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1.
J Pediatr Genet ; 12(2): 144-149, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37090838

RESUMO

Acute necrotizing encephalopathy (ANE) is clinically characterized by fever, acute alteration of consciousness, seizures, and rapid progression to coma within days of onset of a viral illness occurring in healthy children without evidence of central nervous system infection. Brain magnetic resonance imaging (MRI) shows multiple symmetrical lesions affecting primarily the thalami but also brain stem, putamina, periventricular white matter, and cerebellum. Most cases of ANE are sporadic and nonrecurrent. However, a missense variant in RANBP2 has been identified in some families with recurrent ANE (OMIM # 608033), also named autosomal dominant ANE (ADANE). Clinical manifestation, clinical course, and brain MRI imaging findings of six affected members of two distinct families with ADANE were described. Sequencing revealed heterozygous c.1754C > T variant in RANBP2 (p.Thr585Met) in affected and asymptomatic family members. Only few ADANE families have been reported and it is the first description in South America. Differential diagnosis of Leigh disease and acute disseminated encephalomyelitis is discussed. Our report reinforces incomplete penetrance of ADANE and intrafamilial phenotypic variability of outcome.

2.
Cytogenet Genome Res ; 161(3-4): 160-166, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34107486

RESUMO

Pure partial duplications of the long arm of chromosome 16 are rare and few cases are described with delineation by chromosomal microarray. Data about clinical abnormalities of pure partial 16q duplications are incomplete because many individuals die during the perinatal period. We describe the clinical features of a 47-month-old Brazilian girl with 16q21q24.1 duplication. To the best of our knowledge, she is the first person with this specific chromosome segment duplication, and we compare her phenotype with the only reported individual alive with intermediate-distal pure 16q duplication.


Assuntos
Anormalidades Múltiplas/genética , Transtornos Cromossômicos/genética , Duplicação Cromossômica , Cromossomos Humanos Par 16/genética , Brasil , Pré-Escolar , Bandeamento Cromossômico , Feminino , Humanos , Fenótipo
3.
Am J Med Genet A ; 182(7): 1796-1800, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32420688

RESUMO

Variants in MBTPS1 (membrane-bound transcription factor peptidase, site 1) encoding the protein convertase site-1 protease (S1P) were recently reported in a single individual with skeletal dysplasia and elevated plasma lysosomal enzymes. Here, we report the second individual with this newly described autosomal recessive spondyloepiphyseal dysplasia (OMIM #618392), presenting severe growth retardation, cataract and dysmorphic features, mainly retromicrognathia. Epilepsy and craniosynostosis were novel findings in our proband. She was found to be homozygous for a novel nonsense variant p.Trp983Ter in MBTPS1. In addition, she had normal levels of lysosomal enzyme activity in leukocytes but elevated levels in plasma. Our description confirms the existence of this new skeletal dysplasia and expands the phenotype and genotype of the disease.


Assuntos
Catarata/genética , Doenças por Armazenamento dos Lisossomos/genética , Lisossomos/genética , Pró-Proteína Convertases/genética , Serina Endopeptidases/genética , Catarata/diagnóstico por imagem , Catarata/patologia , Pré-Escolar , Feminino , Humanos , Doenças por Armazenamento dos Lisossomos/sangue , Doenças por Armazenamento dos Lisossomos/diagnóstico por imagem , Doenças por Armazenamento dos Lisossomos/patologia , Lisossomos/enzimologia , Linhagem , Fenótipo
4.
Genet Med ; 22(5): 857-866, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31949312

