillance gastroscopy for Lynch syndrome patients carrying an MLH1 or MSH2 mutation should therefore be considered.

Síndrome da apneia e hipoapneia obstrutiva do sono e o enfoque fonoaudiológico: revisão de literatura

TEMA: Síndrome da Apneia e Hipoapneia Obstrutiva do Sono (SAHOS) é considerada um transtorno respiratório do sono, que afeta a população geral, com sintomas noturnos e diurnos que causam grande impacto na qualidade de vida do portador da síndrome. O interesse por tal patologia intensificou a partir do final dos anos de 1970 e recentemente vislumbra-se a fonoterapia como uma das alternativas para o tratamento da SAHOS. OBJETIVO: analisar as principais causas da síndrome da apneia e hipoapneia obstrutiva do sono e correlacioná-las ao trabalho fonoaudiológico. CONCLUSÃO: as causas mais encontradas relacionadas ao quadro da síndrome da apneia e hipoapneia obstrutiva do sono foram: redução da tonicidade do músculo genioglosso, comprimento excessivo de palato mole e úvula, obesidade, retrognatia e a prevalência em indivíduos do sexo masculino. O tratamento fonoaudiológico direcionado a estes indivíduos, seja ela em qual grau apresentar-se, proporciona uma melhora significativa do quadro, uma vez que o foco é a adequação da tonicidade e a mobilidade da musculatura orofacial.

A model for offering carrier screening for fragile X syndrome to nonpregnant women: results from a pilot study

PurposeTo develop a model of offering population carrier screening for fragile X syndrome to nonpregnant women in primary care, using a program evaluation framework. MethodsA three-phase approach included: (I) needs assessment exploring staff and client attitudes, and informing development of educational materials, questionnaires and protocols; (II) offering screening to women, with questionnaires at baseline (Q1) and another (Q2) 1-month later; (III) genetic counseling for test-positive women and interviews with a subgroup of participants. ResultsOf 338 volunteering for Phase II, 94% completed Q1, 59% completed Q2, and 20% (N = 65) chose testing revealing one premutation carrier and three gray zone results; 31 women were interviewed. Tested women had more positive attitudes toward screening (Q1: P < 0.001; Q2: P < 0.001) compared with untested, although there was no significant difference in mean knowledge scores or anxiety. Women generally supported being offered prepregnancy screening; however, reasons against being tested included: not currently planning a family; perceiving benefits of screening as unimportant; and having to return for testing. ConclusionThis is the first prospective study exploring informed decision-making for fragile X syndrome carrier screening, using a thorough process of consultation, with no apparent harms identified. It provides a model for development of future genetic screening programs.

S2-04-05: What are neuropsychological criteria for differential diagnosis of dementia syndromes

Background: Neuropsychological characteristics are incompletely specified for dementia syndromes such as Alzheimer’s Disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), Huntington’s Disease (HD) as well as other syndromes. Objective: Specific neuropsychological features of AD, VaD, FTD, and HD were investigated in preclinical and clinical stages of disease course. Methods: Departing from familial types of AD, VaD, FTD and HD, cognitive function was described in three groups of subjects in each dementia syndrome, i.e., demented and nondemented mutation carriers as well as healthy non-carriers from the same families. Results: Specific patterns of cognitive dysfunction were found for AD, VaD, FTD, and HD in preclinical and clinical stages of disease. AD was characterized by marked impairment in episodic memory (learning and retention), whereas a relatively large impairment was found in cognitive speed and motor performance for VaD. FTD was particularly associated with difficulties in executive function. For HD, there was a pronounced deficit in verbal fluency. Comment: Research findings support the view that phenotypes of familial and sporadic types of dementia diseases are similar. Therefore, patterns of cognitive dysfunction in familial forms may help differentiate dementia syndromes in sporadic types. Conclusion: In future, revision, specification and differentiation of clinical diagnostic criteria for common dementing diseases seem to be possible.

