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PubMed2005

[Progressive ataxia and cognitive deficits caused by premutation in the fragile-X-mental retardation gene].

A 75-year-old man had progressive difficulty with walking, intention tremor, ataxia, and mild cognitive deficits. MRI scan ofthe brain showed symmetrical hyperintensities in the middle cerebellar peduncles. DNA analysis ofthe fragile-X gene revealed an expansion of 150-200 repetitions in the FMR1-gene, compatible with a premutation in the fragile-X gene. Two years later, after progression of the symptoms, the patient was admitted to a nursing home. The clinical picture of intention tremor, parkinsonism and ataxia with white matter lesions and atrophy on MRI occurs in carriers of this premutation and has recently been described as the fragile-X-associated tremor/ataxia syndrome. Recognition of this clinical picture is important for the patient but also for the relatives, since female carriers of the premutation have an increased risk of offspring with the fragile-X syndrome.

Aged↗
PubMed2006

Clinical phenotype associated with homozygosity for a HOXD13 7-residue polyalanine tract expansion.

Synpolydactyly (SPD) is an autosomal dominant malformation of the distal limbs caused by mutations in the homeobox gene HOXD13 located on chromosome 2q31. We detail the clinical findings in a consanguineous Pakistani family segregating a HOXD13 7-residue polyalanine tract expansion. Three members of this pedigree were heterozygotes with features typical of SPD. Two further members demonstrate a more severe phenotype consistent with homozygosity for the familial mutation. We also report a child from a consanguineous Somali family homozygous for the same molecular lesion. Characteristic changes include a complex central polydactyly in the hands, abnormal modelling of the metacarpals and metatarsals, an increased number of carpal bones with abnormal shapes, hypoplasia or absence of the fifth digital rays in the feet, hypoplasia of the middle phalanges and abnormally long proximal phalanges in hands and feet. These cases illustrate the distinct phenotype associated with homozygosity for a HOXD13 mutation and also highlight the importance of considering homozygosity for a dominant mutation in consanguineous pedigrees.

Consanguinity↗
PubMed2005

Polyglutamine expansion diseases: failing to deliver.

Polyglutamine (polyQ)-expansion diseases are dominantly inherited adult-onset neurodegenerative diseases with unknown pathogenic mechanisms. Current models for pathogenesis include potential toxic effects of polyQ proteins, interference with survival pathways and deregulated gene transcription. Recently, nuclear and aggregate-independent alterations in fast axonal transport (FAT) have been demonstrated for several different polyQ disease models. Given the unique vulnerability of neurons to decrements in FAT, we propose an alternative model for polyQ disease pathogenesis. In this model, FAT is compromised because polyQ proteins affect enzymatic activities involved in FAT regulation. Decrements in FAT ultimately result in a failure to deliver essential cargos to specific neuronal subdomains, including presynaptic terminals, eventually leading to neuronal dysfunction and death. Pharmacological manipulation of such activities might provide the basis for new therapeutic strategies for treating polyQ diseases.

Axonal Transport↗
PubMed2004

Deranged neuronal calcium signaling and Huntington disease.

Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). HD is caused by polyglutamine (polyQ) expansion (exp) in the amino-terminal region of a protein huntingtin (Htt). The connection between polyQ expansion in Httexp and MSN neurodegeneration remains elusive. Here we discuss recent data that link polyQ expansion in Httexp and deranged Ca2+ signaling in MSN neurons. Experimental evidence indicates that (1) Ca2+ homeostasis is abnormal in mitochondria isolated from lymphoblasts of HD patients and from brains of the YAC72 HD mouse model; (2) Httexp leads to potentiation of NR1/NR2B NMDA receptor activity in heterologous expression systems and in MSN from YAC72 HD mouse model; and (3) Httexp binds to the type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1) carboxy-terminus and causes sensitization of InsP3R1 to activation by InsP3 in planar lipid bilayers and in MSN. Based on these results we propose that Httexp-induced cytosolic and mitochondrial Ca2+ overload of MSN plays an important role in the pathogenesis of HD and that Ca2+ signaling blockers may play a beneficial role in treatment of HD.

