Analysis of CAG repeat expansion in Huntington's disease gene (IT 15) in a Hungarian population

Huntington's disease (HD) is a neurodegenerative disorder with autosomal dominant inheritance. The genetic defect is a CAG trinucleotide repeat expansion at the 5' end of the IT 15 gene on chromosome 4. This gene has not been analyzed in the Hungarian population yet. To obtain data DNA from 26 HD patients, 18 members of their families and 70 normal controls was amplified in the involved region by polymerase chain reaction. The CAG repeat numbers varied from 37 to 70 (median: 43) in HD patients and asymptomatic carriers, while individuals of the normal control group had 10-36 CAG repeat numbers (median: 18). The length of CAG repeat expansion in Hungarian HD patients was similar to that reported from other countries. The group of normal controls had the same CAG repeat expansion as populations reported from Western European countries. It is a useful piece of data for population genetics to prove that the population of Hungary is a mélange of different nations that influenced the history of the country in the last 11 centuries. As opposed to this, the only closely related nation, the Finnish, was genetically more isolated during this time, so the frequency of HD (and also the number of CAG repeats in normal individuals) proved to be exceptionally low.     

Family history and DNA analysis in patients with suspected Huntington's disease

OBJECTIVES: Until recently a definite diagnosis of Huntington's disease could be made by a combination of clinical findings, a positive family history, and pathological confirmation. Prevalence data are based on these criteria. After finding the gene and its pathogenic mutation direct diagnostic confirmation became available. The aim of this study was to determine to what extent the direct assessment of CAG repeat length has allowed the diagnoses of additional patients, with atypical psychiatric or neurological disease, or those without a family history, that could otherwise not be diagnosed using traditional criteria. PATIENTS AND METHODS: From all 191 referred patients suspected of having Huntington's disease between July 1993 and January 1996 CAG repeat length was determined and the family history was reviewed in the Leiden roster. After a retrospective search the patients were subdivided in positive, negative, suspect, and unknown family histories. Patients with an expanded repeat (>35) were finally diagnosed as having Huntington's disease. The family history was compared with the repeat length and the clinical features. RESULTS: Clinical information was obtained for 172 patients. Of these, 126 patients had an expanded repeat, 77 had a positive, eight a negative, 40 a suspect, and one an unknown family history. Of the 44 patients with a normal repeat length four had a positive family history. Of the two patients with an intermediate repeat (between 30-36 repeats), one with a negative family history received a clinical diagnosis of Gilles de la Tourette's syndrome. The other had an unknown family history. CONCLUSION: Despite verification of the family history through the Leiden roster, many more patients and families could be diagnosed with the new approach than would have been possible with the traditional criteria. Because prevalence studies have been based on this type of information, the data suggest an underestimation of the prevalence of Huntington's disease in the community of 14%.     

Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington's disease.

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the IT-15 gene; however, it remains unknown how the mutation leads to selective neurodegeneration. Several lines of evidence suggest impaired mitochondrial function as a component of the neurodegenerative process in HD. We assessed energy metabolism in the skeletal muscle of 15 HD patients and 12 asymptomatic mutation carriers in vivo using 31P magnetic resonance spectroscopy. Phosphocreatine recovery after exercise is a direct measure of ATP synthesis and was slowed significantly in HD patients and mutation carriers in comparison to age- and gender-matched healthy controls. We found that oxidative function is impaired to a similar extent in manifest HD patients and asymptomatic mutation carriers. Our findings suggest that mitochondrial dysfunction is an early and persistent component of the pathophysiology of HD.     

Incidence of mutations in the PARK2, PINK1, PARK7 genes in Polish early-onset Parkinson disease patients