Radiation‐induced DNA damage and repair in peripheral blood mononuclear cells from Nijmegen breakage syndrome patients and carriers assessed by the Comet assay

Nijmegen breakage syndrome (NBS) patients and carriers are predisposed to malignancy and are often treated with X-irradiation. In the present study, the single-cell gel electrophoresis (Comet) assay was used to examine radiation-induced DNA damage and repair in peripheral blood mononuclear cells from NBS patients (n=13) and carriers (n=36) of six unrelated families. Cells from apparently healthy donors (n=10) and from breast cancer patients with normal clinical radiosensitivity (n=10) served as controls. Cells were irradiated with 5 Gy of X-rays and assayed for initial DNA damage and for residual DNA damage after 40 min of repair; the kinetics of DNA repair also was estimated. In addition, the nuclear area of unirradiated cells was extracted from the Comet data. The initial radiation-induced DNA fragmentation indicated that cells from members of two out of six NBS families were significantly more sensitive to X-irradiation than cells from the controls. Cells from four NBS families had longer DNA repair half-time values, while cells from five NBS families had significantly increased residual DNA damage following repair. The mean nuclear area of unirradiated cells processed in the Comet assay was 1.3-fold higher in cells from all NBS families than in the controls (P<0.05). Notably, the Comet assay parameters (initial and residual DNA damage and the repair kinetics) of irradiated NBS cells predicted the carrier status of the majority (86%) of blindly tested individuals. The prediction of NBS status was higher if the nuclear area of unirradiated cells was used as the endpoint. The results of this study suggest that the impaired radiation response of NBS cells should be taken into account if radiotherapy of NBS patients and carriers is required.

Feasibility of the use of primary breast epithelial cell cultures to identify genotype-specific preventive agents

3140 Background: Recent progress has intensified efforts to discover agents that target genetically determined events in order to treat, or even prevent, cancer. We have chosen to study clinically normal cells from Li Fraumeni Syndrome (LFS) and BRCA2 mutation carriers, individuals who carry a dominantly inherited increased risk for breast cancer. Our purpose was 1) to determine the feasibility of initiating short-term breast epithelial cell cultures from normal breast parenchyma obtained from incisional or core biopsies, and 2) to determine the effects of potential chemopreventive agents on growth inhibition of clinically normal cells from gene-carriers and controls. Methods: Uninvolved breast parenchyma was obtained from mastectomies for breast cancer, or contralateral prophylactic mastectomies, via incisional or 16G core biopsy. Specimens were digested in collagenase, and epithelial cells grown in MEGM (Clonetics, CA). Epithelial cell growth (passage 2–3) after 72 hours’ drug treatment was assessed with sulforhodamine B assay. Results: Breast epithelial cells were cultured from 28 (93%) of 30 incisional biopsies, with 100% success in the last 15. Cultures were initiated in 24 (83%) of 29 samples from 4 core biopsies, with 100% success in the last 20. Epithelial cells from four patients with LFS, two with BRCA2, and six controls were treated with tamoxifen, celecoxib, 4HPR, SAHA, CP31398, and rapamycin. All agents produced similar growth inhibitory effects for most genotypes. However, there was a trend toward more pronounced growth inhibition of LFS cells than of controls with p53-stabilizing agent CP31398 (28.3% vs 15% at 10 μM, p=0.08). Conclusions: It is feasible to culture breast epithelial cells from incisional as well as core biopsies, holding promise for individualized in vitro testing of chemopreventive agents. The agents in our study appear to have growth inhibitory effects in all genotypes tested. Further work is needed to determine whether novel genotype-specific preventive agents can be identified and temporal and concentration-dependent short-term biomarkers of response can be developed with this in vitro approach. Supported by NCI grant NO1-CN-15102 (to L.C.S.). No significant financial relationships to disclose.

