Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly.

The transmembrane protein TMEM147 has a dual function: first at the nuclear envelope, where it anchors lamin B receptor (LBR) to the inner membrane, and second at the endoplasmic reticulum (ER), where it facilitates the translation of nascent polypeptides within the ribosome-bound TMCO1 translocon complex. Through international data sharing, we identified 23 individuals from 15 unrelated families with bi-allelic TMEM147 loss-of-function variants, including splice-site, nonsense, frameshift, and missense variants. These affected children displayed congruent clinical features including coarse facies, developmental delay, intellectual disability, and behavioral problems. In silico structural analyses predicted disruptive consequences of the identified amino acid substitutions on translocon complex assembly and/or function, and in vitro analyses documented accelerated protein degradation via the autophagy-lysosomal-mediated pathway. Furthermore, TMEM147-deficient cells showed CKAP4 (CLIMP-63) and RTN4 (NOGO) upregulation with a concomitant reorientation of the ER, which was also witnessed in primary fibroblast cell culture. LBR mislocalization and nuclear segmentation was observed in primary fibroblast cells. Abnormal nuclear segmentation and chromatin compaction were also observed in approximately 20% of neutrophils, indicating the presence of a pseudo-Pelger-Huët anomaly. Finally, co-expression analysis revealed significant correlation with neurodevelopmental genes in the brain, further supporting a role of TMEM147 in neurodevelopment. Our findings provide clinical, genetic, and functional evidence that bi-allelic loss-of-function variants in TMEM147 cause syndromic intellectual disability due to ER-translocon and nuclear organization dysfunction.

A disorder clinically resembling cystic fibrosis caused by biallelic variants in the AGR2 gene.

PURPOSE: We sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause. METHODS: Exome/genome sequencing and human phenotype ontology data of nearly 40 000 patients from our Bio/Databank were analysed. RNA sequencing of samples from the nasal mucosa from patients, carriers and controls followed by transcriptome analysis was performed. RESULTS: We identified 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in AGR2, (1) two splice-site variants, (2) gene deletion and (3) three missense variants. We confirmed aberrant AGR2 transcripts caused by an intronic variant and complete absence of AGR2 transcripts caused by the large gene deletion, resulting in loss of function (LoF). Furthermore, transcriptome analysis identified significant downregulation of components of the mucociliary machinery (intraciliary transport, cilium organisation), as well as upregulation of immune processes. CONCLUSION: We describe a previously unrecognised autosomal recessive disorder caused by AGR2 variants. AGR2-related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets.

The Mutational Landscape Of Genetic Cholestatic Diseases In Pakistani Children.

Objectives: To report the mutational landscape of a clinically diagnosed cohort of paediatric patients with cholestasis liver diseases. METHODS: 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.

Robust Output Feedback Control of Single-Link Flexible-Joint Robot Manipulator with Matched Disturbances Using High Gain Observer.

This article focuses on the output feedback control of single-link flexible-joint robot manipulators (SFJRMs) with matched disturbances and parametric uncertainties. Formally, four sensing elements are required to design the controller for single-link manipulators. We have designed a robust control technique for the semiglobal stabilization problem of the angular position of the link in the SFJRM system, with the availability of only a position sensing device. The sliding mode control (SMC) based output feedback controller is devised for SFJRM dynamics. The nonlinear model of SFJRM is considered to estimate the unknown states utilizing the high-gain observer (HGO). It is shown that the output under SMC using HGO-based estimated states coincides with that using original states when the gains of HGO are sufficiently high. Finally, the results are presented showing that the designed control technique works well when the SFJRM model is uncertain and matched perturbations are expected.

Very early onset inflammatory bowel disease: Spectrum of clinical presentation, diagnostic tools and outcome in children.

