Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care.

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.

HostSeq: a Canadian whole genome sequencing and clinical data resource.

HostSeq was launched in April 2020 as a national initiative to integrate whole genome sequencing data from 10,000 Canadians infected with SARS-CoV-2 with clinical information related to their disease experience. The mandate of HostSeq is to support the Canadian and international research communities in their efforts to understand the risk factors for disease and associated health outcomes and support the development of interventions such as vaccines and therapeutics. HostSeq is a collaboration among 13 independent epidemiological studies of SARS-CoV-2 across five provinces in Canada. Aggregated data collected by HostSeq are made available to the public through two data portals: a phenotype portal showing summaries of major variables and their distributions, and a variant search portal enabling queries in a genomic region. Individual-level data is available to the global research community for health research through a Data Access Agreement and Data Access Compliance Office approval. Here we provide an overview of the collective project design along with summary level information for HostSeq. We highlight several statistical considerations for researchers using the HostSeq platform regarding data aggregation, sampling mechanism, covariate adjustment, and X chromosome analysis. In addition to serving as a rich data source, the diversity of study designs, sample sizes, and research objectives among the participating studies provides unique opportunities for the research community.

Increased intestinal permeability and Parkinson disease patients: chicken or egg?

UNLABELLED: Gastrointestinal involvement is a frequent and early event in the course of Parkinson Disease (PD), and may have a prominent role in the early pathophysiology of the disease. On the other hand, derangement in intestinal permeability could also result from the involvement of the gastrointestinal tract over the course of the disease. PATIENTS AND METHODS: The intestinal permeability of 12 non-selected PD patients was studied using a validated, non-invasive test; these results were compared to predefined age-adjusted reference values. RESULTS: 4/12 PD patients had abnormal gastrointestinal permeability; two had both an abnormal lactulose/mannitol ratio and an abnormal sucrose concentration, and two an isolated abnormal result. An increased lactulose/mannitol ratio is consistent with defect of either the enterocytes or the tight junctions between them. CONCLUSION: Intestinal permeability is increased in a significant proportion of unselected PD patients with minimal gastrointestinal symptoms. The significance of this finding needs to be further evaluated.

Gastrointestinal symptoms in Parkinson disease: clinical aspects and management.

Although it is now generally recognized that the clinical spectrum of Parkinson disease (PD) is broader than its defining motor aspects, its various non-motor symptoms are often not routinely assessed in the clinical setting. As most of these symptoms are amenable to treatment, improved recognition would lead to more comprehensive management of the disease, and ultimately improve the quality of life for PD patients. In an attempt to increase the general awareness of physicians caring for these patients, this article focuses on the clinical manifestations and treatment of the gastrointestinal symptoms most commonly experienced by PD patients, as well as on the gastrointestinal side effects of antiparkinsonian treatments.

Outcomes of patients with Parkinson disease and pathological gambling.

OBJECTIVE: To determine the outcomes of patients with Parkinson disease (PD) with pathological gambling (PG) from one Canadian Movement Disorders Clinic. METHODS: Assessments were performed in-person during routine clinic visits of all patients currently followed by one neurologist (OS). Pathological gambling was defined according to DSM-IV-TR criteria. Chart review was performed to obtain details on medication use, dosages, and patient demographics. Follow-up of patients with PG collected information on gambling behavior, PG management interventions, medications, treatment, and psychosocial outcomes. RESULTS: 146 patients were surveyed with an overall prevalence of PG of 4.1% (6/146). The rate of pathological gambling for those patients on dopamine agonist therapy (DA) was 8.1% (6/74). Only patients who were recreational gamblers prior to starting DA developed PG. All PG patients discontinued, decreased, or switched to another DA, and experienced a partial or full remission of PG. 3 (50%) patients described financial losses of $100,000 or more, and 75% (3/4) patients described significant marital stresses. At follow-up (August 2008), 4 of the 6 patients with PG continued to gamble in a controlled fashion despite medication changes. No significant difference in levodopa equivalent daily dose (LEDD) pre- and post-PG were observed; however, the relative amount of DA was decreased (p= 0.0593), while levodopa was relatively increased (p= 0.5277). Despite control of PG, patients still experience financial and marital strains. CONCLUSIONS: DA (in combination with levodopa) was associated with a significantly higher prevalence of PG in PD, particularly in patients who were recreational gamblers previously. Despite control of PG, patients continued to experience significant financial and marital stresses that should be regularly enquired upon in follow-up care and managed appropriately.

