A heterozygous variant in the SLC22A12 gene in a Sri Lanka family associated with mild renal hypouricemia

Abstract Background Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport, reabsorption insufficiency and /or acceleration of secretion. The affected individuals are predisposed to nephrolithiasis and recurrent episodes of exercise-induced acute kidney injury. Type 1 is caused by dysfunctional variants in the SLC22A12 gene (URAT1), while type 2 is caused by defects in the SLC2A9 gene (GLUT9). To date, more than 150 patients with the loss-of-function mutations for the SLC22A12 gene have been found (compound heterozygotes and/or homozygotes), most of whom are Japanese and Koreans. Case presentation Herein, we report a nine year old Sri Lankan boy with renal hypouricemia (serum uric acid 97 μmol/L, fractional excretion of uric acid 33%).The sequencing analysis of SLC22A12 revealed a potentially deleterious missense variant c.1400C > T (p.T467 M, rs200104135) in heterozygous state. This variant has been previously identified in homozygous and/or compound heterozygous state with other causative SLC22A12 variant c.1245_1253del (p.L415_G417del) in Roma population. Conclusions This is the first identification of a family with mild renal hypouricemia1 associated to the p.T467 M variant. Detailed investigations of urate blood and urine concentrations in patients with unexplained hypouricemia are needed and renal hypouricemia should also be considered in patients other than those from Japan and/or Korea. Our finding confirms an uneven geographical and ethnic distribution of Romany prevalent SLC22A12 variant that need to be considered in Asian patients (population data Genome Aggregation Database: allele frequency in South Asia 0.007055, in East Asia 0.001330)

Association of selected genetic variants in CBS and MTHFR genes in a cohort of children with homocystinuria in Sri Lanka

Abstract Background Homocystinuria is an inherited, inborn error of homocysteine metabolism, which leads to the abnormal accumulation of homocysteine and its metabolites in blood and urine, resulting in various complications. Variants in the cystathionine β-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) genes interrupt the formation of the corresponding enzymes and prevent homocysteine from being metabolised; hence, the homocysteine levels in plasma increase than the optimum levels. Materials and methods In the current study, eight clinically confirmed children with homocystinuria were detected to study the chosen variants in the CBS gene (c.833 T>C and c.19del) and in the MTHFR gene (c.665 C>T, c.1286 A>C) using SNaPshot mini-sequencing and direct sequencing. Results After screening eight patients, none had the c.833T>C, but four patients were in the homozygous state for the c.19del variant in the CBS gene. Furthermore, seven were heterozygous for c.1286A>C, while one patient was heterozygous for c.665C>T in the MTHFR gene. Conclusion According to the results, c.19del is common in the studied cohort of Sri Lankan children, while c.833T>C is absent, whereas c.1286A>C was more frequent than c.665C>T. To our knowledge, the current study was the first report to discuss the genetic impact of homocystinuria in Sri Lanka; further comprehensive studies are necessary with a larger sample size to establish the association of these variants with the disease in Sri Lanka, which can be beneficial in enhanced patient care and for prospective studies

Evaluation of biochemical and haematological changes in dengue fever and dengue hemorrhagic fever in Sri Lankan children: a prospective follow up study