OBJECTIVE: To explore the spectrum of presentation, underlying monogenetic defects and outcome in very early onset inflammatory bowel disease (VEO-IBD). METHOD: The prospective, observational study was conducted at the Children's Hospital, Lahore, Pakistan, from January 2017 to December 2018, and comprised children developing features of inflammatory bowel disease aged <6 years. Data included demography, clinical presentation, diagnostic tools and outcome. Data was analysed using SPSS 21. RESULTS: Of the 60 children with relevant symptoms, 26(43.3%) were diagnosed as having very early onset inflammatory bowel disease. Of them, 13(50%) had underlying monogenic defect, and 16(61.5%) had ulcerative colitis. There were 22(84.6%) males with median age of 1.5(11) months in monogenic inflammatory bowel disease versus 24(43) months for non-monogenic inflammatory bowel disease (p<0.05). In the monogenic group, isolated rectal bleeding was the major presentation 13(100%) versus non-monogenic who presented mainly with failure to thrive 13(100%). Upper and lower endoscopies with histopathology had good diagnostic yield and inflammatory infiltrates on the biopsied tissues were the major findings. Mutations detected among the subjects were XIAP, PRKDC, PIK3CD, RAG-1, LRBA, DOCK8, TTC7, MEFV and EPCAM. Mortality was significantly higher in the monogenic group 7(54%) than in the non-monogenic group 2(15%) (p<0.05). CONCLUSIONS: Very early onset inflammatory bowel disease should be suspected when conventional management fails to rectify common disease mimickers. Testing for underlying immunological defect and genetic mutation would be helpful for managing these rare disorders.

Analgesic, anti-inflammatory and anti-platelet activities of Buddleja crispa.

BACKGROUND: Buddleja crispa Benth (Buddlejaceae) is a dense shrub; several species of genus Buddleja have been used in the management of various health conditions including pain and inflammation. The present study was aimed to investigate the analgesic, anti-inflammatory and anti-platelet properties of B. crispa. METHODS: Male rats (220-270 gm,) and mice (25-30 gm) were randomly divided into different groups (n = 6). Various doses of plant extract of B. crispa, its fractions and pure compounds isolated from the plant were administered intraperitoneally (i.p). The analgesic, anti-inflammatory and anti-platelet activities were assessed using acetic acid and formalin-induced nociception in mice, carrageenan-induced rat paw edema and arachidonic acid-induced platelets aggregation tests. RESULTS: The intraperitoneal administration of the methanolic extract (50 and 100 mg/kg), hexane fraction (10 and 25 mg/kg i.p) exhibited significant inhibition (P < 0.01) of the acetic acid-induced writhing in mice and attenuated formalin-induced reaction time of animals in second phase of the test. Pure compounds BdI-2, BdI-H3 and BH-3 isolated from B. crispa produced significant (P < 0.01) analgesic activity in acetic acid-induced and formalin tests. The crude extract of B. crispa (50-200 mg/kg i.p.) and its hexane fraction inhibited carrageenan-induced rat paw edema with maximum inhibition of 65 and 71% respectively (P < 0.01). The analgesic and anti-inflammatory effect of the plant extract and isolated pure compounds were comparable to diclofenac sodium. B. crispa plant extract (0.5-2.5 mg/mL) produced significant anti-platelet effect (P < 0.01) with maximum inhibition of 78% at 2.5 mg/ml. CONCLUSION: The findings from our present study suggest that B. crispa possesses analgesic, anti-inflammatory and anti-platelet properties. B. crispa could serve a potential novel source of compounds effective in pain and inflammatory conditions.

The association of factor V leiden mutation with recurrent pregnancy loss.

OBJECTIVE: To determine the association of factor V Leiden mutation with recurrent pregnancy loss. METHODS: The case-control study was conducted at the Department of Haematology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from January to June 2012, and comprised women of 18 to 45 years of age who had a history of recurrent pregnancy loss, and controls with no history of pregnancy loss. All the subjects belonged to Punjabi ethnic group. Three ml blood was taken from cases and controls and deoxyribonucleic acid was extracted. In order to identify Factor V Leiden mutation, polymerase chain reaction method was utilised combined with the amplification refractory mutation system. Data was analysed using SPSS 17. RESULTS: Of the 112 subjects, 56(50%) were in each of the two groups. The presence of factor V Leiden mutation among the cases was 3(5.4%) while it was absent among the controls. The mutation was significantly associated with recurrent pregnancy loss (p=0.017).Recurrent pregnancy loss was higher in cases than controls (p=0.001). CONCLUSIONS: Factor V Leiden mutation, Recurrent pregnancy loss, PCR (Polymerase chain reaction).

To determine the frequency of Factor V Leiden in cases of Deep Vein Thrombosis and Healthy controls.

