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1.
J Child Neurol ; 28(2): 198-203, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23266945

RESUMO

Schizencephaly is a rare malformation of cortical development characterized by congenital clefts extending from the pial surface to the lateral ventricle that are lined by heterotopic gray matter. The clinical presentation is variable and can include motor or cognitive impairment and epilepsy. The causes of schizencephaly are heterogeneous and can include teratogens, prenatal infection, or maternal trauma. Reported genetic causes include chromosomal aneuploidy, EMX2 mutations, and possible autosomal recessive familial cases based on recurrence in siblings. In an effort to identify risk factors for schizencephaly, we conducted a survey of 48 parents or primary caretakers of patients with schizencephaly born between 1983 and 2004. We discovered that young maternal age, lack of prenatal care, and alcohol use were all significantly associated with risk of schizencephaly. Our results suggest that there are important nongenetic, intrauterine events that predispose to schizencephaly.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Malformações do Desenvolvimento Cortical/etiologia , Idade Materna , Cuidado Pré-Natal , Adolescente , Adulto , Transtornos Cognitivos/etiologia , Epilepsia/etiologia , Feminino , Inquéritos Epidemiológicos , Proteínas de Homeodomínio/genética , Humanos , Modelos Logísticos , Imageamento por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/patologia , Malformações do Desenvolvimento Cortical/psicologia , Pessoa de Meia-Idade , Transtornos dos Movimentos/etiologia , Mutação/genética , Estudos Retrospectivos , Fatores de Risco , Fatores de Transcrição/genética , Adulto Jovem
2.
Nat Genet ; 42(3): 245-9, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20118933

RESUMO

Maintenance of DNA integrity is crucial for all cell types, but neurons are particularly sensitive to mutations in DNA repair genes, which lead to both abnormal development and neurodegeneration. We describe a previously unknown autosomal recessive disease characterized by microcephaly, early-onset, intractable seizures and developmental delay (denoted MCSZ). Using genome-wide linkage analysis in consanguineous families, we mapped the disease locus to chromosome 19q13.33 and identified multiple mutations in PNKP (polynucleotide kinase 3'-phosphatase) that result in severe neurological disease; in contrast, a splicing mutation is associated with more moderate symptoms. Unexpectedly, although the cells of individuals carrying this mutation are sensitive to radiation and other DNA-damaging agents, no such individual has yet developed cancer or immunodeficiency. Unlike other DNA repair defects that affect humans, PNKP mutations universally cause severe seizures. The neurological abnormalities in individuals with MCSZ may reflect a role for PNKP in several DNA repair pathways.


Assuntos
Enzimas Reparadoras do DNA/genética , Distúrbios no Reparo do DNA/genética , Microcefalia/genética , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Convulsões/genética , Criança , Cromossomos Humanos Par 19 , Consanguinidade , Reparo do DNA/genética , Distúrbios no Reparo do DNA/complicações , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Embrião de Mamíferos , Família , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Masculino , Microcefalia/complicações , Mutação/fisiologia , Linhagem , Polimorfismo de Nucleotídeo Único , Convulsões/complicações
3.
Am J Hum Genet ; 85(6): 897-902, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20004763

RESUMO

Although autosomal genes are increasingly recognized as important causes of intellectual disability, very few of them are known. We identified a genetic locus for autosomal-recessive nonsyndromic intellectual disability associated with variable postnatal microcephaly through homozygosity mapping of a consanguineous Israeli Arab family. Sequence analysis of genes in the candidate interval identified a nonsense nucleotide change in the gene that encodes TRAPPC9 (trafficking protein particle complex 9, also known as NIBP), which has been implicated in NF-kappaB activation and possibly in intracellular protein trafficking. TRAPPC9 is highly expressed in the postmitotic neurons of the cerebral cortex, and MRI analysis of affected patients shows defects in axonal connectivity. This suggests essential roles of TRAPPC9 in human brain development, possibly through its effect on NF-kappaB activation and protein trafficking in the postmitotic neurons of the cerebral cortex.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/fisiologia , Deficiência Intelectual/genética , Microcefalia/genética , Mutação , Animais , Encéfalo/metabolismo , Mapeamento Cromossômico , Consanguinidade , Regulação da Expressão Gênica no Desenvolvimento , Genes Recessivos , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Imageamento por Ressonância Magnética/métodos , Camundongos , Mitose , NF-kappa B/genética , Neurônios/metabolismo
4.
Science ; 321(5886): 218-23, 2008 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-18621663

RESUMO

To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of "homozygosity mapping" in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.