AVALIAÇÃO DOS COMPONENTES DA SINDROME PLURIMETABÓLICA VISANDO PREVENÇÃO DAS DOENÇAS CARDIOVASCULARES

Para avaliar a prevalência da síndrome dos distúrbios metabólicos cardiovasculares, entre março/abril/ 2003, em Passo Fundo – RS, foram levantados registros de oito medidas, em duzentos adultos atendidos em consultório de cardiologia, quanto aos fatores de risco: dislipidemias (quatro medidas), pressão arterial (duas medidas), alterações nos níveis de glicose (uma medida) e nos índice de massa corporal (uma medida). Foi encontrada correlação significativa (r = 0,891) entre alterações no colesterol LDL e na pressão arterial diastólica.Aanálise da variância mostrou valores significativos de F para a interação tabagismo e HDL colesterol, pressão arterial diastólica e estresse, bem como pressão arterial diastólica e histórico familiar; o X2 foi significativo para sexo e níveis de glicose. Três pacientes (2,3 %) entre 128 mostraram alterações nos quatro fatores, preenchendo os requisitos descritos para a síndrome, enquanto quatro (3,1%) não apresentaram alteração. Em 96,9% houve de 1 a 7 medidas alteradas evidenciando a complexidade dos fatores envolvidos. Se propõe a ênfase na prevenção através de atividades educativas sob a coordenação de profissionais da área da saúde em núcleo interdisciplinar.

Fragile X syndrome carrier screening in the prenatal genetic counseling setting

PurposeTo document our experience with fragile X carrier screening. MethodsIn this study, 29,103 women with no known or suspected family history of fragile X syndrome were offered fragile X carrier screening during their prenatal genetic counseling visit. Screening acceptance was analyzed by referral indication, carrier frequencies documented, and prenatal outcome data presented. ResultsOverall, 7.9% accepted carrier screening. The premutation frequency was 1 in 382, and the intermediate allele frequency was 1 in 143. ConclusionsFragile X screening is a desirable option for some women seeking prenatal genetic counseling and should be made available to this population.

Cholesterol Metabolism and Suicidality in Smith-Lemli-Opitz Syndrome Carriers

The authors examined the relationship between cholesterol metabolism and suicidality in carriers of Smith-Lemli-Opitz syndrome and their families. This population has a partial deficiency in 7-dehydrocholesterol reductase (DHCR7), the enzyme that catalyzes the last step in cholesterol biosynthesis. Suicidal behavior, depression, misuse of alcohol and drugs, and family history of psychopathology, including attempted or completed suicide, were assessed by structured interview in 51 carriers of Smith-Lemli-Opitz syndrome and 54 matched comparison subjects. There were significantly more suicide attempters and completers among the biological relatives of Smith-Lemli-Opitz syndrome carriers than comparison subjects, but family history of psychopathology did not significantly differ between the groups. More suicide attempts were reported among Smith-Lemli-Opitz syndrome carriers than among the comparison subjects. These results, based on a unique study design, provide additional evidence supporting the relationship between cholesterol metabolism and suicidal behavior.

X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport Syndrome Concerted Action" study.

Alport syndrome (AS) is a type IV collagen hereditary disease characterized by progressive hematuric nephritis, hearing loss, and ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease characterized by much less severe disease in girls and women. A "European Community Alport Syndrome Concerted Action" (ECASCA) group was established to delineate the Alport syndrome phenotype in each gender and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of heterozygous girls and women belonging to the 195 families with proven COL4A5 mutation are compared with those of hemizygous boys and men. Hematuria was observed in 95% of carriers and consistently absent in the others. Proteinuria, hearing loss, and ocular defects developed in 75%, 28%, and 15%, respectively. The probability of developing end-stage renal disease or deafness before the age of 40 yr was 12% and 10%, respectively, in girls and women versus 90 and 80%, respectively, in boys and men. The risk of progression to end-stage renal disease appears to increase after the age of 60 yr in women. Because of the absence of genotype-phenotype correlation and the large intrafamilial phenotypic heterogeneity, early prognosis of the disease in X-linked Alport syndrome carriers remains moot. Risk factors for developing renal failure have been identified: the occurrence and progressive increase in proteinuria, and the development of a hearing defect.

