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1.
J Neurol ; 265(1): 98-107, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29143208

ABSTRACT

BACKGROUND: Huntington disease is a fatal inherited neurodegenerative disease. Because the end result of Huntington disease is death due to Huntington disease-related causes, there is a need for better understanding and caring for individuals at their end of life. AIM: The purpose of this study was to develop a new measure to evaluate end of life planning. DESIGN: We conducted qualitative focus groups, solicited expert input, and completed a literature review to develop a 16-item measure to evaluate important aspects of end of life planning for Huntington disease. Item response theory and differential item functioning analyses were utilized to examine the psychometric properties of items; exploratory factor analysis was used to establish meaningful subscales. PARTICIPANTS: Participants included 508 individuals with pre-manifest or manifest Huntington disease. RESULTS: Item response theory supported the retention of all 16 items on the huntington disease quality of life ("HDQLIFE") end of life planning measure. Exploratory factor analysis supported a four-factor structure: legal planning, financial planning, preferences for hospice care, and preferences for conditions (locations, surroundings, etc.) at the time of death. Although a handful of items exhibited some evidence of differential item functioning, these items were retained due to their relevant clinical content. The final 16-item scale includes an overall total score and four subscale scores that reflect the different end of life planning constructs. CONCLUSIONS: The 16-item HDQLIFE end of life planning measure demonstrates adequate psychometric properties; it may be a useful tool for clinicians to clarify patients' preferences about end of life care.


Subject(s)
Huntington Disease/psychology , Quality of Life/psychology , Terminal Care/methods , Terminal Care/psychology , Adult , Aged , Factor Analysis, Statistical , Female , Humans , Huntington Disease/mortality , Male , Middle Aged , Psychometrics , Reproducibility of Results
2.
Qual Life Res ; 25(10): 2441-2455, 2016 10.
Article in English | MEDLINE | ID: mdl-27522213

ABSTRACT

PURPOSE: Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL-Quality of Life in Neurological Disorders and PROMIS-Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content. METHODS: New item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD. RESULTS: Moderate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between Neuro-QoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding six-item short forms. A four-item short form was developed for Meaning and Purpose. CONCLUSIONS: HDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.


Subject(s)
Huntington Disease/psychology , Sickness Impact Profile , Adult , Female , Humans , Male , Middle Aged , Surveys and Questionnaires
3.
Qual Life Res ; 25(10): 2403-2415, 2016 10.
Article in English | MEDLINE | ID: mdl-27393121

ABSTRACT

PURPOSE: Huntington disease (HD) is an incurable terminal disease. Thus, end of life (EOL) concerns are common in these individuals. A quantitative measure of EOL concerns in HD would enable a better understanding of how these concerns impact health-related quality of life. Therefore, we developed new measures of EOL for use in HD. METHODS: An EOL item pool of 45 items was field tested in 507 individuals with prodromal or manifest HD. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were conducted to establish unidimensional item pools. Item response theory (IRT) and differential item functioning analyses were applied to the identified unidimensional item pools to select the final items. RESULTS: EFA and CFA supported two separate unidimensional sets of items: Concern with Death and Dying (16 items), and Meaning and Purpose (14 items). IRT and DIF supported the retention of 12 Concern with Death and Dying items and 4 Meaning and Purpose items. IRT data supported the development of both a computer adaptive test (CAT) and a 6-item, static short form for Concern with Death and Dying. CONCLUSION: The HDQLIFE Concern with Death and Dying CAT and corresponding 6-item short form, and the 4-item calibrated HDQLIFE Meaning and Purpose scale demonstrate excellent psychometric properties. These new measures have the potential to provide clinically meaningful information about end-of-life preferences and concerns to clinicians and researchers working with individuals with HD. In addition, these measures may also be relevant and useful for other terminal conditions.


