Diabetes mellitus in Huntington disease

There have been conflicting reports that individuals with Huntington disease (HD) are prone to abnormalities of carbohydrate metabolism. In this study information about the incidence and control of diabetes mellitus in 620 probands (278 living, 332 deceased) with HD and in their first and second degree relatives was obtained by questionnaire method from participants of the National HD Research Roster. Among the probands, 65 individuals (10.5%) were identified by the informant or verified by examination of Roster family records as diabetic. The prevalence of diabetes, particularly among those less than 50 years of age, is significantly greater than corresponding figures among the general U.S. Caucasian population (Scott 1977, Krolewski & Warram 1985). Incidence rates were not calculated because of ascertainment and other biases in the data. Results from the analysis of family data indicate that HD affected relatives of an HD proband with diabetes are 7 times as likely to have diabetes over the proband's non-HD relatives. A non-diabetic HD proband is equally likely to have an HD or non-HD relative with diabetes.     

Factors related to genetic testing in adults at risk for Huntington disease: the prospective Huntington at‐risk observational study (PHAROS)

Huntington disease (HD) is a late onset ultimately fatal neurodegenerative disorder caused by a cytosine–adenine–guanine ( CAG) triplet repeat expansion in the Huntingtin gene which was discovered in 1993. The PHAROS study is a unique observational study of 1001 individuals at risk for HD who had not been previously tested for HD and who had no plans to do so. In this cohort, 104 (10%) individuals changed their minds and chose to be tested during the course of the study but outside of the study protocol. Baseline behavioral scores, especially apathy, were more strongly associated with later genetic testing than motor and chorea scores, particularly among subjects with expanded CAG repeat length. In the CAG expanded group, those choosing to be tested were older and had more chorea and higher scores on the behavioral section of the unified Huntington's disease rating scale at baseline than those not choosing to be tested. Following genetic testing, 56% of subjects with CAG < 37 had less depression when compared to prior to testing, but depression generally stayed the same or increased for 64% of subjects in the expanded group. This finding suggests that approaches to testing must continue to be cautious, with appropriate medical, psychological and social support.     

A psychometric study of children at-risk for Huntington disease

Huntington disease (HD) is an autosomal dominant disorder of the central nervous system with an average age of onset between 35 and 45 years and symptoms progressing slowly over the next 10 to 20 years. Research in the past few years has focused on the hypothesis that a presymptomatic or prodromal phase for HD is detectable at least 10 years prior to chronic symptoms. This study attempts to identify possible signs of a prodromal phase for HD in children who are at primary (50%) and secondary (25%) risk for HD using a screening battery of psychometric tests. The children tested were between the ages of 5 1/2 and 15 years and the tests used were the WISC-R, the PPVT-R, and the VMI. Results from this study indicated performance on the WISC-R Digit Span and to a lesser extent Coding subtests might be useful in assessing a possible memory dysfunction in children at-risk for HD.     

亨丁顿舞蹈症家系的调查

目的 寻找由DNA损伤引起的人类表型缺陷,为人类遗传资源的收集与保藏以及人类基因结构与功能的研究打下基础.方法 通过实地调查得到表型缺陷家系,然后进行系谱分析.结果 得到一个亨丁顿舞蹈症家系,4代16位成员中有5例患者.结论 亨丁顿舞蹈症（Huntington disease）是由DNA损伤引起的人类表型缺陷;该病症符合常染色体显性遗传.     

Long-term outcome of presymptomatic testing in Huntington disease

Our study on long-term outcome of presymptomatic testing for Huntington disease had two aims: the comparison of the psychological well-being and social adjustment of carriers and non-carriers of the mutation, and the identification of psychological determinants to improve care/support of testees. We performed a cross-sectional study of 351 persons who underwent presymptomatic testing. Those who had motor signs were excluded from the comparison of asymptomatic carrier and non-carriers. A structured interview including five self-report scales and the MINI (Mini International Neuropsychiatric Inventory) was proposed to detect a psychopathology or problem with social adjustment.We interviewed 119 testees (53%), 62 non-carriers and 57 carriers after a mean delay of 3.7 years (range: 0.32 to 8.9) after their result. Depression was frequent in asymptomatic carriers (58%). Interestingly, the self reported impact of the test showed that 27% of non-carriers did not cope well with a favourable result, and a significant percentage of non-carriers (24%) were depressed during follow-up. Multivariate analysis showed that only a previous episode of depression was predictive of depression after genetic testing in both carriers and non-carriers of the HD mutation (P<0.0001).Psychological support is necessary for all testees regardless of the result of their presymptomatic test, because psychiatric care is often needed by both carriers and non-carriers.     

