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Clinical course, mutations and its functional characteristics of infantile-onset Pompe disease in Thailand.

ABSTRACT: BACKGROUND:Pompe disease is a lysosomal storage disorder caused by the deficiency of acid alpha-glucosidase (EC. 3.2.1.20) due to mutations in human GAA gene. The objective of the present study was to examine clinical and molecular characteristics of infantile-onset Pompe disease (IOPD) in Thailand. METHODS:Twelve patients with infantile-onset Pompe disease (IOPD) including 10 Thai and two other Asian ethnicities were enrolled. To examine the molecular characteristics of Pompe patients, GAA gene was analyzed by PCR amplification and direct Sanger-sequencing of 20 exons coding region. The novel mutations were transiently transfected in COS-7 cells for functional verification. The severity of the mutation was rated by study of the GAA enzyme activity detected in transfected cells and culture media, as well as the quantity and quality of the proper sized GAA protein demonstrated by western blot analysis. The GAA three dimensional structures were visualized by PyMol software tool. RESULTS:All patients had hypertrophic cardiomyopathy, generalized muscle weakness, and undetectable or??G (p.Tyr292X), c.1226insG (p.Asp409GlyfsX95), c.1538G?>?A (p.Asp513Gly), c.1895?T?>?G (p.Leu632Arg), and a previously reported rare allele of unknown significance: c.781G?>?A (p.Ala261Thr) were identified. The rating system ranked p.Tyr292X, p. Asp513Gly and p. Leu632Arg as class "B" and p. Ala261Thr as class "D" or "E". These novel mutations were located in the N-terminal beta-sheet domain and the catalytic domain. CONCLUSIONS:The present study provides useful information on the mutations of GAA gene in the underrepresented population of Asia which are more diverse than previously described and showing the hotspots in exons 14 and 5, accounting for 62% of mutant alleles. Almost all mutations identified are in class A/B. These data can benefit rapid molecular diagnosis of IOPD and severity rating of the mutations can serve as a partial substitute for cross reactive immunological material (CRIM) study.

SUBMITTER: Ngiwsara L

PROVIDER: S-EPMC6737665 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Clinical course, mutations and its functional characteristics of infantile-onset Pompe disease in Thailand.

Ngiwsara Lukana L Wattanasirichaigoon Duangrurdee D Tim-Aroon Thipwimol T Rojnueangnit Kitiwan K Noojaroen Saisuda S Khongkraparn Arthaporn A Sawangareetrakul Phannee P Ketudat-Cairns James R JR Charoenwattanasatien Ratana R Champattanachai Voraratt V Kuptanon Chulaluck C Pangkanon Suthipong S Svasti Jisnuson J

BMC medical genetics 20190911 1

<h4>Background</h4>Pompe disease is a lysosomal storage disorder caused by the deficiency of acid alpha-glucosidase (EC. 3.2.1.20) due to mutations in human GAA gene. The objective of the present study was to examine clinical and molecular characteristics of infantile-onset Pompe disease (IOPD) in Thailand.<h4>Methods</h4>Twelve patients with infantile-onset Pompe disease (IOPD) including 10 Thai and two other Asian ethnicities were enrolled. To examine the molecular characteristics of Pompe pat ...[more]

PMID: 31510962

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Project description:BACKGROUND:Enzyme replacement therapy (ERT) has deeply modified the clinical history of Infantile Onset Pompe Disease (IOPD). However, its long-term effectiveness is still not completely defined. Available data shows a close relationship between clinical outcome and patients' cross-reactive immunological status (CRIM), being CRIM-negative status a negative prognostic factor. At the same time limited data are available on the long-term treatment in CRIM-positive infants. METHODS:A retrospective multicentre observational study was designed to analyse the long-term effectiveness of ERT in IOPD. Thirteen Italian centres spread throughout the country were involved and a cohort of 28 patients (15 females, 13 males, born in the period: February 2002-January 2013) was enrolled. IOPD diagnosis was based on clinical symptoms, enzymatic and molecular analysis. All patients received ERT within the first year of life. Clinical, laboratory, and functional data (motor, cardiac and respiratory) were collected and followed for a median period of 71 months (5 years 11 months). RESULTS:Median age at onset, diagnosis and start of ERT were 2, 3 and 4 months, respectively. CRIM status was available for 24/28 patients: 17/24 (71%) were CRIM-positive. Nineteen patients (67%) survived > 2 years: 4 were CRIM-negative, 14 CRIM-positive and one unknown. Six patients (5 CRIM-positive and one unknown) never needed ventilation support (21,4%) and seven (6 CRIM-positive and one unknown: 25%) developed independent ambulation although one subsequently lost this function. Brain imaging study was performed in 6 patients and showed peri-ventricular white matter abnormalities in all of them. Clinical follow-up confirmed the better prognosis for CRIM-positive patients, though a slow, progressive worsening of motor and/or respiratory functions was detected in 8 patients. CONCLUSIONS:These data are the result of the longest independent retrospective study on ERT in IOPD reported so far outside clinical trials. The data obtained confirmed the better outcome of the CRIM-positive patients but at the same time, showed the inability of the current therapeutic approach to reverse or stabilize the disease progression. The results also evidenced the involvement of central nervous system in Pompe disease. To better understand the disease clinical history and to improve treatment efficacy larger multicentre studies are needed as well as the development of new therapeutic approaches.

Dataset Information

Clinical course, mutations and its functional characteristics of infantile-onset Pompe disease in Thailand.

Publications

Clinical course, mutations and its functional characteristics of infantile-onset Pompe disease in Thailand.

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