Abdulrahman Al-Hussaini

Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene

Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are severe autosomal recessive disorders associated with decreased mtDNA copy number in clinically affected tissues. The hepatocerebral form (mtDNA depletion in liver and brain) has been associated with mutations in the POLG, PEO1 (Twinkle), DGUOK and MPV17 genes, the latter encoding a mitochondrial inner membrane protein of unknown function. The aims of this study were to clarify further the clinical, biochemical, cellular and molecular genetic features associated with MDS due to MPV17 gene mutations. We identified 12 pathogenic mutations in the MPV17 gene, of which 11 are novel, in 17 patients from 12 families. All patients manifested liver disease. Poor feeding, hypoglycaemia, raised serum lactate, hypotonia and faltering growth were common presenting features. mtDNA depletion in liver was demonstrated in all seven cases where liver tissue was available. Mosaic mtDNA depletion was found in primary fibroblasts by PicoGreen staining. These results confirm that MPV17 mutations are an important cause of hepatocerebral mtDNA depletion syndrome, and provide the first demonstration of mosaic mtDNA depletion in human MPV17 mutant fibroblast cultures. We found that a severe clinical phenotype was associated with profound tissue-specific mtDNA depletion in liver, and, in some cases, mosaic mtDNA depletion in fibroblasts.

Long‐term outcome and management of hepatopulmonary syndrome in children

Al‐Hussaini A, Taylor RM, Samyn M, Bansal S, Heaton N, Rela M, Mieli‐Vergani G, Dhawan A. Long‐term outcome and management of hepatopulmonary syndrome in children.u2028Pediatr Transplantation 2010:14:276–282.

Clinical and Molecular Characteristics of Mitochondrial DNA Depletion Syndrome Associated with Neonatal Cholestasis and Liver Failure

OBJECTIVEnTo determine the frequency of mitochondrial DNA depletion syndrome (MDS) in infants with cholestasis and liver failure and to further clarify the clinical, biochemical, radiologic, histopathologic, and molecular features associated with MDS due to deoxyguanosine kinase (DGUOK) and MPV17 gene mutations.nnnSTUDY DESIGNnWe studied 20 infants with suspected hepatocerebral MDS referred to our tertiary care center between 2007 and 2013. Genomic DNA was isolated from blood leukocytes, liver, and/or skeletal muscle samples by standard methods. Mitochondrial DNA copy number relative to nuclear DNA levels was determined in muscle and/or liver DNA using real-time quantitative polymerase chain reaction and compared with age-matched controls. Nuclear candidate genes, including polymerase γ, MPV17, and DGUOK were sequenced using standard analyses.nnnRESULTSnWe identified pathogenic MPV17 and DGUOK mutations in 11 infants (6 females) representing 2.5% of the 450 cases of infantile cholestasis and 22% of the 50 cases of infantile liver failure referred to our center during the study period. All of the 11 patients manifested cholestasis that was followed by a rapidly progressive liver failure and death before 2 years of life. Mitochondrial DNA depletion was demonstrated in liver or muscle for 8 out of the 11 cases where tissue was available. Seven patients had mutations in the MPV17 gene (3 novel mutations), 4 patients had DGUOK mutations (of which 2 were novel mutations).nnnCONCLUSIONnMutations in the MPV17 and DGUOK genes are present in a significant percentage of infants with liver failure and are associated with poor prognosis.

Variable degree of liver involvement in siblings with PiZZ alpha-1-antitrypsin deficiency-related liver disease.

PiZZ alpha-1-antitrypsin deficiency is the commonest genetic cause of chronic liver disease, but only 10-15% of PiZZ individuals develop liver disease in childhood. Studies have demonstrated varying patterns of disease progression within siblings with the PiZZ phenotype. We retrospectively analysed the case-notes of all patients diagnosed with PiZZ A1ATD between 1978-2002 and compared the pattern of liver disease between affected siblings. We identified 29 families with more than 1 child with the PiZZ phenotype. Twenty-one (72%) PiZZ siblings of the 29 probands had liver disease, which was concordant for severity in 6 (29%), while 8 (28%) had no liver involvement. Five of 7 children requiring liver transplantation had siblings with no persistent liver dysfunction. This study suggests that there is a variable degree of liver involvement in siblings with PiZZ A1ATD-related liver disease and environmental and/or other genetic factors must be involved in determining disease severity.

Therapeutic applications of octreotide in pediatric patients.

