RESUMO
OBJECTIVE: To describe the phenotypic spectrum and genetics of periventricular nodular heterotopia (PNH) caused by FLN1 mutations in four men. BACKGROUND: X-linked PNH caused by FLN1 mutations (MIM #300049) implies prenatal or early postnatal lethality in boys and 50% recurrence risk in daughters of affected women. METHODS: Clinical examination, cognitive testing, MRI, and mutation analysis (denaturing high-performance liquid chromatography and direct sequencing) on blood lymphocytes and single hair roots were performed for nine affected individuals, including three men. Neuropathologic study of the brain was performed for an affected boy. RESULTS: In two families, missense mutations were transmitted from mother to son (Met102Val) and from father to daughter (Ser149Phe), causing mild phenotypes in both genders, including unilateral PNH. In a third family, a man was mosaic for an A>G substitution (intron 11 acceptor splice site) on leukocyte DNA and hair roots (mutant = 42% and 69%). Single hair root analysis confirmed that the mutation was not present in all ectodermal derivative cells. A healthy daughter had inherited the X chromosome from her father's wild-type germinal cell population. In the fourth family, an eight-base deletion (AGGAGGTG, intron 25 donor splice site) led to early deaths of boys. Postmortem study in a newborn boy revealed PNH and cardiovascular, genitourinary, and gut malformations. CONCLUSIONS: Periventricular nodular heterotopia caused by FLN1 mutations in men has a wide clinical spectrum and is caused by different genetic mechanisms, including somatic mosaicism. Mutation analysis of FLN1 should support genetic counseling in men with periventricular nodular heterotopia.
Assuntos
Encefalopatias/genética , Ventrículos Cerebrais/anormalidades , Coristoma/genética , Cromossomos Humanos X/genética , Cisterna Magna/anormalidades , Proteínas Contráteis/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação em Linhagem Germinativa , Proteínas dos Microfilamentos/genética , Mosaicismo , Anormalidades Múltiplas/genética , Movimento Celular/genética , Pré-Escolar , Proteínas Contráteis/deficiência , Análise Mutacional de DNA , Mecanismo Genético de Compensação de Dose , Feminino , Filaminas , Genes Letais , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Folículo Piloso/química , Humanos , Recém-Nascido , Íntrons/genética , Masculino , Proteínas dos Microfilamentos/deficiência , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Neurônios/patologia , Linhagem , Fenótipo , Mutação Puntual , Sítios de Splice de RNA/genética , Deleção de SequênciaRESUMO
BACKGROUND: Subcortical band heterotopia (SBH) is a neuronal migration disorder. DCX mutations are responsible for almost all familial cases, 80% of sporadic female cases, and 25% of sporadic male cases of SBH, and are associated with more severe gyral and migration abnormality over the anterior brain regions. Somatic mosaicism has previously been hypothesized in a patient with posteriorly predominant SBH and a mutation of the LIS1 gene, which is usually mutated in patients with severe lissencephaly. The authors identified mosaic mutations of LIS1 in two patients (Patients 1 and 2) with predominantly posterior SBH. METHODS: After ruling out DCX mutations, the authors performed sequencing of the LIS1 gene in lymphocyte DNA. Because sequence peaks in both patients were suggestive of mosaic mutations, they followed up with denaturing high-pressure liquid chromatography analysis on blood and hair root DNA and compared the areas of heteroduplex and homoduplex peaks. A third patient showing the same mutation as Patient 2 but with no evidence of mosaicism was used for comparing the phenotype of mosaic vs full mutation. RESULTS: The two patients with posterior SBH harbored a missense (Arg241Pro) and a nonsense (R8X) mosaic mutation of LIS1. The rate of mosaicism in Patient 1 was 18% in the blood and 21% in the hair roots, whereas in Patient 2 it was 24% and 31% in the same tissues. The patient with a full R8X mutation of LIS1 had severe lissencephaly. CONCLUSIONS: Subcortical band heterotopia can occur with mosaic mutations of the LIS1 gene. Mutation analysis of LIS1, using highly sensitive techniques such as denaturing high-pressure liquid chromatography, should be considered for patients with posteriorly predominant subcortical band heterotopia and pachygyria.
Assuntos
Encéfalo/anormalidades , Coristoma/genética , Proteínas Associadas aos Microtúbulos/genética , Mosaicismo/genética , Malformações do Sistema Nervoso/genética , 1-Alquil-2-acetilglicerofosfocolina Esterase , Adolescente , Adulto , Encéfalo/patologia , Encéfalo/fisiopatologia , Coristoma/complicações , Coristoma/diagnóstico , Análise Mutacional de DNA , Eletroencefalografia , Humanos , Deficiência Intelectual/genética , Imageamento por Ressonância Magnética , Masculino , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/diagnóstico , Quadriplegia/genética , Convulsões/genéticaRESUMO
To evaluate the efficacy and safety of phenytoin (PHT) in the treatment of situation-related seizures and epilepsies in the newborn and infant; the clinical histories of 82 patients were retrospectively reviewed. Sixty patients received for status epilepticus (SE), intravenous PHT followed by long-term oral administration for 27 of them. The other 22 patients had oral treatment only. Intravenous administration made 55% of these patients seizure-free, whereas oral administration produced lasting seizure control in only 9.1%. During chronic oral treatment, it was most difficult to obtain adequate plasma concentrations in 69.1% of the patients, and 43.6% had side effects, most of which were related to very high plasma concentrations. In conclusion, in the first 2 years of life, intravenous administration of PHT is useful for SE, but oral treatment is poorly effective with difficulty to achieve appropriate and stable therapeutic plasma concentrations, and with frequent side effects.