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1.
Dev Med Child Neurol ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31468510

RESUMO

AIM: To collect preliminary functional data on ataxia telangiectasia and create a disease specific scale: the Ataxia Telangiectasia Functional Scale (ATFS). METHOD: Retrospective information on patients with ataxia telangiectasia referred to the Assistive Technology Unit was included. Functional mobility scales (the Gross Motor Function Classification System [GMFCS] and the Functional Mobility Scale [FMS]-5, FMS-50, FMS-500) and activities of daily living [ADL] parameters were recorded. We created a 51-point ATFS, that consisted of three ambulation items adapted for ataxia telangiectasia in the frame of FMS (home, school, outdoors), five ADL items, and one schooling item. RESULTS: Twenty-seven participants (17 males, 10 females; mean age 10y 8mo [SD 5y 1mo], range 1y 9mo-25y 6mo), were enrolled; 168 measurements were recorded. Patients walked at a mean age of 1 year 4 months (SD 5y 4mo) and lost ambulatory capacity at 8 years 8 months (SD 2y 1mo). GMFCS level and FMS-5, FMS-50, FMS-500 assessments correlated with age (Spearman's correlations r=0.555, -0.617, -0.639, -0.662 respectively, p<0.01 for all), but plateaued after 12 years of age. ATFS mean score was 37.46 (SD 7.88) and increased with age (Spearman's correlation r=0.585, p<0.01). The scale showed three stages of disease progression. INTERPRETATION: In this pilot study we show longitudinal functional data of ambulation and ADL skills in ataxia telangiectasia, and created a framework for a functional scale. This functional scale closely approximated disease course, but further validation is required. WHAT THIS PAPER ADDS: The Gross Motor Function Classification System and the Functional Mobility Scale are ill-suited for ataxia telangiectasia assessments. Three functional mobility scales (home, school, outdoors) suited to ataxia telangiectasia were created. The Ataxia Telangiectasia Functional Scale (ATFS) combines mobility and items of activities of daily living. The ATFS closely approximates the three-stage progression of the disorder.

2.
PLoS One ; 14(2): e0211901, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30735520

RESUMO

Mutations in the SCN1A gene, which encodes for the voltage-gated sodium channel NaV1.1, cause Dravet syndrome, a severe developmental and epileptic encephalopathy. Genetic testing of this gene is recommended early in life. However, predicting the outcome of de novo missense SCN1A mutations is difficult, since milder epileptic syndromes may also be associated. In this study, we correlated clinical severity with functional in vitro electrophysiological testing of channel activity and bioinformatics prediction of damaging mutational effects. Three patients, bearing the mutations p.Gly177Ala, p.Ser259Arg and p.Glu1923Arg, showed frequent intractable seizures that had started early in life, with cognitive and behavioral deterioration, consistent with classical Dravet phenotypes. These mutations failed to produce measurable sodium currents in a mammalian expression system, indicating complete loss of channel function. A fourth patient, who harbored the mutation p.Met1267Ile, though presenting with seizures early in life, showed lower seizure burden and higher cognitive function, matching borderland Dravet phenotypes. In correlation with this, functional analysis demonstrated the presence of sodium currents, but with partial loss of function. In contrast, six bioinformatics tools for predicting mutational pathogenicity suggested similar impact for all mutations. Likewise, homology modeling of the secondary and tertiary structures failed to reveal misfolding. In conclusion, functional studies using patch clamp are suggested as a prognostic tool, whereby detectable currents imply milder phenotypes and absence of currents indicate an unfavorable prognosis. Future development of automated patch clamp systems will facilitate the inclusion of such functional testing as part of personalized patient diagnostic schemes.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30100180