Background/Aim: We report our experience with the use of octreotide as primary or adjunctive therapy in children with various gastrointestinal disorders. Patients and Methods: A pharmacy database identified patients who received octreotide for gastrointestinal diseases. Indications for octreotide use, dosing, effectiveness, and adverse events were evaluated by chart review. Results: A total of 21 patients (12 males), aged 1 month to 13 years, were evaluated. Eleven received octreotide for massive gastrointestinal bleeding caused by portal hypertension-induced lesions (n=7), typhlitis (1), Meckels diverticulum (1), and indefinite source (2). Blood transfusion requirements were reduced from 23±9 mL/kg (mean±SD) to 8±15 mL/kg (P<0.01). Four patients with pancreatic pseudocyst and/or ascites received octreotide over 14.0±5.7 days in 2 patients. In 3 children, pancreatic pseudocyst resolved in 12±2 days and pancreatic ascites resolved in 7 days in 2. Three patients with chylothorax received octreotide for 14±7 days with complete resolution in each. Two infants with chronic diarrhea received octreotide over 11±4.2 months. Stool output decreased from 85±21 mL/kg/day to 28±18 mL/kg/day, 3 months after initiation of octreotide. The child with dumping syndrome responded to octreotide in a week. Adverse events developed in 4 patients: Q-T interval prolongation and ventricular fibrillation, hyperglycemia, growth hormone deficiency, and hypertension. Conclusion: Octreotide provides a valuable addition to the therapeutic armamentum of the pediatric gastroenterologist for a wide variety of disorders. Serious adverse events may occur and patients must be closely monitored.

Does vitamin E improve the outcomes of pediatric nonalcoholic fatty liver disease? A systematic review and meta-analysis.

Background and Aims: To systemically evaluate the efficacy of adjuvant vitamin E on the outcomes of nonalcoholic fatty liver disease (NAFLD) and/or nonalcoholic steatohepatitis (NASH) in children. Materials and Methods: We searched MEDLINE, PUBMED, EMBASE, the Cochrane Central Register Controlled Trials, and the Cochrane Database of Systematic Reviews over the period between January 1980 and September 2012 for the studies that examined the role of adjuvant vitamin E given at any dose or duration, alone or in combination with other interventions, on the outcome of pediatric NAFLD. The outcomes are alanine aminotransferase (ALT) normalization and histological improvement. Results: Five randomized trials were eligible to be included in our analysis, with a total of 270 participants. There was no statistically significant difference in the effect of adjuvant vitamin E on normalizing serum ALT [risk ratio (RR) =1.18, confidence interval (CI) =0.92-1.53, P = 0.77 for heterogeneity, I2 = 0%]. Sensitivity analysis showed that using higher doses of vitamin E, a longer duration of therapy or adding vitamin C did not change the effect on the measured outcome. Only two studies looked at histological changes as an outcome. We observed substantial heterogeneity between the two studies. Conclusions: Our meta-analysis did not find a significant effect of adjuvant vitamin E over placebo in normalizing serum ALT. Data on the long-term effect of adjuvant vitamin E on histological improvements in NAFLD patients are still lacking. Larger, well-designed randomized controlled trials (RCTs) in children with histological endpoints are still needed to answer this question.

Isolated cortisol deficiency: a rare cause of neonatal cholestasis.

For decades, congenital panhypopituitarism has been recognized to cause infantile cholestasis. However, the identity of the hormone whose deficiency causes such derangement of the liver is not clear. Here, we report four cases of isolated severe cortisol deficiency presenting with neonatal cholestasis and hypoglycemia, of whom two had familial primary glucocorticoid deficiency and the other two had isolated adrenocorticotropin deficiency. The resolution of cholestasis by hydrocortisone replacement therapy suggests a causal relationship between cortisol deficiency and the development of neonatal cholestasis. In conclusion, the presentation of a young infant with cholestasis and hypoglycemia should alert pediatricians to the possibility of cortisol deficiency and prompt investigation of adrenal function should be undertaken.