Animals↗
PubMed2004

Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population.

CONTEXT: Premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are frequent in the general population, with estimated prevalences of 1 per 259 females and 1 per 813 males. Several articles have recently described the presence of late-onset neurological symptoms in male carriers of premutation (FMR1) alleles. The main clinical features described in this newly identified syndrome are cerebellar ataxia and intention tremor. Additional documented symptoms include short-term memory loss, executive functional deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower-limb proximal muscle weakness, and autonomic dysfunction. OBJECTIVE: To study the penetrance of the fragile X-associated tremor/ataxia syndrome (FXTAS) among premutation carriers. DESIGN, SETTING, AND PARTICIPANTS: Family-based study of 192 individuals (premutation carriers and controls) whose families belong to the Northern or Southern California Fragile X Associations. Data were collected (March 2002-April 2003) through a survey and a standardized neurological examination, which was videotaped and subsequently scored in a blinded fashion. MAIN OUTCOME MEASURES: Penetrance of intention tremor and ataxia among adult carriers (aged > or =50 years) of premutation expansions of the FMR1 gene. RESULTS: Data from the survey of 192 individuals demonstrated an age-related penetrance of the combination of reported intention tremor and gait ataxia in male carriers (17%, 38%, 47%, and 75% [lower-bound estimates] for participants aged 50-59, 60-69, 70-79, and > or =80 years, respectively). The male carrier group had an age-adjusted 13-fold increased risk (95% confidence interval, 3.9-25.4; P =.003) of combined intention tremor and gait ataxia when compared with male controls. The clinical examination data from 93 individuals demonstrated that male carriers experienced more difficulties on each of 3 standardized neurological rating scales compared with controls (P<.05). Female carrier scores were also higher than those of female controls (P<.05) on 2 of the 3 neurological rating scales, but no participant was identified with probable or definite FXTAS. CONCLUSIONS: The study demonstrates that older male carriers of premutation alleles of the FMR1 gene are at high risk of developing FXTAS. Since male premutation carriers are relatively common in the general population, older men with ataxia and intention tremor should be screened for the FMR1 mutation, especially if these signs are accompanied by parkinsonism, autonomic dysfunction, or cognitive decline, regardless of family history.

Aged↗
PubMed2026

Toward the clinical application of long-read sequencing in repeat-expansion disorders.

Repeat-expansion disorders (REDs) are a mechanistically and clinically well-defined subgroup of rare diseases caused by the expansion of short tandem repeats (STRs). These expansions can exceed several kilobases and show complex features, such as noncanonical secondary structures, somatic instability, repeat interruptions and allele-specific methylation. These characteristics are highly relevant for understanding disease mechanisms, clinical variability, prognosis and potentially therapeutic decision-making, but cannot be fully resolved using traditional diagnostic methods or short-read sequencing technologies. By contrast, long-read sequencing (LRS) enables accurate investigation of STR complexity in a single assay, facilitates the discovery of new pathogenic repeat expansions and drives advances in diagnostics, clinical and basic research, which may allow for better patient stratification in future clinical trials. This Perspective discusses recent LRS-driven discoveries, methodological and bioinformatic advances, and emerging diagnostic applications to illustrate the potential of LRS in reshaping both research and clinical practice.

Humans↗
PubMed2006

Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers.

Aberrant folding and fibrillar aggregation by polyglutamine (polyQ) expansion proteins are associated with cytotoxicity in Huntington's disease and other neurodegenerative disorders. Hsp70 chaperones have an inhibitory effect on fibril formation and can alleviate polyQ cytotoxicity. Here we show that the cytosolic chaperonin, TRiC, functions synergistically with Hsp70 in this process and is limiting in suppressing polyQ toxicity in a yeast model. In vitro reconstitution experiments revealed that TRiC, in cooperation with the Hsp70 system, promotes the assembly of polyQ-expanded fragments of huntingtin (Htt) into soluble oligomers of approximately 500 kDa. Similar oligomers were observed in yeast cells upon TRiC overexpression and were found to be benign, in contrast to conformationally distinct Htt oligomers of approximately 200 kDa, which accumulated at normal TRiC levels and correlated with inhibition of cell growth. We suggest that TRiC cooperates with the Hsp70 system as a key component in the cellular defense against amyloid-like protein misfolding.