Subject(s)
Huntington Disease/psychology , Sickness Impact Profile , Terminal Care/psychology , Adolescent , Adult , Aged , Aged, 80 and over , Death , Female , Humans , Huntington Disease/mortality , Male , Middle Aged , Patient Reported Outcome Measures , Surveys and Questionnaires , Young Adult
4.
Qual Life Res ; 25(10): 2417-2427, 2016 10.
Article in English | MEDLINE | ID: mdl-27038054

ABSTRACT

PURPOSE: Huntington disease (HD) is an autosomal dominant neurodegenerative disease which results in several progressive symptoms, including bulbar dysfunction (i.e., speech and swallowing difficulties). Although difficulties in speech and swallowing in HD have a negative impact on health-related quality of life, no patient-reported outcome measure exists to capture these difficulties that are specific to HD. Thus, we developed a new patient-reported outcome measure for use in the Huntington Disease Health-Related Quality of Life (HDQLIFE) Measurement System that focused on the impact that difficulties with speech and swallowing have on HRQOL in HD. METHODS: Five hundred and seven individuals with prodromal and/or manifest HD completed 47 newly developed items examining speech and swallowing difficulties. Unidimensional item pools were identified using exploratory factor analysis and confirmatory factor analysis (EFA and CFA, respectively). Item response theory (IRT) was used to calibrate the final measures. RESULTS: EFA and CFA identified two separate unidimensional sets of items: Speech Difficulties (27 items) and Swallowing Difficulties (16 items). Items were calibrated separately for these two measures and resulted in item banks that can be administered as computer adaptive tests (CATs) and/or 6-item, static short forms. Reliability of both of these measures was supported through high correlations between the simulated CAT scores and the full item bank. CONCLUSIONS: CATs and 6-item calibrated short forms were developed for HDQLIFE Speech Difficulties and HDQLIFE Swallowing Difficulties. These measures both demonstrate excellent psychometric properties and may have clinical utility in other populations where speech and swallowing difficulties are prevalent.


Subject(s)
Computers/statistics & numerical data , Deglutition Disorders/therapy , Huntington Disease/psychology , Speech Disorders/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Reproducibility of Results , Sickness Impact Profile , Surveys and Questionnaires , Young Adult
5.
Clin Genet ; 84(3): 276-80, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23140253

ABSTRACT

Mutations in SGCE represent the major cause of the myoclonus-dystonia syndrome (DYT11), an autosomal dominant disorder of reduced penetrance. Virtually all affected individuals have myoclonus, which is concentrated in the upper extremities, neck and trunk. Over half of patients have dystonia, usually affecting the neck or arms. SGCE is maternally imprinted. Of the more than 70 SGCE mutations reported in the literature, 18 are large deletions disrupting at least one exon. Therefore, testing for exonic deletions should be considered in individuals with a classic phenotype in whom Sanger sequencing is unrevealing. However, standard methodologies for detection of exonic deletion mutations are expensive, labor intensive and can produce false negatives. Herein, we report the use of cDNA derived from leukocyte RNA to identify a deletion mutation (exons 4 and 5) of SGCE in a family with DYT11. Residual RNA from incomplete nonsense-mediated decay permitted reverse transcription to cDNA. Breakpoints of the 8939 bp heterozygous deletion were then defined with long-range polymerase chain reaction and Sanger sequencing. Use of cDNA generated by reverse transcription of leukocyte RNA can reduce the costs associated with diagnostic genetic testing and can facilitate detection of deletion mutations.


Subject(s)
Exons , Nonsense Mediated mRNA Decay , Sarcoglycans/genetics , Sequence Deletion , Adult , Dystonic Disorders/diagnosis , Dystonic Disorders/genetics , Female , Genetic Association Studies , Humans , Male
6.
Neurology ; 62(11): 2005-9, 2004 Jun 08.
Article in English | MEDLINE | ID: mdl-15184605

ABSTRACT

BACKGROUND: Similarities between Alzheimer disease (AD) and Parkinson disease (PD) suggest a possible role for apolipoprotein E (APOE) in PD. Most previous studies seeking to establish such a link used case-control datasets and results have been inconsistent. OBJECTIVE: To investigate APOE's role in PD using family-based association analyses. METHODS: APOE functional polymorphisms were genotyped for 658 PD affected families, including 282 multiplex and 376 singleton families. The pedigree disequilibrium test (PDT) and the genotype-PDT were used to test the risk effect of APOE. The Monks-Kaplan test was used to evaluate the effect of APOE on age at onset of PD. RESULTS: APOE was significantly associated with risk of developing PD. Stratified analysis revealed that APOE was most strongly associated with families with a positive PD family history (global p = 0.003). Like AD, the APOE-4 allele increases disease risk while the APOE-3 allele decreases risk. We detected a positive association of APOE-3 (p = 0.019) and a negative association of APOE-4 (p = 0.015) with age at onset in PD. CONCLUSIONS: The APOE-4 allele increases risk and decreases age at onset of PD, an association that may not be dependent upon cognitive impairment.