Founder mutation for Huntington disease in Caucasus Jews

Huntington disease (HD), an autosomal dominant disorder involving HTT, is characterized by chorea, psychiatric illness and cognitive decline. Diagnosis and age of onset depend on the degree of expansion of the trinucleotide CAG repeat within the gene. The prevalence of HD is known for Europeans but has not been studied in the Israeli population. Between 2006 and 2011 we diagnosed in our adult genetics clinic ten HD probands, nine of whom were Caucasus Jews (CJ) (Azerbaijani), and one Ashkenazi Jewish. We performed haplotype analysis to look for evidence of a founder mutation, and found that of the nine CJ, eight shared the same haplotype that was compatible with the A1 haplogroup. We calculated the coalescence age of the mutation to be between 80 and 150 years. Ninety percent of our HD patients are CJ, as are 27% of the HD patients in Israel, although the CJ comprise only 1.4% of the Israeli population. Our findings suggest a higher prevalence of HD among CJ compared to the general Israeli population and are consistent with a recent founder mutation. We recommend a higher degree of suspicion for HD in CJ with subtle clinical findings.     

Huntington舞蹈症的IT15基因诊断

为了对Huntington舞蹈症进行早期准确的基因诊断,作者应用聚合酶链反应直接检测IT15基因CAG三核苷酸重复序列,对武汉某Huntington舞蹈症(HD)家系两代11名家庭成员进行了基因诊断.PCR产物的取丙烯酰胺凝胶电脉结果显示5例HD高风险者有4例携带异常HD基因.     

Psychological impact of news of genetic risk for Huntington disease

A one‐year longitudinal study was conducted investigating the psychological effects of the news of genetic testing for the Huntington disease (HD) gene. Participants were assessed at baseline (before obtaining news of test results) and at three, six, and 12 months after test results on stress‐specific symptom measures. Among carriers of the HD gene, a considerable number (55%) showed evidence of neurological impairment at baseline, indicative of HD. Also noteworthy, these individuals had significantly higher psychological symptom scores at baseline than carriers without neurological impairment or noncarriers. Despite this, these individuals were no more aware of their carrier status at baseline than carriers without HD symptoms or noncarriers. Furthermore, the psychological symptom levels of HD carriers with neurological impairment remained elevated across the follow‐up assessments. Results for noncarriers and carriers without HD neurological symptoms were consistent with the findings of previous studies indicating that news of genetic testing for the HD gene had limited detrimental impact. The clinical implications of the results are discussed. © 2001 Wiley‐Liss, Inc.     

Uptake of Huntington disease predictive testing in a complete population

Using the Northern Ireland Huntington disease (HD) register, the number of prospectively recorded predictive tests was analysed over a 20-year period. Two hundred and twelve patients completed predictive testing. Ninety-two (43%) received mutation-positive results and 119 (56%) mutation negative. There was one intermediate allele result. There was no significant gender difference. One hundred and eighty affected cases confirmed by molecular genetic testing were alive on 1 January 2001. The uptake of predictive testing in the entire HD 50% at-risk population in 2001 was calculated by three methods giving a range of 12.3-14.6%. Uptake after 20 years was estimated to be 14.7%. The minimum prevalence of affected HD cases was calculated as 10.6/100,000 in 2001. The total uptake of predictive testing was calculated and it suggests that a substantial number of at-risk patients do not come forward for testing until symptomatic. Pre-symptomatic testing for this late-onset condition with no present treatment, and limited management options, still presents challenges for families.     

Severe ultrastructural mitochondrial changes in lymphoblasts homozygous for Huntington disease mutation

Mutated huntingtin is expressed in nervous and non nervous system included lymphoblasts. Eneregetic metabolism is impaired in Huntington's disease (HD) and other neurodegenerative diseases. Human HD lymphoblasts have provided clear-cut data on mitochondnal disruption. Here we report morphological, morphometric and membrane potential differences in mitochondria from lymphoblasts obtained from patients homozygous and heterozygous for the CAG mutation, and controls. Homozygotes, who despite a similar age at onset show a more aggressive phenotype than heterozygotes, had giant mitochondria and a reduced membrane potential. We argue that early mitochondrial impairment at basal level may affect the severity of HD progression in patients.     