Chaperonins↗
PubMed2026

C9orf72-associated poly-GR in skeletal muscle leads to neuromuscular junction deficits and muscle atrophy.

Hexanucleotide repeat expansions in C9orf72 produce dipeptide repeat (DPR) proteins that are widely expressed, including in the nervous system and skeletal muscle. Among these DPRs, arginine-containing proteins, poly-GR and poly-PR, are toxic in the nervous system, but whether DPRs in skeletal muscle contribute to amyotrophic lateral sclerosis (ALS) pathogenesis is unclear. Here, we show that muscle-restricted expression of poly-GR drives motor deficits in mice, including muscle atrophy and neuromuscular junction (NMJ) deficits. Poly-GR in muscle interacted with the NMJ key organizer MuSK and promoted MuSK degradation, disrupting postsynaptic structure and impairing neuromuscular transmission. Importantly, a MuSK agonist antibody (X-17) stabilized NMJs and rescued neuromuscular transmission. Moreover, poly-GR in muscle activated the integrated stress response (ISR), elevating eIF2&#x3b1; phosphorylation and broadly suppressing protein translation. ISR inhibition with ISRIB restored translation and MuSK protein levels and ameliorated both muscle atrophy and NMJ deficits. These findings demonstrate that skeletal muscle actively contributes to C9orf72-ALS pathology. Targeting muscle with ISRIB offers a therapeutic strategy to preserve motor function in C9orf72-ALS.

Animals↗
PubMed2006

Short G-rich oligonucleotides as a potential therapeutic for Huntington's Disease.

BACKGROUND: Huntington's Disease (HD) is an inherited autosomal dominant genetic disorder in which neuronal tissue degenerates. The pathogenesis of the disease appears to center on the development of protein aggregates that arise initially from the misfolding of the mutant HD protein. Mutant huntingtin (Htt) is produced by HD genes that contain an increased number of glutamine codons within the first exon and this expansion leads to the production of a protein that misfolds. Recent studies suggest that mutant Htt can nucleate protein aggregation and interfere with a multitude of normal cellular functions. RESULTS: As such, efforts to find a therapy for HD have focused on agents that disrupt or block the mutant Htt aggregation pathway. Here, we report that short guanosine monotonic oligonucleotides capable of adopting a G-quartet structure, are effective inhibitors of aggregation. By utilizing a biochemical/immunoblotting assay as an initial screen, we identified a 20-mer, all G-oligonucleotide (HDG) as an active molecule. Subsequent testing in a cell-based assay revealed that HDG was an effective inhibitor of aggregation of a fusion protein, comprised of a mutant Htt fragment and green fluorescent protein (eGFP). Taken together, our results suggest that a monotonic G-oligonucleotide, capable of adopting a G-quartet conformation is an effective inhibitor of aggregation. This oligonucleotide can also enable cell survival in PC12 cells overexpressing a mutant Htt fragment fusion gene. CONCLUSION: Single-stranded DNA oligonucleotides capable of forming stable G-quartets can inhibit aggregation of the mutant Htt fragment protein. This activity maybe an important part of the pathogenecity of Huntington's Disease. Our results reveal a new class of agents that could be developed as a therapeutic approach for Huntington's Disease.

Analysis of Variance↗
PubMed2005

cAMP-response element-binding protein contributes to suppression of the A2A adenosine receptor promoter by mutant Huntingtin with expanded polyglutamine residues.