Assuntos
Transtorno Autístico/genética , Mapeamento Cromossômico , Mutação , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Transtorno Autístico/fisiopatologia , Encéfalo/metabolismo , Caderinas/genética , Consanguinidade , Feminino , Forminas , Deleção de Genes , Dosagem de Genes , Regulação da Expressão Gênica , Genes Recessivos , Predisposição Genética para Doença , Homozigoto , Humanos , Escore Lod , Masculino , Neurônios/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Polimorfismo de Nucleotídeo Único , Protocaderinas , Ratos , Trocadores de Sódio-Hidrogênio/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
5.
Am J Med Genet A ; 143A(15): 1692-8, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17603806

RESUMO

Patients with distal deletions of chromosome 1q have a recognizable syndrome that includes microcephaly, hypoplasia or agenesis of the corpus callosum, and psychomotor retardation. Although these symptoms have been attributed to deletions of 1q42-1q44, the minimal chromosomal region involved has not been identified. Using microsatellite and single nucleotide polymorphism (SNP) markers, we have mapped the deleted regions in seven patients with terminal deletions of chromosome 1q to define a 2.0-Mb microcephaly critical region including the 1q43-1q44 boundary and no more than 11 genes.


Assuntos
Agenesia do Corpo Caloso , Deleção Cromossômica , Cromossomos Humanos Par 1 , Microcefalia/genética , Adolescente , Encéfalo/patologia , Criança , Mapeamento Cromossômico , DNA/sangue , DNA/genética , DNA/isolamento & purificação , Feminino , Humanos , Cariotipagem , Imageamento por Ressonância Magnética , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Transtornos Psicomotores/genética , Convulsões/genética
6.
Am J Med Genet A ; 143A(12): 1313-6, 2007 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-17506092

RESUMO

Schizencephaly is a brain malformation disorder characterized by one or more full-thickness clefts through the cerebral cortex. While initial reports suggested that EMX2 mutations are a common cause of schizencephaly, more recent evidence suggests that EMX2 mutations are not a common cause of this malformation. To determine the frequency of EMX2 mutations in patients with schizencephaly, we sequenced EMX2 in a cohort of 84 affected probands. No pathologic mutations were identified in this cohort, suggesting that EMX2 mutations are an uncommon cause of schizencephaly.


Assuntos
Proteínas de Homeodomínio/genética , Malformações do Desenvolvimento Cortical/genética , Fatores de Transcrição/genética , Córtex Cerebral/patologia , Análise Mutacional de DNA , Primers do DNA , Genótipo , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Malformações do Desenvolvimento Cortical/patologia , Polimorfismo de Nucleotídeo Único/genética
7.
Am J Med Genet A ; 140(14): 1504-10, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16761294

RESUMO

Cerebral palsy (CP) is defined as any nonprogressive motor deficits resulting from cerebral abnormalities that occur in the prenatal or perinatal period. Symptoms become apparent during the first year of life. Genetic forms of CP account for about 2% in European populations but are thought to cause a substantial proportion in consanguineous families. We have identified a large consanguineous family from Oman with spastic diplegia, microcephaly, and mental retardation. Additional manifestations include hyperreflexia, clumsiness, unstable gait, drooling, and dysarthria. There was phenotypic variability among different individuals, but spastic diplegia, microcephaly, and mental retardation were three constant traits present in all affected individuals.


Assuntos
Paralisia Cerebral/genética , Deficiência Intelectual/genética , Microcefalia/genética , Adolescente , Criança , Consanguinidade , Feminino , Genes Recessivos , Humanos , Imageamento por Ressonância Magnética , Masculino , Microcefalia/patologia , Omã , Linhagem , Fenótipo , Síndrome
8.
Epilepsia ; 47(1): 211-4, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16417552

