Exercise testing and training in people with Huntington's disease.

OBJECTIVE: To explore exercise response in people with Huntington's disease (HD). DESIGN: Experimental observational study with a randomly allocated subgroup before/after interventional study. SETTING: Community. SUBJECTS: People with HD (n=30) and a healthy comparator group (n=20). Thirteen people from the HD group were randomly allocated to an exercise training program. MAIN MEASURES: Heart rate (HR) and perceived exertion on the Borg-CR10 scale (RPE) during a submaximal cycle ergometer exercise test (three minute unloaded and nine minute 65%-75%HRmaximum phase). Expired air and lactate measures were available for 8 people with HD during the exercise. INTERVENTION: A 12 week gym and home walking exercise programme (n=13). RESULTS: People with HD achieved a lower work rate at nine minutes (82±42(0-195) v 107±35(50 -185) Watts (p<0.05)), but higher RPE at both three (3±2(0-7) v 1±1(0-4)) and nine minutes (7±3(1-10) v 5± 2(2-9)) both p<0.01, compared to the healthy group and did not achieve a steady state HR during unloaded cycling. People with HD also demonstrated higher than expected lactate at three 2.5±2.5(1.1-8)mmo.L-1 and nine 3.8±1.9(1.2-6.6)mmo.L-1 minutes and respiratory exchange ratio at three 0.78±0.03 (0.74-0.81) and nine minutes 0.94±0.11(0.81-1.15). After exercise training there were no changes observed in HR or RPE responses during the exercise test. CONCLUSIONS: There was a large variability in the observed metabolic and physiological responses to exercise in people with HD. The observed exercise responses suggest that altered exercise prescription parameters may be required for people with HD and that exercise response and factors' affecting this requires further investigation.

A conserved sorting-associated protein is mutant in chorea-acanthocytosis.

Chorea-acanthocytosis (CHAC, MIM 200150) is an autosomal recessive neurodegenerative disorder characterized by the gradual onset of hyperkinetic movements and abnormal erythrocyte morphology (acanthocytosis). Neurological findings closely resemble those observed in Huntington disease. We identified a gene in the CHAC critical region and found 16 different mutations in individuals with chorea-acanthocytosis. CHAC encodes an evolutionarily conserved protein that is probably involved in protein sorting.

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series.

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.

Alterations in the metabolic and cardiorespiratory response to exercise in Huntington's Disease.

BACKGROUND: Limited data suggests that an altered metabolic and cardiorespiratory exercise response may affect exercise performance in individuals with Huntington's disease (HD). There is no clear exploration of the response in individuals at different stages of the disease or in relation to genetic markers. This study aimed to examine the exercise response and recovery of HD participants, and the relationship to genetic and clinical markers. METHOD: HD gene-positive participants (n = 31; 9 pre-manifest; 22 manifest HD) and a healthy control group (n = 29) performed an incremental exercise test until exhaustion. Performance, cardiorespiratory, metabolic and perceptual responses to exercise were determined from a maximal cycle ergometer test throughout the exercise test and during a recovery period. RESULTS: During sub-maximal exercise, metabolic (lactate levels, oxygen uptake) and cardiorespiratory markers (heart rate) were elevated in HD participants compared to controls. Lactate elevation was specific to pre-manifest HD participants. Work capacity was reduced in both pre-manifest and manifest HD participants with tests terminated with no difference in metabolic, perceptual or cardiorespiratory markers. Submaximal oxygen uptake was correlated with motor score, whilst peak measures were unrelated to genetic or clinical markers. Heart rate recovery was attenuated in pre-manifest and manifest HD participants. CONCLUSIONS: Our findings confirm metabolic and cardiorespiratory deficits reduce exercise performance and affect recovery from an early stage in HD, with submaximal deficits related to phenotypic expression. Exercise capacity appears to be limited by an altered movement economy, thus clinicians should consider an altered exercise response and recovery may affect prescription in HD.

Clinical and molecular genetics of primary dystonias.

Primary dystonias are movement disorders with dystonia as a major symptom. They are frequently inherited as Mendelian traits. There are at least eight clinically distinct autosomal dominant and two X-linked recessive forms. In addition, pedigree analyses suggest the occurrence of an autosomal recessive variant. The clinical classification is increasingly being replaced by a genetic one. To date gene loci have been identified in at least six autosomal dominant forms, i.e., in idiopathic torsion dystonia (9q34), focal dystonia (18p), adult-onset idiopathic torsion dystonia of mixed type (8p21-q22), dopa-responsive dystonia (14q22.1-q22.2), and paroxysmal dystonic choreoathetosis (2q25-q33; 1p21-p13.3). Gene loci in the X-linked recessive forms have been assigned to Xq13.1 in the X-linked dystonia parkinsonism syndrome and to Xq22 in X-linked sensorineural deafness, dystonia, and mental retardation. The disease genes have been identified in two autosomal dominant forms and in one X-linked recessive form. Mutations in a gene coding for an ATP-binding protein were detected in idiopathic torsion dystonia (DYT1), and the GTP cyclohydrolase 1 gene is mutated in dopa-responsive dystonia (DYT5). In sensorineural deafness, dystonia, and mental retardation, mutations were found in the gene DDP coding for a polypeptide of unknown function. This article reviews the clinical and molecular genetics of primary dystonias, critically discusses present findings, and proposes referring to the known forms, most of which can be distinguished by genetic criteria, as dystonias 1-12.