Huntington's disease is a neurodegenerative disease resulting from a CAG (glutamine) trinucleotide expansion in exon 1 of the Huntingtin (Htt) gene. The role of the striatum-enriched A2A adenosine receptor (A2A-R) in Huntington's disease has attracted much attention lately. In the present study, we found that expression of mutant Htt with expanded poly(Q) significantly reduced the transcript levels of the endogenous A2A-R in PC12 cells and primary striatal neurons. Cotransfection of various promoter constructs of the A2A-R gene and an expression construct of poly(Q)-expanded Htt revealed that the Htt mutant suppressed the core promoter activity of the A2A-R gene. Stimulation of the A2A-R using CGS21680, forskolin, and a constitutively active cAMP-response element-binding protein (CREB) mutant elevated the reduced promoter activity of the A2A-R gene by mutant Htt. Moreover, the effect of CGS was blocked by an A2A-R-selective antagonist (CSC), two inhibitors of protein kinase A, and two dominant negative mutants of (CREB). The protein kinase A/CREB pathway therefore is involved in regulating A2A-R promoter activity. Consistently, an atypical CRE site (TCCAGG) is located in the core promoter region of the A2A-R gene. Electrophoretic gel mobility shift assay and mutational inactivation further demonstrated the functional binding of CREB to the core promoter region and showed that expression of poly(Q)-expanded Htt abolished the binding of CREB to this site. Stimulation of the A2A-R restored the reduced CREB binding caused by the mutant and concurrently reduced mutant Htt aggregation. Collectively, the poly(Q)-expanded mutant Htt suppressed expression of the A2A-R by inhibiting its core promoter at least partially by preventing CREB binding.

Animals↗
PubMed2005

Sex differences in clinical and genetic determinants of levodopa peak-dose dyskinesias in Parkinson disease: an exploratory study.

BACKGROUND: Several factors, both clinical and genetic, may account for the risk of developing levodopa-induced peak-dose dyskinesias (PDD) in patients with Parkinson disease, but it is unclear how these factors interact for modulating the individual susceptibility for PDD. OBJECTIVE: To examine clinical and genetic risk factors for determining individual susceptibility of PDD in patients with Parkinson disease. DESIGN: Cohort study. SETTING: Referral center for Parkinson disease in Calabria, southern Italy. Patients Two hundred fifty patients with Parkinson disease were screened for the presence or absence of PDD following a short-term levodopa administration, and 215 subjects were available for further evaluations, including genotypic analysis of the CA dinucleotide short tandem repeat (CAn-STR) polymorphism located in the dopamine receptor D2 gene (DRD2). RESULTS: One hundred five patients (48.8%) exhibited PDD following short-term levodopa administration, and 110 patients (51.2%) did not. Multivariate logistic regression analysis showed that independent predictors for the occurrence of PDD were female sex, earlier age at onset of Parkinson disease, longer duration of treatment, and higher dose of levodopa. Genetic factors related to the DRD2 CAn-STR polymorphism were not independent predictors for PDD in the total population, but they had a strong protective effect on the appearance of PDD when the multivariate analysis was performed in men (odds ratio, 0.34 [95% confidence interval, 0.14-0.84]). In women, a genetic protective effect on PDD was not evident. CONCLUSIONS: Risk factors for PDD, both clinical and genetic, act in different ways for men and women. Genetic factors related to the DRD2 polymorphic status have a protective effect on PDD development in men but not in women. A female sex-related effect for the risk of PDD may be so strong that it overcomes any protective effect due to genetic factors.

Age of Onset↗
PubMed2004

Clinical signs and symptoms in a large hereditary spastic paraparesis pedigree with a novel spastin mutation.

The most common form of autosomal dominant hereditary spastic paraparesis (HSP), SPG4, is caused by mutations in the spastin gene on chromosome 2p. This disease is characterized by intra- and interfamilial phenotypic variation. To determine the predictive values of clinical signs and symptoms in SPG4, we examined 43 members of a large pedigree with autosomal dominant HSP. We then identified the genetic etiology of the disorder in this family, a novel nonsense mutation in exon 1 of spastin, carried by 24 of the examined family members. The best clinical predictors of positive gene status were the presence of hyperreflexia in the lower extremities, >2 beats of ankle clonus, pes cavus, bladder symptoms and increased tone in the legs. The mean age of onset was 32.2 +/- 7.4 years, but the age of onset was earlier in children from 10 of 12 child-parent gene-positive pairs, with a mean difference of 10.8 +/- 3.3 years. The finding of leg weakness was especially common in older-onset affected family member with leg hyperreflexia. These results suggest that specific clinical signs and symptoms may be of value in differentiating individuals affected with SPG4 from family members with nonspecific neurological findings.

