Cerebrovascular Phenotype in Fabry Disease Patients Assessed by Ultrasound.

OBJECTIVES: Fabry disease (FD) is a rare X-linked lysosomal storage disorder with variable phenotypes, including neurological symptoms. These can be influenced by vascular impairment. Extracranial and transcranial vascular sonography is an effective and noninvasive method for measuring arterial structures and blood flow. The study aims to investigate cerebrovascular phenotype characteristics in FD patients compared to controls using neurosonology. METHODS: This is a single-center, cross-sectional study of 130 subjects-65 patients (38 females), with genetically confirmed FD, and 65 sex- and age-matched controls. Using ultrasonography, we measured structural and hemodynamic parameters, including distal common carotid artery intima-media thickness, inner vertebral artery diameter, resting blood flow velocity, pulsatility index, and cerebral vasoreactivity (CVR) in the middle cerebral artery. To assess differences between FD and controls and to identify factors influencing investigated outcomes, unadjusted and adjusted regression analyses were performed. RESULTS: In comparison to sex- and age-matched controls, FD patients displayed significantly increased carotid artery intima-media thickness (observed FD 0.69 ± 0.13 mm versus controls 0.63 ± 0.12 mm; Padj = .0014), vertebral artery diameter (observed FD 3.59 ± 0.35 mm versus controls 3.38 ± 0.33 mm; Padj = .0002), middle cerebral artery pulsatility index (observed FD 0.98 ± 0.19 versus controls 0.87 ± 0.11; Padj < .0001), and significantly decreased CVR (observed FD 1.21 ± 0.49 versus controls 1.35 ± 0.38; Padj = .0409), when adjusted by age, BMI, and sex. Additionally, FD patients had significantly more variable CVR (0.48 ± 0.25 versus 0.21 ± 0.14; Padj < .0001). CONCLUSIONS: Our results suggest the presence of multiple vascular abnormalities and changes in hemodynamic parameters of cerebral arteries in patients with FD.

Novel Associations of BST1 and LAMP3 With REM Sleep Behavior Disorder.

OBJECTIVE: To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated REM sleep behavior disorder (iRBD). METHODS: We fully sequenced 25 genes previously identified in GWASs of PD in a total of 1,039 patients with iRBD and 1,852 controls. The role of rare heterozygous variants in these genes was examined with burden tests. The contribution of biallelic variants was further tested. To examine the potential effect of rare nonsynonymous BST1 variants on the protein structure, we performed in silico structural analysis. Finally, we examined the association of common variants using logistic regression adjusted for age and sex. RESULTS: We found an association between rare heterozygous nonsynonymous variants in BST1 and iRBD (p = 0.0003 at coverage >50× and 0.0004 at >30×), driven mainly by 3 nonsynonymous variants (p.V85M, p.I101V, and p.V272M) found in 22 (1.2%) controls vs 2 (0.2%) patients. All 3 variants seem to be loss-of-function variants with a potential effect on the protein structure and stability. Rare noncoding heterozygous variants in LAMP3 were also associated with iRBD (p = 0.0006 at >30×). We found no association between rare heterozygous variants in the rest of genes and iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD. CONCLUSION: Our results suggest that rare coding variants in BST1 and rare noncoding variants in LAMP3 are associated with iRBD. Additional studies are required to replicate these results and to examine whether loss of function of BST1 could be a therapeutic target.

Validation of the REM sleep behavior disorder screening questionnaire in the Czech population.

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) affects 1-2% of people over 60 years of age and presents a high risk of developing a neurodegenerative disorder from the group of synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Therefore, screening tools are needed. In 2007, the rapid eye movement sleep behavior disorder screening questionnaire (RBD-SQ) was developed and has been translated into several languages. The aim of study was to assess the validity and reliability of the Czech version of the RBD-SQ in a mixed population of sleep clinic patients, supplemented by healthy volunteers and RBD patients. METHODS: Participants included 81 iRBD patients, 205 patients with other sleep disorders (obstructive sleep apnea, insomnia, restless legs syndrome and periodic limb movement disorder, other parasomnias, or central hypersomnias including narcolepsy) and 20 healthy volunteers. RESULTS: The mean RBD-SQ score in the iRBD patients was 9.4 ± 2.8 points, and in the non-RBD group it was 4.5 ± 3.0 (P < 0.0001). Receiver -operator analysis yielded an area under the curve of 0.864, suggesting good diagnostic performance of the scale. When using a cut-off value for positivity of 5 points, sensitivity was 0.89 and specificity was 0.62. CONCLUSIONS: The Czech version of the RBD-SQ is a sensitive tool for screening for iRBD patients and helps to identify subjects for complete clinical workup.

Prepulse inhibition of the blink reflex is abnormal in functional movement disorders.

