PHENOTYPIC AND GENOTYPIC CHARACTERISTICS OF PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS TYPE 3 IN PEDIATRIC POPULATION IN PAKISTAN

OBJECTIVE: To determine the phenotypic and genotypic characteristics of progressive familial intrahepatic cholestasis (PFIC) type 3 in Pakistani children in a hospital setting. METHODS: This cross-sectional observational study was conducted at department of Pediatrics Gastroenterology & Hepatology, The Children’s Hospital Lahore, Pakistan from October 2020 to March 2021. Patients of either sex under 16 years of age presenting with jaundice, pruritus, neonatal cholestasis or with chronic liver and gamma glutamyl transferase >100 IU/ml were included in the study after taking informed consent by parents. For Molecular genetics 2ml blood in EDTA was sent to an international laboratory free of cost on research basis. Reports were assessed and levels were noted and genetic coding was also recorded. Data was entered and analyzed in SPSS version 22. Molecular data was interpreted with the help of clinical geneticist. RESULTS: Out of 34 children, 14 (41.2%) were males and 20 (58.8%) were females. Mean age of children was 6.71±3.10 years. Consanguinity was noted in 32 (94.1%) parents having positive family history in 24 (70.6%) cases. The most common mutation was c. 1783C>T p.(Arg595*),  noted in 12 (35.3%) cases, followed by c. 2861G>T p.(Gly954 ASP) [8 (23.5%) cases], c. 153G>A p.(Trp51) [3 (8.8%) cases], c. 1714 C>T p.(Gln572*) c. 1906C>T p. (Gln636), c. 3220G>A p.(Gly1074Arg, c. 3433del p. (val1145Leufsx7)  in 2 (5.9%) cases each, c. 3859 C>T p.(1287Argext*) c. 88-91del p.(Lys30gly fsx7) and c. 1429c>T p. (Gln477) in one (2.9%) case each. CONCLUSION: Children with PFIC type 3 have variable phenotypic and genotypic presentation

Etiological and Clinical Spectrum of Acute Liver Failure of Infancy in Pakistan

  Objective: To describe the aetiology and clinical spectrum of acute liver failure of infancy at a tertiary care hospital Study Design: Cross-sectional study. Place and Duration of Study: Department of Paediatric Gastroenterology, Hepatology & Nutrition, Children Hospital and Institute of Child Health, Lahore, from Nov 2020 to May 2021. Methodology: Infants under 12 months of age were enrolled having liver-based coagulopathy (not corrected after two doses of parenteral vitamin K, 10 mg) with INR > 2, whether encephalopathy was present or not. Encephalo-pathy is difficult to identify in infants, so it was not essential for the diagnosis of ALFI in our study. Infants diagnosed with chronic liver disease at presentation or those without final etiological diagnosis were excluded. Results: A total of 31 infants were enrolled fulfilling the criteria of acute liver failure of infancy and were studied about aetiology and clinical presentation. The mean age of presentation was 4.64±3.16 months, and males predominated in the study group (64.5%). Common clinical features were in descending order ascites in 29 (93.5%), jaundice in 28 (90.3%), pallor in 24 (77.4%) and peripheral oedema in 21 (67.7%). Metabolic liver diseases were the common cause of ALFI, constituting around(18, 58%) followed by sepsis (9, 29%).Galactosemia (11, 35.5%) stands out among the metabolic causes. Conclusion: Metabolic disorders followed by sepsis are the most common cause of ALFI

GALACTOSAEMIA -PRESENTATION, DIAGNOSIS AND MANAGEMENT

Galactosaemia is a rare autosomal recessive metabolic disorder. It presents in early life of glycosuria as determined by negative Clinistix test and (c) rapid clinical improvement on elimination of galactose from the diet of infants. Diagnosis of galactosaemia was made in 18 infants over the study period. Their age at presentation ranged from 35 days -9 months (median 10 weeks). There were 12 males and 6 females (M: F ratio 2:1). Most common mode of presentation was fulminant hepatic failure (FHF). Cataract was present in the majorit

The mutational landscape of genetic cholestatic diseases in Pakistani children

Objective: To report the mutational landscape of a clinically diagnosed cohort of paediatric patients with cholestasis liver diseases. Method: The retrospective study was conducted at the University of Child Health Sciences, The Children Hospital, Lahore, Pakistan, from December 10, 2021, to March 31, 2022, and comprised data collected from the Paediatric Gastroenterology and Hepatology unit on demographics, clinical and laboratory findings related to children of either gender aged <12 years and diagnosed with cholestatic liver disease from July 2018 to June 2021. The diagnosis was based on clinical and biochemical findings, with no evidence of biliary atresia and metabolic liver disease. Molecular characterisation was done through whole exome sequencing. Results: Of the 171 children evaluated, 92(53.8%) were diagnosed with genetic cholestatic disorders. There were 52(56%) boys and 41(44%) girls. The median age at presentation was 19.5 months (interquartile range: 51 months). Consanguinity was found in 82(88.1%) cases, and positive family history with one or more affected siblings was noted in 60(64.5%). Exome sequencing identified pathogenic mutations in 13 genes underlying the hereditary cholestasis; ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, DCDC2, ACOX2, AKR1D1, HSD3B7, ABCC2, USP53, SLC10A1, and SLC51A. Of the 70 variants identified, 50(71.4%) were novel variants. The ABCB11-related hereditary cholestasis was the most frequent 27(29%), followed by ABCB4 (26(27.9%).  Homozygosity was frequently seen in all except 8(8.6%) children, who had compound heterozygous pathogenic variants. There was no evidence of phenotypic expression in the carrier parents despite the severe nature of the respective mutations identified in the patients. Conclusions: Genetic heterogeneity of paediatric intrahepatic cholestasis showed recurrent and novel mutations. Key Words: Cholestasis, Progressive familial intrahepatic cholestasis, Neonatal sclerosing cholangitis, Genetic mutation, USP53, Bile acid synthetic defects, CLD

An integrated multiomic approach as an excellent tool for the diagnosis of metabolic diseases: our first 3720 patients

To present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Within this cohort, the highest diagnostic yield was obtained for patients from Asia (57.5%, mainly from Pakistan). Overall, 701 pathogenic/likely pathogenic unique SNVs and 40 CNVs were identified. In 620 patients, the result of the biochemical tests guided variant classification and reporting. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We show that integrated genetic and biochemical testing facilitated the decision on clinical relevance of the variants and led to a high diagnostic yield (37%), which is comparable to exome/genome sequencing. More importantly, up to 43% of these patients ( n  = 610) could benefit from medical treatments (e.g., enzyme replacement therapy). This multiomic approach constitutes a unique and highly effective tool for the genetic diagnosis of IMDs