Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 19 de 19
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
1.
Am J Hum Genet ; 104(5): 925-935, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982609

RESUMO

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.

2.
Pediatr Neurol ; 84: 21-26, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29859719

RESUMO

BACKGROUND: We attempted to characterize the health-related quality of life in patients with genetically determined leukoencephalopathies as it relates to the severity of clinical features and the presence or absence of a precise molecular diagnosis. METHODS: Health-related quality of life was assessed using the Pediatric Quality of Life Inventory model (Pediatric Quality of Life Inventory 4.0 Self- and Proxy-reports) on 59 patients diagnosed with genetically determined leukoencephalopathies. In total, 38 male and 21 female patients ranging from one to 32 years of age (mean nine years), as well as their parents, completed the Pediatric Quality of Life Inventory health-related quality of life measures. In addition, participants completed detailed standardized clinical assessments or questionnaires. The correlation between health-related quality of life results and the severity of the clinical features, as well as the presence or absence of a molecular diagnosis, were analyzed. RESULTS: Patients with more severe clinical features showed statistically significant lower total Pediatric Quality of Life Inventory scores. More specifically, lower health-related quality of life was noted in children with sialorrhea, gastrostomy, and dystonia and in children who use a wheelchair. CONCLUSIONS: Patients with more severe clinical features experience a lower quality of life. Our study further highlights the importance of addressing both physical and psychosocial issues and discussing perception of quality of life with both parents and children. A larger multicenter prospective study will be needed to further define the burden of these diseases and to identify modifiable factors.

3.
J Child Neurol ; 33(10): 642-650, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29882456

RESUMO

Leukodystrophies and genetic leukoencephalopathies are a heterogeneous group of heritable disorders that affect the glial-axonal unit. As more patients with unsolved leukodystrophies and genetic leukoencephalopathies undergo next generation sequencing, causative mutations in genes leading to central hypomyelination are being identified. Two such individuals presented with arthrogryposis multiplex congenita, congenital hypomyelinating neuropathy, and central hypomyelination with early respiratory failure. Whole exome sequencing identified biallelic mutations in the CNTNAP1 gene: homozygous c.1163G>C (p.Arg388Pro) and compound heterozygous c.967T>C (p.Cys323Arg) and c.319C>T (p.Arg107*). Sural nerve and quadriceps muscle biopsies demonstrated progressive, severe onion bulb and axonal pathology. By ultrastructural evaluation, septate axoglial paranodal junctions were absent from nodes of Ranvier. Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and reduced diffusion in the globus pallidus in both patients. These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the absence of septate paranodal junctions and central hypomyelination with neurodegeneration in CNTNAP1-associated arthrogryposis multiplex congenita.

4.
Am J Med Genet A ; 176(6): 1443-1448, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29696782

RESUMO

Early-onset epileptic encephalopathies (EOEEs) are a genetically heterogeneous collection of severe epilepsies often associated with psychomotor regression. Mutations in SZT2, a known seizure threshold regulator gene, are a newly identified cause of EOEE. We present an individual with EOEE, macrocephaly, and developmental regression with compound heterozygous mutations in SZT2 as identified by whole exome sequencing. Serial imaging characterized the novel finding of progressive loss of central myelination. This case expands our clinical understanding of the SZT2-phenotype and emphasizes the role of this gene in the diagnostic investigation for EOEE and leukoencephalopathies.

5.
Mol Genet Metab ; 122(1-2): 18-32, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28863857

RESUMO

Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.


Assuntos
Doenças Desmielinizantes/terapia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/terapia , Leucoencefalopatias/terapia , Doenças por Armazenamento dos Lisossomos/prevenção & controle , Doenças por Armazenamento dos Lisossomos/terapia , Insuficiência Adrenal/terapia , Adulto , Criança , Doenças Desmielinizantes/congênito , Feminino , Vesícula Biliar/patologia , Predisposição Genética para Doença , Humanos , Leucoencefalopatias/congênito , Masculino , Qualidade de Vida
6.
Neurogenetics ; 18(4): 185-194, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28842795