RESUMO

PURPOSE: Familial periventricular heterotopia (PH) represents a disorder of neuronal migration resulting in multiple gray-matter nodules along the lateral ventricular walls. Prior studies have shown that mutations in the filamin A (FLNA) gene can cause PH through an X-linked dominant pattern. Heterozygotic female patients usually remain asymptomatic until the second or third decade of life, when they may have predominantly focal seizures, whereas hemizygotic male fetuses typically die in utero. Recent studies have also reported mutations in FLNA in male patients with PH who are cognitively normal. We describe PH in three male siblings with PH due to FLNA, severe developmental regression, and West syndrome. METHODS: The study includes the three affected brothers and their parents. Video-EEG recordings and magnetic resonance image (MRI) scanning were performed on all individuals. Mutations for FLNA were detected by using polymerase chain reaction (PCR) on genomic DNA followed by single-stranded conformational polymorphism (SSCP) analysis or sequencing. RESULTS: Two of the siblings are monozygotic twins, and all had West syndrome with hypsarrhythmia on EEG. MRI of the brain revealed periventricular nodules of cerebral gray-matter intensity, typical for PH. Mutational analyses demonstrated a cytosine-to-thymidine missense mutation (c. C1286T), resulting in a threonine-to-methionine amino acid substitution in exon 9 of the FLNA gene. CONCLUSIONS: The association between PH and West syndrome, to our knowledge, has not been previously reported. Males with PH have been known to harbor FLNA mutations, although uniformly, they either show early lethality or survive and have a normal intellect. The current studies show that FLNA mutations can cause periventricular heterotopia, developmental regression, and West syndrome in male patients, suggesting that this type of FLNA mutation may contribute to severe neurologic deficits.


Assuntos
Encefalopatias/genética , Coristoma/genética , Proteínas Contráteis/genética , Deficiências do Desenvolvimento/genética , Proteínas dos Microfilamentos/genética , Mutação/genética , Espasmos Infantis/genética , Encefalopatias/epidemiologia , Encefalopatias/patologia , Ventrículos Cerebrais/patologia , Coristoma/epidemiologia , Coristoma/patologia , Análise Mutacional de DNA , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/patologia , Eletroencefalografia/estatística & dados numéricos , Feminino , Filaminas , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Genótipo , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Fatores Sexuais , Espasmos Infantis/epidemiologia , Gravação de Videoteipe
9.
Ann Neurol ; 58(5): 680-7, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16240336

RESUMO

Human cerebral cortical polymicrogyria is a heterogeneous disorder, with only one known gene (GPR56) associated with an apparently distinctive phenotype, termed bilateral frontoparietal polymicrogyria (BFPP). To define the range of abnormalities that could be caused by human GPR56 mutations and to establish diagnostic criteria for BFPP, we analyzed the GPR56 gene in a cohort of 29 patients with typical BFPP. We identified homozygous GPR56 mutations in all 29 patients with typical BFPP. The total of 11 GPR56 mutations found represented a variety of distinct founder mutations in various populations throughout the world. In addition, we analyzed five patients with BFPP who did not show GPR56 mutation and found that they define a clinically, radiographically, and genetically distinct syndrome that we termed BFPP2. Finally, we studied seven patients with a variety of other polymicrogyria syndromes including bilateral frontal polymicrogyria, bilateral perisylvian polymicrogyria, and bilateral generalized polymicrogyria. No GPR56 mutation was found in these patients. This study provides a molecular confirmation of the BFPP phenotype and provides the wherewithal for diagnostic screening.


Assuntos
Encefalopatias/genética , Mutação , Malformações do Sistema Nervoso/genética , Fenótipo , Receptores Acoplados a Proteínas G/genética , Adolescente , Adulto , Encefalopatias/patologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Saúde da Família , Feminino , Genótipo , Humanos , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino , Malformações do Sistema Nervoso/patologia , Linhagem
10.
Am J Med Genet A ; 133A(1): 53-7, 2005 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-15637732

RESUMO

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder of infancy characterized by hydrocephalus, agyria, retinal dysplasia, congenital muscular dystrophy, and over migration of neurons through a disrupted pial surface resulting in leptomeningeal heterotopia. Although previous work identified mutations in the o-mannosyl transferase, POMT1, in 6 out of 30 WWS families [Beltran-Valero de Bernabe et al., 2002], the incidence of POMT1 mutations in WWS is not known. We sequenced the entire coding region of POMT1 in 30 consecutive, unselected patients with classic WWS. Two novel heterozygous mutations were found in two patients from non-consanguineous parents, whereas 28 other patients failed to show any POMT1 mutations. One patient was found to be heterozygous for a transition, g.1233T > A, which predicts p.Y352X. A second patient was found also to be heterozygous for a transition g.1790C > G, which predicts p.S537R. As an additional determination of the frequency of the POMT1 mutations in WWS, we tested for linkage of WWS to POMT1 in six consanguineous families. All six demonstrated heterozygosity and negative LOD scores at the POMT1 locus. From these data we show that POMT1 is an uncommon cause of WWS, the incidence of coding region mutations in this population of WWS being less than 7%. We conclude that while the incidence of POMT1 mutations in WWS can be as high as 20% as reported by Beltran-Valero de Bernabe et al. [2002] and it can be as low as approximately 7%, as reported here.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades do Olho , Manosiltransferases/genética , Distrofias Musculares/patologia , Mutação , Anormalidades Múltiplas/etnologia , Anormalidades Múltiplas/patologia , Sequência de Bases , Cromossomos Humanos Par 9/genética , Consanguinidade , DNA/química , DNA/genética , Análise Mutacional de DNA , Feminino , Ligação Genética , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Linhagem , Polimorfismo de Nucleotídeo Único , Síndrome
11.
Nat Genet ; 36(9): 1008-13, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15322546