OBJECTIVE: To determine the frequency of Factor V Leiden in cases of Deep Vein Thrombosis and Healthy controls. METHODS: This case control study was performed in Armed Forces Institute of Pathology Rawalpindi, From 21(st) March to 25(th) September 2013. One hundred patients with diagnostic evidence of Deep vein thrombosis on Doppler ultrasound/Magnetic resonance imaging (MRI) scan were included in the study through non probability convenient sampling and compared with 100 matched healthy controls. DNA was extracted from the blood sample by kit method. In order to identify Factor V Leiden mutation, the polymerase chain reaction (PCR) method was utilized combined with the Amplification refractory mutation system. Data was analyzed using statistical package for social sciences (SPSS) version 17. RESULTS: In 100 patients of Deep Vein Thrombosis (DVT), frequency of Factor V Leiden (FVL) was 13% and it is was 2% in healthy control group. A significant association was found between FVL and DVT with odds ratio of 7.32 and with P value (P = 0.003). CONCLUSION: FVL was found to be highly prevalent among patients of DVT, Signifying strong association between the two.

Diabetes and CFAP126 gene mutation; are they really linked together?

OBJECTIVES: We are reporting a rare case series of 2 siblings and their mother with diabetes having a CFAP126 gene mutation. CASE PRESENTATION: Two female siblings, presented with incidental hyperglycemia at the ages of 16 and 13. They had a strong family history of diabetes on the maternal side. The systemic examination was unremarkable. Sibling 1 had HbA1C of 12.3 % with insulin and C-peptide levels of 6.6 IU/L and 1.8 ng/mL, respectively. Sibling 2 had an HbA1C of 12.6 %, an insulin level of 7.3 IU/L, and a C-peptide level of 2.02 ng/mL. Anti-GAD-65 and IA2 antibodies were negative. Mother also shared similar clinical processes and exhibited comparable biochemical changes related to glucose metabolism with elevated HbA1C levels and negative autoimmune markers (anti-GAD65 and IA2 antibodies). Whole exome sequencing (WES) turned out to be negative for MODY variants but revealed a rare heterozygous mutation in the CFAP126 gene (c.310A>T p. (Lys104*) in this family including both siblings and mother. The pathogenicity prediction tool MutationTaster® classified the mutation as disease causing. Oral glibenclamide remarkably reduced insulin requirements and improved HbA1C levels. CONCLUSIONS: This rare genetic mutation is likely associated with diabetes and possibly a novel marker for a yet to be identified type of diabetes, that is responsive to oral sulfonylureas. The influence of this gene on insulin secretion needs to be confirmed through future research.

Consanguinity and inflammatory bowel diseases: is there a relation?

OBJECTIVE: The aim of the present study was to investigate the relation between consanguinity and inflammatory bowel diseases (IBD). METHODS: Review of the medical records of children with a final diagnosis of IBD to determine age, sex, and type of IBD, supplemented by information on consanguinity and family history (FH) of IBD in relatives. There were 138 children, ages 1.4 to 19.3 years, and 50% were girls. RESULTS: The prevalence of consanguinity was 50%, 53%, 39% and 60% in IBD, Crohn disease (CD), ulcerative colitis (UC), and controls, respectively. There was a significantly higher prevalence of consanguinity in controls than in patients with IBD and UC (P = 0.02 and 0.026, respectively), whereas the difference between CD patients and controls was not significant (P = 0.20). The prevalence of first cousin consanguinity was 71%, 73.2%, 61.5% and 70.5% in patients with IBD, CD, UC, and controls, respectively, indicating no significant difference between these conditions and controls (P = 0.95, P = 0.78, P = 0.33, respectively). There was no significant difference in the prevalence of consanguinity in the parents of children with or without a FH of either CD (P = 0.89) or UC (P = 0.32). CONCLUSIONS: There is no significant relation between parental consanguinity and IBD in this population, especially when there is no FH of disease, suggesting reduced genetic susceptibility; however, further studies including larger sample size and details of FH of consanguinity and IBD in multiple generations are needed for further definitions of the role of consanguinity.

Chronic hives associated with Helicobacter pylori in a child.

Chronic urticaria is fairly a common disorder in children and management is sometime challenging. Helicobacter pylori (H. pylori) should be considered as one of the causes for chronic urticaria when the response to conventional treatment is not appropriate. A nine years old girl with suspicion of wheat allergy (celiac disease) and chronic urticaria was referred for endoscopy. Antral nodularity with H. pylori gastritis was observed and confirmed on biopsy specimen with normal small bowel mucosa. Treatment for H. pylori cured her chronic urticaria. H. pylori should be considered as one of the differential if conventional medication does not help curing chronic urticaria.

