RESUMO
INTRODUCTION: Alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) is a congenital disorder of glycosylation. The original patients were described with hypotonia, developmental disability, epilepsy, and increased bleeding tendency. METHODS: Based on Euroglycan database registration, we approached referring clinicians and collected comprehensive data on 41 patients. RESULTS: We found hypotonia and developmental delay in all ALG6-CDG patients and epilepsy, ataxia, proximal muscle weakness, and, in the majority of cases, failure to thrive. Nine patients developed intractable seizures. Coagulation anomalies were present in <50 % of cases, without spontaneous bleedings. Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly. Cyclic behavioral change, with autistic features and depressive episodes, was one of the most significant complaints. Eleven children died before the age of 4 years due to protein losing enteropathy (PLE), sepsis, or seizures. The oldest patient was a 40 year-old Dutch woman. The most common pathogenic protein alterations were p.A333V and p.I299Del, without any clear genotype-phenotype correlation. DISCUSSION: ALG6-CDG has been now described in 89 patients, making it the second most common type of CDG. It has a recognizable phenotype and a primary neurologic presentation.
Assuntos
Ataxia/patologia , Defeitos Congênitos da Glicosilação/patologia , Epilepsia/patologia , Glucosiltransferases/genética , Deformidades Congênitas dos Membros/patologia , Proteínas de Membrana/genética , Transtornos Mentais/patologia , Debilidade Muscular/patologia , Adolescente , Adulto , Ataxia/genética , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/genética , Epilepsia/genética , Feminino , Estudos de Associação Genética/métodos , Glicosilação , Humanos , Lactente , Recém-Nascido , Deformidades Congênitas dos Membros/genética , Masculino , Transtornos Mentais/genética , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Debilidade Muscular/genética , Fenótipo , Estudos Retrospectivos , Convulsões/genética , Convulsões/patologia , Adulto JovemRESUMO
The 15q13.3 microdeletion is a recurrent CNV, presumably mediated by NAHR between segmental duplications in chromosome 15. The 15q13.3 deletion and duplication are associated with a wide range of clinical manifestations, such as intellectual deficits, seizures, autism, language and developmental delay, neuropsychiatric impairments, and behavioral problems illustrating incomplete penetrance and expressivity. This study comprises an evaluation of 106 symptomatic patients carrying the heterozygous deletion, as well as of 21 patients carrying the duplication, who have been described in previous studies. The analysis shows considerable heterogeneity for the manifestation of different key symptoms and familiar occurrence. Furthermore, 8 new patients are introduced. Convoluted familiar connections give new insights into the complexity of symptomatic manifestation. In previous studies, different opinions have been expressed as to the nature and precise location of the deletion breakpoints. Here, we show that not CHRNA7 and CHRFAM7A, but rather FAM7A or GOLGA8, serve as breakpoint regions concerning our patients. The deletion is described as heterogeneous in size. However, we assume that not only different breakpoints but also the imprecision of aCGH analysis on chromosome 15 due to segmental duplications accounts for the variability in size.