Exclusion of Class III malocclusion candidate loci in Brazilian families

The role played by genetic components in the etiology of the Class III phenotype, a class of dental malocclusion, is not yet understood. Regions that may be related to the development of Class III malocclusion have been suggested previously. The aim of this study was to search for genetic linkage with 6 microsatellite markers (D1S234, D4S3038, D6S1689, D7S503, D10S1483, and D19S566), near previously proposed candidate regions for Class III. We performed a two-point parametric linkage analysis for 42 affected individuals from 10 Brazilian families with a positive Class III malocclusion segregation. Analysis of our data indicated that there was no evidence for linkage of any of the 6 microsatellite markers to a Class III locus at = zero, with data supporting exclusion for 5 of the 6 markers evaluated. The present work reinforces that Class III is likely to demonstrate locus heterogeneity, and there is a dependency of the genetic background of the population in linkage studies

Neuromuscular Ultrasound: Clinical Applications and Diagnostic Values

Item does not contain fulltextAdvances in high-resolution ultrasound have provided clinicians with unique opportunities to study diseases of the peripheral nervous system. Ultrasound complements the clinical and electrophysiology exam by showing the degree of abnormalities in myopathies, as well as spontaneous muscle activities in motor neuron diseases and other disorders. In experienced hands, ultrasound is more sensitive than MRI in detecting peripheral nerve pathologies. It can also guide needle placement for electromyography exam, therapeutic injections, and muscle biopsy. Ultrasound enhances the ability to detect carpal tunnel syndrome and other focal nerve entrapment, as well as pathological nerve enlargements in genetic and acquired neuropathies. Furthermore, ultrasound can potentially be used as a biomarker for muscular dystrophy and spinal muscular atrophy. The combination of electromyography and ultrasound can increase the diagnostic certainty of amyotrophic lateral sclerosis, aid in the localization of brachial plexus or peripheral nerve trauma and allow for surveillance of nerve tumor progression in neurofibromatosis. Potential limitations of ultrasound include an inability to image deeper structures, with lower sensitivities in detecting neuromuscular diseases in young children and those with mitochondrial myopathies, due to subtle changes or early phase of the disease. As well, its utility in detecting critical illness neuromyopathy remains unclear. This review will focus on the clinical applications of neuromuscular ultrasound. The diagnostic values of ultrasound for screening of myopathies, neuropathies, and motor neuron diseases will be presented

Early onset facioscapulohumeral dystrophy - a systematic review using individual patient data

Item does not contain fulltextInfantile or early onset is estimated to occur in around 10% of all facioscapulohumeral dystrophy (FSHD) patients. Although small series of early onset FSHD patients have been reported, comprehensive data on the clinical phenotype is missing. We performed a systematic literature search on the clinical features of early onset FSHD comprising a total of 43 articles with individual data on 227 patients. Additional data from four cohorts was provided by the authors. Mean age at reporting was 18.8 years, and 40% of patients were wheelchair-dependent at that age. Half of the patients had systemic features, including hearing loss (40%), retinal abnormalities (37%) and developmental delay (8%). We found an inverse correlation between repeat size and disease severity, similar to adult-onset FSHD. De novo FSHD1 mutations were more prevalent than in adult-onset FSHD. Compared to adult FSHD, our findings indicate that early onset FSHD is overall characterized by a more severe muscle phenotype and a higher prevalence of systemic features. However, similar as in adults, a significant clinical heterogeneity was observed. Based on this, we consider early onset FSHD to be on the severe end of the FSHD disease spectrum. We found natural history studies and treatment studies to be very scarce in early onset FSHD, therefore longitudinal studies are needed to improve prognostication, clinical management and trial-readiness

Functional consequences and structural interpretation of mutations of human choline acetyltransferase

PubMed ID: 21786365Choline acetyltransferase (ChAT; EC 2.3.1.6) catalyzes synthesis of acetylcholine from acetyl-CoA (AcCoA) and choline in cholinergic neurons. Mutations in CHAT cause potentially lethal congenital myasthenic syndromes associated with episodic apnea (ChAT-CMS). Here, we analyze the functional consequences of 12 missense and one nonsense mutations of CHAT in 11 patients. Nine of the mutations are novel. We examine expression of the recombinant missense mutants in Bosc 23 cells, determine their kinetic properties and thermal stability, and interpret the functional effects of 11 mutations in the context of the atomic structural model of human ChAT. Five mutations (p.Trp421Ser, p.Ser498Pro, p.Thr553Asn, p.Ala557Thr, and p.Ser572Trp) reduce enzyme expression to less than 50% of wild-type. Mutations with severe kinetic effects are located in the active-site tunnel (p.Met202Arg, p.Thr553Asn, and p.Ala557Thr) or adjacent to the substrate binding site (p.Ser572Trp), or exert their effect allosterically (p.Trp421Ser and p.Ile689Ser). Two mutations with milder kinetic effects (p.Val136Met and p.Ala235Thr) are also predicted to act allosterically. One mutation (p.Thr608Asn) below the nucleotide binding site of CoA enhances dissociation of AcCoA from the enzyme-substrate complex. Two mutations introducing a proline residue into an ?-helix (p.Ser498Pro and p.Ser704Pro) impair the thermal stability of ChAT. ©2011 Wiley Periodicals, Inc

Facioscapulohumeral dystrophy in children: design of a prospective, observational study on natural history, predictors and clinical impact (iFocus FSHD)

Functional Genomics of Muscle, Nerve and Brain Disorder

Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity

Cell adhesion molecules are membrane-bound proteins predominantly expressed in the central nervous system along principal axonal pathways with key roles in nervous system development, neural cell differentiation and migration, axonal growth and guidance, myelination, and synapse formation. Here, we describe ten affected individuals with bi-allelic variants in the neuronal cell adhesion molecule NRCAM that lead to a neurodevelopmental syndrome of varying severity; the individuals are from eight families. This syndrome is characterized by developmental delay/intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity. Computational analyses of NRCAM variants, many of which cluster in the third fibronectin type III (Fn-III) domain, strongly suggest a deleterious effect on NRCAM structure and function, including possible disruption of its interactions with other proteins. These findings are corroborated by previous in vitro studies of murine Nrcam-deficient cells, revealing abnormal neurite outgrowth, synaptogenesis, and formation of nodes of Ranvier on myelinated axons. Our studies on zebrafish nrcamaD mutants lacking the third Fn-III domain revealed that mutant larvae displayed significantly altered swimming behavior compared to wild-type larvae (p < 0.03). Moreover, nrcamaD mutants displayed a trend toward increased amounts of a-tubulin fibers in the dorsal telencephalon, demonstrating an alteration in white matter tracts and projections. Taken together, our study provides evidence that NRCAM disruption causes a variable form of a neurodevelopmental disorder and broadens the knowledge on the growing role of the cell adhesion molecule family in the nervous system.Alina Kurolap ... Jozef Gecz ... Clare L. van Eyk ... et. a