Huntington's Disease-like Phenotype Research Articles

Mutation analysis of the TATA box-binding protein (TBP) gene in Russian patients with spinocerebellar ataxia and Huntington disease-like phenotype

ObjectiveWe aimed to analyze the occurrence and clinical and genetic characteristics of spinocerebellar ataxia type 17 (SCA17) among Russian patients with progressive cerebellar ataxia or Huntington disease-like phenotype. MethodsGenetic analysis of CAG/CAA repeats in TBP gene was carried out in 217 patients, including 153 patients with progressive unspecified ataxia and 64 patients with Huntington disease-like phenotype. SCA types 1, 2, 3, 6 and 8, Friedreich's ataxia, CANVAS and Huntington disease were preliminarily excluded. ResultsSix unrelated patients with SCA17 (2.8 %) were identified (43–57 CAG/CAA repeats in TBP gene). Two patients had a positive family history. Age at the disease onset ranged from 15 to 47 years. The core clinical syndrome included progressive cerebellar ataxia, dysarthria, movement disorders, cognitive impairment, and psychiatric symptoms. One patient had epilepsy with rare generalized tonic-clonic seizures. Another patient with diffuse muscle atrophy and small expansion size (43 CAG/CAA repeats) had myopathic changes in skeletal muscles on EMG study. We also described a patient with a large expansion size of 57 CAA/CAG repeats with early onset and rapid disease progression. ConclusionSCA17 is a relatively rare cause of progressive disorders with ataxia and chorea, but it should be considered in the spectrum of differential diagnosis in such patients. Most of our SCA17 cases were sporadic which should be kept in mind when planning genetic testing in patients with spinocerebellar ataxia and chorea.

Huntington disease-like phenotype in a patient with ANO3 mutation

A 71-year-old previously well white British female developed progressive involuntary tongue movements over one year, resulting in eating difficulty and 10 kg weight loss. She had also noted involuntary perioral, facial and distal limb movements beginning 18 months earlier. These had progressively worsened. In the 3 years prior to presentation, she reported subjective memory decline, word finding difficulty and depressed mood, which improved with mirtazapine 30 mg once daily. She had no history of neuroleptic exposure.

Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype.

Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline, and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations.

An N-terminal Nuclear Export Signal Regulates Trafficking and Aggregation of Huntingtin (Htt) Protein Exon 1*

Huntington disease is a dominantly inherited neurodegenerative condition caused by polyglutamine expansion in the N terminus of the huntingtin protein (Htt). The first 17 amino acids (N17) of Htt play a key role in regulating its toxicity and aggregation. Both nuclear export and cytoplasm retention functions have been ascribed to N17. We have determined that N17 acts as a nuclear export sequence (NES) within Htt exon and when fused to yellow fluorescent protein. We have defined amino acids within N17 that constitute the nuclear export sequence (NES). Mutation of any of the conserved residues increases nuclear accumulation of Htt exon 1. Nuclear export of Htt is sensitive to leptomycin B and is reduced by knockdown of exportin 1. In HEK293 cells, NES mutations decrease overall Htt aggregation but increase the fraction of cells with nuclear inclusions. In primary cultured neurons, NES mutations increase nuclear accumulation and increase overall aggregation. This work defines a bona fide nuclear export sequence within N17 and links it to effects on protein aggregation. This may help explain the important role of N17 in controlling Htt toxicity.

Clinical and genetic analysis of 29 Brazilian patients with Huntington's disease-like phenotype

Huntington's disease (HD) is a neurodegenerative disorder characterized by chorea, behavioral disturbances and dementia, caused by a pathological expansion of the CAG trinucleotide in the HTT gene. Several patients have been recognized with the typical HD phenotype without the expected mutation. The objective of this study was to assess the occurrence of diseases such as Huntington's disease-like 2 (HDL2), spinocerebellar ataxia (SCA) 1, SCA2, SCA3, SCA7, dentatorubral-pallidoluysian atrophy (DRPLA) and chorea-acanthocytosis (ChAc) among 29 Brazilian patients with a HD-like phenotype. In the group analyzed, we found 3 patients with HDL2 and 2 patients with ChAc. The diagnosis was not reached in 79.3% of the patients. HDL2 was the main cause of the HD-like phenotype in the group analyzed, and is attributable to the African ancestry of this population. However, the etiology of the disease remains undetermined in the majority of the HD negative patients with HD-like phenotype.