RESUMO

BACKGROUND: Ataxia telangiectasia (AT) is a neurodegenerative cerebellar disorder, caused by mutations in the ATM gene, involved in DNA repair. Radiosensitivity, progressive ataxia, immune deficiency and malignancies, are well known symptoms, but urological manifestations are scarcely described. OBJECTIVE: To characterize urologic manifestations in a large cohort of AT patients. METHODS: Retrospective cross-sectional chart study comprising 52 AT patients followed at a National AT Center. RESULTS: 25% of the cohort (13 patients/8 males) had urologic symptoms, which presented at 11 ± 4.3 years. The most common symptom was secondary enuresis affecting 15% of the patients (8 children/4 males). Incontinence appeared at 8 ± 6.2 years of age, and resolved spontaneously within 15 ± 8.3 months in 6 patients. It preceded loss of ambulatory capacity by 1-2 years in 7 patients. Lumbosacral MRI were normal (4 children) and urine cultures (all) were negative. Urodynamic evaluation that was performed in only one patient revealed overactive bladder. Additional manifestations were macroscopic hematuria due to bladder telangiectasia in a 12-year-old, and renal cell carcinoma in a 22-year-old. Other manifestations unrelated to AT were neprolithiasis, vesico-ureteral reflux and scrotal pain, each in 1 patient. DISCUSSION: Transient secondary enuresis is a frequent finding in AT patients, heralding loss of ambulatory capacity, tough it's pathophysiological mechanism is largely no understood.

4.
Nutrition ; 46: 48-52, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29290356

RESUMO

OBJECTIVE: Ataxia telangiectasia (A-T) is a rare genetic disease involving multiple organs, but, to our knowledge, data on long-term gastrointestinal and nutritional involvement are scarce. The aim of this study was to longitudinally review the nutritional and gastrointestinal aspects of A-T. METHODS: This was a retrospective chart review of patients followed from 1986 to 2015 at one center. Demographic, laboratory, and nutritional data were retrieved. Body mass index (BMI) values were converted to BMI Z-score (BMI-Z). Caloric intake was estimated by food diaries and compared with estimated energy requirements for sex and age with a physical activity level factor for light physical activity. RESULTS: The study included 53 patients (28 males [53%], ages 14.6 ± 5.2 y). BMI-Z was inversely correlated with age (r = 0.48; P < 0.004). A decline below minimal BMI percentiles was observed after the age of 4 y in boys and 7 y in girls. The relative percentage of caloric intake decreased with age (r = -0.5; P < 0.002), and was positively correlated with BMI-Z (r = 0.35; P < 0.05). Presence of cough during meals was associated with recurrent lower respiratory tract infections (Fisher exact test, P < 0.01). Gastrostomy tubes were inserted in 12 patients, leading to improvement in BMI-Z from -5.1 ± 2.4 to -4 ± 2.9 (P < 0.05). CONCLUSIONS: There is a progressive growth failure and low nutritional intake with age in patients with A-T, starting in early childhood in males, and more prominent in patients with cough and choking during meals. A proactive approach and insertion of a percutaneous gastrostomy tube as soon as the BMI-Z starts to decrease should be considered.

5.
Eur J Paediatr Neurol ; 22(1): 39-45, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29079079

RESUMO

BACKGROUND: While many individuals with severe developmental impairments learn to communicate with augmentative and alternative communication (AAC) devices, a significant number of individuals show major difficulties in the effective use of AAC. Recent technological innovations, i.e., eye-tracking technology (ETT), aim to improve the transparency of communication and may also enable a more valid cognitive assessment. OBJECTIVES: To investigate whether ETT in forced-choice tasks can enable children with very severe motor and speech impairments to respond consistently, allowing a more reliable evaluation of their language comprehension. METHODS: Participants were 17 girls with Rett syndrome (M = 6:06 years). Their ability to respond by eye gaze was first practiced with computer games using ETT. Afterwards, their receptive vocabulary was assessed using the Peabody Picture Vocabulary Test-4 (PPVT-4). Target words were orally presented and participants responded by focusing their eyes on the preferred picture. RESULTS: Remarkable differences between the participants in receptive vocabulary were demonstrated using ETT. The verbal comprehension abilities of 32% of the participants ranged from low-average to mild cognitive impairment, and the other 68% of the participants showed moderate to severe impairment. Young age at the time of assessment was positively correlated with higher receptive vocabulary. CONCLUSIONS: The use of ETT seems to make the communicational signals of children with severe motor and communication impairments more easily understood. Early practice of ETT may improve the quality of communication and enable more reliable conclusions in learning and assessment sessions.


