RESUMO
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of familial vascular dementia, is caused by mutations of the NOTCH3 gene. Approximately two hundred pathogenic mutations have been reported within five exons (exons 3, 4, 6, 11 and 19) which accounted for 78% of known mutations in worldwide series. We reported twenty-one NOTCH3 pathogenic mutations (including five novel ones) identified in 53 index Italian patients. Exons 4 (28%), 7 (21%) and 19 (24%) were the most frequently involved. To dissect genetic heterogeneity, we analyzed five haplotyped tagging single nucleotide polymorphisms (rs1044009, rs4809030, rs10426042, rs10423702 and rs3815188) in 95 patients, 39 unaffected pedigree members and 50 healthy controls. SNPs were analyzed using the Illumina VeraCode Universal Capture Beads technology by Allele Specific Primer Extension (ASPE). We identified ten different haplotypes named H1-H10; H1 was the most common haplotype in patients and controls and it was associated with at least twelve out of the twenty-one mutations. Detected mutations were not associated to specific haplotypes while genotyping was compatible with a possible founder effect for the novel p.S396C mutation which clustered in a restricted geographical area of northeast Italy. The results added on to the genetic heterogeneity of CADASIL and emphasized difficulties in designing algorithms for molecular diagnosis.
Assuntos
CADASIL/genética , Haplótipos , Mutação , Receptores Notch/genética , População Branca/genética , Estudos de Coortes , Análise Mutacional de DNA , Efeito Fundador , Genótipo , Humanos , Itália , Polimorfismo de Nucleotídeo Único , Receptor Notch3Assuntos
CADASIL/genética , Éxons , Mutação , Fenótipo , Receptores Notch/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Análise Mutacional de DNA , Família , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Linhagem , Receptor Notch3 , População Branca/genéticaRESUMO
BACKGROUND: The frequent occurrence of movement disorders such as myoclonus, parkinsonism and dystonia, strongly suggests an involvement of the dopaminergic system in sporadic Creutzfeldt-Jakob disease (sCJD), but this issue has not been specifically addressed yet. METHODS: We report a patient who after a sub-acute focal clinical onset, developed the full clinical picture of probable sCJD. Given the early unilateral right extrapyramidal rigidity, the patient was assessed by single-photon emission computed tomography of the dopamine transporter (DAT) using [123I] FP-CIT. RESULTS: DAT-scan demonstrated reduced values of presynaptic receptorial trace in the putamen, particularly on the left side, consistent with functional putaminal dopaminergic presynaptic alteration. CONCLUSIONS: The present observation emphasizes the possible role of DAT imaging studies in the investigation of the pathogenesis of movement disorders in CJD.
Assuntos
Síndrome de Creutzfeldt-Jakob/diagnóstico por imagem , Síndrome de Creutzfeldt-Jakob/fisiopatologia , Dopamina/metabolismo , Putamen/fisiopatologia , Idoso , Radioisótopos de Carbono , Síndrome de Creutzfeldt-Jakob/patologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Radioisótopos do Iodo , Imageamento por Ressonância Magnética , Putamen/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único , TropanosRESUMO
CADASIL is an autosomal dominant arteriopathy characterised by diffuse white matter lesions and small subcortical infarcts on neuroimaging and a variable combination of recurrent cerebral ischaemic episodes, cognitive deficits, migraine with aura and psychiatric symptoms. It is caused by mutations in the NOTCH3 gene encoding a NOTCH3 receptor protein. Here, we describe the genetical, clinical, neuropsychological and neuroimaging findings in an Italian CADASIL patient with a rare mutation in exon 10 leading to a Gly528Cys substitution.
Assuntos
CADASIL/genética , Cistina/genética , Éxons/genética , Glicina/genética , Mutação , Receptores Notch/genética , Idoso , CADASIL/patologia , Saúde da Família , Feminino , Humanos , Itália , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Receptor Notch3RESUMO
Here we describe clinical, neuropsychological and neuroradiological findings in 6 subjects belonging to two unrelated Italian cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) kindreds from the same geographic area who shared a common Arg1006Cys mutation. Subjects from Family A were virtually asymptomatic, and yet showed MRI pathological findings and a cluster of sub-clinical neuropsychological defects mainly centred on the visuospatial domain; patients from Family B had presented several clinically relevant episodes and showed a general cognitive impairment compatible with the clinical picture of vascular dementia. The present clinical observations are consistent with the hypothesis of a geographical clustering for CADASIL, and highlight that sub-clinical cognitive impairment may help to identify this syndrome in families presenting with only migraine.
