Genotype, phenotype and treatment outcomes of 17 Malaysian patients with infantile-onset Pompe disease and the identification of 3 novel GAA variants.

BACKGROUND: Pompe disease is a rare glycogen storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to glycogen deposition in multiple tissues. Infantile-onset Pompe disease (IOPD) patients present within the first year of life with profound hypotonia and hypertrophic cardiomyopathy. Treatment with enzyme replacement therapy (ERT) has significantly improved survival for this otherwise lethal disorder. This study aims to describe the clinical and molecular spectrum of Malaysian IOPD patients, and to analyze their long term treatment outcomes. METHODS: Seventeen patients diagnosed with IOPD between 2000 and 2020 were included in this retrospective cohort study. Clinical and biochemical data were collated and analyzed using descriptive statistics. GAA enzyme levels were performed on dried blood spots. Molecular analysis of the GAA gene was performed by polymerase chain reaction and Sanger sequencing. Structural modelling was used to predict the effect of the novel mutations on enzyme structure. RESULTS: Our cohort had a median age of presentation of 3 months and median age of diagnosis of 6 months. Presenting features were hypertrophic cardiomyopathy (100%), respiratory insufficiency (94%), hypotonia (88%), failure to thrive (82%), feeding difficulties (76%), and hepatomegaly (76%). Fourteen different mutations in the GAA gene were identified, with three novel mutations, c.1552-14_1552-1del, exons 2-3 deletion and exons 6-10 deletion. The most common mutation identified was c.1935C > A p.(D645E), with an allele frequency of 33%. Sixteen patients received ERT at the median age of 7 months. Overall survival was 29%. Mean age of death was 17.5 months. Our longest surviving patient has atypical IOPD and is currently 20 years old. CONCLUSIONS: This is the first study to analyze the genotype and phenotype of Malaysian IOPD patients, and has identified the c.1935C > A p.(D645E) as the most common mutation. The three novel mutations reported in this study expands the mutation spectrum for IOPD. Our low survival rate underscores the importance of early diagnosis and treatment in achieving better treatment outcomes.

Pregnancy and pulmonary arterial hypertension-improving surveillance and outcomes with multidisciplinary care and N terminal pro-brain natriuretic peptide trends.

OBJECTIVE: To describe maternal and fetal outcomes and N Terminal pro-brain natriuretic peptide (NT-proBNP) trends in pregnancy with pulmonary arterial hypertension (PAH). METHODS: The medical records of all pregnant women with PAH referred to Pulmonary Hypertension Clinic were retrospectively reviewed and analyzed. RESULTS: We identified 35 pregnancies in 22 women (mean age 27.9 ± 4.7 years, mean weight 50.6 ± 8.1 kg). The diagnoses were Eisenmenger syndrome (16, 72.7%), postoperative residual PAH (3, 13.6%), idiopathic PAH (2, 9.1%), and one (4.5%) had systemic lupus erythematosus. About 23 babies (65.7%) were born alive, gestational age of 35.1 ± 2.9 weeks, 47.8% at term, with a birth weight of 2.1 ± 0.8 kg. There was an elevation of NT-proBNP in the initial 72 h postdelivery (median 138 pg/ml, IQR 112-561). Those with a persistent rise beyond 72 h (median 686 pg/ml, IQR 370-3691) had prolonged recovery postpartum (median postdelivery hospital stay 18 days, IQR 12-22) reflecting continued right ventricular stress and maladaptation. There was single maternal mortality (4.5%). CONCLUSIONS: Maternal and fetal outcomes of pregnancy associated with PAH are better with strict surveillance and multidisciplinary team effort. Postpartum period remains the most vulnerable time. NT-proBNP trends during this period may be a promising objective monitoring tool in identifying at-risk subsets thus improving outcomes.