Subject(s)
Apolipoproteins E/physiology , Parkinson Disease/genetics , Adult , Age of Onset , Aged , Alleles , Apolipoprotein E3 , Apolipoprotein E4 , Apolipoproteins E/genetics , Australia/epidemiology , Cognition , Dementia/epidemiology , Dementia/genetics , Female , Gene Frequency , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Neuropsychological Tests , Parkinson Disease/epidemiology , Parkinson Disease/psychology , Pedigree , Risk , United States/epidemiology
7.
Neurology ; 60(7): 1189-91, 2003 Apr 08.
Article in English | MEDLINE | ID: mdl-12682333

ABSTRACT

Recently, the authors demonstrated linkage in idiopathic PD to a region on chromosome 8p that contains the N-acetyltransferase genes, NAT1 and NAT2. The authors examined NAT1 and NAT2 for association with PD using family-based association methods and single nucleotide polymorphisms (SNPs). The authors did not find evidence for association with increased risk for PD between any individual NAT1 or NAT2 SNP or acetylation haplotype (N = 397 families, 1,580 individuals).


Subject(s)
Arylamine N-Acetyltransferase/genetics , Parkinson Disease/enzymology , Parkinson Disease/genetics , Polymorphism, Genetic , Aged , Alleles , Chromosomes, Human, Pair 8/genetics , Female , Gene Frequency , Genetic Linkage , Genetic Predisposition to Disease , Genotype , Haplotypes , Humans , Isoenzymes/genetics , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Risk Assessment
8.
JAMA ; 286(18): 2239-44, 2001 Nov 14.
Article in English | MEDLINE | ID: mdl-11710888

ABSTRACT

CONTEXT: The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD. OBJECTIVE: To identify genetic risk factors for idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status. MAIN OUTCOME MEASURES: Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis. RESULTS: Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. CONCLUSIONS: Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.


Subject(s)
Parkinson Disease/genetics , Ubiquitin-Protein Ligases , Adult , Age of Onset , Aged , Antiparkinson Agents/therapeutic use , Chromosomes, Human, Pair 17 , Chromosomes, Human, Pair 3 , Chromosomes, Human, Pair 5 , Chromosomes, Human, Pair 6 , Chromosomes, Human, Pair 8 , Chromosomes, Human, Pair 9 , Drug Resistance , Genetic Predisposition to Disease , Genotype , Humans , Levodopa/therapeutic use , Ligases/genetics , Lod Score , Microsatellite Repeats , Middle Aged , Parkinson Disease/drug therapy , Parkinson Disease/epidemiology , Risk Factors
9.
JAMA ; 286(18): 2245-50, 2001 Nov 14.
Article in English | MEDLINE | ID: mdl-11710889

ABSTRACT

CONTEXT: The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease. OBJECTIVE: To investigate whether the tau gene is involved in idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene. MAIN OUTCOME MEASURE: Family-based tests of association, calculated using asymptotic distributions. RESULTS: Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P =.03; SNP 9i, P =.04; and SNP 11, P =.04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P =.11, and SNP 9iii, P =.87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P =.009) and a negative association with another haplotype (P =.007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3, 9i, 9ii, and 11). CONCLUSIONS: This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.


Subject(s)
Parkinson Disease/genetics , tau Proteins/genetics , Age of Onset , Aged , Chromosomes, Human, Pair 17 , Female , Genetic Predisposition to Disease , Haplotypes , Humans , Linkage Disequilibrium , Male , Microsatellite Repeats , Middle Aged , Polymorphism, Single Nucleotide
10.
Article in English | MEDLINE | ID: mdl-11553930

ABSTRACT

Huntington's disease (HD) is an inherited neurodegenerative disorder. The mutation which causes the disease is an expansion in the number of repetitions of three nucleotides, C, A, and G in exon 1 of the huntingtin gene. The gene normally has 15 to 30 repeats and an expansion to 40 or more is associated with HD. HD usually has a mid-life onset, but a juvenile form, defined by onset of symptoms before the age of 21 years, is present in about 7% of HD cases. Juvenile HD is characterized by (1) transmission from an HD affected father, (2) an unusually large repeat size, usually of 60 or more units, and (3) unique clinical features, including rigidity and seizure disorder. Although juvenile onset is associated with a more severe neuropathological involvement, the neuropathological characteristics of juvenile HD are similar to those seen in the adult form in that the striatum bears the brunt of the illness. Clumps of protein, termed inclusion bodies, which stain positive for huntingtin and ubiquitin, are found primarily in the nucleus but also in the cytoplasm and axons in HD neurons. Research suggests that these inclusion bodies sequester a deleterious protein fragment and prolong cell life during the degenerative process of the disease.