Wolfram Syndrome: A Case Report and Review of Clinical Manifestations, Genetics Pathophysiology, and Potential Therapies.

BACKGROUND: Classical Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations in WFS1, a gene implicated in endoplasmic reticulum (ER) and mitochondrial function. WS is characterized by insulin-requiring diabetes mellitus and optic atrophy. A constellation of other features contributes to the acronym DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). This review seeks to raise awareness of this rare form of diabetes so that individuals with WS are identified and provided with appropriate care. CASE: We describe a woman without risk factors for gestational or type 2 diabetes who presented with gestational diabetes (GDM) at the age of 39 years during her first and only pregnancy. Although she had optic atrophy since the age of 10 years, WS was not considered as her diagnosis until she presented with GDM. Biallelic mutations in WFS1 were identified, supporting a diagnosis of classical WS. CONCLUSIONS: The distinct natural history, complications, and differences in management reinforce the importance of distinguishing WS from other forms of diabetes. Recent advances in the genetics and pathophysiology of WS have led to promising new therapeutic considerations that may preserve ß-cell function and slow progressive neurological decline. Insight into the pathophysiology of WS may also inform strategies for ß-cell preservation for individuals with type 1 and 2 diabetes.

Surgery for Parkinson's disease improves disability but not impairment components of the UPDRS-II.

The Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living (ADL) items have been described as reflecting both disability (true ADL items) and impairment (rather than ADLs). As a result of combining these scores, UPDRS part II scores may not accurately reflect the impact of surgery on ADLs [Hariz G.M., Lindberg M., Hariz M.I., Bergenheim A.T. Does the ADL part of the unified Parkinson's disease rating scale measure ADL? An evaluation in patients after pallidotomy and thalamic deep brain stimulation. Mov Disord 2003;18:373-81.]. The goal of the present study was to assess the metric properties of the ADL section of the UPDRS in terms of its ability to measure surgical change. We tested the effects of unilateral pallidotomy (N=14) and bilateral subthalamic nucleus (STN) DBS (N=11) on both disability and impairment components of the UPDRS-II at uniform follow-up assessment periods of 6 months and 1 year, with a subset of pallidotomy patients (N=9) re-assessed at 2 years. Across the follow-up periods in both patient groups, items identified as best reflecting disability showed significant improvement from pre-surgical levels, whereas items representing impairment showed no overall change. Consistent with this, change in total ADL scores was tempered by the inclusion of the impairment items. Because the measurement of a patient's functional status is important in determining the effectiveness of an intervention, analysis of appropriate items from the UPDRS ADL section is imperative.

Referrals for movement disorder surgery: under-representation of females and reasons for refusal.

OBJECTIVE: Referral of movement disorder patients for deep brain stimulation surgery was examined to determine whether referred patients were representative of gender proportions in our population, and reasons why patients do not proceed to surgery. METHODS: Demographic information on referrals to the surgical program was retrospectively reviewed from our database and from a detailed chart review. RESULTS: Although almost equal numbers of movement disorder patients are male and female, of the 91 patients referred for surgery, only 31% were female. Sixty-one percent of referred patients did not undergo surgery. Of these, the majority were denied for medical reasons, including cognitive decline (21%), psychiatric concerns (5%) and neurological reasons (42%). CONCLUSIONS: Almost one-third of patients referred for movement disorder surgery were denied for medical reasons. This underscores the importance of evaluation of all potential patients by a multidisiplinary team to fully assess suitablity for stereotactic surgery. Interestingly, women were under-represented in those referred. In order that all appropriate patients have the opportunity to consider surgery, education of both physicians and patients, and different strategies to approach females regarding surgery may allow more patients to benefit from this treatment.

Presymptomatic neuropsychological impairment in Huntington's disease.

Ten asymptomatic individuals at risk for Huntington's disease (HD) were determined by the use of linked DNA probes to have a high (HD+ group) or low (HD- group) probability of having inherited the mutant gene. Neuropsychological examination, performed without knowledge of DNA results, revealed impairments in five of seven subjects in the HD+ group. Abnormalities were related to visuospatial abilities or to functions associated with the frontal lobes. All three subjects in the HD- group showed no neuropsychological impairment. Statistical analyses confirmed differences between the HD+ and HD- groups. Affected parents of subjects were at least 12 years older at symptom onset. These results demonstrate that clear neuropsychological impairment may be present in HD even when overt signs and symptoms are not expected for a number of years.

Cognitive manifestations of Huntington disease in relation to genetic structure and clinical onset.