Assuntos
Arginina/genética , CADASIL/genética , Cisteína/genética , Saúde da Família , Mutação , Receptores Notch/genética , Idoso , CADASIL/fisiopatologia , Análise Mutacional de DNA/métodos , Éxons , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos/estatística & dados numéricos , Receptor Notch3RESUMO
The objective was to determine the progression of nervous system involvement in spinocerebellar ataxia type 1 (SCA1). Three presymptomatic members of an Italian SCA1 family underwent molecular analysis and showed the SCA1 mutation. They were defined as "at risk/mutated" individuals. A clinical and electrophysiologic 7-9 year follow-up was performed. The Inherited Ataxia Progression Scale was used for clinical staging. Sensory and motor conduction velocities, somatosensory evoked potentials and transcranial magnetic stimulation were performed at least three times in each subject. Clinical examination showed the early corticospinal pathway involvement. Electrophysiologic investigations confirmed that at the asymptomatic stage only magnetic motor cortex stimulation was abnormal and rapidly worsened with time. Somatosensory pathway studies showed a later involvement and a light sensory-motor neuropathy was the last electrophysiologic abnormality to be recognised. These data confirm that SCA1 phenotype is characterised by early and prevalent pyramidal tract involvement and that peripheral neuropathy is a late and moderate complication.
Assuntos
Eletrofisiologia/métodos , Saúde da Família , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/fisiopatologia , Adulto , Ataxina-1 , Ataxinas , Estimulação Elétrica/métodos , Potenciais Somatossensoriais Evocados/fisiologia , Feminino , Seguimentos , Humanos , Magnetismo , Masculino , Condução Nervosa/fisiologia , Condução Nervosa/efeitos da radiação , Tempo de Reação/fisiologia , Tempo de Reação/efeitos da radiação , Nervo Tibial/fisiopatologia , Nervo Tibial/efeitos da radiaçãoRESUMO
OBJECTIVES: To describe wake-sleep and body core temperature (t degrees ) rhythm abnormalities in two patients with bilateral paramedian thalamic calcifications. METHODS: Patients underwent (18F)FDG PET scans and 24 hour polygraphic recordings of wake-sleep and t degrees. RESULTS: PET showed bilateral thalamic hypometabolism in both patients with additional basal ganglia or mesiolateral frontal and cingular hypometabolism. Wake-sleep studies showed abnormal sleep organisation and in the case with frontal and limbic PET hypometabolism, pre-sleep behaviour associated with "subwakefulness" EEG activities, lack of EEG spindles and K complexes, and features of status dissociatus. The t degrees rhythms showed increased mesor in both (37.4 degrees C and 37.75 degrees C) and inverted rhythm in one patient. CONCLUSIONS: Paramedian thalamic structures and interconnected, especially frontal and cingular, areas play a part in the organisation of the wake-sleep cycle and attendant autonomic functions.
Assuntos
Doenças do Sistema Nervoso Autônomo/diagnóstico , Calcinose/diagnóstico , Dominância Cerebral/fisiologia , Imageamento Tridimensional , Transtornos do Sono do Ritmo Circadiano/diagnóstico , Doenças Talâmicas/diagnóstico , Tomografia Computadorizada de Emissão , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Regulação da Temperatura Corporal/fisiologia , Calcinose/fisiopatologia , Ritmo Circadiano/fisiologia , Metabolismo Energético/fisiologia , Humanos , Testes Neuropsicológicos , Polissonografia , Transtornos do Sono do Ritmo Circadiano/fisiopatologia , Fases do Sono/fisiologia , Síndrome , Doenças Talâmicas/fisiopatologia , Tálamo/fisiopatologiaRESUMO
A mutant of the a subunit of the retinal rod cyclic GMP-gated channel, [Arg654(1-bp del)], corresponding to a truncated alphaR654Dstop subunit, was previously described in patients with retinitis pigmentosa: when expressed in HEK-293 cells, this mutated a subunit was retained inside the cell, but had normal channel activity in one case where it reached the plasma membrane, indicating that the mechanism of targeting is altered by the mutation, but not the function of the channel. The corresponding mutants of the bovine rod channel (alphaR656D stop), and of the closely related olfactory neuron channel (alphaR632Dstop) alpha subunits were expressed in Xenopus oocytes and their activity was analyzed by patch-clamp. Like their human homologue, these two channels have no activity, and we show that their GFP fusion proteins are accumulated into intracellular compartments. The truncation alone or the R/D mutation alone do not prevent or modify channel activity, indicating that neither the R656 residue nor the C-terminal domain downstream of R656 is necessary for homomeric channel targeting and function. Several mutations of R656 and of the preceding residues in the R656Dstop mutant disclose that the motif responsible for the absence of channel activity is an endoplasmic reticulum retention signal (KXKXXstop) in which the nature of the residues in positions -1 and -4 is determinant.