Assuntos
Cognição , Compreensão , Movimentos Oculares/fisiologia , Exame Neurológico/métodos , Síndrome de Rett , Criança , Pré-Escolar , Feminino , Humanos , Vocabulário
6.
Am J Hum Genet ; 101(4): 516-524, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28942967

RESUMO

Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. By pooling genetic findings across multiple studies, we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6), each harboring a de novo mutation in PPP3CA. PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin encodes a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. Five individuals with de novo PPP3CA mutations were identified among 4,760 trio probands with neurodevelopmental diseases; this is highly unlikely to occur by chance (p = 1.2 × 10-8) given the size and mutability of the gene. Additionally, a sixth individual with a de novo mutation in PPP3CA was connected to this study through GeneMatcher. Based on these findings, we securely implicate PPP3CA in early-onset refractory epilepsy and further support the emerging role for synaptic dysregulation in epilepsy.


Assuntos
Calcineurina/genética , Epilepsia/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Transmissão Sináptica/fisiologia , Adolescente , Adulto , Calcineurina/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/patologia , Exoma/genética , Feminino , Humanos , Lactente , Recém-Nascido , Síndrome de Lennox Gastaut/patologia , Masculino , Transtornos do Neurodesenvolvimento/patologia , Análise de Sequência de DNA , Índice de Gravidade de Doença , Espasmos Infantis/genética , Espasmos Infantis/patologia , Adulto Jovem
7.
Eur J Paediatr Neurol ; 21(6): 858-863, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28734769

RESUMO

BACKGROUND: Benign childhood epilepsy with centrotemporal spikes is benign childhood epilepsy, presenting between 4 and 10 years of age, characterized by typical clinical and EEG findings. Despite excellent prognosis, there are reports of mild cognitive, language, fine motor and behavioral difficulties. In its atypical form - electrical status epilepticus during slow wave sleep, continuous epileptiform activity during sleep lead to severe neurocognitive deterioration. Our objective was to investigate the influence of abundant sleep epileptiform activity, not fulfilling the criteria for electrical status epilepticus during Slow Wave Sleep, discovered randomly in children without overt intellectual impairment. METHODS: We retrospectively reviewed the charts and EEG's of 34 children with benign childhood epilepsy with centrotemporal spikes, who underwent neurocognitive evaluation. The neurocognitive battery included items in the following domains: attention span, memory, language, fine motor and behavior. Patients were divided into two groups according to the spike wave index on sleep EEG, with a cut-off point of 50%. The groups were compared regarding to neurocognitive performance. OUTCOMES: Children with epileptiform activity of more than 50%, were diagnosed at a significantly younger age (5.13 ± 1.94 years vs. 7.17 ± 2.45, p = 0.014 T test), had less controlled seizures and received more antiepileptic drugs. However, there was no difference in neurocognitive performance, except in fine motor tasks (Pegboard), where children with more abundant activity were scored lower (-0.79 ± 0.96 vs. 0.20 ± 1.05, p = 0.011, T test). CONCLUSION: Our study did not show negative cognitive effect of abundant epileptiform activity discovered randomly in children with benign childhood epilepsy with centrotemporal spikes, warranting aggressive treatment.


Assuntos
Cognição , Epilepsia Rolândica/fisiopatologia , Sono , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Masculino , Estudos Retrospectivos
8.
Brain ; 140(3): 568-581, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28364549

RESUMO

Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Encefalopatias/genética , Encefalopatias/patologia , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/genética , Encefalopatias/diagnóstico por imagem , Encefalopatias/mortalidade , Células Cultivadas , Pré-Escolar , Consanguinidade , Saúde da Família , Feminino , Fibroblastos/patologia , Fibroblastos/ultraestrutura , Estudos de Associação Genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Consumo de Oxigênio/genética , Transporte Proteico/genética , Transfecção
9.
Pediatr Neurol ; 68: 40-43, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28254244

RESUMO

BACKGROUND: Rett syndrome is an X-linked dominant neurodevelopmental disorder manifesting with severe intellectual disability in females caused by various mutations in the MECP2 gene. Brain-derived neurotrophic factor (BDNF) is one of the main proteins regulated by the MECP2 protein; its overexpression in the MeCP2 mouse model partially corrects the Rett phenotype. Pharmacologic manipulations that lead to increased BDNF in individuals with Rett syndrome are expected to have a positive effect on the disorder. Glatiramer acetate, a well-known and safe multiple sclerosis immune modulator, increases BDNF levels in multiple sclerosis animal models and patients responding to treatment, as well as in Rett mouse models. METHODS: Fourteen patients with mutation-proven Rett syndrome were recruited for a clinical trial with glatiramer acetate. Baseline data and follow-up data were collected during the trial, which had to be stopped because of a severe adverse event. Our objective is to describe this unexpected potentially life-threatening event in response to glatiramer in patients with Rett syndrome. RESULTS: Four of 14 patients with Rett syndrome who were recruited and treated with daily injections of glatiramer acetate as part of an open-label clinical trial developed an exaggerated immediate postinjection response, which was experienced as life threatening in three of the patients, necessitating arrest of the trial. CONCLUSION: Despite the known safety profile of glatiramer acetate in adult and pediatric patients with multiple sclerosis, its use in Rett syndrome should be cautiously reconsidered. The described severe adverse event can be related to these patients' primary autonomic nervous system dysfunction.


