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Background: Inborn errors of metabolism are inherited disorders that present in early childhood and are usually caused by monogenic recessive mutations in specific enzymes that metabolize dietary components. Distinct mutations are present in specific populations. Objective: To determine which genomic variants are present in Pakistani cohorts with hepatorenal tyrosinemia type 1 (HT1) and fructose 1,6-bisphosphatase deficiency (FBPD). Materials and Methods: We sequenced the fumaryl acetoacetate hydrolase encoding gene (FAH) including flanking regions in four unrelated HT1 cohorts and the fructose 1,6-bisphosphatase gene (FBP1) in eight FBPD cohorts. Results: We mapped two recessive mutations in FAH gene for HT1; c.1062 + 5G > A(IVS12 + 5G > A) in three families and c.974C > T(pT325M) in one. We identified three mutations in FBP1 gene; c.841G > A(p.E281K) in five FBPD families, c.472C > T(p.R158W) in two families and c.778G > A(p.G260R) in one. Conclusion: Knowledge of common variants for HTI and FBDP in our study population can be used in the future to build a diagnostic algorithm. [ABSTRACT FROM AUTHOR]

Objective: Genetic variation analysis of rare autosomal recessive Niemann-Pick disease (NPD) Pakistani patients. Methods: We sequenced the SMPD1 gene including its all coding and flanking regions in seven unrelated sporadic patients suffering from Niemann-Pick disease through targeted exome sequencing. Genetic variants mapping and their protein predictions were evaluated using different bioinformatics tools and clinical phenotypes were correlated. The study was conducted from January 2018 to March 2019 at The Children's Hospital Lahore. Results: We have mapped five different mutations in SMPD1 gene of enrolled patients with a novel homozygous missense variant (c.1718G>C) (p.Trp573Ser) in one patient. A missense mutation (c.1267C>T) (p.His423Tyr) has been identified in three unrelated patients. A nonsense mutation (c.1327C>T) (p.Arg443Term) and one missense mutation (c.1493G>A) (p.Arg498His) mapped in one patient each. A compound heterozygous mutation has been mapped in one patient (c.740G>A) (p.Gly247Asp); (c.1493G>A) (p.Arg498His). Pathogenic effect of novel variant has been predicted through in-silico analysis and has not been reported in general overall population in the globe. Conclusion: This is the first report of genetic demographic assessment of Niemann-Pick disease in Pakistan. The mapped mutations would be helpful to build a disease variants algorithm of Pakistani population. This will be used for determining disease clinical magnitude along with provision of genetic screening services in affected families. [ABSTRACT FROM AUTHOR]

Monosialotetrahexosylganglioside (GM1) is a rare lysosomal storage disorder caused by the deficiency of beta-galactosidase (β-Gal) encoded by galactose beta 1 (GLB1). It is clinically characterized by developmental delay attributed to multifold accumulation of GM1 gangliosides in nerve cells. In this study, we present a case of infantile GM1 gangliosidosis in a consanguineous Pakistani family. The child was presented with developmental delay, hepatosplenomegaly and recurrent chest infections at 7.5 months of age. Radiological and biochemical investigations including magnetic resonance imaging (MRI), bone marrow biopsy and urine oligosaccharide analyses suggested lysosomal storage disorder. Significantly low levels of β-Gal enzyme confirmed the diagnosis of GM1 gangliosidosis. DNA sequencing of GLB1 identified a homozygous 2-bp deletion c.881-882delAT (p.Tyr294Terfs) in exon 8. In silico analysis supported the deleterious effect of the variant. This study extends GLB1 mutation spectrum and should benefit genetic counselling and prenatal diagnosis of the affected family. [ABSTRACT FROM AUTHOR]

Abstract: Type I galactosemia is an inborn error resulting from mutations on both alleles of the GALT gene, which leads to the absence or deficiency of galactose-1-phosphate uridyltranseferase (GALT), the second of three enzymes catalyzing the conversion of galactose into glucose. On the basis of residual GALT activity, Type I galactosemia is classified into severe “Classical” and mild “Duarte” phenotypes. Classical galactosemia is frequently associated with S135L, Q188R and K285N mutations in the GALT gene. The functionally neutral N314D variation in the GALT gene is associated with Duarte galactosemia and is widespread among various worldwide populations. The present study aimed at detecting S135L, Q188R and K285N mutations and the N314D variant in the GALT gene by PCR using amplification refractory mutation system (ARMS). ARMS assays were established using standard DNA samples and were used for 8 galactosemia patients and 190 unrelated normal subjects all of Pakistani origin. S135L and K285N mutations were present neither in galactosemia patients nor in normal subjects. Only one galactosemia patient carried Q188R mutation that was in homozygous state. However, the N314D variant was frequently found both in affected (7 out of 16 alleles) and normal subjects (55 out of 380 alleles). This finding indicates that Duarte allele D314 might be far more common in Pakistani population than in European and North American ones. [Copyright &y& Elsevier]