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Sleep Disturbance, Obstructive Sleep Apnoea and Abnormal Periodic Leg Movements: Very Common Problems in Fabry Disease.

ABSTRACT: OBJECTIVES:To assess the prevalence of sleep disorder(s) in males with Fabry disease and explore possible association with disease phenotype. BACKGROUND:Fabry disease, an X-linked lysosomal storage disease caused by deficiency in ?-galactosidase, results in intracellular accumulation of globotriaosylceramide. It causes organ dysfunction, most significantly affecting renal, cerebrovascular and cardiovascular systems. Respiratory involvement may include obstructive lung disease, reduced diffusing capacity and thickened soft and hard palates. Patients commonly develop small-fibre sensory peripheral neuropathy manifested by acroparaesthesia and pain crises. Combined with self-reported sleep disturbance and snoring, these features suggest an increased risk of sleep disorders. METHODS:In-laboratory polysomnography (PSG) studies and sleep inventory assessments, including Epworth Sleepiness Scale (ESS), were performed in a cohort of male Fabry patients. PSGs were reviewed by a sleep physician. Sleep-disordered breathing and periodic leg movements were targeted for analysis. Associations with renal, cardiovascular and cerebrovascular function were sought. RESULTS:Twenty males underwent overnight PSG. Patient baseline characteristics included age 43.9?±?10.7 years, BMI 24.3?±?3.8 kg/m2, neck circumference 39.7?±?3.3 cm and ESS 9.8?±?5.1 (7/20, abnormal ESS >10). Abnormal periodic leg movement index (PLMI) was present in 95% (mean frequency 42.4?±?28.5/min) and sleep-disordered breathing in 50% patients. Periodic leg movements were associated with pain and depression but not with increased cortical arousal. CONCLUSIONS:Sleep-disordered breathing and abnormal PLMI are highly prevalent in patients with FD. The presence of abnormal PLMI alone appears to have minimal impact on sleep disturbance, but is associated with depression and analgesic requirement.

SUBMITTER: Talbot A

PROVIDER: S-EPMC5272841 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Sleep Disturbance, Obstructive Sleep Apnoea and Abnormal Periodic Leg Movements: Very Common Problems in Fabry Disease.

Talbot Andrew A Hammerschlag Gary G Goldin Jeremy J Nicholls Kathy K

JIMD reports 20160324

<h4>Objectives</h4>To assess the prevalence of sleep disorder(s) in males with Fabry disease and explore possible association with disease phenotype.<h4>Background</h4>Fabry disease, an X-linked lysosomal storage disease caused by deficiency in α-galactosidase, results in intracellular accumulation of globotriaosylceramide. It causes organ dysfunction, most significantly affecting renal, cerebrovascular and cardiovascular systems. Respiratory involvement may include obstructive lung disease, red ...[more]

PMID: 27008194

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Project description:STUDY OBJECTIVES:To examine association between periodic leg movements (PLM) and 13 single nucleotide polymorphisms (SNPs) in 6 loci known to increase risk of restless legs syndrome (RLS). SETTING:Stanford Center for Sleep Sciences and Medicine and Clinical Research Unit of University of Wisconsin Institute for Clinical and Translational Research. PATIENTS:Adult participants (n = 1,090, mean age = 59.7 years) from the Wisconsin Sleep Cohort (2,394 observations, 2000-2012). DESIGN AND INTERVENTIONS:A previously validated automatic detector was used to measure PLMI. Thirteen SNPs within BTBD9, TOX3/BC034767, MEIS1 (2 unlinked loci), MAP2K5/SKOR1, and PTPRD were tested. Analyses were performed using a linear model and by PLM category using a 15 PLM/h cutoff. Statistical significance for loci was Bonferroni corrected for 6 loci (P < 8.3 × 10(-3)). RLS symptoms were categorized into four groups: likely, possible, no symptoms, and unknown based on a mailed survey response. MEASUREMENTS AND RESULTS:Prevalence of PLMI ? 15 was 33%. Subjects with PLMs were older, more likely to be male, and had more frequent RLS symptoms, a shorter total sleep time, and higher wake after sleep onset. Strong associations were found at all loci except one. Highest associations for PLMI > 15/h were obtained using a multivariate model including age, sex, sleep disturbances, and the best SNPs for each loci, yielding the following odds ratios (OR) and P values: BTBD9 rs3923809(A) OR = 1.65, P = 1.5×10(-8); TOX3/BC034767 rs3104788(T) OR = 1.35, P = 9.0 × 10(-5); MEIS1 rs12469063(G) OR = 1.38, P = 2.0 × 10(-4); MAP2K5/SKOR1 rs6494696(G) OR = 1.24, P = 1.3×10(-2); and PTPRD(A) rs1975197 OR = 1.31, P = 6.3×10(-3). Linear regression models also revealed significant PLM effects for BTBD9, TOX3/BC034767, and MEIS1. Co-varying for RLS symptoms only modestly reduced the genetic associations. CONCLUSIONS:Single nucleotide polymorphisms demonstrated to increase risk of RLS are strongly linked to increased PLM as well, although some loci may have more effects on one versus the other phenotype.

Project description:ObjectiveUsing narrative review techniques, this paper evaluates the evidence for separable underlying patho-mechanisms of periodic limb movements (PLMs) to separable PLM motor patterns and phenotypes, in order to elucidate potential new treatment modalities.BackgroundPeriodic limb movement disorder (PLMD) is estimated to occur in 5-8% of the paediatric population and 4-11% of the general adult population. Due to significant sleep fragmentation, PLMD can lead to functional impairment, including hyperactivity and delayed language development in children, and poor concentration and work performance in adults. Longitudinal data demonstrate that those with PLMD are at greater risk of depression and anxiety, and a 4-fold greater risk of developing dementia. PLMD has been extensively studied over the past two decades, and several key insights into the genetic, pathophysiological, and neural correlates have been proposed. Amongst these proposals is the concept of separable PLM phenotypes, proposed on the basis of nocturnal features such as the ratio of limb movements and distribution throughout the night. PLM phenotype and presentation, however, varies significantly depending on the scoring utilized and the nocturnal features examined, across age, and co-morbid clinical conditions. Furthermore, associations between these phenotypes with major neurologic and psychiatric disorders remain controversial.MethodsIn order to elucidate potential divergent biological pathways that may help clarify important new treatment modalities, this paper utilizes narrative review and evaluates the evidence linking PLM motor patterns and phenotypes with hypothesised underlying patho-mechanisms. Distinctive, underlying patho-mechanisms include: a pure motor mechanism originating in the spinal cord, iron deficiency, dopamine system dysfunction, thalamic glutamatergic hyperactivity, and a more cortical-subcortical interplay. In support of the latter hypothesis, PLM rhythmicity appears tightly linked to the microarchitecture of sleep, not dissimilarly to the apnoeic/hypopneic events seen in obstructive sleep apnea (OSA).ConclusionsThis review closes with a proposal for greater investigation into the identification of potential, divergent biological pathways. To do so would require prospective, multimodal imaging clinical studies which may delineate differential responses to treatment in restless legs syndrome (RLS) without PLMS and PLMS without RLS. This could pave the way toward important new treatment modalities.

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Sleep Disturbance, Obstructive Sleep Apnoea and Abnormal Periodic Leg Movements: Very Common Problems in Fabry Disease.

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Sleep Disturbance, Obstructive Sleep Apnoea and Abnormal Periodic Leg Movements: Very Common Problems in Fabry Disease.

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