OBJECTIVE: To examine the cognitive manifestations of Huntington disease (HD) with respect to age, clinical onset, progression, and genetic analyses. DESIGN: Case series of people with HD or at risk (AR) for HD. SETTING: Movement disorders and medical genetics clinics. PARTICIPANTS: Volunteer sample of 50 patients with HD and 127 AR adults. MEASURES: Neuropsychological evaluation was conducted with multiple measures of cognitive function (intelligence, memory, attention, executive, spatial, language), strength, manual speed/dexterity, somatosensory function, and mood. Quantitative molecular genetic analysis by means of polymerase chain reaction was conducted on 31 patients with HD and 86 AR subjects. RESULTS: In clinical HD, cognitive impairment correlated with number of years affected but not age at onset. The linear regression had a negative intercept, suggesting impaired cognitive function by the time of onset. In AR gene carriers, lower cognitive performance correlated with more trinucleotide repeats. In clinical HD, trinucleotide repeats interacted with disease chronicity such that more repeats were associated with worse performance over time; the overall effect of this was small compared with the effect of disease chronicity alone. Except for one AR subject, mood state was not associated with cognitive performance in either patients with HD or AR subjects. CONCLUSIONS: Cognitive decline appears to start before clinical onset of HD and is correlated with the number of trinucleotide repeats. Subsequent cognitive decline is primarily a function of number of years affected, although there is evidence that the presence of more trinucleotide repeats is associated with faster deterioration.

Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson's disease. Parkinson Study Group.

The manufacturer of deprenyl (selegeline; Eldepryl) (Somerset Pharmaceuticals, Tampa, FL) recently advised physicians to avoid prescribing the drug in combination with an antidepressant because of potentially serious CNS toxicity that may represent the serotonin syndrome. Manifestations of the serotonin syndrome vary but may include changes in mental status and motor and autonomic function. To better estimate the frequency of the serotonin syndrome in patients with Parkinson's disease (PD) treated with deprenyl and an antidepressant, we surveyed all investigators in the Parkinson Study Group. Based on estimates provided by the 47 investigators (75%) who responded, 4,568 patients were treated with the combination of deprenyl and an antidepressant medication. Eleven patients (0.24%) were reported to have experienced symptoms possibly consistent with the serotonin syndrome. Only two patients (0.04%) experienced symptoms considered to be serious. No deaths were reported. We also reviewed all published case reports and adverse experiences reported to the U.S. Food and Drug Administration and the manufacturer of Eldepryl. Available information indicates that serious adverse experiences resulting from the combined use of deprenyl and an antidepressant medication in patients with PD are quite rare and that the frequency of the true "serotonin syndrome" is even rarer.

Practice parameter: initiation of treatment for Parkinson's disease: an evidence-based review: report of the Quality Standards Subcommittee of the American Academy of Neurology.

In 1993, the last AAN Practice Parameter on medical treatment of Parkinson's disease (PD) concluded that levodopa was the most effective drug for management of this disorder. Since then, a number of new compounds including non-ergot dopamine agonists (DA) and sustained-release levodopa have been released and studied. Thus, the issue of treatment in de novo PD patients warrants reexamination. Specific questions include: 1) does selegiline offer neuroprotection; 2) what is the best agent with which to initiate symptomatic treatment in de novo PD; and 3) is there a benefit of sustained release levodopa over immediate-release levodopa? Using evidence-based principles, a literature review using MEDLINE, EMBASE, and the Cochrane Library was performed to identify all human trials in de novo PD between 1966 and 1999. Only articles that fulfilled class I or class II evidence were included. Based on this review, the authors conclude: 1) Selegiline has very mild symptomatic benefit (level A, class II evidence) with no evidence for neuroprotective benefit (level U, class II evidence). 2) For PD patients requiring initiation of symptomatic therapy, either levodopa or a DA can be used (level A, class I and class II evidence). Levodopa provides superior motor benefit but is associated with a higher risk of dyskinesia. 3) No evidence was found that initiating treatment with sustained-release levodopa provides an advantage over immediate-release levodopa (level B, class II evidence).

SCA-2 presenting as parkinsonism in an Alberta family: clinical, genetic, and PET findings.

The authors describe an Alberta family with levodopa-responsive parkinsonism without cerebellar abnormalities. Genetic testing showed expanded repeats for SCA-2; other mutations for parkinsonism were excluded. The expanded allele shows interruption of the CAG repeat with CAA. PET in two affected members showed reduced fluorodopa uptake in striatum and normal raclopride binding. Families with autosomal dominant, levodopa-responsive parkinsonism should be tested for the SCA-2 mutation.