Background and purposeParkinson disease (PD) is a complex disease, comprising genetic and environmental factors. Despite the vast majority of sporadic cases, three genes, i.e. PARK2, PINK1 and PARK7 (DJ-1), have been identified as responsible for the autosomal recessive form of early-onset Parkinson disease (EO-PD). Identified changes of these genes are homozygous or compound heterozygous mutations. The frequency of PARK2, PINK1 and PARK7 mutations is still under debate, as is the significance and pathogenicity of the single heterozygous mutations/variants, which are also detected among PD patients. The aim of the study was to analyze the incidence of autosomal recessive genes PARK2, PINK1, PARK7 mutations in Polish EO-PD patients.Material and methodsThe analysis of the PARK2, PINK1 and PARK7 genes was performed in a group of 150 Polish EO-PD patients (age of onset < 45 years). Mutation analysis was based on sequencing and gene dosage abnormality identification.ResultsMutations were identified only in the PARK2 and PINK1 genes with the frequency of 4.7% and 2.7% of subjects, respectively. In PARK2, point mutations and exons' rearrangements, and in PINK1 only missense mutations were detected. In both genes mutations were found as compound heterozygous/homozygous and single heterozygous. EO-PD patients’ genotype-phenotype correlation revealed similarities of clinical features in mutation carriers and non-carriers.ConclusionsThe frequency of the PARK2, PINK1, PARK7 mutations among Polish EO-PD patients seems to be low. The role of single heterozygous mutations remains a matter of debate and needs further investigations.     

Clinical picture of patients with Huntington's disease in relation to the number of trinucleotide CAG repeats in IT-15 gene

Huntington's disease (HD) is a neurological condition of progressive course that results from abnormally increased number of CAG repeats within IT-15 gene, coding for huntington. The main symptoms consist of choraetic movements, dementia, and characteropathy. The aim of the present study was to search for possible correlation between the age of the onset of HD, time from the onset, clinical status of the patients, and CAG repeats number. Ten patients were studied altogether. Modified UHDRS (MUHDRS) was applied for the estimation of patients' clinical status. The number of CAG repeats in examination of the IT-15 gene was determined by polymerase chain reaction (PCR) and separation of radioisotope labelled PCR product against DNA size marker in polyacrylamide gel. A negative significant correlation was found between the CAG repeats number and the disease onset age (r = -0.67; p < 0.05) and MUHDRS score (r = 0.75; p < 0.05), as well. Negative significant correlation between time from the onset and MUHDRS score (r = -0.95; p < 0.05) and negative correlation between summarised: time from the onset and CAG number on the one site and MUHDRS on the other (p = -0.91) were found, as well. Our findings indicate an interdependence between CAG repeats number within the IT-15 gene, the course of the disease and the clinical status of HD patients.     

Visual function in Huntington's disease patients and presymptomatic gene carriers.

Disturbances of visual cognition, visuomotor performance, and visual memory have been described frequently in Huntington's disease (HD). Early stage visual abnormalities could contribute to these deficits. We evaluated visual processing in 20 control subjects who were non-gene carriers at risk for HD, nine presymptomatic gene-positive subjects, and eight subjects with a recent diagnosis of Huntington's disease. Visual perceptual tests of contrast sensitivity and motion discrimination were used to probe early stage visual processing. Extraocular movements were evaluated in a neurologic examination, and the Digit Symbol test was used to test visual motor performance. Contrast sensitivity did not differ among the three groups. Motion discrimination was impaired in HD subjects but not in the presymptomatic gene carriers when compared to gene noncarriers. Among gene carriers, impaired motion discrimination performance was associated with poorer Digit Symbol performance and extraocular abnormalities. These findings suggest that the early stages of HD are associated with disturbances of motion perception as well as disruptions of visual motor and ocular motor performance.     

Attention, inhibition, and proximity to clinical onset in preclinical mutation carriers for Huntington's disease

Research in preclinical mutation carriers for Huntington's disease (HD) aims to find measures sensitive to preclinical decline. This study investigated attentional abilities in mutation carriers and noncarriers. Mutation carriers demonstrated a normal "attentional blink" during rapid serial visual presentation, normal covert visual orienting, and normal directing of attention to tactile stimuli. However, they were more likely than noncarriers to make anticipatory responses before target presentation. Additionally, those closer to estimated onset of HD demonstrated larger "inhibition of return" effects. The findings suggest potential changes in cognitive inhibition of unwanted responses, and in automatic inhibition of visual orienting, in preclinical HD.     

