[Analysis of TUBB4A gene variant in a patient with adolescent-onset hypomyelinating leukodystrophy with atrophy of basal ganglia and cerebellum].

OBJECTIVE: To explore the clinical characteristics and genetic etiology of a patient with adolescent-onset hypomyelinated leukodystrophy with atrophy of basal ganglia and cerebellum (H-ABC). METHODS: A patient who was diagnosed with H-ABC in March 2018 at the First Affiliated Hospital of Nanjing Medical University was selected as the study subject. Clinical data was collected. Peripheral venous blood samples of the patient and his parents were collected. The patient was subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The patient, a 31-year-old male, had manifested with developmental retardation, cognitive decline and abnormal gait. WES revealed that he has harbored a heterozygous c.286G>A variant of the TUBB4A gene. Sanger sequencing confirmed that neither of his parents has carried the same variant. Analysis with SIFT online software indicated the amino acid encoded by this variant is highly conserved among various species. This variant has been recorded by the Human Gene Mutation Database (HGMD) with a low population frequency. The 3D structure constructed by PyMOL software showed that the variant has a harmful effect on the structure and function of the protein. According to the guidelines formulated by the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic. CONCLUSION: The c.286G>A (p.Gly96Arg) variant of the TUBB4A gene probably underlay the hypomyelinating leukodystrophy with atrophy of basal ganglia and cerebellum in this patient. Above finding has enriched the spectrum of TUBB4A gene variants and enabled early definitive diagnosis of this disorder.

Clinical manifestations and acid alpha-glucosidase mutation characterisation of a cohort of patients with late-onset Pompe disease in eastern China.

BACKGROUND: Pompe disease is a rare, progressive, and life-threatening autosomal recessive disorder. In its late-onset form, the disease is primarily characterised by mild progressive proximal limb and respiratory muscle weakness. Mutations in the acid alpha-glucosidase (GAA) gene cause lysosomal enzyme GAA to be significantly reduced or missing altogether, for which supplementation can be given through enzyme replacement therapy. METHODS: Fourteen patients diagnosed with late-onset Pompe disease (LOPD) in the First Affiliated Hospital of Nanjing Medical University from 2017 to 2021 were enrolled. GAA activity was measured based on enzymatic activity in dried blood spots, and next-generation sequencing was used to detect mutations in the GAA gene. The impacts of novel missense variants were determined by five different prediction algorithms. The structural figures of novel variants and their wide types were processed with PyMOL. RESULTS: The study included 14 patients with LOPD (male-to-female ratio, 1:1) from eastern China. The median age at symptom onset and diagnosis was 15.0 years (7-36 years) and 21.5 years (8-47 years), respectively. The median diagnostic delay from onset was 3.0 years (0-22 years). Proximal muscle weakness was the first prominent symptom in 8 patients, while the other 6 patients experienced respiratory failure, chest congestion and asthma, and scoliosis. The most frequent mutation of the GAA gene was c.2238G>C (p.W746C), which was observed at an allele frequency of 14.3% (4/28) and in 28.6% of patients (4/14). Four novel variants potentially related to the pathogenicity of LOPD were found: c.1299G>C (p.Q433H), c.1409A>G (p.N470S), c.2242delG (p.E748Rfs*16), and c.2832delA (p.E945Sfs*78). CONCLUSIONS: The c.2238G>C (p.W746C) mutation was the most common mutation in 14 patients with LOPD from eastern China. This study has identified four novel variants in patients with LOPD. Predicting the pathogenicity of these novel variants may increase the understanding of the genetic mutation spectrum in LOPD. Our findings may also improve recognition of the characteristics of Chinese patients with LOPD.

Recent Advances in Biotransformation of Saponins.

Saponins are a class of glycosides whose aglycones can be either triterpenes or helical spirostanes. It is commonly recognized that these active ingredients are widely found in various kinds of advanced plants. Rare saponins, a special type of the saponins class, are able to enhance bidirectional immune regulation and memory, and have anti-lipid oxidation, anticancer, and antifatigue capabilities, but they are infrequent in nature. Moreover, the in vivo absorption rate of saponins is exceedingly low, which restricts their functions. Under such circumstances, the biotransformation of these ingredients from normal saponins-which are not be easily adsorbed by human bodies-is preferred nowadays. This process has multiple advantages, including strong specificity, mild conditions, and fewer byproducts. In this paper, the biotransformation of natural saponins-such as ginsenoside, gypenoside, glycyrrhizin, saikosaponin, dioscin, timosaponin, astragaloside and ardipusilloside-through microorganisms (Aspergillus sp., lactic acid bacteria, bacilli, and intestinal microbes) will be reviewed and prospected.