Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027066 (myoclonus)
 4,275 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The late-infantile-onset forms are the most genetically heterogeneous group among the autosomal recessively inherited neurodegenerative disorders, the neuronal ceroid lipofuscinoses (NCLs). The Turkish variant was initially considered to be a distinct genetic entity, with clinical presentation similar to that of other forms of late-infantile-onset NCL (LINCL), including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death. However, Turkish variant LINCL was recently found to be genetically heterogeneous, because mutations in two genes, CLN6 and CLN8, were identified to underlie the disease phenotype in a subset of patients. After a genomewide scan with single-nucleotide-polymorphism markers and homozygosity mapping in nine Turkish families and one Indian family, not linked to any of the known NCL loci, we mapped a novel variant LINCL locus to chromosome 4q28.1-q28.2 in five families. We identified six different mutations in the MFSD8 gene (previously denoted "MGC33302"), which encodes a novel polytopic 518-amino acid membrane protein that belongs to the major facilitator superfamily of transporter proteins. MFSD8 is expressed ubiquitously, with several alternatively spliced variants. Like the majority of the previously identified NCL proteins, MFSD8 localizes mainly to the lysosomal compartment. However, the function of MFSD8 remains to be elucidated. Analysis of the genome-scan data suggests the existence of at least three more genes in the remaining five families, further corroborating the great genetic heterogeneity of LINCLs.
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PMID:The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter. 1756 70

Progressive myoclonus epilepsies are severe, intractable, and neurodegenerative. They afflict patients of all ages, but more commonly adolescents, and comprise the main differential diagnosis of common juvenile myoclonic epilepsy. Genetic or minimally invasive pathologic diagnoses are available for many but not all teenage-onset progressive myoclonus epilepsies. We describe a multiplex family with autosomal recessive teenage-onset progressive myoclonus epilepsy that had remained undiagnosed despite extensive genetic and pathologic testing. We describe whole exome sequencing combined with homozygosity mapping to identify the disease gene directly and diagnose the family. The affected gene is CLN6, previously known to underlie variant late-infantile and adult-onset neuronal ceroid lipofuscinoses. Combined with other recent work, our results add CLN6 to the genetic mutations causing teenage-onset progressive myoclonus epilepsy, expand the group of teenage-onset progressive myoclonus epilepsy patients who can be diagnosed by genetic testing, and extend the clinical spectrum of CLN6 mutations to include teenage-onset progressive myoclonus epilepsy. This work also exemplifies the potentiality of next-generation sequencing in the genetic identification and diagnosis of patients with neurologic diseases of unknown cause.
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PMID:Mutation of the CLN6 gene in teenage-onset progressive myoclonus epilepsy. 2288 87

The neuronal ceroid-lipofuscinosis (NCL) are a heterogeneous group of neurodegenerative diseases characterized by the lysosomal accumulation of ceroid and lipofuscin with mitochondrial ATP synthase subunit C in various tissues. Clinical features include progressive mental and motor deterioration, myoclonus, seizure, visual failure and premature death. Ten CLN genes have been identified, among them CLN6 genes for which 55 disease-causing mutations have already been reported. The authors describe here a large consanguineous Moroccan family with three affected patients due to the p.I154del mutation that has been exclusively reported in Portuguese patients. This is the first published report of a genetic study in a Moroccan family with NCL. A relatively inexpensive CLN6 mutation screening should be considered first in Morocco as an initial diagnosis step when the disease course is consistent with late infantile neuronal ceroid-lipofuscinosis.
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PMID:CLN6 p.I154del mutation causing late infantile neuronal ceroid lipofuscinosis in a large consanguineous Moroccan family. 2318 Mar 98

The neuronal ceroid-lipofuscinoses (NCL) is a group of neurodegenerative disorders characterized by epilepsy, visual failure, progressive mental and motor deterioration, myoclonus, dementia and reduced life expectancy. Classically, NCL-affected individuals have been classified into six categories, which have been mainly defined regarding the clinical onset of symptoms. However, some patients cannot be easily included in a specific group because of significant variation in the age of onset and disease progression. Molecular genetics has emerged in recent years as a useful tool for enhancing NCL subtype classification. Fourteen NCL genetic forms (CLN1 to CLN14) have been described to date. The variant late-infantile form of the disease has been linked to CLN5, CLN6, CLN7 (MFSD8) and CLN8 mutations. Despite advances in the diagnosis of neurodegenerative disorders mutations in these genes may cause similar phenotypes, which rends difficult accurate candidate gene selection for direct sequencing. Three siblings who were affected by variant late-infantile NCL are reported in the present study. We used whole-exome sequencing, direct sequencing and in silico approaches to identify the molecular basis of the disease. We identified the novel c.1219T>C (p.Trp407Arg) and c.1361T>C (p.Met454Thr) MFSD8 pathogenic mutations. Our results highlighted next generation sequencing as a novel and powerful methodological approach for the rapid determination of the molecular diagnosis of NCL. They also provide information regarding the phenotypic and molecular spectrum of CLN7 disease.
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PMID:Exome sequencing is an efficient tool for variant late-infantile neuronal ceroid lipofuscinosis molecular diagnosis. 2533 61

Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo mutation, c.959G>A (p.Arg320His), in KCNC1 was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation. KCNC1 encodes KV3.1, a subunit of the KV3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6 and SERPINI1). Identification of mutations in PRNP, SACS and TBC1D24 expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of de novo mutations in this disease entity.
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PMID:A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. 2540 Dec 98

The clinical phenotypes of neuronal ceroid lipofuscinoses (NCLs) have been determined based on the age of onset and clinical symptoms. NCLs with onset between age 2 and 4years are known as late infantile neuronal ceroid lipofuscinoses (LINCLs). The clinical features of LINCLs include visual loss and progressive myoclonus epilepsy (PME) characterized by myoclonus, seizures, ataxia, and both mental and motor deterioration. There have been reports of several genes associated with LINCLs, with mutations in the CLN6 gene reported to cause variant forms of LINCLs (vLINCLs). Here, we report the first Japanese vLINCL caused by novel CLN6 mutations, found in a patient diagnosed by whole-exome sequencing. Visual acuity in our patient was preserved until the early teens. It remains to be elucidated if preserved visual function is related to the novel mutations of CLN6. Our case reveals the efficacy of whole-exome sequencing for examination of PMEs and highlights the existence of the CLN6 mutation in the Japanese population.
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PMID:First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations. 2716 43

Reports on the clinical presentation of adult-onset neuronal ceroid lipofuscinoses (NCL) are scarce compared to infantile- and childhood-onset forms. Here, we aimed to present detailed temporal evolution of clinical and electrophysiological features of two siblings with adult-onset NCL and homozygous mutation in the CLN6 gene. We retrospectively analysed medical records and electrophysiological data in order to delineate evolution of clinical and electrophysiological findings. Electrophysiological studies included routine EEG and video-EEG, as well as polymyographic analysis of myoclonus and brainstem reflex studies. Both patients had seizures and cerebellar signs. Despite the slow progression of ataxia, they developed no mental deterioration, but had severe obsessive compulsive disorder and depression. EEG revealed frequent generalized spikes, polyspikes, and waves, prominent on awakening and during photic stimulation without significant change throughout the clinical course. Abnormalities concerning the blink reflex, auditory startle response, and startle response to somatosensory inputs manifested within four years. The patients underwent transient and mild improvement with valproate, whereas ataxia and seizures were dramatically ameliorated following high-dose piracetam. Patients with adult-onset NCL may present with slowly progressive ataxia, persistent photosensitivity, and seizures without dementia or extrapyramidal findings. Brainstem abnormalities become more evident with time, in line with ataxia. Piracetam is effective for both seizures and ataxia.
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PMID:Long-term follow-up of two siblings with adult-onset neuronal ceroid lipofuscinosis, Kufs type A. 2858 97

A neutered male domestic medium-haired cat presented at a veterinary neurology clinic at 20 months of age due to progressive neurological signs that included visual impairment, focal myoclonus, and frequent severe generalized seizures that were refractory to treatment with phenobarbital. Magnetic resonance imaging revealed diffuse global brain atrophy. Due to the severity and frequency of its seizures, the cat was euthanized at 22 months of age. Microscopic examination of the cerebellum, cerebral cortex and brainstem revealed pronounced intracellular accumulations of autofluorescent storage material and inflammation in all 3 brain regions. Ultrastructural examination of the storage material indicated that it consisted almost completely of tightly-packed membrane-like material. The clinical signs and neuropathology strongly suggested that the cat suffered from a form of neuronal ceroid lipofuscinosis (NCL). Whole exome sequence analysis was performed on genomic DNA from the affected cat. Comparison of the sequence data to whole exome sequence data from 39 unaffected cats and whole genome sequence data from an additional 195 unaffected cats revealed a homozygous variant in CLN6 that was unique to the affected cat. This variant was predicted to cause a stop gain in the transcript due to a guanine to adenine transition (ENSFCAT00000025909:c.668G > A; XM_003987007.5:c.668G > A) and was the sole loss of function variant detected. CLN6 variants in other species, including humans, dogs, and sheep, are associated with the CLN6 form of NCL. Based on the affected cat's clinical signs, neuropathology and molecular genetic analysis, we conclude that the cat's disorder resulted from the loss of function of CLN6. This study is only the second to identify the molecular genetic basis of a feline NCL. Other cats exhibiting similar signs can now be screened for the CLN6 variant. This could lead to establishment of a feline model of CLN6 disease that could be used in therapeutic intervention studies.
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PMID:Neuronal Ceroid Lipofuscinosis in a Domestic Cat Associated with a DNA Sequence Variant That Creates a Premature Stop Codon in CLN6. 3251 81