A novel point mutation in X-linked adrenoleukodystrophy presenting as a spinocerebellar degeneration.

X-linked adrenoleukodystrophy (ALD) usually presents in childhood as severe cerebral demyelination accompanied by axonal loss or in adults as a progressive spinal cord syndrome (adrenomyeloneuropathy). Rarely, patients present with adult onset spinocerebellar ataxia. We performed mutation analysis in a family with several members who had this rare phenotype and identified a single nucleotide deletion in exon 2 of the ALD gene. This is the first mutation analysis to be reported in this unusual phenotypic variant of ALD and the first deletion to be reported in exon 2.

A bidirectional YAC walk from the Norrie disease (NDP) locus.

The region of Xp between DXS7 and the centromere contains the gene for Norrie disease in addition to the genes for several other ophthalmic disorders. A 650-kb YAC containing the loci MAOA, MAOB, and NDP has been used as the starting point for a bidirectional chromosomal walk. A contig of 16 YACs covering between 2 and 3 Mb has been developed in which the following markers/genes are located (in physical order): Xpter--DXS1201 (256ze5)--DXS6668--DXS228--DXS77--MAOA--++ +MAOB--FR12 (pseudogene)--NDP--DXS6670--RRM2P3--DXS6671--DXS742 --Xcen. Seven new STSs are described both for end clones and for internal Alu PCR products from the contig. The contig contains the breakpoint of the t75-2ma-1b (t75) translocation, close to the 5' end of the MAOB gene.

A 1.8-Mb YAC contig in Xp11.23: identification of CpG islands and physical mapping of CA repeats in a region of high gene density.

The genes ARAF1, SYN1, TIMP, and PFC are clustered within 70 kb of one another, and, as reported in the accompanying paper (J. Knight et al., 1994, Genomics 21: 180-187), at least four more genes map within 400 kb: a cluster of Krüppel-type zinc finger genes (including ZNF21, ZNF41, and ZNF81) and ELK-1, a member of the ets oncogene superfamily. This gene-rich region is of particular interest because of the large number of disease genes mapping to Xp11.23: at least three eye diseases (retinitis pigmentosa type 2, congenital stationary night blindness CSNB1, and Aland Island eye disease), Wiskott-Aldrich syndrome, X-linked nephrolithiasis, and a translocation breakpoint associated with synovial sarcoma. We have constructed a 1.8-Mb YAC contig in this region, confirming the link between TIMP and OATL1 reported by Knight et al. (1994) and extending the map in the distal direction. To investigate the likelihood that more genes are located within this region, we have carried out detailed mapping of rare-cutter restriction sites in these YACs and identified seven CpG islands. At least six of these islands are located over 50 kb from any known gene locations, suggesting that the region contains at least this many as yet unidentified genes. We have also mapped the physical locations of six highly polymorphic CA repeats within the contig, thus integrating the physical, genetic, and transcriptional maps of the region and facilitating the mapping and identification of disease genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Do the same genes predispose to Gilles de la Tourette syndrome and dystonia? Report of a new family and review of the literature.

Gilles de la Tourette syndrome (TS) and idiopathic focal torsion dystonia are both movement disorders in which the pathologic process is thought to arise within the basal ganglia. However, despite their possible functional links, they are clinically distinct and are generally considered to have different underlying etiologies. There are several reports in the literature that suggest a relationship between eye winking tics, excessive blinking, and blepharospasm and a report of the coexistence of tics and dystonia. We describe a three-generation family in which TS and dystonias cosegregate. In total, eight patients were affected, five with dystonia and three with TS/facial tics. One of the patients with historic evidence of dystonia subsequently died of motor neuron disease. The identification of this family further strengthens the evidence in favor of an etiologic relationship between some cases of Gilles de la Tourette syndrome and focal dystonia.

A novel gene, DXS8237E, lies within 20 kb upstream of UBE1 in Xp11.23 and has a different X inactivation status.

A novel X-linked gene, DXS8237E, was isolated from human fetal brain cDNA, and its 3' end was mapped to within 20 kb upstream of UBE1 in Xp11.23. A 1.3-kb cDNA for DXS8237E detects homologous sequences in other mammals and a 3-kb mRNA that is widely expressed in human cell lines and mouse tissues. Sequence analysis indicated that the 1.3-kb cDNA contains the 3' end of the DXS8237E gene, but the sequence shows no significant homology to known genes. DXS8237E was shown to be subject to X inactivation in five somatic cell hybrids that contain an inactive human X chromosome but no active homologue. Since UBE1 escapes X inactivation, DXS8237E and UBE1 are the closest mapped genes with discordant X inactivation profiles. Sequences in the vicinity of these two genes may be important determinants of X inactivation status.