Neuroacanthocytosis Syndromes

Neuroacanthocytosis (NA) syndromes are a group of genetically defined diseases characterized by the association of red blood cell acanthocytosis and progressive degeneration of the basal ganglia. NA syndromes are exceptionally rare with an estimated prevalence of less than 1 to 5 per 1'000'000 inhabitants for each disorder. The core NA syndromes include autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome which have a Huntington´s disease-like phenotype consisting of a choreatic movement disorder, psychiatric manifestations and cognitive decline, and additional multi-system features including myopathy and axonal neuropathy. In addition, cardiomyopathy may occur in McLeod syndrome. Acanthocytes are also found in a proportion of patients with autosomal dominant Huntington's disease-like 2, autosomal recessive pantothenate kinase-associated neurodegeneration and several inherited disorders of lipoprotein metabolism, namely abetalipoproteinemia (Bassen-Kornzweig syndrome) and hypobetalipoproteinemia leading to vitamin E malabsorption. The latter disorders are characterized by a peripheral neuropathy and sensory ataxia due to dorsal column degeneration, but movement disorders and cognitive impairment are not present. NA syndromes are caused by disease-specific genetic mutations. The mechanism by which these mutations cause neurodegeneration is not known. The association of the acanthocytic membrane abnormality with selective degeneration of the basal ganglia, however, suggests a common pathogenetic pathway. Laboratory tests include blood smears to detect acanthocytosis and determination of serum creatine kinase. Cerebral magnetic resonance imaging may demonstrate striatal atrophy. Kell and Kx blood group antigens are reduced or absent in McLeod syndrome. Western blot for chorein demonstrates absence of this protein in red blood cells of chorea-acanthocytosis patients. Specific genetic testing is possible in all NA syndromes. Differential diagnoses include Huntington disease and other causes of progressive hyperkinetic movement disorders. There are no curative therapies for NA syndromes. Regular cardiologic studies and avoidance of transfusion complications are mandatory in McLeod syndrome. The hyperkinetic movement disorder may be treated as in Huntington disease. Other symptoms including psychiatric manifestations should be managed in a symptom-oriented manner. NA syndromes have a relentlessly progressive course usually over two to three decades.

Spinocerebellar ataxia type 17 in Indian patients: two rare cases of homozygous expansions

We screened a cohort of 181 patients with features of primary progressive ataxia and chorea for spinocerebellar ataxias 17 (SCA17) mutation after excluding other known SCAs, Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and non-genetic causes. This study included patients with known family history of SCA, those with sporadic onset and cases of uncertain family history. Two unrelated patients with Huntington's disease-like phenotype and cerebellar signs are described with homozygous expansions of 47 and 48 CAG/CAA repeats. A family member with early signs of ataxia was found to carry 37 and 48 repeats. There were fewer CAA interruptions in the repeat sequences of patients than in the controls. The normal repeat range in controls was 21-42, with 91% of the alleles located between 33 and 39 repeats. This is the first report of rare homozygous SCA17 mutation in Indian patients presenting with HD-like phenotype.

Behavioral variant of frontotemporal dementia mimicking Huntington's disease

Behavioral changes and cognitive decline are the core clinical manifestations in the behavioral variant of frontotemporal dementia (bv-FTD). The behavioral changes may include characteristic stereotypic movements. These movements, although without clear purpose, are not involuntary. Involuntary movements are usually not seen in FTD.Two patients with involuntary choreoathetoid movements but otherwise presenting a bv-FTD-phenotype were referred and Huntington's disease (HD) was suspected. The diagnoses of bv-FTD were made after comprehensive assessment and exclusion of other diagnoses, including HD and Huntington's disease-like (HDL) phenotypes. Although a definite diagnosis will require neuropathological confirmation, we conclude that a HDL phenotype may be part of the clinical spectrum of the bv-FTD phenotype.