RNA-Mediated Neurodegeneration Caused by the Fragile X Premutation rCGG Repeats in Drosophila

Fragile X syndrome carriers have FMR1 alleles, called premutations, with an intermediate number of 5′ untranslated CGG repeats between patients (>200 repeats) and normal individuals (<60 repeats). A novel neurodegenerative disease has recently been appreciated in some premutation carriers. As no neurodegeneration is seen in fragile X patients, who do not express FMR1, we hypothesize that lengthened rCGG repeats of the premutation transcript may lead to neurodegeneration. Here, using Drosophila melanogaster, we show that 90 rCGG repeats alone are sufficient to cause neurodegeneration. This phenotype is neuron specific and rCGG repeat dosage sensitive. Although devoid of mutant protein, this neurodegeneration exhibits neuronal inclusion bodies that are Hsp70 and ubiquitin positive. Overexpression of Hsp70 could suppress the neurodegeneration. These results demonstrate that neurodegenerative phenotype associated with fragile X premutation is indeed caused by the lengthened rCGG repeats and provide the first in vivo experimental demonstration of RNA-mediated neurodegeneration.

Wolfram syndrome and suicide: Evidence for a role of WFS1 in suicidal and impulsive behavior.

There is evidence suggesting that subjects affected with the Wolfram syndrome (WFS) and normal carriers present an increased risk of psychiatric disorders, particularly depression and suicidal behavior. We investigated a possible role of the gene involved in WFS (WFS1) in the neurobiology of suicide and the potential modulatory effect on traits associated to suicidal behavior. Genetic variation at WFS1 (H611R, R456H, and I333V) was investigated in 111 suicide victims and 129 normal controls. Possible effects on psychopathology and behavioral traits were investigated in a subsample of suicide cases (N = 31) for whom phenotyping was carried out by means of structured psychiatric interviews and questionnaires adapted for psychological autopsies. We found a significantly higher frequency of the 611R/611R genotype in suicide completers as compared to controls (chi(2) = 19.21, df=2, P = 0.001). Suicide completers with this genotype had higher scores on measures of impulsivity (t = -3.15, df = 15.3, P = 0.006); novelty seeking (NS) (t = -3.35, df = 13.8, P = 0.005); and conversely, lower scores of persistence (t = 2.4, df = 16.6, P = 0.028). Scores of impulsivity and NS remained higher in subjects with the associated genotype after adjusting for age, gender, and psychopathology. These results suggest a role for WFS1 in the pathophysiology of impulsive suicide, and are consistent with previous clinical reports suggesting an increased risk of suicidal behavior in WFS homozygotes and heterozygotes. However, these findings are preliminary and should be confirmed in independent samples.

Implicações do estresse oxidativo sobre o metabolismo eritrocitário de pessoas com Síndrome de Down

Portadores da Síndrome de Down estão sob estresse oxidativo endógeno e crônico que pode ser resultado do excesso de atividade da SOD-1. Este trabalho descreve alguns indicadores e adaptações das defesas frente aos danos oxidativos. Observamos que, nas pessoas com Síndrome de Down, a presença de estresse oxidativo (aumento de 48% na atividade da SOD-1) induziu várias adaptações no metabolismo eritrocitário, sendo que a redução da meta-hemoglobina, via aumento da atividade da meta-hemoglobina redutase (29%), garantiria a eficiência do transporte de oxigênio, enquanto o aumento da GSH (61%) propiciaria a integridade funcional do eritrócito. A diminuição dos valores de concentração de hemoglobina e hematócrito, possivelmente, resulta do aumento de atividade da enzima Glicose-6-fosfato desidrogenase e redução da meia-vida eritrocítica. Os efeitos destas adaptações sob a oxigenação do sangue merecem maiores investigações.