Rescue of a single yeast artificial chromosome from a cotransformation event utilizing segregation at meiosis.

During the construction of yeast artificial chromosome (YAC) libraries to facilitate mapping of the human genome, two YACs may be cotransformed into the same yeast cell, making further analysis very difficult. We present a simple method to rescue the required YAC that utilizes the segregation of chromosomes at meiosis. In brief, we crossed the cotransformed yeast cell with a non-YAC-containing strain and induced the resulting diploid to sporulate and undergo meiosis. The new haploid generation included some yeast cells that contained only the desired YAC. These YACs were analyzed by conventional methods. To exclude the possibility that major rearrangement occurred during the procedure, we analyzed the YACs with restriction enzymes that cut only rarely. We conclude that this is a useful technique to rescue cotransformed YACs.

Autosomal recessive cerebellar ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome) is linked to chromosome 9q34.

Ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome [AOA]; MIM 208920) is an autosomal recessive disorder characterized by ataxia, oculomotor apraxia, and choreoathetosis. These neurological features resemble those of ataxia-telangiectasia (AT), but in AOA there are none of the extraneurological features of AT, such as immunodeficiency, neoplasia, chromosomal instability, or sensitivity to ionizing radiation. It is unclear whether these patients have a true disorder of chromosomal instability or a primary neurodegenerative syndrome, and it has not been possible to identify the defective gene in AOA, since the families have been too small for linkage analysis. We have identified a new family with AOA, and we show that the patients have no evidence of chromosomal instability or sensitivity to ionizing radiation, suggesting that AOA in this family is a true primary cerebellar ataxia. We have localized the disease gene, by linkage analysis and homozygosity mapping, to a 15.9-cM interval on chromosome 9q34. This work will ultimately allow the disease gene to be identified and its relevance to other types of autosomal recessive cerebellar ataxias to be determined.

Genetic mapping of a cone and rod dysfunction (Aland Island eye disease) to the proximal short arm of the human X chromosome.

A five generation family with an X linked ocular disorder has been investigated. The major clinical features were reduced visual acuity, nystagmus, and myopia. Although impaired night vision was not a symptom, using psychophysical and electrophysiological testing both rod and cone function were found to be abnormal in all affected males. No abnormality was detected in carrier females. Gene location studies showed X linked transmission of a gene that maps to proximal Xp11. The findings observed in this cohort are similar to those previously reported in both congenital stationary night blindness type 2 (CSNB2) and Aland Island eye disease (AIED). This study addresses whether CSNB2 and AIED are a single entity or whether the latter is a subset of the former.

Refined linkage disequilibrium and physical mapping of the gene locus for X-linked dystonia-parkinsonism (DYT3).

X-linked dystonia-parkinsonism (XDP) is a recessive disorder characterized by generalized dystonia with some patients exhibiting parkinsonism. The disease gene, DYT3, is located between DXS453 (DXS993) and DXS559, and strongest linkage disequilibrium is found distal to DXS7117 and proximal to DXS559. We have isolated and analyzed four novel polymorphic markers between DXS7117 and DXS559 and, by haplotype analysis, have narrowed the candidate interval to <350 kb. A sequence-ready contig of 700 kb has been constructed spanning DXS7117 to DXS559 and is composed of 35 PACs, BACs, and cosmids. Nine genes and novel ESTs have been mapped into this contig, and mutations in the coding regions and intron-exon borders of two genes have been excluded as the cause of XDP. Several of the other genes and ESTs located within the contig code for proteins implicated in normal brain development and function and are candidates for DYT3.

Chorea-acanthocytosis: genetic linkage to chromosome 9q21.

Chorea-acanthocytosis (CHAC) is a rare autosomal recessive disorder characterized by progressive neurodegeneration and unusual red-cell morphology (acanthocytosis), with onset in the third to fifth decade of life. Neurological impairment with acanthocytosis (neuroacanthocytosis) also is seen in abetalipoproteinemia and X-linked McLeod syndrome. Whereas the molecular etiology of McLeod syndrome has been defined (Ho et al. 1994), that of CHAC is still unknown. In the absence of cytogenetic rearrangements, we initiated a genomewide scan for linkage in 11 families, segregating for CHAC, who are of diverse geographical origin. We report here that the disease is linked, in all families, to a 6-cM region of chromosome 9q21 that is flanked by the recombinant markers GATA89a11 and D9S1843. A maximum two-point LOD score of 7.1 (theta = .00) for D9S1867 was achieved, and the linked region has been confirmed by homozygosity-by-descent, in offspring from inbred families. These findings provide strong evidence for the involvement of a single locus for CHAC and are the first step in positional cloning of the disease gene.