Purpose-Huntington disease (HD) is an autosomal dominant neurodegenerative disease which results ... more 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 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 and confirmatory factor analyses (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.
Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation, 2016
Huntington disease (HD) is an incurable terminal disease. Thus, end of life (EOL) concerns are co... more 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. 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. 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...
Purpose Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical,... more 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,
Background: Similarities between Alzheimer disease (AD) and Parkinson disease (PD) suggest a poss... more 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 ϭ 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 ϭ 0.019) and a negative association of APOE-4 (p ϭ 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.
Recently, the authors demonstrated linkage in idiopathic PD to a region on chromosome 8p that con... more 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 ϭ 397 families, 1,580 individuals).
We and many others have pondered why some patients respond to cholinesterase inhibitors while oth... more We and many others have pondered why some patients respond to cholinesterase inhibitors while others do not. Apo E genotyping may play a role but at the moment data from large scale studies are as yet unclear. In addition, since this study was initiated in 1989, the role of apolipoprotein E, was not yet appreciated. In addition to apolipoprotein E, genotype, other factors are likely to play a role in drug response. For example, an early report noted that individuals with senile dementia of the Lewy body type appeared to have a better response to the cholinesterase inhibitor tacrine.5 However, a later series refuted this finding.6 Undoubtedly, many other factors are also operative. Please note that in our cohort, dose titration nonresponders were slightly more demented than responders and had an MMSE score 1.1 points lower. In our opinion, however, this slight difference probably does not explain their lack of response to physostigmine. We believe that the lack of response is multifactorial and remains to be determined.
Huntington disease is a fatal inherited neurodegenerative disease. Because the end result of Hunt... more 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. The purpose of this study was to develop a new measure to evaluate end of life planning. 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 included 508 individuals with pre-manifest or manifest Huntington disease. Item response theory supported the retention of all 16 items on the huntington disease quality of life ("HDQLIFE") end of life planning measure. Explorato...
Clinician-rated measures of functioning are often used as primary endpoints in clinical trials an... more Clinician-rated measures of functioning are often used as primary endpoints in clinical trials and other behavioral research in Huntington disease. As study costs for clinician-rated assessments are not always feasible, there is a question of whether patient self-report of commonly used clinician-rated measures may serve as acceptable alternatives in low risk behavioral trials. The purpose of this paper was to determine the level of agreement between self-report and clinician-ratings of commonly used functional assessment measures in Huntington disease. 486 participants with premanifest or manifest Huntington disease were examined. Total Functional Capacity, Functional Assessment, and Independence Scale assessments from the Unified Huntington Disease Rating scale were completed by clinicians; a self-report version was also completed by individuals with Huntington disease. Cronbach's α was used to examine internal consistency, one-way analysis of variance was used to examine grou...
The symptoms of Huntington's disease are well known, yet the symptoms of juvenile Huntington&... more The symptoms of Huntington's disease are well known, yet the symptoms of juvenile Huntington's disease (JHD) are less established due to its rarity. The study examined a cluster of symptoms considered to be common, but under-recognized in JHD: pain, itching, sleeping difficulties, psychosis and tics. A symptom survey was constructed using the online tool Qualtrics and dispersed to JHD caregivers through websites. A total of 33 surveys were completed. Disrupted sleep was the most prevalent symptom (87%), followed by tics (78%), pain (69%), itching (60%) and psychosis (39%). Despite limitations, the study supports that there are symptoms in the JHD population that are not considered classic, however, are common and significant for patients and caregivers.
Huntington's disease (HD), is a neurodegenerative disorder that is associated with cognitive,... more Huntington's disease (HD), is a neurodegenerative disorder that is associated with cognitive, behavioral, and motor impairments that diminish health related quality of life (HRQOL). The HD-PRO-TRIADTM is a quality of life measure that assesses health concerns specific to individuals with HD. Preliminary psychometric characterization was limited to a convenience sample of HD participants who completed measures at home so clinician-ratings were unavailable. The current study evaluates the reliability and validity of the HD-PRO-TRIADTM in a well-characterized sample of individuals with HD. Four-hundred and eighty-two individuals with HD (n = 192 prodromal, n = 193 early, and n = 97 late) completed the HD-PRO-TRIADTM questionnaire. Clinician-rated assessments from the Unified Huntington Disease Rating Scales, the short Problem Behaviors Assessment, and three generic measures of HRQOL (WHODAS 2.0, RAND-12, and EQ-5D) were also examined. Internal reliability for all domains and the to...
To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-do... more To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was gener...
Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for t... more Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285*), c.247_250del (p.Asn83Hisfs*4), and splice site c.830þ2_830þ3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.
Infantile-and juvenile-onset spinal cerebellar ataxia (SCA) is associated with expansion of 130 t... more Infantile-and juvenile-onset spinal cerebellar ataxia (SCA) is associated with expansion of 130 to more than 200 CAG-repeats in the SCA2 and SCA7 genes. Routine clinical assays for SCA2 and SCA7, which use polymerase chain reaction (PCR) and denaturing PAGE (polyacrylamide gel electrophoresis), will not reliably detect such large expansions. An assay based on separation of PCR products on an agarose gel, blotting, and hybridization with a (CAG)6 oligonucleotide probe was used to test DNA from individuals more than 10 years of age who had a possible diagnosis of SCA. Among 25 cases, the PCR-blot assay confirmed the presence of SCA2 expansions between 230 and 500 repeats in four unrelated individuals, but did not detect any cases of extreme expansion in the SCA7 gene. The PCR-blot assay provides reliable detection of extreme expansion mutations. Routine incorporation of this assay in clinical laboratories may reveal that infantile-juvenile forms of SCA2 and SCA7 are more prevalent than previously recognized.