Subject(s)
Basal Ganglia/pathology , Huntington Disease/diagnosis , Huntington Disease/genetics , Adolescent , Carrier Proteins/genetics , Female , Humans , Huntingtin Protein , Huntington Disease/metabolism , Inclusion Bodies/genetics , Inclusion Bodies/metabolism , Male , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Trinucleotide Repeats/genetics
11.
Am J Hum Genet ; 68(5): 1077-85, 2001 May.
Article in English | MEDLINE | ID: mdl-11309678

ABSTRACT

Pure hereditary spastic paraplegia (SPG) type 4 is the most common form of autosomal dominant hereditary SPG, a neurodegenerative disease characterized primarily by hyperreflexia and progressive spasticity of the lower limbs. It is caused by mutations in the gene encoding spastin, a member of the AAA family of ATPases. We have screened the spastin gene for mutations in 15 families consistent with linkage to the spastin gene locus, SPG4, and have identified 11 mutations, 10 of which are novel. Five of the mutations identified are in noninvariant splice-junction sequences. Reverse transcription-PCR analysis of mRNA from patients shows that each of these five mutations results in aberrant splicing. One mutation was found to be "leaky," or partially penetrant; that is, the mutant allele produced both mutant (skipped exon) and wild-type (full-length) transcripts. This phenomenon was reproduced in in vitro splicing experiments, with a minigene splicing-vector construct only in the context of the endogenous splice junctions flanking the splice junctions of the skipped exon. In the absence of endogenous splice junctions, only mutant transcript was detected. The existence of at least one leaky mutation suggests that relatively small differences in the level of wild-type spastin expression can have significant functional consequences. This may account, at least in part, for the wide ranges in age at onset, symptom severity, and rate of symptom progression that have been reported to occur both among and within families with SPG linked to SPG4. In addition, these results suggest caution in the interpretation of data solely obtained with minigene constructs to study the effects of sequence variation on splicing. The lack of full genomic sequence context in these constructs can mask important functional consequences of the mutation.


Subject(s)
Adenosine Triphosphatases/genetics , Mutation/genetics , RNA Splicing/genetics , Spastic Paraplegia, Hereditary/genetics , Adolescent , Adult , Age of Onset , Aged , Animals , Base Sequence , Cell Line , Child , Child, Preschool , DNA Mutational Analysis , Exons/genetics , Genes, Dominant/genetics , Humans , Infant , Introns/genetics , Lod Score , Middle Aged , Nuclear Family , Penetrance , RNA Splice Sites/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Spastic Paraplegia, Hereditary/epidemiology , Spastin
12.
Genet Test ; 5(3): 213-8, 2001.
Article in English | MEDLINE | ID: mdl-11788086

ABSTRACT

The widespread use of a predictive genetic test for Huntington's disease (HD) since 1993 has brought to the forefront issues regarding genetic privacy. Although the possibility of anonymous genetic testing has been discussed, its use in the United States has not been described previously. We review the experiences of 11 genetics specialists with anonymous predictive testing for HD. We found that more men than women requested anonymous testing, for reasons that more often related to personal privacy than to insurance or discrimination concerns. A number of approaches to anonymity were used, and genetics specialists varied in the degree to which they were comfortable with the process. A number of legal, medical, and practical questions are raised, which will require resolution if anonymous testing is to be performed with a greater frequency in the future.