BACKGROUND: Patients with functional movement disorders also typically have functional somatic symptoms, including pain, fatigue, and sensory disturbance. A potentially unifying mechanism for such symptoms is a failure in processing of sensory inputs. Prepulse inhibition is a neurophysiological method that allows for the study of preconscious somatosensory processing. OBJECTIVE: The objective of this study was to assess prepulse inhibition in patients with functional movement disorders and healthy control subjects. METHODS: We analyzed the effect of a weak electrical stimulus to the index finger (prepulse) on the magnitude of the R2 response of the blink reflex induced by electrical stimuli delivered to the supraorbital nerve in 22 patients with clinically established functional movement disorders and 22 matched controls. Pain, depression, anxiety, and obsessive-compulsive symptoms were assessed using self-rated questionnaires. In addition, in patients we assessed motor symptom severity. RESULTS: Prepulses suppressed the R2 response of the blink reflex in both groups, by 36.4% (standard deviation: 25.6) in patients and by 67.3% (standard deviation: 16.4) in controls. This difference was significant (P < 0.001). There was no significant correlation between motor and nonmotor symptom measures and prepulse inhibition size. CONCLUSIONS: Impaired prepulse inhibition of the blink reflex suggests an abnormal preconscious processing of somatosensory inputs, which can be interpreted within predictive coding accounts of both functional movement disorders and functional somatic syndromes. Our results, along with previous findings of a reduced prepulse inhibition in fibromyalgia syndrome, support a possible unified pathophysiology across functional neurological and somatic syndromes with noteworthy implications for diagnostic classification and development of novel biomarkers and treatments. © 2019 International Parkinson and Movement Disorder Society.

Molecular diversity of combined and complex dystonia: insights from diagnostic exome sequencing.

Combined and complex dystonias are heterogeneous movement disorders combining dystonia with other motor and/or systemic signs. Although we are beginning to understand the diverse molecular causes of these disease entities, clinical pattern recognition and conventional genetic workup achieve an etiological diagnosis only in a minority of cases. Our goal was to provide a window into the variable genetic origins and distinct clinical patterns of combined/complex dystonia more broadly. Between August 2016 and January 2017, we applied whole-exome sequencing to a cohort of nine patients with varied combined and/or complex dystonic presentations, being on a diagnostic odyssey. Bioinformatics analyses, co-segregation studies, and sequence-interpretation algorithms were employed to detect causative mutations. Comprehensive clinical review was undertaken to define the phenotypic spectra and optimal management strategies. On average, we observed a delay in diagnosis of 23 years before whole-exome analysis enabled determination of each patient's genetic defect. Whereas mutations in ACTB, ATP1A3, ADCY5, and SGCE were associated with particular phenotypic clues, trait manifestations arising from mutations in PINK1, MRE11A, KMT2B, ATM, and SLC6A1 were different from those previously reported in association with these genes. Apart from improving counseling for our entire cohort, genetic findings had actionable consequences on preventative measures and therapeutic interventions for five patients. Our investigation confirms unique genetic diagnoses, highlights key clinical features and phenotypic expansions, and suggests whole-exome sequencing as a first-tier diagnostic for combined/complex dystonia. These results might stimulate independent teams to extend the scope of agnostic genetic screening to this particular phenotypic group that remains poorly characterized through existing studies.

Smoking Prevalence and Its Clinical Correlations in Patients with Narcolepsy-cataplexy.

Narcolepsy-cataplexy (NC) is a chronic neurological disease with suggested autoimmune etiopathogenesis. Nicotine stimulates central nervous system and smoking increases the risk of autoimmune diseases. Assessment of smoking habits and its correlation to clinical parameters among 87 adult NC patients (38 male, 49 female) included night polysomnography and multiple sleep latency test. In our sample, 43.7% NC patients were regular smokers, and 19.5% former smokers compared to 22.2%, and 12.6%, respectively, in the general population. Patients started to smoke in the mean age of 20.0 (SD ±6.0) years. 72.2% of NC smokers started to smoke before the onset of NC and the mean of the delay between smoking onset and NC onset was 9.1 (±5.8) years. We found a direct correlation between smoking duration and the number of awakenings, duration of N1 sleep, REM sleep latency, and apnoea/hypopnoea index (AHI), and, on the contrary, indirect correlation between smoking duration and N3 sleep duration, showing that smoking duration consistently correlates with sleep macrostructure. Smoking is highly prevalent in NC and has relationship with clinical features of NC.

Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients.

BACKGROUND: Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. METHODS: Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient. RESULTS: In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations. CONCLUSIONS: Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trials.

Hypothalamo-pituitary-adrenal axis, glucose metabolism and TNF-α in narcolepsy.