Genome-wide scan for Parkinson's disease: the GenePD Study.

A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine beta-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.

Epidemiologic study of 203 sibling pairs with Parkinson's disease: the GenePD study.

OBJECTIVE: To examine patterns of familial aggregation and factors influencing onset age in a sample of siblings with PD. METHODS: Sibling pairs (n = 203) with PD were collected as part of the GenePD study. Standardized family history, medical history, and risk factor data were collected and analyzed. RESULTS: The mean age at onset was 61.4 years and did not differ according to sex, exposure to coffee, alcohol, or pesticides. Head trauma was associated with younger onset (p = 0.03) and multivitamin use with later onset (p = 0.007). Age at onset correlation between sibling pairs was significant (r = 0.56, p = 0.001) and was larger than the correlation in year of onset (r = 0.29). The mean difference in onset age between siblings was 8.7 years (range, 0 to 30 years). Female sex was associated with increased frequency of relatives with PD. The frequency of affected parents (7.0%) and siblings (5.1%) was increased when compared with frequency in spouses (2.0%). CONCLUSIONS: The greater similarity for age at onset than for year of onset in sibling pairs with PD, together with increased risk for biological relatives over spouses of cases, supports a genetic component for PD. Risk to siblings in this series is increased over that seen in random series of PD cases; however, patients in this sample have similar ages at onset and sex distribution as seen for PD generally. These analyses suggest that factors influencing penetrance are critical to the understanding of this disease.

A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease.

BACKGROUND: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. RESULTS: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. CONCLUSION: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Dialysis encephalopathy and osteomalacic bone disease: a case-controlled study.

Nine patients on long-term hemodialysis with dialysis encephalopathy were studied, with sex matched control subjects for eight of the patients. Each patient with dialysis encephalopathy and control subject were contemporaries in a similar dialysis environment. Rib and other fractures were found in excess in the patients with dialysis encephalopathy (p less than 0.005 and p less than 0.01). These patients had less radiographic hyperparathyroid bone disease, and no more osteopenia as measured by metacarpal thickness than did their control counterparts. Severe osteomalacia was documented by bone biopsy in four of te patients. In a retrospective review of clinical, biochemical and pharmacologic differences, the patients with dialysis encephalopathy were significantly older at the start of dialysis (45.6 years versus 38.6 years, p less than 0.02) and had higher mean concentrations of blood urea nitrogen (BUN) and lower serum hemoglobin in the first year of dialysis than the control subjects. Blood pressure weight, creatinine, calcium, phosphate, alkaline phosphatase and a number of transfusions did not differ significantly. There was no difference in prescribed vitamin D and elemental aluminum in phosphate binders. This study demonstrates that patients with dialysis encephalopathy had more rib fractures without more parathyroid or osteopenic bone disease than did the control subjects and suggests that the etiology of dialysis encephalopathy and osteomalacia is multifactorial.

Congenital autosomal dominant distal spinal muscular atrophy.

We present a father and son with congenital foot deformity. The father at age 41 years used crutches and the son at 7 years walked unaided. Both had atrophy and weakness of lower leg muscles and mild proximal and hand intrinsic weakness. Knee and ankle myotactic reflexes were absent and sensation was intact. Creatine kinase level was normal, nerve conduction studies wer normal and electromyography showed chronic neurogenic change. In both, nerve biopsies were normal and muscle biopsies showed type 1 predominance. The boy's serum hexosaminidase, spinal MRI and SMN gene were normal. This may be the first well documented example of congenital autosomal dominant distal spinal muscular atrophy affecting legs and arms.

Investigation of the potential role of genetic imprinting in Gilles de la Tourette syndrome.

Genetic imprinting refers to the phenomenon whereby the precise expression of a specific trait (or disease) may depend on the sex of the transmitting parent. The purpose of the present project was to investigate the possibility for the involvement of genetic imprinting in Tourette syndrome (TS), a disease of the central nervous system in which many cases show evidence of an autosomal dominant mode of inheritance. The justification for the study arose from the noted variable expression of the associated symptoms in TS. Through the method of chart review, information regarding sex of the transmitting parent, age of onset of motor tics, as well as associated symptoms, was gathered from patients with a clear family history of TS consistent with autosomal dominant mode of transmission. No evidence was found for genetic imprinting in TS. The potential criticisms and implications of this finding are discussed.