Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013362 (dysarthria)
 3,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary motor and sensory neuropathy Lom type (HMSNL), also called CMT 4D, a hereditary autosomal recessive neuropathy, caused by mutation in N-Myc downstream regulated gene 1 (NDRG1 gene), was first described in a Bulgarian Gypsy population near Lom and later has been found in Gypsy communities in Italy, Spain, Slovenia and Hungary. We present two siblings with HMSNL, female and male, aged 30 and 26, respectively in a Serbian non-consanguineous family of Gypsy ethnic origin. They had normal developmental milestones. Both had symptoms of lower limb muscle weakness and walking difficulties with frequent falls, which began at the age of seven. At the age of 12, they developed hearing problems and at the age of 15 hand muscle weakness. Neurological examination revealed sensorineural hearing loss, dysarthria, severe distal and mild proximal muscle wasting and weakness, areflexia and impairment of all sensory modalities of distal distribution. Electrophysiological study revealed denervation with severe and early axonal loss. Sensorineural hearing loss was confirmed on electrocochleography and brainstem evoked potentials. Molecular genetic testing confirmed homozygote C564t (R148X) mutation in NDRG1 gene.
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PMID:Hereditary motor and sensory neuropathy Lom type in a Serbian family. 1936 63

Autosomal recessive spastic ataxia of Charlevoix-Saguenay, more commonly known as ARSACS, is an early-onset cerebellar ataxia with spasticity, amyotrophy, nystagmus, dysarthria, and peripheral neuropathy. SACS is the only gene known to be associated with the ARSACS phenotype. To date, 55 mutations have been reported; of these, only five in Italian patients. We found two novel homozygous nonsense mutations in the giant exon of SACS gene in two unrelated patients with classical ARSACS phenotype. Characterization of the homozygous nature of the mutations through genotyping of the parents, quantitative DNA analysis and indirect STS studies permitted us to confirm in one of the cases that uniparental isodisomy of the paternal chromosome 13 carrying the mutated SACS gene played an etiologic role in the disease.
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PMID:Two novel homozygous SACS mutations in unrelated patients including the first reported case of paternal UPD as an etiologic cause of ARSACS. 2085 69

Mitofusin-2 gene (MFN2) mutations cause Charcot-Marie-Tooth type 2A (CMT2A), sometimes complicated by additional features such as optic atrophy, hearing loss, upper motor neuron signs and cerebral white-matter abnormalities. Here we report, for the first time, the occurrence of motor neuron disease, consistent with amyotrophic lateral sclerosis (ALS), in a 62-year-old woman affected by early-onset slowly progressive CMT2A, due to a novel MFN2 mutation. After age 60, rate of disease progression changed and she rapidly developed generalised muscle wasting, weakness, and fasciculations, together with dysarthria and dysphagia. Clinical features, EMG findings, and fast progression were consistent with ALS superimposed on CMT.
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PMID:Co-occurrence of amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease type 2A in a patient with a novel mutation in the mitofusin-2 gene. 2095 Oct 41

A 12-year-old female child with motor developmental delay presented with persistent vomiting, recurrent falls and unsteadiness in dark since 2 years of age. There was decline in scholastic performance, bulbar symptoms and aggravation of symptoms during intercurrent illness. Clinically, she had frontal and parietal lobar dysfunction, dysarthria, optic atrophy and LMN VII, IX, X, XII cranial nerve involvement. There was generalized hypotonia, distal muscle wasting, weakness, cerebellar signs and impaired vibration/position sense in distal extremities. Biochemical investigations revealed elevated serum/cerebrospinal fluid (CSF) lactate and CSF lactate pyruvate ratio. Neuroimaging demonstrated bilateral symmetrical T2 hyperintensities in basal ganglia, subcortical white matter, cerebellar hemispheres and posterior aspect of spinal cord. As certain atypical features like bilateral symmetrical T2 hyperintensities in subcortical white matter were also seen, metachromatic leukodystrophy was considered in differential diagnosis but ruled out by nerve biopsy. This case is reported for the presence of atypical neuroimaging features that are rarely found in Leigh's disease.
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PMID:An interesting case of Leigh-like syndrome. 2334 1

Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is an X-linked recessive disease affecting lower motor neurons. In the present case report, we describe morphological changes in a muscle biopsy obtained from a 62-year-old patient with gynecomastia and with the following neurological symptoms: dysphagia, dysarthria, wasting and fasciculation of the tongue, proximal weakness, fasciculations in the limb muscles, and an absence of all tendon reflexes. Neurogenic alternations were predominantly observed using light and electron microscopy. The angulated atrophic muscle fibers formed bundles. The numerous nuclei were pyknotic or pale, some of them were also ubiquitin positive; they were grouped inside so-called "nuclear sacks". At the ultrastructural level, atrophic muscle fibers revealed disruption and loss of sarcomeres, duplication of Z-line, and rod-like structures. The nuclei, often with irregular shapes, revealed varying degrees of chromatin condensation, from dispersed to highly condensed, like pyknotic nuclei. Occasionally electron-dense inclusions in the nuclei were found. Some myogenic features like hypertrophic muscle fibers and proliferation of connective tissue were also visible. The neurogenic and myogenic pathological changes suggested SBMA, which was confirmed with genetic analysis (trinucleotide CAG (glutamie)-repeat expansion in the androgen-receptor gene).
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PMID:Morphological changes of skeletal muscle in spinal and bulbar muscular atrophy (SBMA), Kennedy's disease: a case report. 2582 75

Spinal and bulbar muscular atrophy (SBMA) is regarded as a disorder with adult onset between third and fifth decade of life. However, there is increasing evidence that SBMA may start already before adulthood. The present study investigated the following: (1) Which clinical manifestations have been described so far in the literature as initial manifestations? (2) Which was the age at onset of these manifestations? and (3) Is age at onset dependent on the CAG-repeat length if non-motor manifestations are additionally considered? Data for this review were identified by searches of MEDLINE using appropriate search terms. Onset manifestations in SBMA can be classified as frequent, rare, motor, non-motor, or questionable. Frequent are muscle weakness, cramps, fasciculations/twitching, tremor, dysarthria, dysphagia, or gynecomastia. Rare are myalgia, easy fatigability, exercise intolerance, polyneuropathy, hyper-CKemia, under-masculinized genitalia, scrotal hypospadias, microphallus, laryngospasm, or oligospermia. Questionable manifestations include sensory disturbances, cognitive impairment, increased pituitary volume, diabetes, reduced tongue pressure, elevated creatine-kinase, or low androgens/high estrogens. Age at onset is highly variable ranging from 4-76 years. Non-motor manifestations develop usually before motor manifestations. Age at onset depends on what is considered as an onset manifestation. Considering non-motor onset manifestations, age at onset is independent of the CAG-repeat size. In conclusion, age at onset of SBMA depends on what is regarded as onset manifestation. If non-motor manifestations are additionally considered, age at onset is independent of the CAG-repeat length. Since life expectancy is hardly reduced in SBMA, re-investigation of patients from published studies with regard to their initial disease profiles is recommended.
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PMID:Onset Manifestations of Spinal and Bulbar Muscular Atrophy (Kennedy's Disease). 2648 45

Pathogenic mutations in the KIF5A-SPG10 gene, encoding the kinesin HC5A, can be associated with autosomal dominant hereditary spastic paraplegia (ADHSP). It accounts for about 10% of the complicated forms of ADHSP. Peripheral neuropathy, distal upper limb amyotrophy, and cognitive decline are the most common additional clinical features. We examined a 66-year-old Japanese woman manifesting gait disturbance and spastic dysarthria for 6years with positive family history. She showed evidence of upper and lower motor neuron involvement and fasciculations, thus mimicking amyotrophic lateral sclerosis (ALS). Genetic analysis revealed a heterozygous variant in KIF5A (c.484C>T, p.Arg162Trp) in 2 symptomatic members. The mutation was also identified in 4 asymptomatic members, including 2 elderly members aged over 78years. Electromyography in the 2 symptomatic members revealed evidence of lower motor neuron involvement and fasciculation potentials in distal muscles. This report describes the first known Asian family with a KIF5A mutation and broadens the clinical and electrophysiological spectrum associated with KIF5A-SPG10 mutations. Given that our cases showed pseudobulbar palsy, fasciculation and altered penetrance, KIF5A-SPG10 might well be considered as a differential diagnosis of sporadic ALS.
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PMID:Late-onset spastic paraplegia type 10 (SPG10) family presenting with bulbar symptoms and fasciculations mimicking amyotrophic lateral sclerosis. 2708 14