Narcolepsy with cataplexy is caused by a deficiency in the production of hypocretin/orexin, which regulates sleep and wakefulness, and also influences appetite, neuroendocrine functions and metabolism. In this case-control study, 11 patients with narcolepsy with cataplexy and 11 healthy adults underwent an oral glucose tolerance test, and dexamethasone suppression/corticotropin-releasing hormone stimulation test. The average age of patients and controls was 35.1 ± 13.2 and 41.0 ± 2.9 years, respectively, body mass index was 28.1 ± 6.6 and 25.5 ± 4.7 kg m(-2) . We did not find evidence of a significantly increased prevalence of disturbed glucose tolerance in patients with narcolepsy. After hypothalamo-pituitary-adrenal axis suppression, the number of non-suppressors did not differ between the groups, indicating normal negative feedback sensitivity. The level of cortisol after dexamethasone suppression was significantly lower in patients with narcolepsy, suggesting a slight basal downregulation and/or a slightly increased negative feedback sensitivity of the major endocrine stress system in narcolepsy. Following corticotropin-releasing hormone stimulation, there were no significant differences in levels of adrenocorticotropic hormone or cortisol, and in adrenocortical responsivity to adrenocorticotropic hormone. Finally, patients with narcolepsy displayed significantly higher plasma levels of tumour necrosis factor alpha, soluble tumour necrosis factor receptor p55, soluble tumour necrosis factor receptor p75 and interleukin 6 after adjustment for body mass index. The present study confirms that narcolepsy by itself is not associated with disturbances of glucose metabolism, but goes along with a subtle dysregulation of inflammatory cytokine production. We also found that dynamic hypothalamo-pituitary-adrenal system response is not altered, whereas negative feedback to dexamethasone might be slightly enhanced.

ImmunoChip study implicates antigen presentation to T cells in narcolepsy.

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

High-dose immunoablation with autologous haematopoietic stem cell transplantation in aggressive multiple sclerosis: a single centre 10-year experience.

There are multiple sclerosis patients who suffer from an aggressive course of the disease with severe relapses and rapid accumulation of disability despite adequate treatment. In such cases high-dose immunoablation with autologous haematopoietic stem cell transplantation (ASCT) may be considered. Our objective was to report our experience with 26 multiple sclerosis patients treated with ASCT within the years 1998-2008. Twenty-six patients (Expanded Disability Status Scale 2.5-7.5 (median 6.0), multiple sclerosis duration 2-19 years (median 7)) with aggressive multiple sclerosis underwent autologous haematopoietic stem cell transplantation. Stem cells were mobilized by high-dose cyclophosphamide and granulocyte colony-stimulating factor, BEAM (carmustine, etoposide, cytarabine, melphalan) was used for immunoablation. Patients were evaluated at baseline and every six months post ASCT for adverse events and clinical outcome. Follow-up period was 11-132 months (median 66). Progression-free survival was calculated using the Kaplan- Meier method. At 3 and 6 years of follow-up 70.8% and 29.2% of patients respectively were free of progression. Patients with relapsing multiple sclerosis course, disease duration <5 years and age <35 years had a more favourable outcome. There was no death within 100 days after ASCT. We conclude that ASCT represents a viable and effective treatment option for aggressive multiple sclerosis.

Does age at the onset of narcolepsy influence the course and severity of the disease?

OBJECTIVE: The aim of the study is to compare the course and severity of narcolepsy in relation to different ages at the disease onset. METHODS: Clinical interviews with the completion of the Stanford questionnaire, Epworth Sleepiness Scale (ESS) and Multiple Sleep Latency Test (MSLT) were evaluated in 105 patients (44 males, 61 females, mean age 45.4+/-19.2, BMI 29.2+/-5.8) suffering from narcolepsy. RESULTS: The severity of the disease was judged by clinical complaints, ESS value and MSLT results. No relations with the age at onset and clinical tetrad were found, however, smoking may be associated with an increased risk of hypnagogic hallucinations. There was no correlation between the number of sleep and cataplectic attacks and the age at onset, nor did subjective ESS show any significant dependence. However, earlier onset of the disease correlated with shorter MSLT mean latency. A correlation was found between the BMI and narcolepsy sleepiness rating in the elderly and between degree of education attained and subjective complaints. CONCLUSIONS: The clinical severity of narcolepsy does not depend on the age at onset.

Sleep apnea in carotid stenosis.

OBJECTIVES: Sleep apnea is associated with advanced atherosclerosis. This study was focused on sleep breathing in patients with hemodynamically significant carotid stenosis, currently free from clinical symptoms. DESIGN AND SETTINGS: 17 patients with carotid artery stenosis of 70% and more in the absence of actual neurological symptoms indicated for non-acute endarterectomy, and 17 age- and sex-matched controls were examined using sleep polygraphy. 12 patients had a follow-up sleep polygraphy a month after the surgery. RESULTS: The criteria of obstructive sleep apnea (OSA) were met by 4 patients prior to operation, by 2 patients after the operation, and by 2 control subjects. The pre-surgery apnea/hypopnea index (AHI) was 14 (+/-SD=17.0), post-surgery 8.3 (+/-9.0) and in the controls 6.7(+/-6.7). The pre-surgery oxygen desaturation index was 20.1 (+/-17.7), post-surgery 15.0 (+/-12.0) and in the controls 11.6 (+/-6.1). A comparison between the pre-surgery results seen in the patients and in controls after adjustment for BMI revealed no significant difference. The only significant difference between the pre-surgery and post-surgery values was found in the AHI (P=0.045). CONCLUSION: According to this study there exists an association between carotid stenosis and OSA, however this association is explainable by a higher BMI. The study also found a tendency toward OSA alleviation in response to endarterectomy.