Abstract Background Series of biochemical and haematological changes occur during the course of dengue infection, which vary depending on the clinical disease. The patterns of change are not well documented and identifying these patterns in children with dengue infection would help to anticipate the progression to different clinical stages thus enabling effective management. Methods A prospective follow up study was conducted during the period of July 2013 – April 2014 at Professorial Pediatric unit, Lady Ridgeway Hospital for Children, Colombo, Sri Lanka. Children (5–12 years) admitted within the first 84 h of fever, with a clinical diagnosis of dengue infection were recruited. Children who became positive for dengue IgM were included in the final analysis. Blood was collected on admission for complete blood count, Alanine aminotransferase, Aspartate aminotransferase, albumin, cholesterol and corrected calcium. These tests were repeated at 12 hourly intervals during the hospital stay. Results Data of 130-subjects were analyzed (Dengue fever /Dengue hemorrhagic fever: 100/30). There was a significant difference in the pattern of white cell counts, platelets and haematocrit in the two clinical groups. Both transaminase rose initially in both dengue fever and dengue hemorrhagic fever and a steep rise were seen between 8th and 9th days in hemorrhagic fever. Both albumin and cholesterol decreased significantly at the time of entering into the critical phase. According to Receiver operating characteristic curve analysis, albumin level crossing 37.5g/L (sensitivity 86.7%, specificity 77.8%) and a 0.38 mmol/L reduction in cholesterol level (sensitivity 77.3%, specificity 71.9%) between day 3 and 4 were the best predictors of entering into critical phase. Calcium levels did not show any distinct pattern. Conclusions There is a clear difference in the pattern of change of both hematological and biochemical parameters in dengue fever and dengue hemorrhagic fever. Reduction in albumin and cholesterol levels seen between the completion of day 3 and day 4 were highly valid predictors of entering into critical phase in dengue hemorrhagic fever

Metabolic biomarker testing facilitates genetic diagnosis of Niemann-Pick disease by enabling classification of novel SMPD1 variants

Background: NiemannPick (NP) disease is a genetically heterogeneous metabolic disorder caused by bi-allelic variants in NPC1, NPC2, or SMPD1, with initial symptoms and age at onset varying widely. The interpretation of variants in NP disease genes is challenging when these alterations have never been observed before, and when parental samples are not available. Case Presentation: We clinically, genetically, and biochemically characterized an infant with a complex presentation and a negative family history. Clinical and paraclinical observations were consistent with NP disease. Genetic screening identified two previously unreported SMPD1 missense variants, which were initially classified as variants of unknown significance. Based on strongly increased plasma levels of lysosphingomyelin-509, both variants could be re-classified as likely pathogenic, thus establishing a diagnosis of NP disease type A/B. Conclusion: A combination of genetics with biochemical approaches facilitates conclusive diagnosis of metabolic disorders including NP disease. Blood-based biomarkers are particularly promising in this respect. [JBCGenetics 2019; 2(2.000): 147-150

Lipin-1 Deficiency-Associated Recurrent Rhabdomyolysis and Exercise-Induced Myalgia Persisting into Adulthood: A Case Report and Review of Literature

Phosphatidate phosphatase-1 (lipin-1) is encoded by LPIN1 gene. Lipin-1 deficiency has been reported as the second most common cause of early-onset rhabdomyolysis after primary fatty acid oxidation disorders. We report a case of a 32-year-old Sri Lankan female with a history of more than 10 episodes of rhabdomyolysis and exercise intolerance since childhood. These episodes were triggered by infections and exercise. A temporal relationship between the acute episodes and use of drugs such as theophylline, mefenamic acid, co-trimoxazole, and combined oral contraceptive pills was also noted. There was marked elevation of serum creatine kinase and transaminases during acute episodes. Family history revealed parental consanguinity and an affected sibling who died of an acute episode associated with muscle weakness, dark coloured urine, and cyanosis, at the age of 2 years. The histochemical findings of the patient under discussion were consistent with a metabolic myopathy affecting membrane integrity. A homozygous, likely pathogenic variant c.1684G>T encoding p.(Glu562∗) was identified by clinical exome sequencing. Even though the studies to date give no convincing evidence of a possible causal or contributory relationship between the drugs under discussion and lipin-1 related rhabdomyolysis, this case highlights the importance of pharmacovigilance and reporting adverse drug reactions in patients with lipin-1 deficiency

First contiguous gene deletion causing biotinidase deficiency: The enzyme deficiency in three Sri Lankan children