RESUMO

Joubert syndrome is a congenital brain malformation of the cerebellar vermis and brainstem with abnormalities of axonal decussation (crossing in the brain) affecting the corticospinal tract and superior cerebellar peduncles. Individuals with Joubert syndrome have motor and behavioral abnormalities, including an inability to walk due to severe clumsiness and 'mirror' movements, and cognitive and behavioral disturbances. Here we identified a locus associated with Joubert syndrome, JBTS3, on chromosome 6q23.2-q23.3 and found three deleterious mutations in AHI1, the first gene to be associated with Joubert syndrome. AHI1 is most highly expressed in brain, particularly in neurons that give rise to the crossing axons of the corticospinal tract and superior cerebellar peduncles. Comparative genetic analysis of AHI1 indicates that it has undergone positive evolutionary selection along the human lineage. Therefore, changes in AHI1 may have been important in the evolution of human-specific motor behaviors.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Deficiências do Desenvolvimento/genética , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Adaptadoras de Transporte Vesicular , Animais , Encéfalo/anormalidades , Encéfalo/embriologia , Encéfalo/metabolismo , Tronco Encefálico/anormalidades , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Camundongos , Dados de Sequência Molecular , Linhagem , Filogenia , Síndrome
12.
Brain Dev ; 26(5): 326-34, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15165674

RESUMO

Periventricular heterotopia (PH) represents a neuronal migration disorder that results in gray matter nodules along the lateral ventricles beneath an otherwise normal appearing cortex. While prior reports have shown that mutations in the filamin A (FLNA) gene can cause X-linked dominant PH, an increasing number of studies suggest the existence of additional PH syndromes. Further classification of these cortical malformation syndromes associated with PH allows for determination of the causal genes. Here we report three familial cases of PH with hydrocephalus. One pedigree has a known FLNA mutation with hydrocephalus occurring in the setting of valproic acid exposure. Another pedigree demonstrated possible linkage to the Xq28 locus including FLNA, although uncharacteristically a male was affected and sequencing of the FLNA gene in this individual revealed no mutation. However, in the third family with an autosomal mode of inheritance, microsatellite analysis ruled out linkage with the FLNA gene. Routine karyotyping and fluorescent in situ hybridization using BAC probes localized to FLNA also showed no evidence of genomic rearrangement. Western blot analysis of one of the affected individuals demonstrated normal expression of the FLNA protein. Lastly, sequencing of greater than 95% of the FLNA gene in an affected member failed to demonstrate a mutation. In conclusion, these findings demonstrate the etiological heterogeneity of PH with hydrocephalus. Furthermore, there likely exists an autosomal PH gene, distinct from the previously described X-linked and autosomal recessive forms. Affected individuals have severe developmental delay and may have radiographic findings of hydrocephalus.


Assuntos
Encéfalo/patologia , Coristoma/genética , Hidrocefalia/genética , Adulto , Anticonvulsivantes/efeitos adversos , Western Blotting , Criança , Pré-Escolar , Coristoma/patologia , Proteínas Contráteis/genética , Epilepsia Parcial Complexa/genética , Feminino , Filaminas , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Ligação Genética/genética , Humanos , Hidrocefalia/patologia , Hibridização in Situ Fluorescente , Imageamento por Ressonância Magnética , Masculino , Proteínas dos Microfilamentos/genética , Mutação/efeitos dos fármacos , Mutação/genética , Linhagem , Gravidez , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ácido Valproico/efeitos adversos , Derivação Ventriculoperitoneal
13.
Science ; 303(5666): 2033-6, 2004 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-15044805

RESUMO

The mammalian cerebral cortex is characterized by complex patterns of anatomical and functional areas that differ markedly between species, but the molecular basis for this functional subdivision is largely unknown. Here, we show that mutations in GPR56, which encodes an orphan G protein-coupled receptor (GPCR) with a large extracellular domain, cause a human brain cortical malformation called bilateral frontoparietal polymicrogyria (BFPP). BFPP is characterized by disorganized cortical lamination that is most severe in frontal cortex. Our data suggest that GPCR signaling plays an essential role in regional development of human cerebral cortex.