Terminal deletion of chromosome 4p (4p16.3) shows a breakpoint between loci linked to Huntington disease

A 15-year-old boy with a terminal deletion of the short arm of chromosome 4 is described. The patient has a mild clinical phenotype that is incompatible with Wolf-Hirschhorn syndrome. Careful neurological examination including CT scan did not show any signs of Huntington disease. The chromosomal breakpoint was analyzed by means of polymorphic DNA probes localized close to the tentative Huntington (HD) locus. The breakage has occurred between D4S43 and D4S90 loci and thus deletes part of the chromosomal candidate regions for the HD locus. © 1992 Wiley-Liss, Inc.     

Predictive testing for Huntington disease in a developing country

Predictive testing for Huntington disease (HD), by means of direct mutation analysis, has been offered at the Division of Human Genetics, University of Cape Town, from 1995. The aim of this study was to compile a comprehensive profile of the participants who had undergone predictive testing in the Western Cape from 1995 to 2005. The sociodemographic data, uptake and outcome of tests were analyzed to inform changes to improve the current genetic counseling services. A retrospective cross-sectional design using a 'multi-method' approach of both qualitative and quantitative methods was used. Data were gathered from the participants' hospital files and genetic database. Psychosocial data were obtained by face-to-face interviews with the participants in their homes or venues of choice. A total of 36 predictive tests were performed. The uptake for predictive testing was approximately 4.5% of the estimated at-risk population. The cohort of 27 individuals comprised 16 females and 11 males. Their mean age was 35.3 years; 6 were mixed ancestry and 21 were White people (European ancestry); 11 tested gene positive, 15 gene negative and 1 was in the reduced penetrance range. The most important issue identified was that the uptake of individuals classified as mixed ancestry was substantially lower than that of the White people possibly due to limited access to the predictive testing program because of the low levels of income and education in the general population of families with HD. Strategies to address these aspects have been incorporated into the program and will be reassessed after 1 year.     

Hypocretin and melanin-concentrating hormone in patients with Huntington disease

Abstract To evaluate whether hypocretin-1 (orexin-A) and melanin-concentrating hormone (MCH) neurotransmission are affected in patients with Huntington disease (HD), we immunohistochemically stained hypocretin and MCH neurons and estimated their total numbers in the lateral hypothalamus of both HD patients and matched controls. In addition, hypocretin-1 levels were determined in prefrontal cortical tissue and post-mortem ventricular cerebrospinal fluid (CSF) using a radioimmunoassay. The total number of hypocretin-1 neurons was significantly reduced by 30% in HD brains (P = 0.015), while the total number of MCH neurons was not significantly altered (P = 0.100). Levels of hypocretin-1 were 33% lower in the prefrontal cortex of the HD patients (P = 0.025), but ventricular CSF levels were similar to the control values (P = 0.306). Neuronal intranuclear and cytoplasmic inclusions of mutant huntingtin were present in all HD hypothalami, although with a variable distribution across different hypothalamic structures. We found a specific reduction in hypocretin signaling in patients with HD as MCH cell number was not significantly affected. It remains to be shown whether the moderate decrease in hypocretin neurotransmission could contribute to clinical symptoms. As the number of MCH-expressing neurons was not affected, alterations in MCH signaling are unlikely to have clinical effects in HD patients.     

Factors associated with HD CAG repeat instability in Huntington disease

Background

The Huntington disease (HD) CAG repeat exhibits dramatic instability when transmitted to subsequent generations. The instability of the HD disease allele in male intergenerational transmissions is reflected in the variability of the CAG repeat in DNA from the sperm of male carriers of the HD gene.

Results

In this study, we used a collection of 112 sperm DNAs from male HD gene‐positive members of a large Venezuelan cohort to investigate the factors associated with repeat instability. We confirm previous observations that CAG repeat length is the strongest predictor of repeat‐length variability in sperm, but we did not find any correlation between CAG repeat instability and either age at the time of sperm donation or affectedness status. We also investigated transmission instability for 184 father–offspring and 311 mother–offspring pairs in this Venezuelan pedigree. Repeat‐length changes were dependent upon the sex of the transmitting parent and parental CAG repeat length but not parental age or birth order. Unexpectedly, in maternal transmissions, repeat‐length changes were also dependent upon the sex of the offspring, with a tendency for expansion in male offspring and contraction in female offspring.