RESUMO

PURPOSE: Four patients with Saul-Wilson syndrome were reported between 1982 and 1994, but no additional individuals were described until 2018, when the molecular etiology of the disease was elucidated. Hence, the clinical phenotype of the disease remains poorly defined. We address this shortcoming by providing a detailed characterization of its phenotype. METHODS: Retrospective chart reviews were performed and primary radiographs assessed for all 14 individuals. Four individuals underwent detailed ophthalmologic examination by the same physician. Two individuals underwent gynecologic evaluation. Z-scores for height, weight, head circumference and body mass index were calculated at different ages. RESULTS: All patients exhibited short stature, with sharp decline from the mean within the first months of life, and a final height Z-score between -4 and -8.5 standard deviations. The facial and radiographic features evolved over time. Intermittent neutropenia was frequently observed. Novel findings included elevation of liver transaminases, skeletal fragility, rod-cone dystrophy, and cystic macular changes. CONCLUSIONS: Saul-Wilson syndrome presents a remarkably uniform phenotype, and the comprehensive description of our cohort allows for improved understanding of the long-term morbidity of the condition, establishment of follow-up recommendations for affected individuals, and documentation of the natural history into adulthood for comparison with treated patients, when therapeutics become available.


Assuntos
Nanismo , Adulto , Feminino , Humanos , Fenótipo , Estudos Retrospectivos
5.
Am J Hum Genet ; 103(4): 553-567, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30290151

RESUMO

The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.


Assuntos
Síndrome do Cromossomo X Frágil/genética , Transporte Proteico/genética , Proteoglicanas/genética , Proteínas de Transporte Vesicular/genética , Adulto , Substituição de Aminoácidos/genética , Animais , Animais Geneticamente Modificados/genética , Linhagem Celular , Criança , Pré-Escolar , Retículo Endoplasmático/genética , Matriz Extracelular/genética , Feminino , Fibroblastos/patologia , Glicosilação , Complexo de Golgi/genética , Heterozigoto , Humanos , Lactente , Masculino , Peixe-Zebra
6.
Clin Case Rep ; 6(7): 1300-1307, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29988626

RESUMO

We report a patient who was followed for a long time under an ectrodactyly ectodermal dysplasia-clefting (EEC) syndrome and was subsequently diagnosed with a 19q13.11 microdeletion. After a review of the related literature, we suggest testing patients with EEC for 19q13.11 microdeletion and include WTIP and UBA2 to a minimal overlapping region.

7.
Eur J Med Genet ; 61(3): 134-138, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29169895

RESUMO

Gillespie syndrome (GS) [MIM: 206700] is a very rare condition characterized by bilateral iris defect, congenital hypotonia, cerebellar ataxia and intellectual disability. The typical iris anomaly is considered necessary to the diagnosis of GS. Recently, variants in ITPR1 were described causing GS. Non-neurological features were reported in few patients. Here we describe two consanguineous siblings with GS and a novel homozygous ITPR1 pathogenic variant (p.N984fs). They also present a cardiac defect (pulmonary valve stenosis) and one sib had a genitourinary malformation (ureteropelvic junction obstruction). Our report reinforces ITPR1 as the cause of GS and suggests a possible role of ITPR1 in the development of other organs.


Assuntos
Aniridia/genética , Aniridia/patologia , Ataxia Cerebelar/genética , Ataxia Cerebelar/patologia , Homozigoto , Receptores de Inositol 1,4,5-Trifosfato/genética , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Mutação , Brasil , Pré-Escolar , Consanguinidade , Feminino , Humanos , Lactente , Masculino , Linhagem , Irmãos
8.
J Inherit Metab Dis ; 39(3): 331-340, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27038030