Purpose-Huntington disease (HD) is an autosomal dominant neurodegenerative disease which results ... more 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 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 and confirmatory factor analyses (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.
Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation, 2016
Huntington disease (HD) is an incurable terminal disease. Thus, end of life (EOL) concerns are co... more 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. 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. 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...
Purpose Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical,... more 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,
Background: Similarities between Alzheimer disease (AD) and Parkinson disease (PD) suggest a poss... more 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 ϭ 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 ϭ 0.019) and a negative association of APOE-4 (p ϭ 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.
Recently, the authors demonstrated linkage in idiopathic PD to a region on chromosome 8p that con... more 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 ϭ 397 families, 1,580 individuals).
We and many others have pondered why some patients respond to cholinesterase inhibitors while oth... more We and many others have pondered why some patients respond to cholinesterase inhibitors while others do not. Apo E genotyping may play a role but at the moment data from large scale studies are as yet unclear. In addition, since this study was initiated in 1989, the role of apolipoprotein E, was not yet appreciated. In addition to apolipoprotein E, genotype, other factors are likely to play a role in drug response. For example, an early report noted that individuals with senile dementia of the Lewy body type appeared to have a better response to the cholinesterase inhibitor tacrine.5 However, a later series refuted this finding.6 Undoubtedly, many other factors are also operative. Please note that in our cohort, dose titration nonresponders were slightly more demented than responders and had an MMSE score 1.1 points lower. In our opinion, however, this slight difference probably does not explain their lack of response to physostigmine. We believe that the lack of response is multifactorial and remains to be determined.
Huntington disease is a fatal inherited neurodegenerative disease. Because the end result of Hunt... more 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. The purpose of this study was to develop a new measure to evaluate end of life planning. 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 included 508 individuals with pre-manifest or manifest Huntington disease. Item response theory supported the retention of all 16 items on the huntington disease quality of life ("HDQLIFE") end of life planning measure. Explorato...
Clinician-rated measures of functioning are often used as primary endpoints in clinical trials an... more Clinician-rated measures of functioning are often used as primary endpoints in clinical trials and other behavioral research in Huntington disease. As study costs for clinician-rated assessments are not always feasible, there is a question of whether patient self-report of commonly used clinician-rated measures may serve as acceptable alternatives in low risk behavioral trials. The purpose of this paper was to determine the level of agreement between self-report and clinician-ratings of commonly used functional assessment measures in Huntington disease. 486 participants with premanifest or manifest Huntington disease were examined. Total Functional Capacity, Functional Assessment, and Independence Scale assessments from the Unified Huntington Disease Rating scale were completed by clinicians; a self-report version was also completed by individuals with Huntington disease. Cronbach's α was used to examine internal consistency, one-way analysis of variance was used to examine grou...
The symptoms of Huntington's disease are well known, yet the symptoms of juvenile Huntington&... more The symptoms of Huntington's disease are well known, yet the symptoms of juvenile Huntington's disease (JHD) are less established due to its rarity. The study examined a cluster of symptoms considered to be common, but under-recognized in JHD: pain, itching, sleeping difficulties, psychosis and tics. A symptom survey was constructed using the online tool Qualtrics and dispersed to JHD caregivers through websites. A total of 33 surveys were completed. Disrupted sleep was the most prevalent symptom (87%), followed by tics (78%), pain (69%), itching (60%) and psychosis (39%). Despite limitations, the study supports that there are symptoms in the JHD population that are not considered classic, however, are common and significant for patients and caregivers.
Huntington's disease (HD), is a neurodegenerative disorder that is associated with cognitive,... more Huntington's disease (HD), is a neurodegenerative disorder that is associated with cognitive, behavioral, and motor impairments that diminish health related quality of life (HRQOL). The HD-PRO-TRIADTM is a quality of life measure that assesses health concerns specific to individuals with HD. Preliminary psychometric characterization was limited to a convenience sample of HD participants who completed measures at home so clinician-ratings were unavailable. The current study evaluates the reliability and validity of the HD-PRO-TRIADTM in a well-characterized sample of individuals with HD. Four-hundred and eighty-two individuals with HD (n = 192 prodromal, n = 193 early, and n = 97 late) completed the HD-PRO-TRIADTM questionnaire. Clinician-rated assessments from the Unified Huntington Disease Rating Scales, the short Problem Behaviors Assessment, and three generic measures of HRQOL (WHODAS 2.0, RAND-12, and EQ-5D) were also examined. Internal reliability for all domains and the to...
To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-do... more To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was gener...
Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for t... more Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285*), c.247_250del (p.Asn83Hisfs*4), and splice site c.830þ2_830þ3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.
Infantile-and juvenile-onset spinal cerebellar ataxia (SCA) is associated with expansion of 130 t... more Infantile-and juvenile-onset spinal cerebellar ataxia (SCA) is associated with expansion of 130 to more than 200 CAG-repeats in the SCA2 and SCA7 genes. Routine clinical assays for SCA2 and SCA7, which use polymerase chain reaction (PCR) and denaturing PAGE (polyacrylamide gel electrophoresis), will not reliably detect such large expansions. An assay based on separation of PCR products on an agarose gel, blotting, and hybridization with a (CAG)6 oligonucleotide probe was used to test DNA from individuals more than 10 years of age who had a possible diagnosis of SCA. Among 25 cases, the PCR-blot assay confirmed the presence of SCA2 expansions between 230 and 500 repeats in four unrelated individuals, but did not detect any cases of extreme expansion in the SCA7 gene. The PCR-blot assay provides reliable detection of extreme expansion mutations. Routine incorporation of this assay in clinical laboratories may reveal that infantile-juvenile forms of SCA2 and SCA7 are more prevalent than previously recognized.
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Papers by Martha Nance