Corticosterone Methyl Oxidase Type 1 (CMO1) Deficiency Due to CYP11B2 Mutation: Two Case Reports.

Aldosterone synthase deficiency (ASD) is a rare autosomal recessive condition due to an inactivating mutation in CYP11B2. There are two types of ASD depending upon level of defect in aldosterone synthesis, corticosterone methyl oxidase type 1 (CMO 1) and type 2 (CMO 2) deficiency. We are reporting two cases of CMO 1 deficiency presented with failure to thrive. Both cases were born to consanguineous parents and presented at around 17 months and 15 months with complaints of repeated vomiting and failure to thrive. They were found to have persistent hyponatremia, hyperkalemia, low aldosterone level, raised renin levels, normal cortisol and normal 17 hydroxyprogesterone level, suggesting the diagnosis of isolated aldosterone deficiency. Whole exome sequencing revealed that Case 1 is carrying a novel homozygous mutation in CYP11B2, c.1391_1393dup p.(Leu464dup) and Case 2 has a homozygous pathogenic variant in CYP11B2, c.922T>C p.(Ser308Pro), confirming the diagnosis of CMO 1 deficiency in both cases. After initial stabilization, both cases were started on oral fludrocortisone. They responded well and showed a good catch-up in growth and development. Aldosterone synthase deficiency is a rare condition, but it shall be suspected in infants presented with failure to thrive, hyponatremia and hyperkalemia without pigmentation and virilization.

Clinical spectrum and diagnostic challenges of vitamin D dependent rickets type 1A (VDDR1A) caused by CYP27B1 mutation in resource limited countries.

OBJECTIVES: Vitamin D dependent rickets type 1A (VDDR1A) is a rare autosomal recessive condition due to inactivating mutation of CYP27B1. It mimics clinically, biochemically and rediologically to nutritional and hypophosphatemic rickets. In developing countries like Pakistan, VDDR1A is often misdiagnosed as nutritional rickets or hypophosphatemic rickets due lack of free access to 1,25 (OH) 2 D level and genetic testing. This study was aimed to determine the clinical spectrum and diagnostic challenges of VDDR1A due to CYP27B1 mutation in developing countries. METHODS: Retrospective review of all cases of VDDR1A due to CYP27B1 mutation over a period of two years presenting in the Pediatric Endocrine clinic of Hameed Latif Hospital, Lahore, Pakistan. RESULTS: Six cases of VDDR1A (4 males) were identified. Mean age of clinical manifestation was 14 (9-24) months. Mean age of presentation to endocrine department was 5.5 (1.5-11.8) years. Growth failure and bony deformities were the most common presentation (n=6), followed by repeated diarrheas and abdominal distension (n=3) and recurrent fractures (n=1). All cases shared same biochemical profile of low/normal calcium, hypophosphatemia, raised alkaline phosphatase, raised PTH, normal/high 25(OH)D and tubular reabsorption of phosphate (TRP) <85%. Patients treated with calcitriol showed rapid healing as compared to those treated with 1-alfacalcidol. CONCLUSIONS: We should have a high index of suspicion of VDDR1A in rickets not responding to cholecalciferol therapy.

Clinical and Genetic Description of Hereditary Chronic Pancreatitis in Pakistani Children.

BACKGROUND/AIMS: The purpose of this study was to identify the spectrum and frequency of pathogenic variants as well as the clinical and genetic insight of hereditary chronic pancreatitis in Pakistani children. MATERIALS AND METHODS: The deoxyribonucleic acid of affected probands of 44 unrelated Pakistani families, having hereditary chronic pancreatitis-affected children, were subjected to massive parallel sequencing for candidate reported genes (SPINK1, PRSS1, CFTR, CPA1, CTRC, CBS, AGL, PHKB, and LPL). Data were analyzed using different bioinformatics tools for the variants and in-silico analysis. All the identified variants were validated by direct sequencing of the targeted exons in the probands and their parents. RESULTS: There were 50 patients included in this study with confirmed hereditary chronic pancreatitis. Nine known mutations in SPINK1, PRSS1, CFTR, CTRC, CBS, and AGL genes, and 10 novel variants in LPL, CFTR, CTR, and PHKB genes were identified. The identified variants were found in heterozygous, compound heterozygous, and trans-heterozygous forms, with rare allele frequency in the normal population. The novel variants were [c.378C>T(p.Lys126Asn) and c.719G>A(p.Arg240Gln) in CTRC, c.586-3C>A and c.763A>G(p.Arg255Gly) in CPA1, c.1160_1161insT(p.Lys387Asnfs*26), c.784C>T(p.Gln262*), c.1139+1G>A, c.175G>A(p.Gly59Arg) in LPL, c.388C>G(p.leu130val) in CFTR, and c.2327G>A(p.Arg776His in PHKB)]. The phenotypic characteristics were variable and correlated with the relevant variant. CONCLUSIONS: The genetic composition plays a significant role in the predisposition of hereditary chronic pancreatitis. The clinical presentation varies with the genetic determinant involved. This information would help in building up a diagnostic algorithm for our population that can be used for genetic screening services in affected cohorts.