Adenosine Triphosphatases↗
PubMed2005

Clinical features of familial moyamoya disease.

OBJECTS: This study aims to clarify the genetic background of moyamoya disease by comparing clinical features between familial and sporadic cases to reveal the responsible genes for familial moyamoya disease. METHODS: This study included 155 Japanese patients with moyamoya disease, which included 24 familial cases (10 family pedigrees) and 131 sporadic cases. Clinical features were compared between the familial and sporadic cases. RESULTS AND CONCLUSION: A female preponderance was significantly more prominent in the familial than in the sporadic group (P=0.0421). Mean age at onset was significantly lower in familial than in sporadic cases (P=0.004). In eight parent-offspring pairs, mean age at onset was significantly lower in the second than in the first generation (P<0.0001). These results suggest that familial moyamoya disease is associated with genetic anticipation and female predominance and that a genetic analysis study focused on expanded triplet repeats may clarify the pathogenesis of the disease.

Adolescent↗
PubMed2003

Oculopharyngeal muscular dystrophy with limb girdle weakness as major complaint.

This first description of the oculopharyngeal muscular dystrophy (OPMD) phenotype in Dutch patients shows that limb girdle weakness can occur early in the course of disease and can give the first and major complaint in OPMD patients. The aim of this study was to examine clinically, histologically and genetically all Dutch OPMD patients known at the Neuromuscular Centre Nijmegen, to measure the limb girdle weakness (MRC scale) and to quantify the consequences of the limb girdle weakness on daily activities (Rankin scale). Remarkable in this population was the early onset and the severity of the limb girdle weakness. We found a higher percentage of patients with limb girdle weakness than reported before in non-Dutch OPMD populations. This limb girdle weakness caused limitations in daily activities more than the other symptoms of OPMD. It was difficult to compare the severity of the limb girdle weakness of Dutch patients with other patients because of the lack of data related to quantification of limb girdle weakness in non-Dutch OPMD patients. Because of the influence of the limb girdle weakness on the daily activities of the patients, we recommend that more attention is paid to the proximal limb muscles in OPMD patients early in the course of the disease.

Adult↗
PubMed2005

Spinocerebellar ataxia type 4. Investigation of 34 candidate genes.

The spinocerebellar ataxias (SCAs) with autosomal dominant inheritance are a clinically and genetically heterogeneous group of neurodegenerative disorders. To date 24 different loci have been identified for these conditions. A locus at chromosome 16q22.1 co-segregates with the disease phenotype in families of Scandinavian, Japanese and German origin. The corresponding SCA4 locus was narrowed down to 7.94 Mb for the two European and to 1.25 Mb for Japanese pedigrees. Unfortunately, because of the phenotypic differences between patients from Japan and Europe it is not possible to decide if SCA families linked to chromosome 16q22.1 share a common disease genotype or not. To look for mutations in the German family we screened 34 candidate genes in a 3.69 cM region. With the exception of two cSNPs, no segregation of DNA variations with the disease phenotype was found.

Chromatography, High Pressure Liquid↗
PubMed2003

Dementia, ataxia, extrapyramidal features, and epilepsy: phenotype spectrum in two Italian families with spinocerebellar ataxia type 17.

We observed two families with a dominantly inherited complex neurological syndrome with onset in adulthood. Family F included 9 affected in four generations. One patient showed prominent anticipation of onset age. Onset was with cerebellar signs followed by dementia, psychiatric symptoms, seizures, and extrapyramidal features. Family M included 14 affected individuals in five generations. Presenting symptoms were either psychiatric and cognitive impairment or a cerebellar syndrome. Extrapyramidal features, dysphagia, incontinence, seizures, and myoclonus may occur. In both families magnetic resonance imaging showed marked atrophy of the brain and cerebellum. Molecular analyses demonstrated an expanded CAG/CAA repeat in the in the TATA box-binding protein (TBP) gene (SCA17).

Adolescent↗