Conclusion

Significant sibling–sibling correlation for repeat instability suggests that genetic factors play a role in intergenerational CAG repeat instability.     

Huntington disease and Huntington disease‐like in a case series from Brazil

The aim of this study was to identify the relative frequency of Huntington's disease (HD) and HD‐like (HDL) disorders HDL1, HDL2, spinocerebellar ataxia type 2 (SCA2), SCA17, dentatorubral‐pallidoluysian degeneration (DRPLA), benign hereditary chorea, neuroferritinopathy and chorea‐acanthocytosis (CHAC), in a series of Brazilian families. Patients were recruited in seven centers if they or their relatives presented at least chorea, besides other findings. Molecular studies of HTT, ATXN2, TBP, ATN1, JPH3, FTL, NKX2‐1/TITF1 and VPS13A genes were performed. A total of 104 families were ascertained from 2001 to 2012: 71 families from South, 25 from Southeast and 8 from Northeast Brazil. There were 93 HD, 4 HDL2 and 1 SCA2 families. Eleven of 104 index cases did not have a family history: 10 with HD. Clinical characteristics were similar between HD and non‐HD cases. In HD, the median expanded (CAG)n (range) was 44 (40–81) units; R² between expanded HTT and age‐at‐onset (AO) was 0.55 (p = 0.0001, Pearson). HDL2 was found in Rio de Janeiro (2 of 9 families) and Rio Grande do Sul states (2 of 68 families). We detected HD in 89.4%, HDL2 in 3.8% and SCA2 in 1% of 104 Brazilian families. There were no cases of HDL1, SCA17, DRPLA, neuroferritinopathy, benign hereditary chorea or CHAC. Only six families (5.8%) remained without diagnosis.     

Problems assessing uptake of Huntington disease predictive testing and a proposed solution

The uptake of predictive testing for Huntington disease informs our understanding of decision making by those at risk and assists with planning for service provision. Uptake figures have been reported from several centers based on the total number of people who have undertaken predictive testing as a percentage of those estimated to be at 50% risk in the region. This method produced a figure of 35% from our own service, much higher than observation of the local pedigrees indicated, and higher than other published reports. We have identified some errors in the commonly used formula. The major errors are the use of the cumulative total of those who have had testing with a static denominator of those at 50% risk, and the failure to exclude from the at-risk group those who are too young and therefore ineligible to test.We report data from the Huntington Disease Register of Victoria and estimate the prevalence to be 8 per 100,000 in 1999. Additional data on individuals at risk were collated. We found that for every diagnosed person there were 4.2 individuals at 50% risk, a lower ratio than one to five hypothesized in the literature. We examined these ratios in the context of uptake.Significantly, we provide a solution to the calculation of uptake with a formula that factors in a dynamic denominator and corrects for the number of years testing has been offered. Using this formula, we calculated an uptake of 13.0-15.4% for the state of Victoria, Australia. This formula can be used to compare uptake across different centers.     

Targeting the proteostasis network in Huntington’s disease

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion mutation in the huntingtin protein. Expansions above 40 polyglutamine repeats are invariably fatal, following a symptomatic period characterised by choreiform movements, behavioural abnormalities, and cognitive decline. While mutant huntingtin (mHtt) is widely expressed from early life, most patients with HD present in mid-adulthood, highlighting the role of ageing in disease pathogenesis. mHtt undergoes proteolytic cleavage, misfolding, accumulation, and aggregation into inclusion bodies. The emerging model of HD pathogenesis proposes that the chronic production of misfolded mHtt overwhelms the chaperone machinery, diverting other misfolded clients to the proteasome and the autophagy pathways, ultimately leading to a global collapse of the proteostasis network. Multiple converging hypotheses also implicate ageing and its impact in the dysfunction of organelles as additional contributing factors to the collapse of proteostasis in HD. In particular, mitochondrial function is required to sustain the activity of ATP-dependent chaperones and proteolytic machinery. Recent studies elucidating mitochondria-endoplasmic reticulum interactions and uncovering a dedicated proteostasis machinery in mitochondria, suggest that mitochondria play a more active role in the maintenance of cellular proteostasis than previously thought. The enhancement of cytosolic proteostasis pathways shows promise for HD treatment, protecting cells from the detrimental effects of mHtt accumulation. In this review, we consider how mHtt and its post translational modifications interfere with protein quality control pathways, and how the pharmacological and genetic modulation of components of the proteostasis network impact disease phenotypes in cellular and in vivo HD models.