Troyer syndrome (MIM#275900) is an autosomal recessive form of complicated hereditary spastic paraplegia. It is characterized by progressive lower extremity spasticity and weakness, dysarthria, distal amyotrophy, developmental delay, short stature, and subtle skeletal abnormalities. It is caused by deleterious mutations in the SPG20 gene, encoding spartin, on Chromosome 13q13. Until now, six unrelated families with a genetically confirmed diagnosis have been reported. Here we report the clinical findings in three brothers of a consanguineous Moroccan family, aged 24, 17, and 7 yr old, with spastic paraplegia, short stature, motor and cognitive delay, and severe intellectual disability. Targeted exon capture and sequencing showed a homozygous nonsense mutation in the SPG20 gene, c.1369C>T (p.Arg457*), in the three affected boys.
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PMID:SPG20 mutation in three siblings with familial hereditary spastic paraplegia. 2867 90

Dystrophia myotonica (DM) type 1 is an autosomal dominant disorder, caused by a trinucleotide CTG repeat expansion in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene (chromosome 19q13.3). The disorder affects different organ systems, including the skeletal muscles, ocular lens, lungs, heart and gastrointestinal tract, as well as the endocrine and central nervous systems. The skeletal muscles are most frequently involved, whereby the disorder manifests as myotonia, muscle weakness and amyotrophy. However, DM type 1 presenting with dysarthria is rare. The current study presents a case of a 28-year-old male with DM type 1 presenting with dysarthria and associated multifocal hyperintense lesions in the white matter. Although electromyogram measurements identified myotonic discharges in all extremities, a muscle biopsy failed to detect the characteristic pathological features of DM type 1. A lack of a positive family history for DM type 1 also obscured diagnosis. However, genetic analysis detected a single allele in the P12 segment of the DMPK gene that included a CTG expansion of 13 repeats and a three-base gradient fragment in the P134 segment that included a CTG expansion of >600 repeats. According to the characteristics of dysarthria, multifocal hyperintense lesions in the white matter, electromyogram measurement results and genetic testing results, a diagnosis of DM type 1 was confirmed.
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PMID:Dystrophia myotonica type 1 presenting with dysarthria: A case report and literature review. 2881 May 63

Chorea-acanthocytosis (ChAc), a neurodegenerative disease, results from loss-of-function-mutations of the chorein-encoding gene VPS13A. Affected patients suffer from a progressive movement disorder including chorea, parkinsonism, dystonia, tongue protrusion, dysarthria, dysphagia, tongue and lip biting, gait impairment, progressive distal muscle wasting, weakness, epileptic seizures, cognitive impairment, and behavioral changes. Those pathologies may be paralleled by erythrocyte acanthocytosis. Chorein supports activation of phosphoinositide-3-kinase (PI3K)-p85-subunit with subsequent up-regulation of ras-related C3 botulinum toxin substrate 1 (Rac1) activity, p21 protein-activated kinase 1 (PAK1) phosphorylation, and activation of several tyrosine kinases. Chorein sensitive PI3K signaling further leads to stimulation of the serum and glucocorticoid inducible kinase SGK1, which in turn upregulates ORAI1, a Ca2+-channel accomplishing store operated Ca2+-entry (SOCE). The signaling participates in the regulation of cytoskeletal architecture on the one side and cell survival on the other. Compromised cytoskeletal architecture has been shown in chorein deficient erythrocytes, fibroblasts and endothelial cells. Impaired degranulation was observed in chorein deficient PC12 cells and in platelets from ChAc patients. Similarly, decreased ORAI1 expression and SOCE as well as compromised cell survival were seen in fibroblasts and neurons isolated from ChAc patients. ORAI1 expression, SOCE and cell survival can be restored by lithium treatment, an effect disrupted by pharmacological inhibition of SGK1 or ORAI1. Chorein, SGK1, ORAI1 and SOCE further confer survival of tumor cells. In conclusion, much has been learned about the function of chorein and the molecular pathophysiology of chorea-acanthocytosis. Most importantly, a treatment halting or delaying the clinical course of this devastating disease may become available. A controlled clinical study is warranted, in order to explore whether the in vitro observations indeed reflect the in vivo pathology of the disease.
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PMID:Neurons, Erythrocytes and Beyond -The Diverse Functions of Chorein. 2917 76


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