Is there a relationship between Wolfram syndrome carrier status and suicide?

Wolfram syndrome (WFS) is a rare, autosomal recessive neurodegenerative disorder. An increased risk of psychiatric disorders and suicide has been reported for heterozygote carriers. In this study we investigated whether mutations in the WFS gene are associated with suicide in the general population. The gene for WFS (WFS1) has recently been mapped to chromosome 4p16.1, and its genomic structure has been characterized. We screened the entire WFS1 ORF in a panel of 100 completed suicides, 60 blood donors not known to have psychiatric illness, and 100 donors with a negative history of depression or suicidal behavior. We did not find evidence of an increased incidence of WFS carriers in the suicide panel and concluded that WFS1 carrier status is not a significant contributor to suicide in the general population. Screening of this highly polymorphic gene resulted in the detection of 33 variants, 13 of which cause amino acid changes. Seven of these changes have not been previously reported and six were unique to our suicide panel.

Low maternal serum estriol as a marker for steroid sulfatase deficiency

Maternal serum screening began in the early 1980's with the evaluation of alpha-feto-protein (AFP) levels to identify pregnancies at an increased risk for neural tube defects and later for Down syndrome. Elevated levels of AFP have been found to be markers for other conditions like gastroschisis, kidney abnormalities and placental bleeding. Maternal serum screening now includes hCG and estriol to increase aneuploidy detection, with estriol being added in the mid 1990's. Since that time many screening tests have shown abnormally low levels of estriol (≤0.10 MoM). These low values have been reported in association with anencephaly, Smith-Lemli-Opitz, fetal adrenal hypoplasia, high-dose corticosteroid therapy and steroid sulfatase deficiency. We report on 4 cases of very low estriol levels detected through maternal serum screening and referred to our center. The values were 0.02 MoM, <0.03 MoM, 0.06 MoM and 0.10 MoM. In all cases the mothers were found to be carriers of a microdeletion in the steroid sulfatase (STS) region at Xp22.3 by FISH analysis. All had affected sons. Three were detected by amniocentesis and one was tested after delivery. Three cases had a family history of very dry skin consistent with an X-linked recessive inheritance pattern. STS deficiency should be considered when counseling patients presenting with very low maternal serum estriol levels. STS deficiency or X-linked ichthyosis is characterized by dark scaly skin most prominent on the back, neck, face and extremities. Approximately 25% of affected males may develop mild comeal opacities. Carrier females may have mild symptoms. In an estimated 5% of cases, a more severe phenotype may be present resulting from a larger deletion and leading to a contiguous gene syndrome. Other conditions mapped to Xp22.3 include short statue, chondrodysplasia punctata, mental retardation. Kallmann syndrome and ocular albinism Carrier testing and prenatal diagnosis are available. Testing can help elucidate the reason for low estriol levels and identify women at risk for prolonged labor and failure to dilate due to placental sulfatase deficiency. A detailed family history may assist in determining the risk of STS deficiency or a more severe contiguous gene syndrome.

A rare coding variant within the wolframin gene in bipolar and unipolar affective disorder cases

A recent report has shown that Wolfram syndrome carriers (heterozygotes) are 26-fold more likely to require psychiatric hospitalization compared with non-carriers, and that Wolfram syndrome heterozygotes may constitute approximately 25% of individuals hospitalized with depression and suicide attempts. We analyzed a His611Arg polymorphism of the wolframin gene by the polymerase chain reaction (PCR) and HhaI restriction digestion, in 158 bipolar I and 163 unipolar major affective disorder cases, and 316 controls. Statistical analyses of allele or genotype frequencies do not support a major role for wolframin in affective disorder. HhaI restriction digestion and sequencing of PCR products from four affective disorder cases showed a heterozygous Ala559Thr change. The Ala559Thr variant was not detectable in 382 controls tested. Thus, the rare wolframin 559Thr allele deserves consideration as a risk allele for affective disorder.