Genetic Analysis In Four Families With Early-onset Cognitive Dysfunction

Background:Alzheimer,s disease(AD), one of the most common neurodegenerative diseases, is characterized by progressive cognitive impairment, mental and behavioral abnormalities and disorder in abilities of daily living. On the basis of onset age, two forms are distinguished: late onset AD(LOAD) with onset of symptoms beginning at 65 years or later, and early-onset AD(EOAD) with symptoms beginning before 65 years of age; the latter countsfor about 1%~2%. Even thoughmost ADs occur sporadically,approximately 25%of cases have positive family histories. Furthermore, it is transmitted as an autosomal dominant trait in a limited percent of cases. Early-onset familial Alzheimer’s disease(EOFAD) is a condition characterized by early onset dementia(age at onset < 65 years) and a positive family history for dementia. Up to now, more than ten genes that may cause EOAD have been identified, mainly includingpresenilin 1(PSEN1) gene,the presenilin 2(PSEN2) gene, amyloid precursor protein(APP) gene. Currently, the genetic anylysis of AD mainly performed abroad, there are limited studies done in this subject in domestic.Objective:To analyze the phenotype and genotypeof early-onset Alzheimer,s disease in the region.Methods:The clinical features and the results of auxiliary examinationwere analyzed carefully in three EOAD families. By using technology of polymerase chain reaction(PCR) and direct DNA sequencing, mutational analysis of presenilin1(PSEN1), presenilin2(PSEN2), the exons 16, 17 in amyloid precursor protein(APP)gene was performed successively.Results:Three EOAD pedigrees were found.Among them, 2 pedigrees had obvious familial history. The patients with an early-onset age(<44y) developed an insidious onset of difficulties in memory. Some patients showed epilepsy, hypermyotonia and some other symptoms which were rarely found in the course of the Alzheimer’s disease.Molecular genetic analysis revealed that the patients in family A had the AT inversion in c.765 and c.766 in exon 7 of PSEN1 gene, resulting mutations of P.V255 V and P.Y256N; The two living patients of family B both had a mutation c.2149 G>A in exon 17 of APP gene, which resulted in the amina acid substitution Val717Ile; The proband of family C had the mutation of P.G206V(C. 617G>T). In the three families, the genotypes were fully co-segregated with the phenotypes. Furthermore we did not find theabove three gene mutationsin unrelated 200 controls. These results demonstrated that the three mutations were the disease-causing mutations in the threepedigrees.Conlusions:1. We firstly report a novel mutation of Y256 N in exon 7of PSEN1 gene in EOFAD.2. We report the APP V717 I mutation, which futher demonstrate that APP gene mutation is the important pathogenesis of EOFAD.3. We report a PSEN1 G206 V mutation in the EOADpatient, and confirm it is a de novo mutation.Background:Neurological disorders have a close relation to hypogonadism and they always perform a series clinical syndroms because of the complex clinicalmanifestations.Unsatisfactorily, the causative genes in mostrelated families are still unknown. High-throughput sequencing is a high-throughput sequencing technology developed in recent years. Owing to its advantage of speediness, the lower sample requirements,comparatively cost-cheap and high sensitivity to common and rare variants, it has become an efficient method to identify causative genes in related complex hereditary disorders.Objective:We obtained a family with cognitive disorder, hypogonadism, epilepsy andleukodystrophy. This study was designed using exome sequencing technology to further explore causative gene in this clinical syndrome.Methods:1. In this study, we collected clinical data for all family members with detailed physical examination andneuropsychiatry assessment. All the patients were performed routine biochemical examination.2. Whole-exome sequencing and followed bioinformatic analysis were performed in the proband to investigate the candidate disease-causing gene.3. Sanger sequencing was used to further validate the mutations.4. All the patients and the health father were performed chromatography-mass spectrometry(GC-MS) examinations to measure urine concentrations of organic acids.Results:1. All the patients manifested as cognitive disorder, hypergonadotropic hypogonadism, episephy, leukodystrophy.2. We identified compound heterozygous mutations: c.482 G > A(p.R161Q) and c.609 G > A(p.W203X) in MMACHC gene in patients. Moreover the healthy father had theheterozygous mutation: c.482 G > A(p.R161Q); the healthy mother and sister had the c.609G>A(p.W203X) heterozygous mutation.3. Biochemical and GC-MS examinations showed obvious homocystinemia and methylmalonic aciduria, whereas no abnormal metabolites were found in the unaffected father.Conclusions:Whole-exome sequencing technology identifies MMACHC is the causative gene of a pedigree presenting as cognitive disorder,hypergonadotropic hypogonadism,epilepsy,and leukodystrophy.Hypergonadotropic hypogonadism may be a novel phenotypeof methylmalonic aciduria(MMA) combined with homocysteinemia, cbl C type(cbl C disease). The study indicatesgonadal function should be monitored in this disorder.