Clinical evaluation of sibling pairs with gaucher disease discordant for parkinsonism.

BACKGROUND: Although the association between mutations in GBA1 and parkinsonism is well established, most GBA1 mutation carriers never develop parkinsonism, implicating the contribution of other genetic, epigenetic, and/or environmental modifiers. OBJECTIVES: To identify factors predisposing to or offering protection from parkinsonism among siblings with Gaucher's disease) discordant for Parkinson disease (PD). METHODS: This prospective, longitudinal study included nine sib pairs with Gaucher disease, but discordant for PD. Assessments included neurological, neuropsychological, olfactory, motor, nonmotor evaluations, and transcranial sonography. Validated mood and nonmotor questionnaires assessed fatigue, olfactory dysfunction, sleepiness, sleep disturbances, anxiety, and/or depression. RESULTS: There was no relationship between Gaucher treatments, genotype, or splenectomy and PD. Male sex predominance, younger age, and milder Gaucher disease symptoms were observed among the patients with PD. Substantia nigral echogenicity, olfactory dysfunction, serum triglycerides levels, and 9-hole peg scores, but not caffeine, alcohol, or tobacco use, environmental exposures, uric acid, or glucose levels, differed significantly between groups. CONCLUSIONS: Longitudinal evaluation of discordant sib pairs may help identify PD risk factors. © 2019 International Parkinson and Movement Disorder Society.

Five-parameter evaluation of dysphagia: A novel prognostic scale for assessing neurological decline in Gaucher disease type 2.

BACKGROUND: Gaucher disease type 2 (GD2) is defined by acute neurological decline, failure to thrive, and early demise. Currently, there is no clear standard for evaluating, staging, and counseling regarding neurological decline in GD2. Due to the high prevalence of progressive dysphagia secondary to acute neurological involvement, we aimed to identify key components of swallow function which could serve as markers of disease progression in GD2. METHODS: A post-hoc analysis of modified barium swallow studies was performed. Six parameters of swallowing were scored in a retrospective chart review of eleven infants with GD2. Mixed effects regression, principal component analysis (PCA), and a transition analysis were used to evaluate swallow function and model disease progression. RESULTS: All patients exhibited impaired swallow function. There was no association between any of the swallow parameters and age, indicating non-linear disease progression. PCA and transition analysis identified five parameters capturing multiple dimensions of swallowing which defined two distinct disease states. CONCLUSION: A five-parameter swallow evaluation was sufficient to identify distinct states of GD2 and model prospective outcomes. This multi-dimensional evaluation could be a useful efficacy parameter for future therapeutic trials in GD2 and other neurodegenerative disorders of infancy.

The natural history of type 2 Gaucher disease in the 21st century: A retrospective study.

OBJECTIVE: To gather natural history data to better understand the changing course of type 2 Gaucher disease (GD2) in order to guide future interventional protocols. METHODS: A structured interview was conducted with parents of living or deceased patients with GD2. Retrospective information obtained included disease presentation, progression, medical and surgical history, medications, family history, management, complications, and cause of death, as well as the impact of disease on families. RESULTS: Data from 23 patients were analyzed (20 deceased and 3 living), showing a mean age at death of 19.2 months, ranging from 3 to 55 months. Fourteen patients were treated with enzyme replacement therapy, 2 were treated with substrate reduction therapy, and 3 underwent bone marrow transplantation. Five patients received ambroxol and one was on N-acetylcysteine, both considered experimental treatments. Fifteen patients had gastrostomy tubes placed; 10 underwent tracheostomies. Neurologic disease manifestations included choking episodes, myoclonic jerks, autonomic dysfunction, apnea, seizures, and diminished blinking, all of which worsened as disease progressed. CONCLUSIONS: Current available therapies appear to prolong life but do not alter neurologic manifestations. Despite aggressive therapeutic interventions, GD2 remains a progressive disorder with a devastating prognosis that may benefit from new treatment approaches.

Variation in cognitive function over time in Gaucher disease type 3.

