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Fulltext Biochemical and molecular characteristics of Malaysian patients with lysinuric protein intolerance

Habib A, Azize NA, Yakob Y, Md Yunus Z, Wee TK

Malays J Pathol, 2016 Dec;38(3):305-310.
PMID: 28028301 MyJurnal

Lysinuric protein intolerance (LPI) is an inborn error of dibasic amino acid transport due to a defect in the dibasic amino acid transporter in the renal and intestine and has a heterogenous presentation. Three Malaysian patients with LPI were studied and their biochemical and molecular findings compared. There were differences and similarities in the biochemical and molecular findings. Molecular analysis of SLC7A7 gene revealed a novel mutation c.235G>A; p.(Gly79Arg) in exon three in Patient 1 and a mutation c.1417C>T; p.(Arg473*) in exon 10 in patient 2 and 3. The degree of concentration of dibasic amino acids may determine the type of disease of the cell membrane transport, however, a positive molecular confirmation will secure the diagnosis.
Fulltext Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia and metabolic acidosis: Clinical and molecular findings in Malaysian patients

Moey LH, Abdul Azize NA, Yakob Y, Leong HY, Keng WT, Chen BC, et al.

Pediatr Neonatol, 2018 08;59(4):397-403.
PMID: 29203193 DOI: 10.1016/j.pedneo.2017.11.006

BACKGROUND: Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare autosomal recessive inborn error of gluconeogenesis. We reported the clinical findings and molecular genetic data in seven Malaysian patients with FBPase deficiency.
METHODS: All patients diagnosed with FBPase deficiency from 2010 to 2015 were included in this study. Their clinical and laboratory data were collected retrospectively.
RESULTS: All the patients presented with recurrent episodes of hypoglycemia, metabolic acidosis, hyperlactacidemia and hepatomegaly. All of them had the first metabolic decompensation prior to 2 years old. The common triggering factors were vomiting and infection. Biallelic mutations in FBP1 gene (MIM*611570) were identified in all seven patients confirming the diagnosis of FBPase deficiency. In four patients, genetic study was prompted by detection of glycerol or glycerol-3-phosphate in urine organic acids analysis. One patient also had pseudo-hypertriglyceridemia. Seven different mutations were identified in FBP1, among them four mutations were new: three point deletions (c.392delT, c.603delG and c.704delC) and one splice site mutation (c.568-2A > C). All four new mutations were predicted to be damaging by in silico analysis. One patient presented in the neonatal period and succumbed due to sepsis and multi-organ failure. Among six survivors (current age ranged from 4 to 27 years), four have normal growth and cognitive development. One patient had short stature and another had neurological deficit following status epilepticus due to profound hypoglycemia.
CONCLUSION: FBPase deficiency needs to be considered in any children with recurrent hypoglycemia and metabolic acidosis. Our study expands the spectrum of FBP1 gene mutations.
Fulltext Clinical and Mutational Analysis of the GCDH Gene in Malaysian Patients with Glutaric Aciduria Type 1

Abdul Wahab SA, Yakob Y, Abdul Azize NA, Md Yunus Z, Huey Yin L, Mohd Khalid MK, et al.

Biomed Res Int, 2016;2016:4074365.
PMID: 27672653

Glutaric aciduria type 1 (GA1) is an autosomal recessive metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase enzyme encoded by the GCDH gene. In this study, we presented the clinical and molecular findings of seven GA1 patients in Malaysia. All the patients were symptomatic from infancy and diagnosed clinically from large excretion of glutaric and 3-hydroxyglutaric acids. Bidirectional sequencing of the GCDH gene revealed ten mutations, three of which were novel (Gln76Pro, Glu131Val, and Gly390Trp). The spectrum of mutations included eight missense mutations, a nonsense mutation, and a splice site mutation. Two mutations (Gln76Pro and Arg386Gln) were homozygous in two patients with parental consanguinity. All mutations were predicted to be disease causing by MutationTaster2. In conclusion, this is the first report of both clinical and molecular aspects of GA1 in Malaysian patients. Despite the lack of genotype and phenotype correlation, early diagnosis and timely treatment remained the most important determinant of patient outcome.
Mutation analysis of glycine decarboxylase, aminomethyltransferase and glycine cleavage system protein-H genes in 13 unrelated families with glycine encephalopathy

Azize NA, Ngah WZ, Othman Z, Md Desa N, Chin CB, Md Yunus Z, et al.

