HDQLIFE: the development of two new computer adaptive tests for use in Huntington disease, Speech Difficulties, and Swallowing Difficulties.

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.

New measures to capture end of life concerns in Huntington disease: Meaning and Purpose and Concern with Death and Dying from HDQLIFE (a patient-reported outcomes measurement system).

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.

HDQLIFE: development and assessment of health-related quality of life in Huntington disease (HD).

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.

Incomplete nonsense-mediated decay facilitates detection of a multi-exonic deletion mutation in SGCE.

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.

Prospective randomized observer-blinded study comparing the analgesic efficacy of ultrasound-guided rectus sheath block and local anaesthetic infiltration for umbilical hernia repair.

BACKGROUND: Umbilical hernia repair, a common day-surgery procedure in children, is associated with considerable postoperative discomfort. Possible modes of postoperative analgesia for umbilical hernia repair are rectus sheath block (RSB) and local anaesthetic infiltration of the surgical site (LAI). METHODS: We undertook an observer-blinded, randomized, prospective, observational study to compare the efficacy of ultrasound-guided RSB and LAI in providing postoperative analgesia for umbilical hernia repair. Our primary objective was to compare the use of opioid medication between patients who receive RSB and those who receive LAI. Our secondary objectives were to compare the duration of analgesia based on time to first rescue analgesic, to compare the quality of analgesia based on revised FACES scale, and to determine the incidence of side-effects. RESULTS: Fifty-two patients (26 in each group) completed the study. There was a statistically significant difference in the perioperative opioid medication consumption between the LAI group [mean: 0.13 mg kg(-1), confidence interval (0.09-0.17 mg kg⁻¹)] and the RSB group [mean: 0.07 mg kg⁻¹, confidence interval (0.05-0.09 mg kg⁻¹)] (P=0.008). When we compared the postoperative opioid consumption between the LAI group [mean: 0.1 mg kg⁻¹, 95% confidence interval (0.07-0.13 mg kg⁻¹)] and the RSB group [mean: 0.07 mg kg(-1), 95% confidence interval (0.05-0.09 mg kg⁻¹)] (P=0.09), there was a trend towards statistical significance between the two groups. The difference in time to rescue analgesic administration between the RSB group [49.7 (36.9) min] and the LAI group [32.4 (29.4) min] was not statistically significant (P=0.11). CONCLUSIONS: This study demonstrates that ultrasound-guided RSB provides superior analgesia in the perioperative period compared with infiltration of the surgical site after umbilical hernia repair. In comparing only the postoperative period, analgesia provided by an ultrasound-guided RSB showed a trend towards statistically significant improvement compared with infiltration of the surgical site.

Chaplaincy care pathways and clinical pastoral education.

The authors describe the transforming of a tool originally focused on defining and refining the role of chaplaincy care with specific patient populations into a curriculum component for a Clinical Pastoral Education (CPE) residency program.

Detection of Huntington's disease decades before diagnosis: the Predict-HD study.

OBJECTIVE: The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington's disease (HD), prior to the point of traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measurable aspects of HD relative to the time of eventual diagnosis. METHODS: We studied 438 participants who were positive for the HD gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled non-linearly using estimated time until diagnosis (based on CAG repeat length and current age) as the predictor. RESULTS: Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies. CONCLUSIONS: These findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials.

A new measure for end of life planning, preparation, and preferences in Huntington disease: HDQLIFE end of life planning.

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.

Angiotensin-converting enzyme inhibition limits dysfunction in adjacent noninfarcted regions during left ventricular remodeling.

OBJECTIVES: We hypothesized that angiotensin-converting enzyme inhibitors would limit dysfunction in the first 8 weeks after transmural infarction in adjacent noninfarcted regions, as well as attenuate left ventricular remodeling. BACKGROUND: Angiotensin-converting enzyme inhibition limits ventricular dilation and hypertrophy and improves survival after anterior infarction, but its effect on regional function during remodeling is not well characterized. METHODS: Thirteen sheep underwent coronary ligation to create an anteroapical infarction. At postinfarction day 2, eight sheep were randomized to therapy with the angiotensin-converting enzyme inhibitor ramipril, and five sheep received no therapy. Animals were studied with magnetic resonance myocardial tagging before and 8 weeks after infarction. Left ventricular volume, mass and ejection fraction were measured, as were changes in percent circumferential shortening within the subendocardium and subepicardium of infarcted and noninfarcted myocardium, both adjacent to and remote from the infarction. RESULTS: Angiotensin-converting enzyme inhibition limited the increase in end-diastolic volume from a mean (+/- SD) of +1.5 +/- 0.7 ml/kg in control animals to +0.5 +/- 0.8 ml/kg in the treated group (p < 0.04). Segmental function within infarcted and remote noninfarcted tissue did not differ between groups. However, angiotensin-converting enzyme inhibition limited the decline in function in the adjacent noninfarcted region 8 weeks after infarction. Percent circumferential shortening in the subendocardium decreased by -13 +/- 5% in the control group compared with -5 +/- 5% in the treated group (p < 0.03). CONCLUSIONS: In concert with a reduction in left ventricular remodeling after anterior infarction, angiotensin-converting enzyme inhibition limits the decline in function in the adjacent noninfarcted region. Dysfunction in adjacent noninfarcted regions may be an important determinant of left ventricular remodeling after infarction.