Assuntos
Acetato de Glatiramer/toxicidade , Fatores Imunológicos/toxicidade , Síndrome de Rett/tratamento farmacológico , Adolescente , Criança , Feminino , Acetato de Glatiramer/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Injeções , Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/genética , Absorção Subcutânea , Falha de Tratamento
10.
Am J Hum Genet ; 99(6): 1229-1244, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27817865

RESUMO

Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285∗), c.247_250del (p.Asn83Hisfs∗4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.


Assuntos
Distúrbios Distônicos/genética , Ácidos Graxos/biossíntese , Mitocôndrias/metabolismo , Mutação , Atrofia Óptica/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Gânglios da Base/metabolismo , Células Cultivadas , Criança , Pré-Escolar , Feminino , Fibroblastos , Teste de Complementação Genética , Humanos , Lactente , Masculino , Doenças Mitocondriais/genética , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/química , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Linhagem , Sítios de Splice de RNA/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
11.
Pediatr Res ; 79(6): 889-94, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26891003

RESUMO

BACKGROUND: Ataxia telangiectasia (AT) is a genetic multisystem disorder, presenting with progressive ataxia, immune deficiency, and propensity toward malignancy. Endocrine abnormalities (growth retardation, reproductive dysfunction, and diabetes) have been described, however detailed information regarding this aspect is lacking. We aimed to characterize endocrine anomalies and growth patterns in a large cohort of AT patients. METHODS: Retrospective study comprising all 52 patients (aged 2-26.2 y) followed at a national AT Clinic. Anthropometric and laboratory measurements were extracted from the charts. RESULTS: Median height-SDS was already subnormal during infancy, remaining negative throughout follow up to adulthood. Height-SDS was more impaired than weight-SDS up to age 4 y, thereafter weight-SDS steadily decreased, resulting in progressively lower BMI-SDS. IGF-I-SDS was low (-1.53 ± 1.54), but did not correlate with height-SDS. Gonadal failure was present in all 13 females older than 10 y but only in one male. Two patients had diabetes and 10 had dyslipidemia. Vitamin D deficiency was observed in 52.2% of the evaluated patients. CONCLUSION: Our results suggest a primary growth abnormality in AT, rather than secondary to nutritional impairment or disease severity. Sex hormone replacement should be considered for female patients. Vitamin D levels should be followed and supplementation given if needed.


Assuntos
Ataxia Telangiectasia/fisiopatologia , Estatura , Peso Corporal , Sistema Endócrino/fisiopatologia , Adolescente , Adulto , Antropometria , Ataxia Telangiectasia/complicações , Glicemia/metabolismo , Criança , Pré-Escolar , Estudos Transversais , Dislipidemias/complicações , Feminino , Transtornos do Crescimento , Humanos , Sistema Imunitário , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Estudos Retrospectivos , Deficiência de Vitamina D/complicações , Adulto Jovem
12.
J Pediatr Gastroenterol Nutr ; 62(4): 550-5, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26594831

