RESUMO
Primary microcephaly (MCPH) is a genetically heterogeneous disorder showing an autosomal recessive mode of inheritance. Patients with MCPH present head circumference values two or three standard deviations (SDs) significantly below the mean for age- and sex-matched populations. MCPH is associated with a nonprogressive mild to severe intellectual disability, with normal brain structure in most patients, or with a small brain and gyri without visceral malformations. We present the case of an adult patient born from Argentinian nonconsanguineous healthy parents. He had a head circumference >5 SD below the mean, cerebral neuroimaging showing hypoplasia of the corpus callosum, bilateral migration disorder with heterotopia of the sylvian fissure and colpocephaly. The patient was compound heterozygous for pathogenic variants in the CENPJ gene (c.289dupA inherited from his mother and c.1132 C > T inherited from his father). Our patient represents an uncommon situation for the usual known context of CENPJ and MCPH, including family origin (Argentinian), pedigree (nonconsanguineous), and genotype (a compound heterozygous case with two variants predicting a truncated protein). Next-generation sequencing studies applied in a broader spectrum of clinical presentations of MCPH syndromes may discover additional similar patients and families.
RESUMO
Spinal muscular atrophy (SMA) type 0 is the most severe form of SMA, associated with the SMN1 gene and manifesting at birth. Most patients die in the first weeks of life. In this work, we present 3 patients with SMA type 0 who survived >1 year and presented diffuse and progressive brain abnormalities on magnetic resonance imaging, which are not usually seen in patients with SMA. Thus, severe brain involvement may likely be the full end manifestation of an already extreme SMA phenotype caused by substantial reduction of the SMN protein in the brain. ANN NEUROL 2019;86:458-462.
Assuntos
Encéfalo/patologia , Atrofia Muscular Espinal/patologia , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Atrofia Muscular Espinal/genética , Neuroimagem , Fenótipo , Proteína 1 de Sobrevivência do Neurônio Motor/genéticaRESUMO
17α-hydroxylase/17,20-lyase deficiency is a rare form of congenital adrenal hyperplasia caused by mutations in CYP17A1. Two phenotypic female sisters, aged 17 and 15 years and with 46,XY and 46,XX karyotypes, respectively, presented with primary amenorrhea and absent secondary sexual characteristics. The elder sib also presented with high blood pressure. Both patients had elevated levels of ACTH, gonadotropins, progesterone, corticosterone, and deoxycorticosterone, and reduced levels of estradiol, testosterone, androstenedione, 17-OH-P, DHEA-S, cortisol, aldosterone, and renin activity. The CYP17A1 gene was sequenced, and polymorphic haplotypes were further analyzed in the Spanish family and in Brazilian patients. The 2 sisters were compound heterozygous for p.Arg362Cys and p.Trp406Arg mutations, previously described as the most prevalent mutations in Brazilian families of Spanish (p.Trp406Arg) or Portuguese (p.Arg362Cys) origin. Analysis of polymorphisms in CYP17A1 suggested that the paternal allele with p.Arg362Cys may share a common origin with the Brazilian carriers, while the maternal allele with p.Trp406Arg did not. Hydrocortisone and sex hormone replacement therapy was initiated in both patients. In conclusion, one CYP17A1 mutation (p.Arg362Cys) may share a common ancestry in Brazilian and our present Spanish patients, while p.Trp406Arg may have arisen separately. The elder patient (46,XY) developed a more severe phenotype and a poorer response to estradiol replacement therapy.
Assuntos
Alelos , Mutação/genética , Irmãos , Esteroide 17-alfa-Hidroxilase/genética , Adolescente , Sequência de Bases , Brasil , Feminino , Genótipo , Heterozigoto , Hormônios/sangue , Humanos , Masculino , Fenótipo , Espanha , Testículo/patologiaRESUMO
BACKGROUND/PURPOSE: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, considered one of the leading causes of infant mortality. It is caused by mutations in the SMN1 gene. A highly homologous copy of this gene named SMN2 and other neighbouring genes, SERF1A and NAIP, are considered phenotypic modifiers of the disease. In recent years, notable advances have been made in SMA research regarding evaluation, prognosis, and therapeutic options. Thus, genotype-phenotype studies in SMA are important to stratify patients for motor function tests and for envisaged clinical trials. The aim of this study was to provide clinical and molecular data of a series of Argentinean children with SMA to establish a comprehensive genotype-phenotype correlation. METHODS: 144 Argentinean children with SMA (56 children with type I, 58 with type II, and 30 with type III) were evaluated. The copy number of SMN2, SERF1A, and NAIP genes was established using MLPA (Multiplex Ligation-dependent Probe Amplification) and then correlated with the patients clinical subtypes. To improve clinical characterization we considered the initial symptoms that prompted the consultation, age of acquisition of motor abilities to independent walking and age at loss of gait. We also evaluated clinical and molecular features of sibling pairs in seven families. RESULTS: A strong correlation was observed between the SMN2 copy number and SMA phenotype while SERF1A and NAIP copy number showed a moderate correlation. We observed intra- and inter-family differences among the SMA types. CONCLUSION: This first genotype-phenotype correlation study in Argentinean SMA children provides data to improve patient stratification and define more adequate follow-up parameters.