Assuntos
GMP Cíclico/genética , Canais Iônicos/genética , Mutagênese Sítio-Dirigida/genética , Segmento Externo da Célula Bastonete/metabolismo , Sequência de Aminoácidos , Animais , Bovinos , Canais de Cátion Regulados por Nucleotídeos Cíclicos , DNA/genética , DNA Complementar/genética , Feminino , Humanos , Técnicas In Vitro , Ativação do Canal Iônico , Dados de Sequência Molecular , Neurônios Receptores Olfatórios/metabolismo , Oócitos/metabolismo , Técnicas de Patch-Clamp/métodos , RNA Mensageiro/genética , Retinose Pigmentar/genética , XenopusRESUMO
The authors report a large pedigree from southern Italy with Charcot-Marie-Tooth disease type 2A (CMT2A). The clinical picture was uniform and characterized by distal muscular weakness and atrophy in the lower limbs, reduced or absent tendon reflexes mainly in the lower limbs, and mild sensory impairment in the feet. Significant linkage to the CMT2A locus on chromosome 1p35-p36 was detected. Based on informative recombination in affected individuals, the authors mapped the CMT2A gene between D1S160 and D1S170.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Cromossomos Humanos Par 1 , Saúde da Família , Ligação Genética , Adolescente , Adulto , Idade de Início , Criança , Feminino , Haplótipos , Humanos , Lactente , Itália , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
OBJECTIVE: To explore motor control reorganization in a 40-year-old, left-handed patient with perinatally acquired mirror movements. METHODS: We performed simultaneous bilateral recordings of motor evoked potentials (MEPs) following focal transcranial magnetic stimulation (fTMS) and of central silent period (cSP) during unilateral voluntary contraction in abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. RESULTS: For both muscles the MEP study showed bilateral fast-conducting corticospinal projections from the right undamaged hemisphere, and residual contralateral projections from the left hemisphere. The cSP findings differed in the two muscles: the mirror phenomenon was bilateral in the ADM, but present only on the right side in the APB muscles; the mirror activity of right ADM and APB muscles was inhibited only by fTMS of the ipsilateral right motor cortex; the mirror phenomenon in the left ADM muscle was inhibited only by fTMS of the contralateral right motor cortex. CONCLUSIONS: Mirror movements of right APB and ADM muscles were sustained by the ipsilateral connections from the undamaged motor cortex, while the mirror phenomenon in the left ADM muscle could be explained by hypothesizing a bilateral activation of motor cortices. This previously unreported electrophysiological picture demonstrates that different patterns of motor control may realize after perinatal cerebral lesions, even in different distal muscles of the same patient.
Assuntos
Encéfalo/fisiopatologia , Potencial Evocado Motor/fisiologia , Transtornos dos Movimentos/fisiopatologia , Adulto , Encéfalo/patologia , Eletromiografia , Humanos , Imageamento por Ressonância Magnética , Magnetismo , MasculinoRESUMO
Coexpression of the betawt and alphawt subunits of the bovine rod channel restores two characteristics of the native channels: higher sensitivity to cAMP and potentiation of cGMP-induced currents by low cAMP concentrations. To test whether the increased sensitivity to cAMP is due to the uncharged nature of the asparagine residue (N1201) situated in place of aspartate D604 in the beta subunit as previously suggested (, Neuron. 15:619-625), we compared currents from wild-type (alphawt and alphawt/betawt) and from mutated channels (alphaD604N, alphaD604N/betawt, and alphawt/betaN1201D). The results show that the sensitivity to cAMP and cAMP potentiation is partly but not entirely determined by the charge of residue 1201 in the beta subunit. The D604N mutation in the alpha subunit and, to a lesser extent, coexpression of the betawt subunit with the alphawt subunit reduce the open probability for cGMP compared to that of the alphawt channel. Interpretation of the data with the MWC allosteric model (model of Monod, Wyman, Changeux;, J. Mol. Biol. 12:88-118) suggests that the D604N mutation in the alpha subunits and coassembly of alpha and beta subunits alter the free energy of gating by cAMP more than that of cAMP binding.