Assuntos
Córtex Cerebral/anormalidades , Lobo Frontal/anormalidades , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiologia , Substituição de Aminoácidos , Animais , Elementos Antissenso (Genética) , Evolução Biológica , Padronização Corporal , Córtex Cerebral/embriologia , Ventrículos Cerebrais/citologia , Ventrículos Cerebrais/embriologia , Feminino , Mutação da Fase de Leitura , Lobo Frontal/embriologia , Ordem dos Genes , Humanos , Ligantes , Masculino , Camundongos , Mutação de Sentido Incorreto , Neurônios/fisiologia , Lobo Parietal/anormalidades , Lobo Parietal/embriologia , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Deleção de Sequência , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Células-Tronco/fisiologia
14.
Nat Genet ; 36(1): 69-76, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14647276

RESUMO

Disruption of human neural precursor proliferation can give rise to a small brain (microcephaly), and failure of neurons to migrate properly can lead to an abnormal arrest of cerebral cortical neurons in proliferative zones near the lateral ventricles (periventricular heterotopia). Here we show that an autosomal recessive condition characterized by microcephaly and periventricular heterotopia maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2). By northern-blot analysis, we found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, we found that the mRNA is widely distributed throughout the embryonic central nervous system (CNS). ARFGEF2 encodes the large (>200 kDa) brefeldin A (BFA)-inhibited GEF2 protein (BIG2), which is required for vesicle and membrane trafficking from the trans-Golgi network (TGN). Inhibition of BIG2 by BFA, or by a dominant negative ARFGEF2 cDNA, decreases cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion. Inhibition of BIG2 also disturbed the intracellular localization of such molecules as E-cadherin and beta-catenin by preventing their transport from the Golgi apparatus to the cell surface. Our findings show that vesicle trafficking is an important regulator of proliferation and migration during human cerebral cortical development.


Assuntos
Fatores de Ribosilação do ADP/genética , Córtex Cerebral/fisiologia , Fatores de Troca do Nucleotídeo Guanina/genética , Proteínas de Saccharomyces cerevisiae , Adolescente , Sequência de Aminoácidos , Animais , Divisão Celular , Movimento Celular , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Imageamento por Ressonância Magnética , Camundongos , Dados de Sequência Molecular , Mutação , Neurônios/fisiologia
15.
Ann Neurol ; 53(5): 596-606, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12730993

RESUMO

Polymicrogyria is a common malformation of cortical development characterized by an excessive number of small gyri and abnormal cortical lamination. Multiple syndromes of region-specific bilateral symmetric polymicrogyria have been reported. We previously have described two families with bilateral frontoparietal polymicrogyria (BFPP), an autosomal recessive syndrome that we mapped to a locus on chromosome 16q12-21. Here, we extend our observations to include 19 patients from 10 kindreds, all linked to the chromosome 16q locus, allowing us to define the clinical and radiological features of BFPP in detail. The syndrome is characterized by global developmental delay of at least moderate severity, seizures, dysconjugate gaze, and bilateral pyramidal and cerebellar signs. Magnetic resonance imaging demonstrated symmetric polymicrogyria affecting the frontoparietal regions most severely, as well as ventriculomegaly, bilateral white matter signal changes, and small brainstem and cerebellar structures. We have refined our genetic mapping and describe two apparent founder haplotypes, one of which is present in two families with BFPP and associated microcephaly. Because 11 of our patients initially were classified as having other malformations, the syndrome of BFPP appears to be more common than previously recognized and may be frequently misdiagnosed.


Assuntos
Cromossomos Humanos Par 16/genética , Lobo Frontal/anormalidades , Imageamento por Ressonância Magnética , Lobo Parietal/anormalidades , Adolescente , Adulto , Tronco Encefálico/anormalidades , Cerebelo/anormalidades , Ventrículos Cerebrais/patologia , Criança , Pré-Escolar , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/etiologia , Análise Mutacional de DNA , Erros de Diagnóstico , Feminino , Lateralidade Funcional/fisiologia , Humanos , Lactente , Masculino , Microcefalia/complicações , Microcefalia/genética , Microcefalia/patologia , Transtornos da Motilidade Ocular/epidemiologia , Transtornos da Motilidade Ocular/etiologia , Linhagem , Mutação Puntual/genética , Convulsões/epidemiologia , Convulsões/etiologia , Índice de Gravidade de Doença , Síndrome
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