RESUMEN
Phelan-McDermid syndrome (PMS) is a hereditary disorder associated with microdeletions of chromosome 22q13 or point mutations in SHANK3, characterized by mental and speech delays, intellectual disability, epilepsy and autism spectrum disorder. We describe a case PMS associated with a heterozygous mutation c.2486delC (p.Pro829fs) in SHANK3. The diagnostic pathway of a female patient with PMS took more than 7 years; the reason for treatment was the onset of epileptic seizures and impaired speech development. The existence of different types of rearrangements and genomic variations can explain the high clinical variability observed in individuals with PMS. Only molecular diagnosis can accurately diagnose individuals with PMS for follow-up and medical genetic counselling of families.
Asunto(s)
Trastorno del Espectro Autista , Trastornos de los Cromosomas , Trastornos del Desarrollo del Lenguaje , Femenino , Humanos , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/genética , Heterocigoto , Mutación , Proteínas del Tejido Nervioso/genéticaRESUMEN
Spinocerebellar ataxia 17 (SCA17) is one of the most heterogeneous forms of autosomal dominant cerebellar ataxia with a wide clinical spectrum, which can imitate other motor disorders. The article presents an observation of a 51-year-old woman with slowly progressive coordination disorders and changes in handwriting manifested at the age of 39 years. Neurologic examination reveals severe cerebellar ataxia, choreiform hyperkinesis, polyneuropathy, cognitive and mental disorders; magnetic resonance imaging (MRI) of the brain shows moderate diffuse atrophy of the cerebral cortex, severe atrophy of the cerebellum hemispheres. Molecular analysis of the TBP demonstrates an allele with 42 CAG/CAG-repeats suggesting that an allele of this size could be an allele associated with the full clinical spectrum of SCA17.
Asunto(s)
Ataxias Espinocerebelosas , Adulto , Encéfalo , Femenino , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Fenotipo , Ataxias Espinocerebelosas/diagnóstico por imagen , Ataxias Espinocerebelosas/genéticaRESUMEN
AIM: To investigate molecular, clinical and genealogical characteristics of SPG4 in a first representative Russian group, to estimate SPG4 proportion among all DNA-diagnosed spastic paraplegias. MATERIAL AND METHODS: Fifty unrelated Russian families with SPG4 detected in the course of clinical and molecular studies of spastic paraplegias were studied. Clinical, genealogical and several molecular methods were used, i.e. Sanger sequencing of SPAST, massive parallel sequencing MPS (panel 'hereditary paraplegias') and multiplex ligation-dependent amplification MLPA. RESULTS: SPG4 proportion was 56% among all DNA verified SPG cases (90 families/14 forms) and 68% in subgroup of dominant SPG. In 50 families, 43 different SPAST mutations were detected, of which 21 were novel; percentage of large rearrangements was 30% (13 mutations in 15 families). Four mutations were detected in two families each, nonsense mutation c.1291C>T (p.Arg431*) in 4 unrelated families. Proportion of familial cases was 68%, pedigrees with 'missing' disease in elderly carriers pointed to incomplete penetrance. Age of onset varied from one year to 58 years, middle-age onset was common but the proportion of early-onset cases, particularly in male index cases, was also high. Onset age showed marked intrafamilial differences (more than 10 years in 14 pedigrees, up to 50 year in one) and between families with identical mutations. Insidious onset, slow development with most patients ambulant and 'uncomplicated' phenotype were typical. Cases with additional signs were: a family with ataxia in both patients, two families with epilepsy in one of SPG4 patients; three families with mild mental deficiency in one of SPG4 patients. A case described separately is a 29-year-old male patient with indeterminate myalgia and no SPG signs in whom SPAST previously reported mutation p.Ala430Thr de novo was an unexpected MPS finding. CONCLUSION: SPG4 substantially predomimates in SPG structure in Russian families as practically everywhere else. Half of 43 detected SPAST mutations are novel, the proportion of large rearrangements is 30% higher than in most of studies. Clinical inter- and intrafamilial variability concerns mostly age of onset. SPG4 is not exclusively adult-onset as was thought earlier.
Asunto(s)
Mutación , Paraplejía Espástica Hereditaria , Espastina , Adenosina Trifosfatasas , Adulto , Edad de Inicio , Anciano , Humanos , Masculino , Persona de Mediana Edad , Federación de Rusia , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética , Espastina/genéticaRESUMEN
Thomsen's and Becker's diseases are the most prevalent nondystrophic myotonias. Their frequency varies, according to different sources, from 1 : 100 000 to 1 : 10 000. Thomsen's myotonia is autosomal dominant, and Becker's myotonia is autosomal recessive. Both diseases result from mutations of the CLCN1 gene encoding chloride ion channels of skeletal muscles. Molecular genetic analysis of the CLCN1 gene has been performed in patients with diagnoses of nondystrophic Thomsen's and Becker's myotonias living in the Russian Federation. A sample of 79 unrelated probands with nondystrophic Thomsen's and Becker's myotonias and 44 their relatives has been formed in the Laboratory of DNA Diagnosis of the Medical Genetic Research Center of the Russian Academy of Medical Sciences. Forty CLCN1 gene mutations have been found in a total of 118 chromosomes of 66 probands, including 21 familial and 45 sporadic cases. About half the mutations detected (45%) have been found for the first time; they are not described in the SNP database (ncbi.nlm.nih.gov). The following mutations (substitutions) have been detected in more than one chromosome, accounting for a total of 59.3% of chromosomes with mutations: Glyl90Ser (5.9%), c.1437-1450del14 (9.3%), Ala493Glu (5.1%), Thr550Met (3.4%), Tyr686Stop (5.1%), and Arg894Stop (30.5%).
Asunto(s)
Canales de Cloruro/genética , Mutación , Miotonía Congénita/genética , Sustitución de Aminoácidos , Femenino , Humanos , Masculino , Miotonía/genética , Linaje , Federación de RusiaRESUMEN
Clinical and genetic analysis of juvenile parkinsonism was performed in 26 sibs from 20 families. Heterogeneity of the disorder was observed. Mutations in the parkin gene (locus PARK2, chromosome 6q25.2-27), with the prevalence of deletions over point mutations, have been identified in 41%. The comparative clinical analyses of patients examined confirmed the phenotypical polymorphism of "parkinopathy". We also showed the absence of asymmetric manifestation--an important and underestimated so far sign of the disease. The results of the study may be considered as a valuable clue to the clinical diagnosis of parkin-related juvenile parkinsonism in Russian population and implemented for mutation screening and medico-genetic counseling of affected families.