Assuntos
AMP Cíclico/fisiologia , GMP Cíclico/fisiologia , Canais Iônicos/fisiologia , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Substituição de Aminoácidos , Animais , Bovinos , Canais de Cátion Regulados por Nucleotídeos Cíclicos , Diltiazem/farmacologia , Ativação do Canal Iônico , Canais Iônicos/química , Canais Iônicos/efeitos dos fármacos , Substâncias Macromoleculares , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Modelos Biológicos , Mutagênese Sítio-Dirigida , Técnicas de Patch-Clamp , ProbabilidadeRESUMO
KC167 Drosophila cells were incubated with low concentrations of ethidium bromide (200 ng/ml), causing changes in mitochondrial DNA (mtDNA) content (2-184% of that of controls). SSCP (single strand conformational polymorphism) analysis of mtDNA indicated that the incubation with ethidium bromide also generated mutations. Compared with controls, there were marked reductions in the activities of respiratory complexes III and IV measured in these cells, and in respiration and ATP synthesis capacities measured in isolated mitochondria. These reductions matched that in mtDNA content. In contrast, no link could be demonstrated between mtDNA content and steady-state concentrations of the transcripts of genes COIII and Cyt b.
Assuntos
DNA Mitocondrial/efeitos dos fármacos , Drosophila , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Etídio , Trifosfato de Adenosina/biossíntese , Animais , Linhagem Celular , Complexo III da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Oxirredução , Polimorfismo Conformacional de Fita Simples , RNA Mensageiro , Especificidade por SubstratoRESUMO
OBJECTIVE: To verify if GAA expansion size in Friedreich's ataxia could account for the severity of sensory neuropathy. METHODS: Retrospective study of 56 patients with Friedreich's ataxia selected according to homozygosity for GAA expansion and availability of electrophysiological findings. Orthodromic sensory conduction velocity in the median nerve was available in all patients and that of the tibial nerve in 46 of them. Data of sural nerve biopsy and of a morphometric analysis were available in 12 of the selected patients. The sensory action potential amplitude at the wrist (wSAP) and at the medial malleolus (m mal SAP) and the percentage of myelinated fibres with diameter larger than 7, 9, and 11 microm in the sural nerve were correlated with disease duration and GAA expansion size on the shorter (GAA1) and larger (GAA2) expanded allele in each pair. Pearson's correlation test and stepwise multiple regression were used for statistical analysis. RESULTS: A significant inverse correlation between GAA1 size and wSAP, m mal SAP, and percentage of myelinated fibres was found. Stepwise multiple regression showed that GAA1 size significantly affects electrophysiological and morphometric data, whereas duration of disease has no effect. CONCLUSION: The data suggest that the severity of the sensory neuropathy is probably genetically determined and that it is not progressive.
Assuntos
Ataxia de Friedreich/diagnóstico , Ataxia de Friedreich/genética , Expansão das Repetições de Trinucleotídeos/genética , Adolescente , Adulto , Alelos , Biópsia , Potenciais Evocados , Humanos , Perna (Membro)/inervação , Nervo Mediano/fisiologia , Condução Nervosa/fisiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Nervo Sural/patologia , Nervo Tibial/fisiologiaRESUMO
We report a 2-year prospective neuropsychological study of five asymptomatic subjects with magnetic resonance imaging (MRI) abnormalities from an Italian kindred affected by cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). These subjects completed tests for attention capacities, processing speed, abstract thinking, short-term memory, learning and constructional praxis. Seven normal subjects matched for age and education, belonging to the same pedigree and not having MRI hyperintensities were examined as controls. The results did not show significant differences between asymptomatic subjects and normal controls. Cognitive performance of asymptomatic subjects did not deteriorate during a 2-year follow-up. Our findings suggest that, at this stage of the disease process, the presence of diffuse leukoencephalopathy does not imply subtle cognitive defects.