We report three symptomatic children with profound biotinidase deficiency from Sri Lanka. All three children presented with typical clinical features of the disorder. The first is homozygous for a missense mutation in the BTD gene (c.98_104 del7insTCC; p.Cys33PhefsX36) that is commonly seen in the western countries, the second is homozygous for a novel missense mutation (p.Ala439Asp), and the third is the first reported instance of a contiguous gene deletion causing the enzyme deficiency. In addition, this latter finding exemplifies the importance of considering a deletion within the BTD gene for reconciling enzymatic activity with genotype, which can occur in asymptomatic children who are identified by newborn screening

Dubin–Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report

Abstract Background Dubin–Johnson syndrome and intrahepatic cholestasis of pregnancy are rare chronic liver disorders. Dubin–Johnson syndrome may manifest as conjugated hyperbilirubinemia, darkly pigmented liver, presence of abnormal pigment in the parenchyma of hepatocytes and abnormal distribution of the coproporphyrin isomers I and III in the urine. Intrahepatic cholestatic jaundice of pregnancy presents as pruritus, abnormal liver biochemistry and increased serum bile acids. Case presentation A Sri Lankan girl presented with recurrent episodes of jaundice. She had conjugated hyperbilirubinaemia with diffuse, coarse brown pigments in the hepatocytes. Urine coproporphyrin examination suggested Dubin–Johnson syndrome. Genetic studies confirmed missense homozygous variant p.Trp709Arg in the ATP-binding cassette sub-family C member 2 gene ABCC2 that encodes the Multidrug resistance-associated protein 2 that causes Dubin–Johnson syndrome. The gene study of the mother revealed the same missense variant in ABCC2/MRP2 but with a heterozygous status, and in addition a homozygous missense variant p.Val444Ala in the ATP-binding cassette, sub-family B member 11 gene ABCB11 that encodes the bile salt export pump. Conclusion Dubin–Johnson syndrome should be considered when the common causes for conjugated hyperbilirubinaemia have been excluded, and patient has an increased percentage of direct bilirubin relative to total bilirubin concentration. Its early diagnosis prevents repeated hospital admissions and investigations. Knowledge of a well known homozygous variant in ABCB11 gene could help in the management of pregnancy

Correction to: Dubin–Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report

Abstract Following publication of the original article [1], the authors requested the following corrections: 1. Author 2—given name should be Dilanthi and family name Warawitage. 2. Author 6—given name should be Nalika and family name de Silva

Dubin–Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report

International audienceBackground: Dubin–Johnson syndrome and intrahepatic cholestasis of pregnancy are rare chronic liver disorders. Dubin–Johnson syndrome may manifest as conjugated hyperbilirubinemia, darkly pigmented liver, presence of abnormal pigment in the parenchyma of hepatocytes and abnormal distribution of the coproporphyrin isomers I and III in the urine. Intrahepatic cholestatic jaundice of pregnancy presents as pruritus, abnormal liver biochemistry and increased serum bile acids.Case presentation: A Sri Lankan girl presented with recurrent episodes of jaundice. She had conjugated hyperbilirubinaemia with diffuse, coarse brown pigments in the hepatocytes. Urine coproporphyrin examination suggested Dubin–Johnson syndrome. Genetic studies confirmed missense homozygous variant p.Trp709Arg in the ATP-binding cassette sub-family C member 2 gene ABCC2 that encodes the Multidrug resistance-associated protein 2 that causes Dubin–Johnson syndrome. The gene study of the mother revealed the same missense variant in ABCC2/MRP2 but with a heterozygous status, and in addition a homozygous missense variant p.Val444Ala in the ATP-binding cassette, sub-family B member 11 gene ABCB11 that encodes the bile salt export pump.Conclusion: Dubin–Johnson syndrome should be considered when the common causes for conjugated hyperbilirubinaemia have been excluded, and patient has an increased percentage of direct bilirubin relative to total bilirubin concentration. Its early diagnosis prevents repeated hospital admissions and investigations. Knowledge of a well known homozygous variant in ABCB11 gene could help in the management of pregnancy