TBC1D24-related familial infantile multifocal myoclonus: Description of a new Chinese pedigree with a 20 year follow up.

INTRODUCTION: Disorders associated with mutations in the Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 gene (TBC1D24) present a wide range of phenotypes, ranging from mild to fatal seizure diseases, non-syndromic deafness, and complex syndromes such as deafness, onychodystrophy, osteodystrophy, and mental retardation(DOOR syndrome). In this study, we introduce three siblings of a previously unreported Chinese family with familial infantile myoclonic epilepsy caused by a homozygous TBC1D24 mutation. METHODS: Genomic DNA was extracted from whole blood of the proband, his parents, and sisters. TBC1D24 exomes were sequenced by whole exome sequencing then analyzed by genetic analysis with Sanger sequencing validation. The patients were followed up for more than 20 years to summarize their clinical features. RESULTS: Genetic analysis identified a homozygous TBC1D24 mutation (c.241_252del12) in the proband and his sisters. Prediction models suggest that the mutation leads to an alteration in the properties and structure of the TBC1D24 protein, especially in the folding direction of the loop region, which is likely to decrease protein activity. The patients manifested with early-onset myoclonic epilepsy, were prone to status epilepticus, and seizures only occurred during wakefulness. Imaging characteristics included cerebellar atrophy and abnormal cerebellar signals. CONCLUSION: We report a pedigree case of infantile myoclonic epilepsy caused by a homozygous TBC1D24 mutation. Our long-term clinical follow-up not only enriches the clinical phenotype of the disease, but also provides a clinical experience for the early diagnosis and clinical treatment of the disease.

[Retrospective Analysis of Hematological Phenotypes in Patients with Gene Mutation and Deletion α-Thalassemia].

OBJECTIVE: To explore the differences between hematological phenotypes of patients with different genotypes in gene mutations and deletion α- thalassemia. METHODS: By screening the α- thalassemia gene test results in the First Affiliated Hospital, Sun Yat-Sen University from January 2015 to April 2020, the patients with mutation and deletion α- thalassemia were obtained, then the differences between hematological phenotypes of patients with different genotypes were analyzed. RESULTS: There were 96 patients with mutation combined with deletion α- thalassemia from the results of 24 054 α- thalassemia patients screened out, including 79 patients with non-deletion Hb H disease (αTα/--SEA) and 17 patients with mild α- thalassemia (αTα/-α), the incidence was 0.42%. Except the number of red blood cells (RBC) and mean corpuscular volume (MCV), the hemoglobin (Hb) concentration, hematocrit (Ht), average red blood cell hemoglobin concentration (MCHC), average red blood cell hemoglobin amount (MCH), average red blood cell volume (MCV) of the patients with αTα/--SEA genotype were significantly lower than those with αTα/-α genotype. The Hb of the patients with αCSα/--SEA and αQSα/--SEA genotype was (86±20)g/L and (84±9)g/L, respectirely, which was significantly lower than (114±16) g/L of αWSα/--SEA genotype (P<0.05); The MCHC of patients with αCSα/--SEA and αQSα/--SEA genotype was (278.8±8.5) g/L and (282.1±21.1)g/L, respectirely, which was also significantly lower than (315.4±19.5) g/L of αWSα/--SEA genotype (P<0.05); There was no significant difference between the patients with αCSα/--SEA and αQSα/--SEA genotype in hematological phenotypes. Except MCH and MCV, there was no significant differences between the patients with αWSα/--SEA and αTα/-α genotype in RBC, Hb, and Ht. The result of Hb A2 was (2.3±0.9)% for only 27 patients who performed electrophoretic analysis. There was no significant difference between the patients with αTα/--SEA and αTα/-α genotype in Hb A2, aslo among 3 types of the patients with αTα/--SEA genotype. CONCLUSION: The hematological phenotype changes caused by αWSα/--SEA genotype are similar to those of mild α- thalassemia, and both of them are significantly lighter than those patients with αCSα/--SEA and αQSα/--SEA genotype.

[Clinical and variation analysis of three Chinese families affected with glutaric acidemia type 1].

OBJECTIVE: To detect potential variation in glutaryl-CoA dehydrogenase (GCDH) gene among three Chinese families affected with glutaric acidemia type Ⅰ(GA-1) and correlate the genotypes with phenotypes. METHODS: Genomic DNA was extracted from peripheral blood samples derived from three patients with GA-1 and their family members. The coding regions of the GCDH gene were amplified with PCR and subjected to Sanger sequencing. RESULTS: The clinical manifestation of the patients varied from macrocephaly to severe encephalopathy, with notable phenotypic difference between siblings carrying the same variation. In pedigrees 1 and 2, the probands have carried compound heterozygous variations c.1133C>T(p.Ala378Val) and c.1244-2A>C, which were derived their fathers and mothers, respectively. In pedigree 3, the proband has carried compound heterozygous variation c.339delT (p.Tyr113) and c.406G>T (p.Gly136Cys). Among these, variations c.339delT and c.1133C>T were verified as novel by retrieval of dsSNP, HGMD and 1000 genome database. Bioinformatic analysis suggested that above variations can affect protein function and are probably pathogenic. CONCLUSION: Above discovery has expanded the mutation spectrum of the GCDH gene. No correlation was found between the clinical phenotype and genotype of GA-1 patients.

[Clinical investigation and genetic analysis of a Chinese family with glutaric acidemia type I].

OBJECTIVE: To review the clinical features of a families affected with glutaric acidemia type I (GA-1) and screen potential mutations in glutaryl-CoA dehydrogenase (GCDH) gene. METHODS: Clinical data of the patients and their family members was analyzed. Genomic DNA was extracted from peripheral blood samples. The 11 exons and flanking sequences of the GCDH gene were amplified with PCR and subjected to direct DNA sequencing. RESULTS: Two patients have manifested macrocephaly. Imaging analysis revealed arachnoid cyst and subdural effusion. The elder sister had encephalopathy crisis. The younger sister had significantly raised glutaric acid, whilst the elder sister was normal during the non-acute phase. Genetic analysis has revealed a homozygous c.1244-2A> C mutation of the GCDH gene in both patients. CONCLUSION: The clinical features and mutation of the GCDH gene have been delineated in a Chinese family affected with GA-1. The c.1244-2A> C mutation may be particularly common in the Chinese population.

[Analysis on mutation of adrenoleukodystrophy gene in exon 1 and exon 5].

OBJECTIVE: To elucidate the molecular mechanism of X-linked adrenoleukodystrophy(ALD) in Chinese. METHODS: Polymerase chain reaction in exon 1, exon 5 and their flanking sequences and direct DNA sequencing of ALD gene were performed in four patients, their mothers and twenty normal individuals as controls. RESULTS: A splice mutation was identified in the interface of exon 5 and intron 5 (1875 G-->A). This splice mutation in 5' end of intron 5 might lead to abnormal splice in exon 5 and exon 6 and bring about unstable and abnormal ALD protein; the lignoceryl CoA ligase could not transport very long chain fatty acids (VLCFA) into peroxisome and could not function normally; consequently, defective beta-oxidation of VLCFA in peroxisome could result in an accumulation of VLCFAS in the central nervous system, adrenal gland and blood. CONCLUSION: The splice mutation in 5' end of intron 5 leading to abnormal splice in exon 5 and exon 6 appears to be one of the causes of X-linked recessive adrenoleukodystrophy.