Assuntos
Doenças Arteriais Cerebrais/fisiopatologia , Cognição , Demência por Múltiplos Infartos/fisiopatologia , Leucoencefalopatia Multifocal Progressiva/fisiopatologia , Adulto , Idoso , Doenças Arteriais Cerebrais/diagnóstico , Demência por Múltiplos Infartos/diagnóstico , Feminino , Seguimentos , Humanos , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Memória , Pessoa de Meia-Idade , Testes Neuropsicológicos , Linhagem , Estudos ProspectivosRESUMO
We describe three siblings from an Italian family affected by an autosomal recessive spinocerebellar degeneration. Gait ataxia, presenting between 38 and 45 years, was the first symptom in all three patients. Dysarthria, dysmetria, brisk tendon reflexes, extensor plantar response, and scoliosis were constant features. Disease progression was slow. Electrophysiologic studies demonstrated a slight reduction in sural nerve sensory action potential in only one patient. Analysis of GAA expansion within the X25 gene showed that patients were homozygous for the expansion, with the shorter expanded allele ranging from 120 to 156 triplets. The size of the GAA expansion may be smaller than we previously described. Such minimal expansions may result in atypical forms of Friedreich's ataxia.
Assuntos
Clonagem Molecular , Ataxia de Friedreich/genética , Espasticidade Muscular/genética , Potenciais de Ação/fisiologia , Idade de Início , Sequência de Bases , Potenciais Somatossensoriais Evocados/fisiologia , Feminino , Ataxia de Friedreich/epidemiologia , Ataxia de Friedreich/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Espasticidade Muscular/epidemiologia , Espasticidade Muscular/fisiopatologia , Condução Nervosa/fisiologia , Linhagem , Fenótipo , Fatores de TempoRESUMO
We describe the first two European cases of acute axonal motor neuropathy with both IgG and IgA anti-GD1a antibodies following Campylobacter enteritis. Both patients acutely developed severe weakness without sensory involvement, had antibodies to Campylobacter jejuni and polyclonal IgG and IgA titers > or = 12,800 to GD1a at onset, which decreased during follow-up. Serial electrophysiologic studies showed: 1, normal or only slightly slowed motor conductions; 2, evidence of a progressive loss of excitability and conduction failure in nerve fibers undergoing axonal degeneration in intermediate nerve segments and evidence of distal axonal involvement in one nerve; 3, normal sensory conductions, sensory potential amplitudes and somatosensory evoked potentials. Although we cannot exclude that axonal degeneration followed demyelination, we think that anti-GD1a antibodies account for the axonal involvement because GD1a is present in the axolemma and exposed at the node of Ranvier and in nerve terminals. The exclusive motor involvement could be explained by the fact that GD1a has a different internal structure in motor and sensory fibers.
Assuntos
Infecções por Campylobacter/imunologia , Campylobacter jejuni/imunologia , Gangliosídeos/imunologia , Doença dos Neurônios Motores/imunologia , Doença dos Neurônios Motores/microbiologia , Adulto , Idoso , Anticorpos Antibacterianos/sangue , Autoanticorpos/sangue , Axônios/patologia , Infecções por Campylobacter/complicações , Europa (Continente) , Potencial Evocado Motor/fisiologia , Potenciais Somatossensoriais Evocados/fisiologia , Feminino , Gangliosídeo G(M1)/imunologia , Gangliosídeo G(M2)/imunologia , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Masculino , Nervo Mediano/fisiologia , Doença dos Neurônios Motores/fisiopatologia , Condução Nervosa/fisiologia , Polirradiculoneuropatia/imunologia , Polirradiculoneuropatia/microbiologia , Polirradiculoneuropatia/fisiopatologia , Nervo Ulnar/fisiologiaRESUMO
A multimodal electrophysiological study was performed on 41 patients from 24 families with autosomal dominant cerebellar ataxia type I (ADCA I). Upper- and lower-limb motor evoked potentials (MEPs) to transcranial magnetic stimulation, median and tibial nerve somatosensory evoked potentials (Mn and Tn-SSEPs), orthodromic sensory (SCV) and motor conduction (MCV) velocity along median and tibial nerve, brainstem auditory evoked potentials (BAEPs), and visual evoked potentials (VEPs) were examined. Molecular analysis showed 2 SCA1 families and 2 families linked to the SCA2 locus. A sural nerve biopsy was performed in 5 patients. Brainstem damage of the auditory pathway was observed in 79% of patients examined. VEP abnormalities possibly of central origin were found in 52% of patients. MEP and SSEP abnormalities were differently distributed along the pathways examined: the longer the pathway, the higher the occurrence and severity of impairment. Peripheral dying-back neuropathy (confirmed by nerve bioptic data) was a frequent finding (56%). A progressive degenerative process involving first the longest tracts of the central motor and central and peripheral branches of somatosensory pathways is hypothesized in ADCA I. MEP abnormalities were more frequent in SCA1, and the sensory-motor neuropathy was more severe in SCA2.