RESUMO

OBJECTIVE: Ataxia telangiectasia (A-T) is a rare genetic multiorgan disease. Although gastrointestinal involvement is known, hepatic involvement in A-T has not been investigated. We aimed to study the hepatic involvement in a large cohort of patients with A-T. METHODS: A retrospective review of patients, studied from January 1986 to January 2015 at a National A-T Center. Clinical data including demographic, genetic, laboratory, nutritional, radiographic, and histological data were retrieved. RESULTS: Fifty-three patients, 27 (49%) boys, age 14.6 ±â€Š5.2 years (range 5.9-26.1 years), were included. Twenty-three patients (43.4%), age 9.9 ±â€Š5.1 years, had consistently abnormal liver enzymes. The mean enzyme levels were alanine aminotransferase 76.8 ±â€Š73.8 IU/L, aspartate aminotransferase 70 ±â€Š50 IU/L, alkaline phosphatase 331 ±â€Š134 IU/L, and gamma glutamyl transferase 114.7 ±â€Š8 IU/L. Evaluation of other etiology of liver disease was negative. Ultrasonography revealed fatty liver in 9 of them (39%). Liver biopsy was performed in 2 patients, revealing mild-to-moderate steatosis in both, and fibrosis in 1 patient. Progression to advanced liver disease occurred in 2 of 23 (9%) patients within 2 to 5 years. Dyslipidemia was significantly associated with abnormal liver enzymes: 3 of 30 (10%) patients without abnormal liver enzymes versus 10 of 23 (45.5%) patients with abnormal liver enzymes, respectively (P < 0.05, Fisher exact test). No correlation was found between hepatic involvement and HbA1C, sex, presence of malignancy, or type of mutation. CONCLUSIONS: Abnormal liver enzymes and fatty liver are common in patients with A-T and may progress to advanced liver disease at a young age. These findings are novel and implicate that patients with A-T with abnormal liver enzymes should be evaluated for the presence of liver disease.


Assuntos
Ataxia Telangiectasia/fisiopatologia , Hepatopatias/etiologia , Fígado/fisiopatologia , Adolescente , Adulto , Ataxia Telangiectasia/sangue , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Biópsia , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Dislipidemias/etiologia , Feminino , Seguimentos , Humanos , Israel/epidemiologia , Fígado/diagnóstico por imagem , Fígado/patologia , Hepatopatias/diagnóstico por imagem , Hepatopatias/epidemiologia , Hepatopatias/fisiopatologia , Masculino , Mutação , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/etiologia , Prevalência , Estudos Retrospectivos , Ultrassonografia , Adulto Jovem
13.
Eur J Paediatr Neurol ; 20(1): 69-79, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26542466

RESUMO

BACKGROUND: TECPR2 was first described as a disease causing gene when the c.3416delT frameshift mutation was found in five Jewish Bukharian patients with similar features. It was suggested to constitute a new subtype of complex hereditary spastic paraparesis (SPG49). RESULTS: We report here 3 additional patients from unrelated non-Bukharian families, harboring two novel mutations (c.1319delT, c.C566T) in this gene. Accumulating clinical data clarifies that in addition to intellectual disability and evolving spasticity the main disabling feature of this unique disorder is autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events. CONCLUSION: We suggest that the disease should therefore be classified as a new subtype of hereditary sensory-autonomic neuropathy. The discovery of additional mutations in non-Bukharian patients implies that this disease might be more common than previously appreciated and should therefore be considered in undiagnosed cases of intellectual disability with autonomic features and respiratory symptoms regardless of demographic origin.


Assuntos
Proteínas de Transporte/genética , Disautonomia Familiar/genética , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Paraplegia Espástica Hereditária/genética , Proteínas de Transporte/química , Pré-Escolar , Biologia Computacional , DNA/genética , Eletrodiagnóstico , Exoma , Mutação da Fase de Leitura/genética , Neuropatias Hereditárias Sensoriais e Autônomas/psicologia , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/psicologia , Judeus , Masculino , Modelos Moleculares , Proteínas do Tecido Nervoso/química , Exame Neurológico , Linhagem , Transtornos Respiratórios/etiologia , Transtornos Respiratórios/genética , Paraplegia Espástica Hereditária/psicologia
14.
Eur J Paediatr Neurol ; 20(1): 140-6, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26493850

RESUMO

INTRODUCTION: Ataxia telangiectasia (AT) is a neurodegenerative disorder with cerebellar and extrapyramidal features. Interventional and epidemiological studies in AT should rely on specific scales which encompass the specific neurological features, as well the early progressive course and the subsequent plateau. The aim of this study was to build a scale of the CGI type (Clinical Global Impression) which is disease specific, as well as to check the feasibility of the ICARS scale for ataxia in this population. METHODS: We recruited 63 patients with ataxia, aged 10.76 ± 3.2 years, followed at 6 international AT centers, 49 of them (77.8%) with classical AT. All patients were evaluated for ataxia with ICARS scale. In patients with AT, two CGI scales were scored, unstructured as structured for which separate anchors were provided. RESULTS: Mean ICARS score was 44.7 ± 20.52, and it's severity positively correlated with age (Spearman correlation, r = 0.46, p < 0.01). Mean CGI score was 2 (moderately involved). There was a high correlation between the structured and unstructured CGIs (Spearman correlation, r = 0.87, p < 0.01). Both CGI scales showed positive correlation between severity and increasing age (Spearman correlation r = 0.59, p < 0.01 for structured CGI and r = 0.61, p < 0.01 for unstructured). DISCUSSION: We succeeded to build two CGI scales: structured and unstructured, which are disease specific for AT. The unstructured scale showed better connection to disease course; the sensitivity of the unstructured scale could be improved by adding anchors related to extrapyramidal features. In addition we showed that ataxia can be reliably measured in children with AT by using ICARS.