RESUMO

An X-linked condition characterized by the combination of hypomyelinating leukodystrophy and spondylometaphyseal dysplasia (H-SMD) has been observed in only four families, with linkage to Xq25-27, and recent genetic characterization in two families with a common AIFM1 mutation. In our study, 12 patients (6 families) with H-SMD were identified and underwent comprehensive assessment accompanied by whole-exome sequencing (WES). Pedigree analysis in all families was consistent with X-linked recessive inheritance. Presentation typically occurred between 12 and 36 months. In addition to the two disease-defining features of spondylometaphyseal dysplasia and hypomyelination on MRI, common clinical signs and symptoms included motor deterioration, spasticity, tremor, ataxia, dysarthria, cognitive defects, pulmonary hypertension, nystagmus, and vision loss due to retinopathy. The course of the disease was slowly progressive. All patients had maternally inherited or de novo mutations in or near exon 7 of AIFM1, within a region of 70 bp, including synonymous and intronic changes. AIFM1 mutations have previously been associated with neurologic presentations as varied as intellectual disability, hearing loss, neuropathy, and striatal necrosis, while AIFM1 mutations in this small region present with a distinct phenotype implicating bone. Analysis of cell lines derived from four patients identified significant reductions in AIFM1 mRNA and protein levels in osteoblasts. We hypothesize that AIFM1 functions in bone metabolism and myelination and is responsible for the unique phenotype in this condition.


Assuntos
Fator de Indução de Apoptose/genética , Genes Ligados ao Cromossomo X/genética , Predisposição Genética para Doença , Mutação/genética , Humanos , Deficiência Intelectual/genética , Masculino , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Osteocondrodisplasias/genética , Linhagem , Fenótipo , Análise de Sequência de DNA
7.
J Med Genet ; 54(5): 330-337, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27799409

RESUMO

BACKGROUND: Acyl-CoA binding domain containing protein 5 (ACBD5) is a peroxisomal membrane protein with a cytosolic acyl-CoA binding domain. Because of its acyl-CoA binding domain, ACBD5 has been assumed to function as an intracellular carrier of acyl-CoA esters. In addition, a role for ACBD5 in pexophagy has been suggested. However, the precise role of ACBD5 in peroxisomal metabolism and/or functioning has not yet been established. Previously, a genetic ACBD5 deficiency was identified in three siblings with retinal dystrophy and white matter disease. We identified a pathogenic mutation in ACBD5 in another patient and studied the consequences of the ACBD5 defect in patient material and in ACBD5-deficient HeLa cells to uncover this role. METHODS: We studied a girl who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and retinal dystrophy. We performed biochemical, cell biological and molecular studies in patient material and in ACBD5-deficient HeLa cells generated by CRISPR-Cas9 genome editing. RESULTS: We identified a homozygous deleterious indel mutation in ACBD5, leading to complete loss of ACBD5 protein in the patient. Our studies showed that ACBD5 deficiency leads to accumulation of very long-chain fatty acids (VLCFAs) due to impaired peroxisomal ß-oxidation. No effect on pexophagy was found. CONCLUSIONS: Our investigations strongly suggest that ACBD5 plays an important role in sequestering C26-CoA in the cytosol and thereby facilitates transport into the peroxisome and subsequent ß-oxidation. Accordingly, ACBD5 deficiency is a novel single peroxisomal enzyme deficiency caused by impaired VLCFA metabolism, leading to retinal dystrophy and white matter disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Ácidos Graxos/metabolismo , Proteínas de Membrana/deficiência , Peroxissomos/metabolismo , Acil Coenzima A/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Autofagia , Pré-Escolar , DNA Complementar/genética , Feminino , Fibroblastos/metabolismo , Teste de Complementação Genética , Células HeLa , Humanos , Lactente , Imagem por Ressonância Magnética , Proteínas de Membrana/metabolismo , Pele/patologia
8.
Pediatr Neurol ; 66: 59-62, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27843092