Clinical aspects of CAG repeat diseases.

Seven neurodegenerative disorders are known to be caused by unstable expansions of the trinucleotide CAG within human genes, and more will be discovered in the coming years. These disorders share some clinical similarities, as well as some differences, which are summarized here. These diseases have unusual clinical genetic properties related to the dynamic nature of CAG repeat expansions, including instability of the repeat expansion in meiosis, particularly male meiosis; a strong correlation between onset age and size of the repeat expansion; anticipation (earlier disease onset in succeeding generations); new mutations arising from unstable, mutable alleles with a high-normal CAG repeat number; and reduced penetrance for alleles in the low-affected range. Much more remains to be learned about the molecular biology and clinical pathophysiology of this new class of genetic diseases.

Brain glyceraldehyde-3-phosphate dehydrogenase activity in human trinucleotide repeat disorders.

BACKGROUND: Although the abnormal gene products responsible for several hereditary neurodegenerative disorders caused by repeat CAG trinucleotides have been identified, the mechanism by which the proteins containing the expanded polyglutamine domains cause cell death is unknown. The observation that several of the mutant proteins interact in vitro with the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) suggests that interaction between the different gene products and GAPDH might damage brain neurons. OBJECTIVE: To measure the activity of GAPDH in postmortem brain of patients with CAG repeat disorders. PATIENTS AND METHODS: Activity of GAPDH was measured in morphologically affected and unaffected brain areas of patients with 4 different CAG repeat disorders (Huntington disease, spinocerebellar ataxia 1 [SCA1], SCA2, and SCA3-Machado-Joseph disease), in brains of patients with Friedreich ataxia (a GAA repeat disorder) and Alzheimer disease, and in brains of matched control subjects. RESULTS: Brain GAPDH activity was normal in all groups with the exception of a slight but statistically significant region-specific reduction in the patients with Huntington disease (caudate nucleus, -12%) and Alzheimer disease (temporal cortex, -19%). CONCLUSION: The presence of the polyglutamine-containing proteins in CAG repeat disorders does not result in substantial irreversible inactivation or in increased activity of GAPDH in human brain.

Genetic testing of children at risk for Huntington's disease. US Huntington Disease Genetic Testing Group.

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.

Diagnosis of patients presenting to a Huntington disease (HD) clinic without a family history of HD.

About 9% of patients presenting to a Huntington disease (HD) clinic for evaluation of possible HD lacked a family history of the disorder. HD was the final diagnosis in 53 to 83% of these patients. As a group, HD-affected individuals without a family history of HD were older and had fewer CAG repeats than the average HD patient. Some patients presenting with chorea only had HD and others did not; patients developing a movement disorder after long-standing neuroleptic-treated psychiatric illness did not have HD.

Adult-onset neurodegenerative disorder due to proteolipid protein gene mutation in the mother of a man with Pelizaeus-Merzbacher disease.

A 23-year-old man with Pelizaeus-Merzbacher disease had a novel mutation, C344A (Thr115Lys), in exon 3 of the proteolipid protein gene (PLP) His mother, heterozygous for the mutation, developed progressive personality change and a gait disorder in her mid-20s. Her MRI at age 53 showed a diffuse severe leukodystrophy. This report extends the phenotypic range of disease due to PLP gene mutations to include adult-onset dementia in females.

Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington's disease.

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.

Autosomal dominant spinocerebellar ataxia: locus heterogeneity in a Nebraska kindred.

SCA1 is an adult-onset autosomal dominant ataxia that is genetically linked to loci on chromosome 6p. A highly informative GT-repeat marker, D6S89, has been closely linked to the SCA1 locus in five large kindreds. We have used this marker to perform linkage analysis in a smaller autosomal dominant ataxia family consisting of five generations designated as the Nebraska kindred. This kindred includes 33 affected (12 living) and 40 first-generation at-risk individuals. We examined eight affected individuals; all had gait and limb ataxia. We analyzed the D6S89 locus by the polymerase chain reaction. Based on the analysis of 31 individuals from this kindred, we statistically excluded linkage to D6S89 for moderate-to-tight linkage (less than 11% recombination). These data clearly demonstrate genetic heterogeneity among the autosomal dominant ataxias. In addition, we obtained linkage data for HLA-A and SCA1 in this kindred. Comparison of HLA-A with D6S89 shows the latter marker to be more powerful. Use of D6S89 and other highly polymorphic markers in this region will greatly facilitate genetic classification of ataxias and make presymptomatic diagnosis of SCA1 feasible.

Cockayne syndrome: review of 140 cases.

To define diagnostic criteria for Cockayne Syndrome (CS) and to identify in detail the complications of the condition, a comprehensive review of 140 cases of CS was performed. Criteria required for the diagnosis include poor growth and neurologic abnormality; other very common manifestations include sensorineural hearing loss, cataracts, pigmentary retinopathy, cutaneous photosensitivity, and dental caries. The mean age of death in reported cases is 12 3/12 years, though a few affected individuals have lived into their late teens and twenties. Prenatal growth failure, congenital structural eye anomalies, severe neurologic dysfunction from birth, and the presence of cataracts within the first 3 years of life are predictors of severe disease and early death. In contrast with other disorders of chromosome or DNA repair, cancer has never been reported in a classical CS patient, and there appears to be no predisposition to infectious complications. The wide spectrum of symptoms and severity of the disease suggest that biochemical and genetic heterogeneity exist. CS is an uncommon but devastating genetic condition which will be better understood as the biochemical interrelationships between DNA replication and repair, and between growth, homeostasis, and oncogenesis are unraveled.

Knowledge of genetics and attitudes toward genetic testing in two hereditary ataxia (SCA 1) kindreds.

Molecular genetic predictive or prenatal genetic testing is now possible in families with one form of adult-onset, autosomal dominant ataxia (SCA 1). Before the SCA 1 gene was isolated, we began a study of the knowledge of genetics, the perception of the disease, and the intended use of genetic testing among members of two large SCA 1 kindreds. Questionnaires were sent to 210 consenting affected, at-risk, and spouse members of two SCA 1 kindreds; data from the 117 respondents were analyzed on a personal computer. Sixty-nine percent of respondents thought predictive testing (by genetic linkage) should be made available immediately, and 42% thought prenatal testing should be made available. The kindreds differed in several important aspects: knowledge of genetic concepts, family size, and anticipated emotional responses to genetic testing. No respondent had obtained individualized genetic counseling. There is moderate interest in genetic testing for this fatal neurodegenerative disease of adulthood. Members of our kindreds have not received genetic counseling outside of the research setting. Finally, factors specific to a particular kindred may influence or predict individual responses to genetic testing.

X-linked mental retardation with thin habitus, osteoporosis, and kyphoscoliosis: linkage to Xp21.3-p22.12.

We reevaluated a family previously described as having nonspecific X-linked mental retardation (XLMR) by Snyder and Robinson [1969: Clin Pediatr 8:669-674] (MIM 309583). Clinical and DNA studies were conducted on 17 relatives, including 6 males with mild-to-moderate mental retardation, 3 carrier females, and 8 normal males. In contrast to the normal appearance and minimal clinical findings reported 22 years ago, affected males were found to have a characteristic set of clinical findings. These developed gradually over the first 2 decades, and included thin body build with diminished muscle mass, osteoporosis and kyphoscoliosis, slight facial asymmetry with a prominent lower lip, nasal speech, high narrow or cleft plate, and long great toes. Carrier females were clinically normal. Multipoint linkage analysis indicated linkage to markers distal to the 3' end of DMD (DXS41 and DXS989), with a maximal lod score of 4.7. On the basis of these findings, this entity is redefined as XLMR syndrome.

Protocol for genetic testing in Huntington disease: three years of experience in Minnesota.

Molecular genetic testing for Huntington disease (HD) by linkage analysis of DNA markers close to the HD gene has been possible since the mid-1980s. Because of ethical and practical concerns about this kind of testing, most groups performing the test in the past have operated under lengthy research protocols designed to assess the psychological morbidity of the presymptomatic diagnosis of a fatal disease. Our approach to HD testing is service-oriented, and our testing process has been designed to be flexible, to meet the varying needs of our patients. Between 1988 and 1990, 87 inquiries about the test have been received; 22 inquiries had family structures which were unsuitable for linkage analysis. Eleven of the 37 individuals who entered the testing program have not completed it. Of 19 patients who have received DNA results, seven received an increased risk of carrying the HD gene, and ten, a decreased risk. For two additional individuals, nonpaternity resulted in a negligible risk for HD. Several of those consulted, or their spouses, have had continuing outpatient counseling since completing the test; none have required hospitalization. Our short-term results indicate that molecular genetic testing for HD can be performed safely in a clinical setting using our protocol. As molecular genetic testing for HD and other diseases moves out of research centers and into clinics, clinicians must devise practical strategies for providing the medical, genetic, and psychological services needed for the growing number of individuals who will seek such testing.