Assuntos
Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/epidemiologia , Pediatria/métodos , Índice de Gravidade de Doença , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino
16.
Eur Respir Rev ; 24(138): 565-81, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26621971

RESUMO

Ataxia telangiectasia (A-T) is a rare, progressive, multisystem disease that has a large number of complex and diverse manifestations which vary with age. Patients with A-T die prematurely with the leading causes of death being respiratory diseases and cancer. Respiratory manifestations include immune dysfunction leading to recurrent upper and lower respiratory infections; aspiration resulting from dysfunctional swallowing due to neurodegenerative deficits; inefficient cough; and interstitial lung disease/pulmonary fibrosis. Malnutrition is a significant comorbidity. The increased radiosensitivity and increased risk of cancer should be borne in mind when requesting radiological investigations. Aggressive proactive monitoring and treatment of these various aspects of lung disease under multidisciplinary expertise in the experience of national multidisciplinary clinics internationally forms the basis of this statement on the management of lung disease in A-T. Neurological management is outwith the scope of this document.


Assuntos
Ataxia Telangiectasia/terapia , Pneumopatias/terapia , Pulmão , Equipe de Assistência ao Paciente/normas , Pneumologia/normas , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/imunologia , Ataxia Telangiectasia/mortalidade , Ataxia Telangiectasia/fisiopatologia , Terapia Combinada , Comorbidade , Comportamento Cooperativo , Predisposição Genética para Doença , Humanos , Comunicação Interdisciplinar , Pulmão/imunologia , Pulmão/patologia , Pulmão/fisiopatologia , Pneumopatias/diagnóstico , Pneumopatias/genética , Pneumopatias/imunologia , Pneumopatias/mortalidade , Pneumopatias/fisiopatologia , Valor Preditivo dos Testes , Fatores de Risco , Espirometria/normas , Tomografia Computadorizada por Raios X/normas , Resultado do Tratamento
17.
Handb Clin Neurol ; 132: 199-214, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26564081

RESUMO

Ataxia telangiectasia (AT) is an autosomal recessive multisystem genetic disorder caused by a mutation in the ATM gene encoding for the ATM protein. AT systemic manifestations include cutaneous telangiectasias, radiosensitivity, immune deficiency with recurrent sinopulmonary infections, and a tendency to develop lymphoid malignancies. These complications are explained by the major role played by ATM in DNA repair. AT is also the second most common childhood onset neurodegenerative disorder of the cerebellum, presenting with progressive ataxia and oculomotor apraxia and often accompanied by extrapyramidal movement disorders. Ataxia typically begins around the time children start to walk at about 1 year of age and leads to wheelchair dependence by the second decade of life. Cerebellar atrophy is evident on imaging after 2 years of life and is progressive. Abnormal DNA repair mechanisms do not entirely explain the pathophysiology in nondividing neurons. The nervous system involvement is better explained by the role ATM plays in antioxidative defense, mitochondrial homeostasis, and DNA chromatin packing. A better understanding of the underlying pathophysiologic mechanisms of this devastating disease may enable disease-modifying treatments in the future. Meanwhile, treatment is mainly supportive and does not change the poor prognosis of the disease although it improves the patient's quality of life.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/fisiopatologia , Mutação/genética , Ataxia Telangiectasia/genética , Humanos
18.
Eur J Paediatr Neurol ; 19(6): 688-93, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26233519

RESUMO

Identification of CD59 p.Cys89Tyr mutation in 5 patients from North-African Jewish origin presenting with chronic inflammatory demyelinating polyradiculoneuropathy like disease and chronic hemolysis, led us to reinvestigate an unsolved disease in 2 siblings from the same origin who died 17 years ago. The two patients carried the same CD59 gene mutation previously described by our group. These children had quiet similar disease course but in addition developed devastating recurrent brain infarctions, retinal and optic nerve involvement. Revising the brain autopsy of one of these patients confirmed the finding of multiple brain infarctions of different ages. CD59 protein expression was missing on brain endothelial cells by immunohistochemical staining. This new data expands the clinical spectrum of CD59 mutations and further emphasizes the need for its early detection and treatment.