Assuntos
Ataxia Cerebelar/fisiopatologia , Aberrações Cromossômicas , Transtornos Cromossômicos , Adolescente , Adulto , Idoso , Biópsia , Sistema Nervoso Central/fisiopatologia , Ataxia Cerebelar/genética , Criança , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Potencial Evocado Motor/fisiologia , Potenciais Somatossensoriais Evocados/fisiologia , Potenciais Evocados Visuais/fisiologia , Feminino , Humanos , Magnetismo , Masculino , Pessoa de Meia-Idade , Condução Nervosa/fisiologia , Sistema Nervoso Periférico/fisiopatologia , Nervo Sural/patologia , Nervo Sural/fisiopatologiaRESUMO
We studied 83 patients from 36 Italian families with autosomal dominant cerebellar ataxia type I. Mean onset age +/- SD was 34.2 +/- 12.8 years with a mean anticipation of 12.8 +/- 15.1 in 52 parent-offspring pairs. Onset age anticipation occurred predominantly through paternal transmission. Mean age at death was at 56.5 +/- 15.5 years. The most common associated features were supranuclear ophthalmoplegia, corticospinal signs, peripheral neuropathy and cognitive impairment. Cerebellar atrophy was constant at MRI and usually associated with shrinkage of the pons and degeneration of the pontine transverse fibres. Direct mutation analysis in 29 families showed two families with SCA1 and none with Machado-Joseph/SCA3 mutation. We performed linkage analysis in the ten largest families. Two of them showed linkage to SCA2 locus and none to SCA4 and SCA5 loci. SCA2 patients showed higher occurrence of peripheral neuropathy and slow saccades, rarer corticospinal signs and a milder course of the disease in comparison with SCA1 patients.
Assuntos
Ataxia Cerebelar/genética , Aberrações Cromossômicas , Transtornos Cromossômicos , Adolescente , Adulto , Idade de Início , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/fisiopatologia , Criança , Pré-Escolar , Progressão da Doença , Eletrofisiologia , Feminino , Ligação Genética , Genótipo , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Mutação/genética , FenótipoRESUMO
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently identified autosomal dominant cerebral arteriopathy characterized by the recurrence of subcortical infarcts leading to dementia. A genetic linkage analysis conducted in two large families recently allowed us to map the affected gene on chromosome 19 in a 12-cM interval bracketed by D19S221 and D19S215. In the present study, these first 2 families and 13 additional ones, including a total of 199 potentially informative meiosis, have been genotyped with eight polymorphic markers located between D19S221 and D19S215. All families were linked to chromosome 19. The highest combined lod score (Zmax = 37.24 at theta = .01) was obtained with marker D19S841, a new CAn microsatellite marker that we isolated from chromosome 19 cosmids. The recombinant events observed within these families were used to refine the genetic mapping of CADASIL within a 2-cM interval that is now bracketed by D19S226 and D19S199 on 19p13.1. These data strongly suggest the genetic homogeneity of this recently identified condition and establish the value of its clinical and neuroimaging diagnostic criteria. Besides their importance for the ongoing positional cloning of the CADASIL gene, these data help to refine the genetic mapping of CADASIL relative to familial hemiplegic migraine and hereditary paroxysmal cerebellar ataxia, conditions that we both mapped within the same chromosome 19 region.
Assuntos
Doenças Arteriais Cerebrais/genética , Infarto Cerebral/genética , Cromossomos Humanos Par 19 , Demência/genética , Doenças Desmielinizantes/genética , Mapeamento Cromossômico , DNA/sangue , DNA Satélite/genética , Europa (Continente) , Feminino , Genes Dominantes , Ligação Genética , Marcadores Genéticos , Humanos , Masculino , Linhagem , Polimorfismo Genético , Recombinação Genética , SíndromeRESUMO
We report on a family in which a mother and her 3 daughters have delayed psychomotor development and/or psychosis, hydrocephalus with white matter alterations, arachnoid cysts, skeletal anomalies consisting of brachydactyly, and Sprengel anomaly. Biochemical and cytogenetic analyses were normal on all 4 patients. The pattern of inheritance, clinical manifestations, and variability of expression suggest that this is a new hydrocephalus syndrome possibly transmitted as an X-linked dominant trait.