RESUMO

BACKGROUND: Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD). This hypothesis-generating study explored clinical phenotypes, metabolic profiles, molecular genetics, and treatment approaches in a cohort of children and adults with ARG1 deficiency to add to our understanding of the underlying pathophysiology. METHODS: Clinical data were retrieved retrospectively from physicians using a questionnaire survey. Plasma aminoacids, guanidinoacetate (GAA), parameters indicating oxidative stress and nitric oxide (NO) synthesis as well as asymmetric dimethylarginine (ADMA) were measured at a single study site. RESULTS: Nineteen individuals with ARG1 deficiency and 19 matched controls were included in the study. In patients, paraparesis, cognitive impairment, and seizures were significantly associated suggesting a shared underlying pathophysiology. In patients plasma GAA exceeded normal ranges and plasma ADMA was significantly elevated. Compared to controls, nitrate was significantly higher, and the nitrite:nitrate ratio significantly lower in subjects with ARG1 deficiency suggesting an advantage for NO synthesis by inducible NO synthase (iNOS) over endothelial NOS (eNOS). Logistic regression revealed no significant impact of any of the biochemical parameters (including arginine, nitrates, ADMA, GAA, oxidative stress) or protein restriction on long-term outcome. CONCLUSION: Three main hypotheses which must be evaluated in a hypothesis driven confirmatory study are delineated from this study: 1) clinical manifestations in ARG1 deficiency are not correlated with arginine, protein intake, ADMA, nitrates or oxidative stress. 2) GAA is elevated and may be a marker or an active part of the pathophysiology of ARG1 deficiency. 3) Perturbations of NO metabolism merit future attention in ARG1 deficiency.


Assuntos
Arginase/genética , Arginase/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/sangue , Distúrbios Congênitos do Ciclo da Ureia/genética , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Adolescente , Adulto , Aminoácidos/sangue , Arginina/análogos & derivados , Arginina/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Glicina/análogos & derivados , Glicina/sangue , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/fisiologia , Fenótipo , Estudos Retrospectivos , Adulto Jovem
9.
Mol Syndromol ; 6(1): 32-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25852445

RESUMO

Sotos syndrome (SoS) is a multiple anomaly, congenital disorder characterized by overgrowth, macrocephaly, distinctive facial features and variable degree of intellectual disability. Haploinsufficiency of the NSD1 gene at 5q35.3, arising from 5q35 microdeletions, point mutations, and partial gene deletions, accounts for a majority of patients with SoS. Recently, mutations and possible pathogenetic rare CNVs, both affecting a few candidate genes for overgrowth, have been reported in patients with Sotos-like overgrowth features. To estimate the frequency of NSD1 defects in the Brazilian SoS population and possibly reveal other genes implicated in the etiopathogenesis of this syndrome, we collected a cohort of 21 Brazilian patients, who fulfilled the diagnostic criteria for SoS, and analyzed the NSD1 and PTEN genes by means of multiplex ligation-dependent probe amplification and mutational screening analyses. We identified a classical NSD1 microdeletion, a novel missense mutation (p.C1593W), and 2 previously reported truncating mutations: p.R1984X and p.V1760Gfs*2. In addition, we identified a novel de novo PTEN gene mutation (p.D312Rfs*2) in a patient with a less severe presentation of SoS phenotype, which did not include pre- and postnatal overgrowth. For the first time, our study implies PTEN in the pathogenesis of SoS and further emphasizes the existence of ethno-geographical differences in NSD1 molecular alterations between patients with SoS from Europe/North America (70-93%) and those from South America (10-19%).

10.
Eur J Med Genet ; 58(5): 279-92, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25792522

RESUMO

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1, and TRPS II, caused by a contiguous gene deletion affecting (amongst others) TRPS1 and EXT1. We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype-phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5 it remained uncertain whether TRPS1 was partially or completely deleted. Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella. The facial manifestations in patients with TRPS I and TRPS II do not show a significant difference. In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened. Nails of fingers and toes are typically thin and dystrophic. The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses. Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally. Variability for all findings, also within a single family, can be marked. Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate in severity. Missense mutations are located exclusively in exon 6 and 7 of TRPS1. Other mutations are located anywhere in exons 4-7. Whole gene deletions are common but have variable breakpoints. Most of the phenotype in patients with TRPS II is explained by the deletion of TRPS1 and EXT1, but haploinsufficiency of RAD21 is also likely to contribute. Genotype-phenotype studies showed that mutations located in exon 6 may have somewhat more pronounced facial characteristics and more marked shortening of hands and feet compared to mutations located elsewhere in TRPS1, but numbers are too small to allow firm conclusions.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Síndrome de Langer-Giedion/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Lactente , Síndrome de Langer-Giedion/patologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Proteínas Repressoras , Adulto Jovem
11.
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
12.
Nat Genet ; 46(8): 815-7, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25017102