Huntington's disease-like and ataxia syndromes: Identification of a family with a de novo SCA17/ TBP mutation

The autosomal dominant spinocerebellar ataxias, commonly referred to as SCAs, are clinically and genetically heterogeneous neurodegenerative disorders. Twenty-eight genetic subtypes have been identified, of which 7 are caused by expansion of a CAG trinucleotide repeat that encodes a polyglutamine tract in the respective proteins. SCA17 is caused by a CAG/CAA repeat expansion in the TATA box-binding protein-gene ( TBP). In some cases the clinical phenotype of SCA17 overlaps that of Huntington's disease (HD), hence the use of the term Huntington's disease-like. We screened 89 patients with a Huntington's disease-like phenotype without the HD-gene mutation and 178 patients with genetically unclassified cerebellar ataxia for the mutation in TBP. A 33-year old woman presenting with an HD like phenotype with a de novo 54 CAG/CAA repeat expansion was identified. Her normal allele included 38 repeats. The patient's mother and father both carried normal range repeats, 38/38 and 33/39 respectively. Analysis of the repeat structures revealed that the expansion had occurred upon expansion of the longer paternal allele. We conclude that, however rare, SCA17 must be considered as a cause of Huntington's disease-like phenotypes and ataxia syndromes, also in isolated cases.

Exclusion of mutations in the PRNP, JPH3, TBP, ATN1, CREBBP, POU3F2 and FTL genes as a cause of disease in Portuguese patients with a Huntington-like phenotype.

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterised by chorea, cognitive impairment, dementia and personality changes, caused by the expansion of a CAG repeat in the HD gene. Often, patients with a similar clinical presentation do not carry expansions of the CAG repeat in this gene [Huntington disease-like (HDL) patients]. We report the genetic analysis of 107 Portuguese patients with an HDL phenotype. The HDL genes PRNP and JPH3, encoding the prion protein and junctophilin-3, respectively, were screened for repeat expansions in these patients. Given the partial clinical overlap of SCA17, DRPLA and neuroferritinopathy with HD, their causative genes (TBP, ATN1, and FTL, respectively) were also analysed. Finally, repeat expansions in two candidate genes, CREBBP and POU3F2, which encode the nuclear transcriptional coactivator CREB-binding protein and the CNS-specific transcription factor N-Oct-3, respectively, were also studied. Expansions of the repetitive tracts of the PRNP, JPH3, TBP, ATN1, CREBBP and POU3F2 genes were excluded in all patients, as were sequence alterations in the FTL gene. Since none of the genes already included in the differential diagnosis of HD was responsible for the disease in our sample, the genetic heterogeneity of the HDL phenotype is still open for investigation.

Minimum prevalence of spinocerebellar ataxia 17 in the north east of England

Objective To determine the minimum prevalence of spinocerebellar ataxia type 17 (SCA17) in the north east of England. Patients and methods A defined region containing 2,516,500 individuals with 192 families with undiagnosed ataxia, 90 patients with a Huntington's disease-like phenotype and 292 controls. The number of (CAG/CAA) n repeats in the SCA17/ TBP gene was determined by fluorescent PCR and sequenced in affected individuals. Results The mean repeat size for 584 control alleles was 34 (S.D. = 3.58), ranging from 25 to 40. Two index cases had larger alleles with repeat lengths greater than the control range. Affected family members presented in adult life with ataxia followed by extrapyramidal features and cognitive impairment. In one family 44 repeats were associated with a younger age of onset than has been previously described. Conclusions The minimum prevalence of SCA17 in the north east of England was 0.16/100,000 (upper 95% confidence interval 0.31/100,000).

Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice.

Huntington's disease (HD) results from the expansion of a glutamine repeat near the N-terminus of huntingtin (htt). At post-mortem, neurons in the central nervous system of patients have been found to accumulate N-terminal fragments of mutant htt in nuclear and cytoplasmic inclusions. This pathology has been reproduced in transgenic mice expressing the first 171 amino acids of htt with 82 glutamines along with losses of motoric function, hypoactivity and abbreviated life-span. The relative contributions of nuclear versus cytoplasmic mutant htt to the pathogenesis of disease have not been clarified. To examine whether pathogenic processes in the nucleus disproportionately contribute to disease features in vivo, we fused a nuclear localization signal (NLS) derived from atrophin-1 to the N-terminus of an N171-82Q construct. Two lines of mice (lines 8A and 61) that were identified expressed NLS-N171-82Q at comparable levels and developed phenotypes identical to our previously described HD-N171-82Q mice. Western blot and immunohistochemical analyses revealed that NLS-N171-82Q fragments accumulate in nuclear, but not cytoplasmic, compartments. These data suggest that disruption of nuclear processes may account for many of the disease phenotypes displayed in the mouse models generated by expressing mutant N-terminal fragments of htt.

Huntington's disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes.

We report a group of 252 patients with a Huntington's disease-like (HDL) phenotype, including 60 with typical Huntington's disease, who had tested negative for pathological expansions in the IT15 gene, the major mutation in Huntington's disease. They were screened for repeat expansions in two other genes involved in HDL phenotypes: those encoding the junctophilin-3 (JPH3/HDL2) and prion (PRNP/HDL1) proteins. In addition, because of the clinical overlap between patients with HDL disease and autosomal dominant cerebellar ataxia or dentatorubral and pallidoluysian atrophy (DRPLA), we investigated trinucleotide repeat expansions in genes encoding the TATA-binding protein (TBP/SCA17) and atrophin-1 (DRPLA). Two patients carried 43 and 50 uninterrupted CTG repeats in the JPH3 gene. Two other patients had 44 and 46 CAA/CAG repeats in the TBP gene. Patients with expansions in the TBP or JPH3 genes had HDL phenotypes indistinguishable from Huntington's disease. Taking into account patients with typical Huntington's disease, their frequencies were evaluated as 3% each in our series of typical HDL patients. Interestingly, incomplete penetrance of the 46 CAA/CAG repeat in the TBP gene was observed in a 59-year-old transmitting, but healthy, parent. Furthermore, we report a new configuration of the expanded TBP allele, with 11 repeats on the first polymorphic stretch of CAGs. Expansions in the DRPLA gene and insertions in the PRNP gene were not found in our group of patients. Further genetic heterogeneity of the HDL phenotype therefore exists.