Savary Dilation Is Safe and Effective Treatment for Esophageal Narrowing Related to Pediatric Eosinophilic Esophagitis

Objectives: Data on management of esophageal narrowing related to eosinophilic esophagitis (EoE) in children are scanty. The aim of the present study is to assess the safety and effectiveness of esophageal dilation in pediatric EoE from the largest case series to date. Methods: Children diagnosed with EoE during 2004 to 2015 were reviewed for the presence of esophageal narrowing. Esophageal narrowing was categorized as short segment narrow caliber, long segment narrow caliber, and single short stricture. The characteristics of the narrowed esophagus, therapeutic approach, clinical outcome, and complications were reviewed. Results: Of the 50 EoE cases diagnosed during the study period, 11 cases (9 boys; median age 9 years, range 4–12) were identified with esophageal narrowing (22%). Six had short segment narrow caliber esophagus and 5 had long segment narrow caliber esophagus (median length of the narrowing was 4 cm, range 3–20 cm). Three cases with narrow caliber esophagus also had esophageal stricture 2 to 3 cm below the upper esophageal sphincter. Nineteen dilation sessions were performed in 10 cases using Savary dilator. Esophageal size improved from median 7 mm to median 13.4 mm. Good response was obtained in all cases. Following the dilation procedure, longitudinal esophageal mucosal tear occurred in all cases without esophageal perforation or chest pain. Conclusions: Esophageal dilation using Savary dilator is safe and highly effective in the management of esophageal narrowing related to EoE in children. Dilation alone does not improve the inflammatory process, and hence a combination with dietary or medical intervention is required.

Bile Acid Synthesis Disorders in Arabs: A 10-year Screening Study

Objectives: Early diagnosis of bile acid synthesis disorders (BASDs) is important because, untreated, these conditions can be fatal. Our objectives were to screen children with cholestasis or unexplained liver disease for BASD and in those with confirmed BASD to evaluate the effectiveness of cholic acid therapy. Methods: A routine serum total bile acid measurement was performed on children with cholestasis, liver cirrhosis, and liver failure. Patients were screened for BASD by fast atom bombardment ionization-mass spectrometry (FAB-MS) analysis of urine, and molecular analysis confirmed diagnosis. Treatment response to oral cholic acid (10–15 mg/kg bw/day) was assessed from liver function tests and fat-soluble vitamin levels. FAB-MS analysis of urine was used to monitor compliance and biochemical response. Results: Between 2007 and 2016, 626 patients were evaluated; 450 with infantile cholestasis. Fifteen cases of BASD were diagnosed: 12 presented with infantile cholestasis (2.7%, 7 boys), an 8-year-old boy presented with cirrhosis, and two 18-month-old boys presented with hepatomegaly and rickets. Eleven were caused by 3&bgr;-hydroxy-&Dgr;5-C27-steroid oxidoreductase dehydrogenase deficiency, 3 from &Dgr;4-3-oxosteroid 5&bgr;-reductase deficiency, and 1 had Zellweger spectrum disorder. In all but 1, serum total bile acids were normal or low. With cholic acid therapy, 10 are alive and healthy with their native liver. Liver failure developed in 3 infants despite therapy; 2 died and 1 underwent liver transplantation. Conclusions: BASDs are rare but treatable causes of metabolic liver disease in Saudi Arabia. BASD should be considered in infants with cholestasis and low or normal serum total bile acid concentrations.

The Clinical Burden of Rotavirus Gastroenteritis: A Prospective Study

Background In Saudi Arabia, there is a lack of recently published, appropriately conducted epidemiological studies on rotavirus (RV) diarrhea, which emphasizes the need for up-to-date and comprehensive studies. Objective Our objective was to provide more recent data on the clinical and epidemiological characteristics as well as the economic burden of RV diarrhea among young children admitted to a tertiary care hospital in the city of Riyadh in the year prior to the initiation of the RV vaccine. Design We conducted a prospective observational study at a children’s specialized hospital at King Fahad Medical City. We included children under five years of age who were hospitalized for gastroenteritis over a 12-month period from January 2012 to December 2012. Stool samples were collected on admission and tested for the presence of RV using an enzyme immunoassay. Results Of the 204 children included over the study period (mean age, 9.8 months ± 10.2; 124 males), 102 (50%) were RV-positive. Two-thirds (69.6%) were under one year old, and 38.2% were under six months of age. RV infections occurred throughout the year, with the highest proportion occurring during the spring and summer. RV-positive diarrhea was more severe than the RV-negative diarrhea as indicated by a significantly lower bicarbonate level (68.6% versus 31.3%, P-value < 0.0001), a higher frequency of severe dehydration (11.7% versus 3%, P-value = 0.015), and longer hospital stay (mean duration, 8.78 versus 6.56 days, P-value = 0.027). In addition, the financial burden of the RV-positive cases was greater than the RV-negative cases (median 1692 USD versus 1287 USD, P-value = 0.001). Conclusion Our study shows a high prevalence of RV infections among young children admitted to the hospital for acute gastroenteritis. Furthermore, RV infections are associated with severe diarrhea and significant financial burden.