J Hum Genet, 2014 Nov;59(11):593-7.
PMID: 25231368 DOI: 10.1038/jhg.2014.69

Glycine encephalopathy (GCE) or nonketotic hyperglycinemia is an inborn error of glycine metabolism, inherited in an autosomal recessive manner due to a defect in any one of the four enzymes aminomethyltransferase (AMT), glycine decarboxylase (GLDC), glycine cleavage system protein-H (GCSH) and dehydrolipoamide dehydrogenase in the glycine cleavage system. This defect leads to glycine accumulation in body tissues, including the brain, and causes various neurological symptoms such as encephalopathy, hypotonia, apnea, intractable seizures and possible death. We screened 14 patients from 13 families with clinical and biochemical features suggestive of GCE for mutation in AMT, GLDC and GCSH genes by direct sequencing and genomic rearrangement of GLDC gene using a multiplex ligation-dependant probe amplification. We identified mutations in all 14 patients. Seven patients (50%) have biallelic mutations in GLDC gene, six patients (43%) have biallelic mutations in AMT gene and one patient (7%) has mutation identified in only one allele in GLDC gene. Majority of the mutations in GLDC and AMT were missense mutations and family specific. Interestingly, two mutations p.Arg265His in AMT gene and p.His651Arg in GLDC gene occurred in the Penan sub-population. No mutation was found in GCSH gene. We concluded that mutations in both GLDC and AMT genes are the main cause of GCE in Malaysian population.
Hyperexcretion of homocitrulline in a Malaysian patient with lysinuric protein intolerance

Habib A, Md Yunus Z, Azize NA, Ch'ng GS, Ong WP, Chen BC, et al.

Eur J Pediatr, 2013 Sep;172(9):1277-81.
PMID: 23358709 DOI: 10.1007/s00431-013-1947-1

Lysinuric protein intolerance (LPI; MIM 222700) is an inherited aminoaciduria with an autosomal recessive mode of inheritance. Biochemically, affected patients present with increased excretion of the cationic amino acids: lysine, arginine, and ornithine. We report the first case of LPI diagnosed in Malaysia presented with excessive excretion of homocitrulline. The patient was a 4-year-old male who presented with delayed milestones, recurrent diarrhea, and severe failure to thrive. He developed hyperammonemic coma following a forced protein-rich diet. Plasma amino acid analysis showed increased glutamine, alanine, and citrulline but decreased lysine, arginine and ornithine. Urine amino acids showed a marked excretion of lysine and ornithine together with a large peak of unknown metabolite which was subsequently identified as homocitrulline by tandem mass spectrometry. Molecular analysis confirmed a previously unreported homozygous mutation at exon 1 (235 G > A, p.Gly79Arg) in the SLC7A7 gene. This report demonstrates a novel mutation in the SLC7A7 gene in this rare inborn error of diamino acid metabolism. It also highlights the importance of early and efficient treatment of infections and dehydration in these patients.
CONCLUSION: The diagnosis of LPI is usually not suspected by clinical findings alone, and specific laboratory investigations and molecular analysis are important to get a definitive diagnosis.
Fulltext Clinical, biochemical and genetic profiles of patients with mucopolysaccharidosis type IVA (Morquio A syndrome) in Malaysia: the first national natural history cohort study

Leong HY, Abdul Azize NA, Chew HB, Keng WT, Thong MK, Mohd Khalid MKN, et al.

Orphanet J Rare Dis, 2019 06 14;14(1):143.
PMID: 31200731 DOI: 10.1186/s13023-019-1105-6

BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive lysosomal storage disease due to N-acetylgalactosamine-6-sulfatase (GALNS) deficiency. It results in accumulation of the glycosaminoglycans, keratan sulfate and chondroitin-6-sulfate, leading to skeletal and other systemic impairments. Data on MPS IVA in Asian populations are scarce.
METHODS: This is a multicentre descriptive case series of 21 patients comprising all MPS IVA patients in Malaysia. Mutational analysis was performed by PCR and Sanger sequencing of the GALNS gene in 17 patients.
RESULTS: The patients (15 females and 6 males) had a mean age (± SD) of 15.5 (± 8.1) years. Mean age at symptom onset was 2.6 (± 2.1) years and at confirmed diagnosis was 6.9 (± 4.5) years. The study cohort included patients from all the main ethnic groups in Malaysia - 57% Malay, 29% Chinese and 14% Indian. Common presenting symptoms included pectus carinatum (57%) and genu valgum (43%). Eight patients (38%) had undergone surgery, most commonly knee surgeries (29%) and cervical spine decompression (24%). Patients had limited endurance with lower mean walking distances with increasing age. GALNS gene analysis identified 18 distinct mutations comprising 13 missense, three nonsense, one small deletion and one splice site mutation. Of these, eight were novel mutations (Tyr133Ser, Glu158Valfs*12, Gly168*, Gly168Val, Trp184*, Leu271Pro, Glu320Lys, Leu508Pro). Mutations in exons 1, 5 and 9 accounted for 51% of the mutant alleles identified.
CONCLUSIONS: All the MPS IVA patients in this study had clinical impairments. A better understanding of the natural history and the clinical and genetic spectrum of MPS IVA in this population may assist early diagnosis, improve management and permit timely genetic counselling and prenatal diagnosis.