Differentialdiagnose hereditärer Chorea-Syndrome

The clinical triad of hereditary chorea syndromes includes (1) choreatiform involuntary movement disorder, (2) psychiatric symptoms, and (3) cognitive impairment. The most frequent hereditary chorea syndrome is Huntington's disease (HD). There are several phenocopies of Huntington's disease, such as the Huntington's disease-like neurodegenerative disorders type 1 and type 2 (HDLD), benign hereditary chorea (BHC), dentato-rubro-pallido-Luysian atrophy (DRPLA), choreoacanthocytosis (CHAC), and McLeod syndrome (MLS). Huntington's disease is caused by an instable CAG trinucleotide expansion in the Huntington disease gene, and onset age and severity of symptoms depend on the number of CAG repeats. The physiological function of the gene product Huntingtin and the disease mechanisms are not fully elucidated yet. However, experimental data strongly suggest that induction of apoptosis through a caspase (cysteine aspartate-specific proteases)-dependent mechanism might be an important factor for the development of the striatal neurodegeneration. The HDLDs are more or less exact phenocopies of Huntington's disease. Two chromosomal localisations are described, and one responsible gene, Junctophilin-3, is identified. The BHC manifests as a pure chorea syndrome, without major psychiatric or cognitive impairment. The disease is located on chromosome 14, but the responsible gene has not yet been identified. Apart from the Huntington's disease-like phenotype, DRPLA may manifest as a spinocerebellar ataxia, a progressive myoclonus epilepsy, or mixed phenotypes. DRPLA is caused by instable CAG expansions in Atrophin-1, whose physiological functions are not yet known. CHAC and MLS belong to the so-called neuroacanthocytosis syndromes. CHAC is an autosomal-recessive disorder characterised by a progressive chorea syndrome, perioral dyskinesias and mutilations, and - less frequently - an akinetic-rigid extrapyramidal syndrome and seizures. The responsible gene is located on chromosome 9, encoding chorein, a protein implicated in intracellular cell sorting. MLS is an X-linked multi-system disorder with haematological, neuromuscular, and CNS involvement. Haematologically, MLS is characterised by absent expression of the Kx erythrocyte antigen, weak expression of Kell antigens, acanthocytosis, and a compensated haemolytic state. Asymptomatic males have elevated serum creatine kinase levels, and are prone to develop neurological symptoms. Neuromuscular manifestations include myopathy, sensory-motor axonal neuropathy, and cardiomyopathy. CNS manifestations comprise a choreatiform movement disorder, neuropsychiatric abnormalities, and - less frequently - generalised seizures. MLS is caused by mutations of the XK gene encoding the XK protein, a putative membrane transport protein containing the Kx erythrocyte antigen. The XK protein is linked to the Kell glycoprotein by a single disulfide bond, probably forming a functional complex. The Kell protein is a member of the metalloproteinase family, and the XK protein has functional similarities to the CED-8 protein in nematodes, in which it controls the timing of apoptosis. These data strongly suggest an important role of the XK-Kell complex in striatal physiology. The advances in the molecular biology of hereditary chorea syndromes offer the possibility for a direct genetic analysis of affected individuals, and presymptomatic testing for individuals at risk.

Neuropathological diagnosis and CAG repeat expansion in Huntington's disease.

To correlate the degree of CAG repeat expansion with neuropathological findings in Huntington's disease. The CAG repeat polymorphism was analysed in a large series of brain samples from 268 patients with a clinical diagnosis of Huntington's disease in which full neuropathological data was available. Analysis by polymerase chain reaction was successful in 63% of samples (169 of 268). Repeat expansions were detected in 152 of 153 (99%) samples with a neuropathological diagnosis of Huntington's disease. The exceptional case (22 CAG repeats) showed mild but definite pathological changes and had a typical clinical illness with a positive family history; it raises the possibility that an alternative mutation in the Huntington's disease gene may be responsible although it is more likely that a mutation in another gene has resulted in an Huntington's disease-like phenotype. Four of 16 cases without pathological changes of Huntington's disease also possessed an expanded repeat sequence; a glioblastoma masked the pathological changes of Huntington's disease in one case but the other three cases had a typical clinical history and a positive family history. These three cases may reliably be classified as Vonsattel's Huntington's disease grade 0. Three of 12 cases with a normal repeat length and no morphological changes of Huntington's disease showed other neuropathology; two had Alzheimer's disease and the other had multiple sclerosis. Review of the clinical notes of two other cases indicated a diagnosis of tardive dyskinesia complicating phenothiazine treatment of schizophrenia. The remaining pathology negative/expansion negative cases had been referred because of a family history of Huntington's disease; all but one were themselves symptom free. Apart from emphasising the possibility that an alternative mutation may result in a clinical phenocopy of Huntington's disease, this case suggests that such a clinical phenocopy may occur without gross or light microscopical neuropathological changes (Vonsattel's Huntington's disease grade 0). The study confirms the value of molecular genetic analysis in cases of suspected Huntington's disease and shows the importance of detailed neuropathological study in the few cases of suspected Huntington's disease with normal CAG repeat lengths.