RESUMO

Primrose syndrome and 3q13.31 microdeletion syndrome are clinically related disorders characterized by tall stature, macrocephaly, intellectual disability, disturbed behavior and unusual facial features, with diabetes, deafness, progressive muscle wasting and ectopic calcifications specifically occurring in the former. We report that missense mutations in ZBTB20, residing within the 3q13.31 microdeletion syndrome critical region, underlie Primrose syndrome. This finding establishes a genetic link between these disorders and delineates the impact of ZBTB20 dysregulation on development, growth and metabolism.


Assuntos
Anormalidades Múltiplas/genética , Calcinose/genética , Otopatias/genética , Deficiência Intelectual/genética , Atrofia Muscular/genética , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular , Deleção Cromossômica , Cromossomos Humanos Par 3 , Deficiências do Desenvolvimento/genética , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos
13.
J Neuroimaging ; 24(2): 155-60, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-22928720

RESUMO

BACKGROUND AND PURPOSE: Hyperargininemia (HA) is a rare autosomal recessive metabolic disorder and the neuroimaging features of this disease have seldom been reported. Hyperammonemic encephalopathy is uncommon in HA, and the clinical presentation of HA is distinct from other urea cycle disorders. This paper describes the brain MRI findings and a magnetic resonance spectroscopy (MRS) study of a series of Brazilian HA patients. METHODS: Brain MR images were obtained in eight male and two female patients with the classic HA phenotype. Six patients were evaluated twice. Single-voxel (1)H-MRS was also performed in six of the patients. RESULTS: Only 1 patient, with less severe neurological symptoms, had normal MRI images. A variable degree of cerebral atrophy was noted in the other patients, and 3 patients also presented mild symptoms of cerebellar atrophy. MRS indicated no metabolic abnormalities in any patient. CONCLUSIONS: We present the MRI and MRS findings of a large series of HA patients. Variable degrees of brain atrophy and mild cerebellar atrophy were observed, and these findings were not specific. No metabolic abnormality was observed using MRS in this series of patients.


Assuntos
Arginina/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Hiperargininemia/diagnóstico , Hiperargininemia/metabolismo , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Prótons por Ressonância Magnética/métodos , Adolescente , Adulto , Atrofia , Biomarcadores/metabolismo , Criança , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
14.
Pediatr Neurol ; 46(6): 369-74, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22633632

RESUMO

Hyperargininemia is an autosomal recessive metabolic disorder caused by a deficiency of enzyme arginase I. It is a rare pan-ethnic disease with a clinical presentation distinct from that of other urea cycle disorders, and hyperammonemic encephalopathy is not usually observed. Hyperargininemia is one of the few treatable causes of pediatric spastic paraparesis, and can be confused with cerebral palsy. We retrospectively evaluated the clinical onset, neurologic manifestations, progression of abnormalities, electroencephalographic abnormalities, and laboratory findings of 16 Brazilian patients with hyperargininemia. Relevant data about the clinical spectrum and natural history of hyperargininemia are detailed. Progressive spastic diplegia constituted the key clinical abnormality in this group, but variability in clinical presentation and progression were evident in our series. Seizures in hyperargininemia may be more common than reported in previous studies. Features distinguishing hyperargininemia from cerebral palsy and hereditary spastic paraplegia are emphasized in this large series of patients.