Subject(s)
Confidentiality , Genetic Testing , Huntington Disease/diagnosis , Anonyms and Pseudonyms , Female , Humans , Huntington Disease/genetics , Informed Consent , Male , United States
13.
Mol Diagn ; 5(2): 91-9, 2000 Jun.
Article in English | MEDLINE | ID: mdl-11066010

ABSTRACT

BACKGROUND: The Ataxia Molecular Diagnostics Testing Group was established to generate quantitative proficiency and outcomes data regarding molecular testing for the autosomal dominant cerebellar ataxias (spinocerebellar ataxia types 1 [SCA-1] through -3, -6, and -7, and dentatorubral-pallidoluysian atrophy) in North America. METHODS AND RESULTS: Twenty-four North American laboratories that offered diagnostic testing for one or more ataxia genes were initially identified through GeneTests (Children's Health Care System, Seattle, WA). Eighteen laboratories agreed to participate in the study, which consisted of completing a technical survey, clinical survey, and molecular proficiency test. One laboratory returned the completed surveys but did not perform the proficiency testing. Ten of 18 laboratories (56%) provided data on test volumes, and these laboratories collectively performed 2,240 tests; approximately 5% of the tests yielded a positive result (i.e., identification of a pathological trinucleotide (CAG) repeat expansion). In proficiency testing, 100% of the laboratories correctly genotyped all samples, and 93% of the laboratories were within 1 SD of the mean for sizing normal alleles (one repeat unit or less). Ninety percent of the laboratories were within 1 SD for sizing expanded alleles. CONCLUSIONS: Proficiency testing showed little difference between laboratories with respect to allele sizing. However, additional phenotype/genotype correlations are necessary to define CAG repeat-length descriptors for SCA-1, SCA-2, and SCA-7 alleles of intermediate size.


Subject(s)
Cytogenetic Analysis/standards , Spinocerebellar Ataxias/diagnosis , Spinocerebellar Ataxias/genetics , Alleles , Data Collection , Humans , North America , Polymerase Chain Reaction , Reproducibility of Results , Spinocerebellar Ataxias/classification
14.
Am J Med Genet ; 92(5): 303-7, 2000 Jun 19.
Article in English | MEDLINE | ID: mdl-10861657

ABSTRACT

Paget disease of the bone is a common skeletal disorder. Recently, a gene for Paget disease was localized to 18q with subsequent evidence for linkage heterogeneity. We report the identification and clinical characterization of a large pedigree of Paget disease and demonstrate that the Paget disease gene in this pedigree is not linked to the region on 18q, thus confirming linkage heterogeneity.


Subject(s)
Genetic Heterogeneity , Osteitis Deformans/genetics , Adult , Aged , Chromosomes, Human, Pair 18 , Female , Genetic Linkage , Humans , Male , Middle Aged , Pedigree
15.
Am J Med Genet ; 82(2): 161-5, 1999 Jan 15.
Article in English | MEDLINE | ID: mdl-9934982

ABSTRACT

Familial lipodystrophy is a genetically heterogeneous set of disorders characterized by a total or partial absence of subcutaneous fat, diabetes mellitus or impaired glucose tolerance, hyperlipidemia, and hypermetabolism [Senior and Gellis, 1964]. One subtype, familial partial lipodystrophy Dunnigan (FPLD), is a rare autosomal dominant trait that results in an gradual loss of subcutaneous fat in the lower trunk and limbs, Type V hyperlipoproteinemia, hypertriglyceridemia, and insulin-resistant diabetes. Previous reports of this condition have been limited to case reports or very small families. Recently, Peters et al. reported on linkage of five families of Western European descent to a 5.3 cM region on chromosome 1q21-22 between the flanking markers D1S305 and D1S1600 [Peters et al., 1998: Nat Genet 18:292-295]. We performed linkage and haplotype analysis using highly polymorphic, microsatellite markers on a large, multigeneration Caucasian kindred of German ancestry. The maximum two-point lod score achieved was 4.96 at theta(max) = 0 for marker D1S2721. Multipoint analysis gave an overall maximum lod score of 6.27 near marker D1S2721. The results of the haplotype analysis support the minimal candidate region as reported by Peters et al.


Subject(s)
Chromosomes, Human, Pair 1 , Genetic Linkage , Lipodystrophy/genetics , Adult , Chromosome Mapping , Female , Haplotypes , Humans , Male , Pedigree
16.
Neurology ; 52(2): 392-4, 1999 Jan 15.
Article in English | MEDLINE | ID: mdl-9932964

ABSTRACT

A patient with juvenile Huntington's disease (HD) of probable maternal inheritance is reported. The expanded IT-15 allele was only detected with the use of modified PCR and Southern transfer techniques, which showed a CAG trinucleotide repeat expansion of approximately 250 repeats-the largest CAG expansion reported within the huntingtin gene. This case emphasizes the need for communication between the diagnostic laboratory and the clinician to define the molecular genetics of unusual cases.


Subject(s)
Huntington Disease/genetics , Trinucleotide Repeats , Adolescent , Age of Onset , Alleles , Blotting, Southern , Humans , Male , Polymerase Chain Reaction
17.
Hum Hered ; 48(3): 169-78, 1998.
Article in English | MEDLINE | ID: mdl-9618065

ABSTRACT

The clinical features of four families with autosomal dominant spastic paraparesis (FSP) are described, along with the results of linkage analysis to markers from the regions of chromosomes 2, 14, and 15 which are known to contain spastic paraplegia genes. All families had 'pure' spastic paraparesis (FSP), but the severity of symptoms varied widely among families, and other mild neurologic signs were observed in some subjects. Although no family individually yielded a lod score >3.0, all families yielded positive lod scores with chromosome 2 markers, and a maximal lod score of 5.7 was obtained for the families combined using marker D2S352. There was no evidence of linkage to chromosome 14 or 15 in any of the families.


Subject(s)
Chromosomes, Human, Pair 2/genetics , Genetic Linkage/genetics , Spastic Paraplegia, Hereditary/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Chromosomes, Human, Pair 14/genetics , Chromosomes, Human, Pair 15/genetics , Female , Genetic Markers/genetics , Humans , Male , Pedigree
18.
J Geriatr Psychiatry Neurol ; 11(2): 61-70, 1998.
Article in English | MEDLINE | ID: mdl-9877527

ABSTRACT

Huntington disease (HD) is a fascinating neurodegenerative disorder whose features straddle the boundaries of psychiatry, neurology, and genetics. The clinical symptoms of HD consist of a triad of motor, cognitive, and psychiatric/behavioral disturbances. In 1993, the HD Collaborative Research Group identified the gene and the mutation responsible for HD. HD was one of the first neurodegenerative disorders discovered to be caused by a novel mutational mechanism known as trinucleotide repeat expansion. Since then, HD has been the model for autosomal dominant neurogenetic disorders. The clinical, pathological, and genetic aspects of the disease are reviewed and some of the questions that remain to be answered by researchers of the 21st century are outlined.


Subject(s)
Dementia/genetics , Genetic Predisposition to Disease/genetics , Huntington Disease/genetics , Adult , Aged , Brain/pathology , Chromosome Aberrations/genetics , Chromosome Disorders , DNA Mutational Analysis , Genes, Dominant/genetics , Humans , Huntingtin Protein , Huntington Disease/diagnosis , Middle Aged , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Proteins/genetics , Trinucleotide Repeats/genetics
19.
Neurology ; 49(4): 1048-53, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9339688

ABSTRACT

We reviewed 44 symptomatic children tested for CAG repeat expansions in the gene responsible for Huntington's disease (HD). Thirty-three patients had CAG repeat expansions, and 11 did not. No patient with a CAG repeat expansion had a negative family history of HD. Of the 15 patients presenting in the first decade, 12 had greater than 80 CAG repeats and a clinical profile at the time of the test that included two or more of the following: declining school performance, seizures, oral motor dysfunction, rigidity, and gait disorder. Three patients with smaller CAG repeat expansions had incomplete or atypical symptom profiles. Symptom patterns in patients presenting in the second decade were more varied but usually included behavioral and motor symptoms. Patients without CAG expansions had incomplete or atypical symptom profiles. We define the historical and clinical profiles of HD presenting in the first two decades and suggest that physicians exercise restraint in using a "diagnostic" gene test for HD in the evaluation of at-risk children with incomplete or atypical symptom profiles or no family history of HD, in whom test results are very likely to be normal or unrelated to the patient's symptoms.


Subject(s)
Genetic Testing , Huntington Disease/genetics , Adolescent , Aging/physiology , Aging/psychology , Child , Child Behavior Disorders/etiology , Child, Preschool , Humans , Huntington Disease/physiopathology , Huntington Disease/psychology , Mental Disorders/etiology , Repetitive Sequences, Nucleic Acid , Retrospective Studies , Risk Factors
20.
Neurology ; 49(2): 643, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9270629
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