Kleefstra Syndrome with Severe Sensory Neural Deafness and De Novo Novel Mutation.

Kleefstra syndrome is a rare inherited neuro-developmental condition characterised by facial dysmorphism, microcephaly, hypotonia, developmental delay, and intellectual disability. It is a rare syndrome; and less than 100 cases with different genetic mutations are reported so far. We report an eight-month baby boy with Kleefstra syndrome type 2 due to a novel de novo pathogenic mutation in the KMT2C (Lysine methyltransferase 2C) gene. Key Words: Kleefstra syndrome, KMT2C gene, Neurodevelopmental disorder, Deafness.

Tricho-Hepato-Eenteric Syndrome: Same Genotype but Different Phenotypes in Two Pakistani Children.

Tricho-hepato-enteric syndrome (THES) is characterised by infantile diarrhea with characteristic facies, trichorrhexis nodosa and hepatic involvement. The underlying genetic mutation is in tetratricopeptide repeat domain 37 (TTC37) gene. It is a very rare syndrome and only 44 cases have been reported so far in the medical literature. We recently diagnosed two children with THES on genetic analysis, who had same genotype but different phenotypes. Using these cases as a precedent, we reviewed what is known about this rare syndrome, as well as the novelties in our cases and treatment options. Key Words: Chronic diarrhea, Liver disease, Genetic mutation, TTC37.

Management challenges of Rabson Mendenhall syndrome in a resource limited country: a case report.

OBJECTIVES: Rabson Mendenhall syndrome  (RMS) is a rare form of insulin resistance syndrome caused by insulin receptor mutation. In term of severity, it lies at an intermediate point on spectrum of insulin resistance with Donohue syndrome flanking the severe and Type A insulin resistance at the mild end. We are reporting a 3.5-month-old boy with RMS along with its management challenges in a resource limited country. CASE PRESENTATION: An infant presented at 3.5-month of an age with failure to thrive and fluctuating blood glucose level (hyperglycaemia and hypoglycaemia) along with clinical features of insulin resistance. He was found to have raised HbA1C, high insulin and C peptide level and a homozygous mutation in INSR gene c.1049C>T, (p.Ser350 Leu) confirming the diagnosis of RMS. He was managed with long-acting insulin (Detemir) along with frequent feeding. CONCLUSIONS: RMS in resource limited countries could be managed with frequent feeding along with insulin. Early diagnosis and management can improve long term outcome.

Viral dysbiosis in children with new-onset celiac disease.

Viruses are common components of the intestinal microbiome, modulating host bacterial metabolism and interacting with the immune system, with a possible role in the pathogenesis of immune-mediated diseases such as celiac disease (CeD). The objective of this study was to characterize the virome profile in children with new-onset CeD. We used metagenomic analysis of viral DNA in mucosal and fecal samples from children with CeD and controls and performed sequencing using the Nextera XT library preparation kit. Abundance log2 fold changes were calculated using differential expression and linear discriminant effect size. Shannon alpha and Bray-Curtis beta diversity were determined. A total of 40 children with CeD and 39 controls were included. We found viral dysbiosis in both fecal and mucosal samples. Examples of significantly more abundant species in fecal samples of children with CeD included Human polyomavirus 2, Enterobacteria phage mEpX1, and Enterobacteria phage mEpX2; whereas less abundant species included Lactococcus phages ul36 and Streptococcus phage Abc2. In mucosal samples however, no species were significantly associated with CeD. Shannon alpha diversity was not significantly different between CeD and non-CeD groups and Bray-Curtis beta diversity showed no significant separation between CeD and non-CeD samples in either mucosal or stool samples, whereas separation was clear in all samples. We identified significant viral dysbiosis in children with CeD, suggesting a potential role in the pathogenesis of CeD indicating the need for further studies.