Assuntos
Progressão da Doença , Hiperargininemia/diagnóstico , Hiperargininemia/fisiopatologia , Adulto , Paralisia Cerebral/diagnóstico , Paralisia Cerebral/fisiopatologia , Criança , Eletroencefalografia/métodos , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Convulsões/diagnóstico , Convulsões/fisiopatologia , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/fisiopatologia , Adulto Jovem
15.
Eur J Hum Genet ; 20(2): 148-54, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21897445

RESUMO

Smith-Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that encompasses multiple genes including the retinoic acid induced 1, RAI1, gene or a mutation in the RAI1 gene. Here we have evaluated 30 patients with suspected SMS and identified SMS-associated classical 17p11.2 deletions in six patients, an atypical deletion of ~139 kb that partially deletes the RAI1 gene in one patient, and RAI1 gene nonsynonymous alterations of unknown significance in two unrelated patients. The RAI1 mutant proteins showed no significant alterations in molecular weight, subcellular localization and transcriptional activity. Clinical features of patients with or without 17p11.2 deletions and mutations involving the RAI1 gene were compared to identify phenotypes that may be useful in diagnosing patients with SMS.


Assuntos
Cromossomos Humanos Par 17 , Deleção de Sequência , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Deleção Cromossômica , Variações do Número de Cópias de DNA , Fácies , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Mutação , Fenótipo , Transativadores , Adulto Jovem
18.
Pediatr Neurol ; 38(4): 296-9, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18358414

RESUMO

Spinocerebellar ataxia type 3, or Machado-Joseph disease, is an autosomal dominant neurodegenerative disease characterized by a wide spectrum of clinical findings that include progressive cerebellar ataxia. All affected individuals have an expanded CAG repeat mutation in one allele of the ATXN3 gene. An inverse relationship exists between the age of onset and the number of repeats in the abnormal expanded allele. The case described is that of a child with Machado-Joseph disease, daughter of a consanguineous affected couple. She inherited the expanded allele in homozygosity with CAG repeat size similar to that of her parents, and had a distinct early onset (4 years of age) and severe clinical phenotype. This case supports the conclusion that homozygosity aggravates the clinical phenotype. Loss of function of the normal expressed ataxin-3, or possibly aggregation of ataxin-3, may be implicated in disease mechanism.


Assuntos
Homozigoto , Doença de Machado-Joseph/genética , Doença de Machado-Joseph/patologia , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Ataxina-3 , Pré-Escolar , Feminino , Humanos , Linhagem , Fenótipo , Índice de Gravidade de Doença
19.
Am J Hum Genet ; 81(4): 713-25, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17846997

RESUMO

Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.


Assuntos
Doenças dos Gânglios da Base/genética , Adolescente , Adulto , Doenças dos Gânglios da Base/líquido cefalorraquidiano , Doenças dos Gânglios da Base/patologia , Encéfalo/patologia , Calcinose/genética , Calcinose/patologia , Pérnio/genética , Pérnio/patologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Exodesoxirribonucleases/genética , Feminino , Humanos , Lactente , Recém-Nascido , Linfocitose/líquido cefalorraquidiano , Linfocitose/genética , Masculino , Dados de Sequência Molecular , Mutação , Fenótipo , Fosfoproteínas/genética , Ribonuclease H/genética , Síndrome
20.
Arq Neuropsiquiatr ; 64(2A): 303-5, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16791374

RESUMO

Prader-Willi syndrome is a mental retardation genetic disorder also characterized by hypogonadism, hyperphagia and obesity. We report on a four-years-old boy, born to consanguineous parents, with uncommon co-occurrence of Prader-Willi syndrome, 47,XXY karyotype (Klinefelter syndrome) and coronal craniosynostosis. These are different unrelated conditions and it was not described before in the same patient to the best of our knowledge.


Assuntos
Craniossinostoses/genética , Síndrome de Klinefelter/genética , Síndrome de Prader-Willi/genética , Pré-Escolar , Craniossinostoses/complicações , Humanos , Síndrome de Klinefelter/complicações , Masculino , Síndrome de Prader-Willi/complicações
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