RESUMO

BACKGROUND: Leukoencephalopathy with temporal lobe cysts may be associated with monogenetic conditions such as Aicardi-Goutières syndrome or RNASET2 mutations and with congenital infections such as cytomegalovirus. In view of the fact that congenital cytomegalovirus is difficult to confirm outside the neonatal period, excluding a Mendelian disorder is extremely relevant, changing family planning and medical management in affected families. We performed diagnostic testing in individuals with leukoencephalopathy with temporal lobe cysts without a definitive diagnosis of congenital cytomegalovirus infection. METHODS: We reviewed a large-scale biorepository of patients with unsolved leukodystrophies and identified two individuals with required for meiotic nuclear division 1 (RMND1) mutations and similar magnetic resonance imaging (MRI) features, including temporal lobe cysts. Ten additional subjects with confirmed RMND1 mutations were identified as part of a separate disease specific cohort. Brain MRIs from all 12 individuals were reviewed for common neuroradiological features. RESULTS: MRI features in RMND1 mutations included temporal lobe swelling, with rarefaction and cystic evolution, enlarged tips of the temporal lobes, and multifocal subcortical white matter changes with confluent periatrial T2 signal hyperintensity. A combination of these features was present in ten of the 12 individuals reviewed. CONCLUSIONS: Despite the small number of reported individuals with RMND1 mutations, a clinically recognizable phenotype of leukoencephalopathy with temporal lobe swelling, rarefaction, and cystic changes has emerged in a subset of individuals. Careful clinical phenotyping, including for lactic acidosis, deafness, and severe muscle involvement seen in RMND1 mutation positive individuals, and MRI pattern recognition will be important in differentiating these patients from children with congenital infections like cytomegalovirus.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/genética , Infecções por Citomegalovirus/congênito , Surdez/genética , Leucoencefalopatias/genética , Neoplasias Encefálicas/diagnóstico por imagem , Criança , Pré-Escolar , Estudos de Coortes , Cistos/diagnóstico por imagem , Infecções por Citomegalovirus/diagnóstico por imagem , Infecções por Citomegalovirus/genética , Surdez/diagnóstico por imagem , Diagnóstico Diferencial , Humanos , Lactente , Leucoencefalopatias/diagnóstico por imagem , Mutação , Fenótipo , Lobo Temporal/diagnóstico por imagem
9.
Ann Neurol ; 79(6): 1031-1037, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27159321

RESUMO

Here we report whole exome sequencing (WES) on a cohort of 71 patients with persistently unresolved white matter abnormalities with a suspected diagnosis of leukodystrophy or genetic leukoencephalopathy. WES analyses were performed on trio, or greater, family groups. Diagnostic pathogenic variants were identified in 35% (25 of 71) of patients. Potentially pathogenic variants were identified in clinically relevant genes in a further 7% (5 of 71) of cases, giving a total yield of clinical diagnoses in 42% of individuals. These findings provide evidence that WES can substantially decrease the number of unresolved white matter cases. Ann Neurol 2016;79:1031-1037.


Assuntos
Análise Mutacional de DNA , Exoma/genética , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Substância Branca/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Leucoencefalopatias/patologia , Masculino , Mutação , Adulto Jovem
10.
Am J Hum Genet ; 96(4): 675-81, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25817015

RESUMO

Mutations in genes encoding aminoacyl-tRNA synthetases are known to cause leukodystrophies and genetic leukoencephalopathies-heritable disorders that result in white matter abnormalities in the central nervous system. Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI. Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase (AARS) in these two unrelated families: the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS. The two identified mutations were found to result in a significant reduction in function. Mutations in AARS were previously associated with an autosomal-dominant inherited form of axonal neuropathy, Charcot-Marie-Tooth disease type 2N (CMT2N). The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations.


Assuntos
Anormalidades Múltiplas/genética , Alanina-tRNA Ligase/genética , Epilepsia/genética , Modelos Moleculares , Bainha de Mielina/patologia , Doenças do Sistema Nervoso Periférico/genética , Fenótipo , Anormalidades Múltiplas/patologia , Alanina-tRNA Ligase/química , Sequência de Aminoácidos , Sequência de Bases , Epilepsia/patologia , Genes Recessivos/genética , Humanos , Lactente , Recém-Nascido , Dados de Sequência Molecular , Mutação/genética , Doenças do Sistema Nervoso Periférico/patologia , Estudos Prospectivos , Análise de Sequência de DNA , Síndrome , Estados Unidos
11.
Mol Genet Metab ; 114(4): 527-36, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25684057

RESUMO

Leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have historically had no etiologic or disease specific therapeutic approaches. Recently, a greater understanding of the pathologic mechanisms associated with leukodystrophies has allowed clinicians and researchers to prioritize treatment strategies and advance research in therapies for specific disorders, some of which are on the verge of pilot or Phase I/II clinical trials. This shifts the care of leukodystrophy patients from the management of the complex array of symptoms and sequelae alone to targeted therapeutics. The unmet needs of leukodystrophy patients still remain an overwhelming burden. While the overwhelming consensus is that these disorders collectively are symptomatically treatable, leukodystrophy patients are in need of advanced therapies and if possible, a cure.


Assuntos
Doenças Desmielinizantes/terapia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/terapia , Leucodistrofia Metacromática/terapia , Leucoencefalopatias/terapia , Encefalopatias/prevenção & controle , Encefalopatias/terapia , Doenças Desmielinizantes/prevenção & controle , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/prevenção & controle , Humanos , Leucodistrofia Metacromática/prevenção & controle , Leucoencefalopatias/prevenção & controle
12.
Mol Genet Metab ; 114(4): 501-515, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25655951

RESUMO

Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison's disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive--many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders.