Assuntos
Anemia Hemolítica/complicações , Infarto Cerebral/genética , Hemoglobinúria/complicações , Doenças Retinianas/genética , Adolescente , Antígenos CD59/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação , Linhagem , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/genética
19.
J Child Neurol ; 30(13): 1749-56, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25895915

RESUMO

We describe the molecular basis of a distinctive syndrome characterized by infantile stress-induced episodic weakness, ataxia, and sensorineural hearing loss, with permanent areflexia and optic nerve pallor. Whole exome sequencing identified a deleterious heterozygous c.2452 G>A, p.(E818K) variant in the ATP1A3 gene and structural analysis predicted its protein-destabilizing effect. This variant has not been reported in context with rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood, the 2 main diseases associated with ATP1A3. The clinical presentation in the family described here differs categorically from these diseases in age of onset, clinical course, cerebellar over extrapyramidal movement disorder predominance, and peripheral nervous system involvement. While this paper was in review, a highly resembling phenotype was reported in additional patients carrying the same c.2452 G>A variant. Our findings substantiate this variant as the cause of a unique inherited autosomal dominant neurologic syndrome that constitutes a third allelic disease of the ATP1A3 gene.


Assuntos
Ataxia Cerebelar/genética , Deformidades Congênitas do Pé/genética , Perda Auditiva Neurossensorial/genética , Atrofia Óptica/genética , Reflexo Anormal/genética , ATPase Trocadora de Sódio-Potássio/genética , Adulto , Pré-Escolar , Família , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Modelos Moleculares , Linhagem , Fenótipo , Homologia de Sequência de Aminoácidos
20.
Epilepsia ; 56(4): 569-76, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25789914

RESUMO

OBJECTIVE: Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the MECP2 gene, and characterized by cognitive and communicative regression, loss of hand use, and midline hand stereotypies. Epilepsy is a core symptom, but literature is controversial regarding genotype-phenotype correlation. Analysis of data from a large cohort should overcome this shortcoming. METHODS: Data from the Rett Syndrome Networked Database on 1,248 female patients were included. Data on phenotypic and genotypic parameters, age of onset, severity of epilepsy, and type of seizures were collected. Statistical analysis was done using the IBM SPSS Version 21 software, logistic regression, and Kaplan-Meier survival curves. RESULTS: Epilepsy was present in 68.1% of the patients, with uncontrolled seizures in 32.6% of the patients with epilepsy. Mean age of onset of epilepsy was 4.68 ± (standard deviation) 3.5 years. Younger age of onset was correlated to severity of epilepsy (Spearman correlation r = 0.668, p < 0.01). Patients with late truncating deletions had lower prevalence of epilepsy. Compared to them, the p.R133C mutation, associated with a milder Rett phenotype, increased the risk for epilepsy (odds ratio [OR] 2.46, confidence interval [CI] 95% 1.3-4.66), but not for severe epilepsy. The p.R255X mutation conferred an increased risk for epilepsy (OR 2.07, CI 95% 1.2-3.59) as well as for severe epilepsy (OR 3.4, CI 95% 1.6-7.3). The p.T158M and p.C306C mutations relatively increased the risk for severe epilepsy (OR 3.09 and 2.69, CI 95% 1.48-6.4 and 1.19-6.05, respectively), but not for epilepsy occurrence. SIGNIFICANCE: Various mutations in the MECP2 gene have a different influence on epilepsy, unrelated to the severity of the general Rett phenotype. This might suggest a site-specific effect of MeCp2 on epileptic pathways. Further investigation of these mechanisms should promote better understanding of epileptogenesis in Rett syndrome.


Assuntos
Bases de Dados Factuais , Epilepsia/diagnóstico , Epilepsia/genética , Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Adolescente , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética/métodos , Humanos , Lactente , Masculino , Adulto Jovem
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