OBJECTIVE: To identify relevant efficacy parameters essential in designing clinical trials for brain-penetrant therapies for Gaucher disease, we evaluated cognitive function longitudinally in 34 patients with Gaucher disease type 3 seen at the NIH Clinical Center. METHODS: Individuals were tested with age-appropriate Wechsler Intelligence Scales administered between 1 and 18 times over 29 years. Variation in all IQ domains was not linear with time and was best characterized with the coefficient of variation (SD/mean) for each individual. Mixed-effects regressions were used to determine whether IQ was associated with clinical features. Models were controlled for variation in test version, participant identification, and test administrator. RESULTS: Mean verbal, performance, and full-scale IQs were 81.77, 75.98, and 82.02, respectively, with a consistent discrepancy between verbal and performance IQs. Mean (SD) verbal, performance, and full-scale coefficient of variations were 0.07 (0.04), 0.09 (0.05), and 0.06 (0.02), respectively. IQ varied about a mean, with no clear trajectory, indicating no clear patterns of improvement or decline over time. EEG lateralization and behavioral issues were consistently associated with IQ. CONCLUSIONS: The observed variation in IQ in Gaucher disease type 3 across the cohort and within single individuals over time may be characteristic of other neuronopathic diseases. Therefore, to reliably use IQ as an efficacy measure in any clinical trial of neurotherapeutics, a normal variation range must be established to assess the clinical relevance of any IQ change.

Recent advances in the diagnosis and management of Gaucher disease.

INTRODUCTION: Gaucher disease, the autosomal recessive deficiency of the lysosomal enzyme glucocerebrosidase, is associated with wide phenotypic diversity including non-neuronopathic, acute neuronopathic, and chronic neuronopathic forms. Overlap between types can render definitive diagnoses difficult. However, differentiating between the different phenotypes is essential due to the vast differences in clinical outcomes and response to therapy. Genotypic information is helpful, but cannot always be used to make clinical predictions. Current treatments for Gaucher disease, including enzyme replacement therapy and substrate reduction therapy, can reverse many of the non-neurological manifestations, but these therapies must be administered continually and are extremely costly. AREAS COVERED: We reviewed the literature concerning the varied clinical presentations of Gaucher disease throughout the lifetime, along with treatment options, management goals, and current and future research challenges. A PubMed literature search was performed for relevant publications between 1991 to January 2018. EXPERT COMMENTARY: Interest and research in the field of Gaucher disease is rapidly expanding. However, significant barriers remain in our ability to predict phenotype, assess disease progression using objective biomarkers, and determine optimal treatment strategy on an individual basis. As the field grows, we anticipate identification of genetic modifiers, new biomarkers, and small-molecule chaperone therapies, which may improve patient quality of life.

Chronic Pain and Telomere Length in Community-Dwelling Adults: Findings From the 1999 to 2002 National Health and Nutrition Examination Survey.

Chronic pain is a common condition associated with psychological distress, functional impairments, and age-associated comorbidity. Preliminary studies, on the basis of relatively small sample sizes, suggest that the combination of chronic pain and stress is associated with telomere shortening, a widely recognized marker of cellular aging. We sought to determine the cross-sectional association of chronic pain with telomere length in 7,816 community-dwelling adults ages 20 years and older who participated in the 1999 to 2002 National Health and Nutrition Examination Survey. Consistent with previous studies, leukocyte telomere length was assessed using the quantitative polymerase chain reaction method and compared with a DNA reference standard to compute a telomere to single copy gene ratio. Standardized, in-person interviews were used to identify chronic regional pain and chronic widespread pain in 784 (10.0%) and 266 (3.4%) participants, respectively. Older age, male sex, obesity, and less physical activity were associated with shorter telomere length (P <.05 for all comparisons); however, there was no association of chronic pain with telomere length. The age-adjusted means (standard error) of telomere length telomere to single copy gene ratios were 1.04 (.02), 1.03 (.02), and 1.02 (.02) in participants with no chronic pain, chronic regional pain, and chronic widespread pain, respectively (P = .69). In addition, chronic pain did not modify the effects of age, sex, race/ethnicity, education, or psychological distress on telomere length. In summary, chronic regional and widespread pain were not associated with telomere length in this nationally representative study; however, we could not determine associations of pain duration and severity with telomere length because of limitations in pain assessment data. PERSPECTIVE: The findings from the current study do not support the hypothesis that chronic pain accelerates cellular aging measured according to leukocyte telomere length. Additional population-based studies with more detailed assessments of pain and stress are needed to further investigate potential interactive effects on telomere length and other biomarkers of aging.