Assuntos
Doenças Desmielinizantes/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças por Armazenamento dos Lisossomos/diagnóstico , Adrenoleucodistrofia/diagnóstico , Anodontia/diagnóstico , Humanos , Imagem por Ressonância Magnética
13.
Am J Med Genet A ; 167A(2): 296-312, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25604658

RESUMO

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.


Assuntos
Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , RNA Helicases DEAD-box/genética , Exodesoxirribonucleases/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Mutação , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Fenótipo , Fosfoproteínas/genética , Ribonuclease H/genética , Estudos de Associação Genética , Genótipo , Humanos , Helicase IFIH1 Induzida por Interferon , Interferons/sangue , Interferons/líquido cefalorraquidiano , Pterinas/líquido cefalorraquidiano , Proteína 1 com Domínio SAM e Domínio HD
14.
Mol Genet Metab ; 114(4): 516-26, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25577286

RESUMO

Leukodystrophies are inherited disorders whose primary pathophysiology consists of abnormal deposition or progressive disruption of brain myelin. Leukodystrophy patients manifest many of the same symptoms and medical complications despite the wide spectrum of genetic origins. Although no definitive cures exist, all of these conditions are treatable. This report provides the first expert consensus on the recognition and treatment of medical and psychosocial complications associated with leukodystrophies. We include a discussion of serious and potentially preventable medical complications and propose several preventive care strategies. We also outline the need for future research to prioritize clinical needs and subsequently develop, validate, and optimize specific care strategies.


Assuntos
Doenças Desmielinizantes , Leucoencefalopatias , Doenças Desmielinizantes/diagnóstico , Doenças Desmielinizantes/terapia , Gerenciamento Clínico , Humanos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/terapia , Bainha de Mielina/fisiologia
15.
Genet Med ; 17(9): 753-6, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25521335

RESUMO

PURPOSE: This study examines the analytic validity of a software tool designed to provide individuals with risk assessments for colorectal cancer based on personal health and family history information. The software is compatible with the US Surgeon General's My Family Health Portrait (MFHP). METHODS: An algorithm for risk assessment was created using accepted colorectal risk assessment guidelines and programmed into a software tool (MFHP). Risk assessments derived from 150 pedigrees using the MFHP tool were compared with "gold standard" risk assessments developed by three expert cancer genetic counselors. RESULTS: Genetic counselor risk assessments showed substantial, but not perfect, agreement. MFHP risk assessments for colorectal cancer yielded a sensitivity for colorectal cancer risk of 81% (95% confidence interval: 54-96%) and specificity of 90% (95% confidence interval: 83-94%), as compared with genetic counselor pedigree review. The positive predictive value for risk for MFHP was 48% (95% confidence interval: 29-68%), whereas the negative predictive value was 98% (95% confidence interval: 93-99%). Agreement between MFHP and genetic counselor pedigree review was moderate (κ = 0.54). CONCLUSION: The analytic validity of the MFHP colorectal cancer risk assessment software is similar to those of other types of screening tools used in primary care. Future investigations should explore the clinical validity and utility of the software in diverse population groups.Genet Med 17 9, 753-756.


Assuntos
Neoplasias Colorretais/genética , Anamnese/métodos , Medição de Risco/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Neoplasias Colorretais/diagnóstico , Saúde da Família , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Anamnese/normas , Pessoa de Meia-Idade , Linhagem , Medição de Risco/normas , Software , Estados Unidos
16.
Neurology ; 84(3): 226-30, 2015 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-25527264

RESUMO

OBJECTIVE: To describe the expanding clinical spectrum of a recently described hereditary leukoencephalopathy, hypomyelination with brainstem and spinal cord involvement and leg spasticity, which is caused by mutations in the aspartyl tRNA-synthetase encoding gene DARS, including patients with an adolescent onset. METHODS: Three patients with mutations in DARS were identified by combining MRI pattern recognition and genetic analysis. RESULTS: One patient had the typical infantile presentation, but 2 patients with onset in late adolescence had a disease mimicking an acquired inflammatory CNS disorder. Adolescent-onset patients presented with subacute spastic paraplegia and had positive response to steroids. They had only minor focal supratentorial white matter abnormalities, but identical spinal cord changes involving dorsal columns and corticospinal tracts. Clinical presentation included subacute spastic paraplegia with partial improvement on steroids. CONCLUSIONS: Focal T2 hyperintense white matter changes on brain MRI in combination with spinal cord signal abnormalities usually suggest acquired inflammatory conditions such as multiple sclerosis, especially in the context of relapsing course and a positive response to steroid treatment. Adolescents with mutations in DARS can present with a comparable clinical picture, broadening the clinical spectrum of hypomyelination with brainstem and spinal cord involvement and leg spasticity.