亨廷顿病基因治疗研究进展

亨廷顿病是一种以运动、认知和精神障碍为主要表现的遗传性中枢神经系统变性疾病,其致病基因IT15突变可引起胞嘧啶腺嘌呤鸟嘌呤(CAG)三核苷酸重复序列异常扩增,导致所编码的亨廷顿蛋白构象变化并产生神经毒性作用。亨廷顿病的基因治疗目前尚处于临床前阶段,主要包括基因沉默、诱导突变亨廷顿蛋白清除、导入神经营养因子基因,以及纠正突变型亨廷顿蛋白的毒性作用所致的基因转录、信号转导和线粒体代谢紊乱等。本文尝试对亨廷顿病的基因治疗研究进展简要叙述。     

Neuropsychological manifestations of the genetic mutation for Huntington's disease in presymptomatic individuals.

A triplet repeat (CAG) expansion mutation in the huntingtin gene on chromosome 4 is responsible for Huntington's disease (HD). Presymptomatic genetic testing for this mutation has identified clinically normal persons who are virtually certain to develop this dementing illness if they live a normal lifespan. The present study sought to determine whether these "mutation-positive" persons have impairments in cognitive functioning. Seventy-five mutation-positive persons did not differ from 128 mutation-negative persons on tests selected for their sensitivity to early-stage HD. Interestingly, however, those with the mutation viewed themselves as more likely to develop HD than did those without the mutation. Among mutation-positive subjects, having a longer CAG repeat mutation was likewise not associated with cognitive impairment. However, being closer to estimated disease onset (a product of repeat length and parent's age at onset) was associated with selected cognitive impairments. When viewed in light of previous studies showing atrophy of the caudate nucleus and putamen in mutation-carriers who are close to onset but not those far from onset, these results suggest that subtle changes in brain and behavior may be detected shortly before subjects with the HD mutation develop sufficient signs and symptoms for diagnosis. Conceptual and methodological problems associated with the search for presymptomatic cognitive and behavioral indicators of dementing illness are discussed.     

Psychosocial, cognitive, and motor functioning in patients with suspected Sotos syndrome: a comparison between patients with and without NSD1 gene alterations

The aim of this study was to investigate psychosocial, cognitive, and motor functioning in patients clinically suspected of Sotos syndrome and to examine differences between patients with deletions or mutations of the gene encoding nuclear SET domain-containing protein 1 (NSD1; the major cause of the syndrome) and those without such alterations. Twenty-nine participants (21 males, 8 females) clinically suspected of Sotos syndrome (mean age 11y 10mo [SD 10y 11mo], range 1y 10mo-48y 5mo) were divided into an NSD1 mutation group (n=12; 8 males, 4 females) and an NSD1 non-mutation group (n=17; 13 males, 4 females). Intelligence, behaviour problems, attention-deficit-hyperactivity disorder (ADHD) symptoms, temperament, adaptive behaviour, and motor functioning were assessed with an extensive test battery. Scores were compared with those of control groups, and scores of the two subgroups were compared with each other. The mean IQ in the 21 individuals tested was 76 (SD 16; range 47-105). High rates of behaviour problems were found and patients lagged 1y 7mo to 2y 7mo behind in aspects of adaptive behaviour. In comparison with a control group of patients with a learning disability, motor functioning was better. NSD1 mutation compared with NSD1 non-mutation patients showed easier temperament, and fewer NSD1 mutation patients scored in the clinical range for 'total behaviour problems' (3/11 vs 13/17), 'internalizing behaviour' (2/11 vs 11/17), and ADHD (0/9 vs 4/15).     

Molecular characterization of genes modifying the age at onset in Huntington's disease in Uruguayan patients

Huntington's disease (HD) is a hereditary neurodegenerative disorder. The genetic cause is an expansion of CAG repeats located in the IT15 gene. Though the number of CAG repeats ((CAG)n) can largely explain the age at onset (AAO) of symptoms, a percentage of its variation could be attributed to modifier genes and to environmental factors. The study aimed to evaluate the influence of genetic modifiers of the AAO of HD including: (CAG)n and del2642 in the IT15 gene, ADORA2A rs5751876, HAP1 rs4523977, PGC1-α rs7665116 and UCH-L1 rs5030732. Eighteen patients with positive family history and HD-suggestive symptoms were recruited. The (CAG)n and gene polymorphisms were determined by different molecular biology techniques. We observed that the (CAG)n influenced in a 64.5% of the variability in the AAO. We also showed that the rs5751876 variant significantly affected this variability. However, the influence of UCH-L1, del2642, HAP1 and PGC1-α gene polymorphisms could not be replicated, perhaps due to small sample size. Genetic studies including the molecular determination of (CAG)n, in addition to other genetic modifiers involved in the variability of the AAO, were first performed in Uruguay. We could replicate in our cohort the anticipation effect on the AAO by the ADORA2A rs5751876. Our results confirm the usefulness of an expanded molecular characterization in HD patients.     

Actin-related myopathy without any missense mutation in the ACTA1 gene

Actinopathies are defined by missense mutations in the ACTA1 gene coding for sarcomeric actin, of which some 70 families have, so far, been identified. Often, but not always, muscle fibers carry large patches of actin filaments. Many such patients also have nemaline myopathy, qualifying actinopathies as a subgroup of nemaline myopathies. This article concerns a then newborn, now 2 1/2-year-old boy, the first and single child of nonconsanguineous parents, who was born floppy, requiring immediate postnatal assisted ventilation. A quadriceps muscle biopsy revealed large patches of thin myofilaments reacting at light and electron microscopic levels with antibodies against actin but only a few sarcoplasmic rods and no intranuclear rods. DNA analysis of the patient's and both parents' blood did not reveal any missense mutation in the ACTA1 gene. Thus, this congenital myopathy can be caused by a new type of ACTA1 gene mutation, a new non-ACTA1 gene mutation, or no mutation at all, designating it as an actin-related myopathy, perhaps a new type of congenital myopathy and a new member of protein aggregate myopathies marked by aggregation of proteins within muscle fibers, among them desminopathies, alpha-beta crystallinopathies, other desmin-related myopathies (also termed myofibrillar myopathies), actinopathies and, now, actin-related myopathies.     

Phenotype of the DYT1 mutation in the TOR1A gene in a Polish population of patients with dystonia. A preliminary report

BACKGROUND AND PURPOSE: DYT1 dystonia is the most common form of inherited primary dystonia. The aim of the study was: 1) to evaluate the prevalence of the DYT1 mutation in a population of Polish patients with early-onset generalized dystonia and with other forms of familial dystonia, 2) to evaluate the frequency of the DYT1 mutation in patients with writer's cramp, 3) to characterize the phenotype of the DYT1 mutation in the Polish population, and 4) to define the group of patients in whom genetic testing is recommended. MATERIAL AND METHODS: The following groups of patients were included in the study: 1) patients with early-onset (<30 years) generalized dystonia and those patients with onset after age 30 years who have relatives with early-onset dystonia, 2) patients with writer's cramp (focal or as part of segmental dystonia) independently of age of onset, 3) asymptomatic (adult only) relatives of the diagnosed DYT1 carriers. Genetic tests were performed in 63 subjects---28 sporadic cases of dystonia, 20 patients with familial dystonia, and 15 asymptomatic relatives of patients with confirmed DYT1 mutation. RESULTS: The DYT1 mutation was found in 17 subjects--10 patients with dystonia and 7 asymptomatic relatives (from 6 families). In all mutation carriers dystonia occurred in one limb before age 26 years. In 8 patients, generalization of dystonia was observed and in 2 cases it remained in a focal form. CONCLUSIONS: 1. The prevalence of DYT1 mutation among patients with early-onset (相似文献   

Environmental stimulation increases survival in mice transgenic for exon 1 of the Huntington's disease gene.

Mice transgenic for the first exon of the human Huntington's disease (HD) gene carrying an expanded CAG repeat expansion (R6/2 line) develop a progressive neurologic phenotype with symptoms resembling those seen in HD. The overt symptoms of R6/2 mice worsen with age, resulting in a rapid decline in health and premature death between 13 and 18 weeks of age. In this study, we characterized the onset and progression of the overt phenotype in R6/2 mice and examined factors that affect the phenotype and life expectancy of these mice. In particular, the effects of altering home cage environment, through changing feeding regimes and providing environmental stimulation, were investigated. We show that changes in feeding regimes significantly improved the general well-being and life expectancy of R6/2 mice. Furthermore, we find that various forms of environmental stimulation, including regular behavioral testing, significantly improved the survival of R6/2 mice over and above that resulting from the enhanced feeding regime. The fact that environmental stimulation improves the health and life expectancy in R6/2 mice not only enables the mice to serve as more useful research tools, but also suggests that environmental stimulation may have a beneficial impact on the progression of HD in patients.