The Epidemiology and Outcome of Biliary Atresia: Saudi Arabian National Study (2000-2018).

Background: The epidemiology and outcomes of biliary atresia (BA) have been well-documented in national cohorts from two main ethnicities, namely, the Asian Orientals and Caucasians, with incidence ranging from 1 in 5,000 to 1 in 9,000 live births in East Asia and 1 in 15,000 to 19,000 live births in Europe and North America. Objective: We report the first nationwide BA study outside North America, Europe, and East Asia to describe the epidemiology and outcomes of BA in Saudi Arabia. Methods: A national database of BA cases diagnosed between 2000 and 2018 was analyzed. We assessed clearance of jaundice (bilirubin <20 µmol/L) in all cases that underwent Kasai portoenterostomy (KPE). We then estimated survival using the Kaplan-Meier method with endpoints of liver transplantation (LT), death, or survival with native liver (SNL). Results: BA was diagnosed in 204 infants (106 females; 10% pre-term). The incidence of BA was 1 in 44,365, or 2.254 in 100,000 live births (range, 0.5-4 in 100,000). Polysplenia was diagnosed in 22 cases (11%). The median age at referral was 65 days. A total of 146 children (71.5%) underwent KPE at a median age of 70 days. Clearance of jaundice was achieved in 66 of the 146 (45%) infants. The 10-year SNL after KPE was 25.5%, and the overall 10-year estimated survival was 72.5%. The Kaplan-Meier survival curves for patients undergoing KPE at the age of <60, 61-90, and >90 days showed a SNL rate at 51.6, 33, and 12.5%, respectively, at 5 years (P < 0.001). The 2-, 5-, and 10-year post-LT survival rates were 92.5, 90.6, and 90%, respectively. Undergoing an initial KPE did not impact negatively on the overall LT survival rate when compared to BA cases that underwent primary LT (P = 0.88). Conclusion: The incidence rate of BA in Saudi Arabia is lower than the incidence reported elsewhere. Late referral of BA cases remains a problem in Saudi Arabia; as a result, the SNL rate was lower than reported by other national registries. Hence, national policies devoted to timely referral and earlier age at KPE are needed.

Variability of clinical and biochemical phenotype in liver phosphorylase kinase deficiency with variants in the phosphorylase kinase (PHKG2) gene.

Background PHKG2-related liver phosphorylase kinase deficiency is inherited in autosomal recessive pattern and is a rare type of liver glycogenosis. We demonstrated the clinical presentation and genetic determinants involved in children with PHKG2- related liver phosphorylase kinase deficiency. Methodology Ten Pakistani children with liver phosphorylase kinase from seven different families, were enrolled over a period of 18 months. All regions of the PHKG2 gene spanning exons and splicing sites were evaluated through targeted exome sequencing. Variants were analyzed using different bioinformatics tools. Novel variants were reconfirmed by direct sequencing. Results Seven different variants were identified in PHKG2 gene including five novel variants: three stop codons (c.226C>T [p.R76*], c.454C>T [p.R152*] and c.958C>T [p.R320*]), one missense variant c.107C>T (p.S36F) and one splice site variant (c.557-3C>G). All five novel variants were predicted to be damaging by in Silico analysis. The variants are being transmitted through recessive pattern of inheritance except one family (two siblings) has compound heterozygotes. Laboratory data revealed elevated transaminases and triglycerides, normal creatinine phosphokinase and uric acid levels but with glycogen loaded hepatocytes on liver histology. Conclusion PHKG2 related liver phosphorylase kinase deficiency can mimic both liver glycogenosis type I (glucose-6-phosphatase deficiency) & III(amylo-1,6 glucosidase) and characterized by early childhood onset of hepatomegaly, growth restriction, elevated liver enzymes and triglycerides. Molecular analysis would be helpful in accurate diagnosis and proper treatment. The symptoms and biochemical abnormalities in liver glycogenosis due phosphorylase kinase deficiency tend to improve with proper dietary restrictions but need to be monitored for long-term complications such as liver fibrosis and cirrhosis.