Assuntos
Aspartato-tRNA Ligase/genética , Encefalite/fisiopatologia , Leucoencefalopatias/tratamento farmacológico , Leucoencefalopatias/genética , Mutação/genética , Esteroides/uso terapêutico , Idade de Início , Córtex Cerebral/patologia , Bases de Dados Factuais , Feminino , Humanos , Lactente , Ácido Láctico/metabolismo , Leucoencefalopatias/complicações , Leucoencefalopatias/diagnóstico , Imagem por Ressonância Magnética , Masculino , Espasticidade Muscular/etiologia , Medula Espinal/patologia , Adulto Jovem
17.
Neurology ; 83(21): 1898-905, 2014 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-25339210

RESUMO

OBJECTIVE: To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B. METHODS: We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. RESULTS: The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the common c.1568T>A POLR3B mutation on one allele, homozygosity for which causes a mild phenotype. Systematic MRI review revealed that the combination of hypomyelination with relative T2 hypointensity of the ventrolateral thalamus, optic radiation, globus pallidus, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum suggests the diagnosis. CONCLUSIONS: 4H is a well-recognizable clinical entity if all features are present. Mutations in POLR3A are associated with a more severe clinical course. MRI characteristics are helpful in addressing the diagnosis, especially if patients lack the cardinal non-neurologic features.


Assuntos
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Mutação/genética , RNA Polimerase III/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Adulto Jovem
18.
Neurology ; 83(10): 898-902, 2014 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-25085639

RESUMO

OBJECTIVE: We present a series of unrelated patients with isolated hypomyelination, with or without mild cerebellar atrophy, and de novo TUBB4A mutations. METHODS: Patients in 2 large institutional review board-approved leukodystrophy bioregistries at Children's National Medical Center and Montreal Children's Hospital with similar MRI features had whole-exome sequencing performed. MRIs and clinical information were reviewed. RESULTS: Five patients who presented with hypomyelination without the classic basal ganglia abnormalities were found to have novel TUBB4A mutations through whole-exome sequencing. Clinical and imaging characteristics were reviewed suggesting a spectrum of clinical manifestations. CONCLUSION: Hypomyelinating leukodystrophies remain a diagnostic challenge with a large percentage of unresolved cases. This finding expands the phenotype of TUBB4A-related hypomyelinating conditions beyond hypomyelination with atrophy of the basal ganglia and cerebellum. TUBB4A mutation screening should be considered in cases of isolated hypomyelination or hypomyelination with nonspecific cerebellar atrophy.


Assuntos
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Sistema de Registros , Tubulina (Proteína)/genética , Adolescente , Atrofia/patologia , Gânglios da Base/patologia , Cerebelo/patologia , Criança , Pré-Escolar , Exoma , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Fenótipo
19.
J Genet Couns ; 23(5): 734-41, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24777551

RESUMO

Uniparental disomy is a genetic cause of disease that may result in the inheritance of an autosomal recessive condition. A child with developmental delay and hypotonia was seen and found to have severely abnormal myelination. Lysosomal enzyme testing identified an isolated deficiency of beta-galactosidase. Subsequently, homozygous missense mutations in the galactosidase, beta 1 (GLB1) gene on chromosome 3 were found. Parental testing confirmed inheritance of two copies of the same mutated maternal GLB1 gene, and no paternal copy. SNP analysis was also done to confirm paternity. The patient was ultimately diagnosed with autosomal recessive GM1 gangliosidosis caused by maternal uniparental isodisomy. We provide a review of this patient and others in which uniparental disomy (UPD) of a non-imprinted chromosome unexpectedly caused an autosomal recessive condition. This is the first case of GM1 gangliosidosis reported in the literature to have been caused by UPD. It is important for genetic counselors and other health care providers to be aware of the possibility of autosomal recessive disease caused by UPD. UPD as a cause of autosomal recessive disease drastically changes the recurrence risk for families, and discussions surrounding UPD can be complex. Working with families to understand UPD when it occurs requires a secure and trusting counselor-family relationship.


Assuntos
Gangliosidose GM1/genética , Dissomia Uniparental , Feminino , Humanos , Lactente , Polimorfismo de Nucleotídeo Único
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA