MPV17 mutation-related mitochondrial DNA depletion syndrome: A case series in infants.

MPV17 is a mitochondrial inner membrane protein, involved in transporting deoxynucleotides into the mitochondria. Pathogenic MPV17 mutations can cause mitochondrial deoxyribonucleic acid (DNA) depletion syndrome, which has a varied presentation with neurological, muscular and hepatic involvement. Presentation as liver failure is relatively uncommon. Here, we report four infants from four separate families with pathogenic, homozygous MPV17 mutations. All had predominant hepatic involvement with cholestasis, lactic acidosis and hypoketotic hypoglycemia. Three of them had presented with liver failure. Interestingly, one of them showed fluctuating liver functions, which worsened with infection and improved after aggressive treatment with antibiotics and supplements. Two of the four cases died in infancy, while the other two improved on conservative management with medium-chain triglyceride-based diet, vitamin supplements, co-enzyme Q and carnitine. The two surviving children are alive at 12 and 25 months of age with native liver with normal to mildly deranged liver function and no neurological dysfunction. Next-generation sequencing confirmed the diagnosis in all of our cases. One of the detected mutations, c.55delC (p.Gln19ArgfsTer3) is a novel pathogenic frameshift mutation, while another mutation c.388G>C (p.Ala130Pro), which was previously reported in Single Nucleotide Polymorphism Database in heterozygous form, is being predicted as likely pathogenic in our case series. We, therefore, propose mutation testing for MPV17 gene during evaluation of indeterminate infantile liver failure, especially those with hypoglycemia and raised plasma lactate.

Efficacy and Predictors of Pain Response to Combined Antioxidants in Children with Chronic Pancreatitis.

BACKGROUND: Pain is a major problem in 90% of patients with chronic pancreatitis (CP). Studies evaluating response to antioxidants (AO) are conflicting and no pediatric studies are available. AIMS: To evaluate markers of oxidative stress (OS), and efficacy and predictors of response to AO in improving pain in children with CP. METHODS: Antioxidants were given to CP children for 6 months. Subjects were assessed at baseline and post-therapy for pain and markers of OS [serum thiobarbituric acid reactive substances (TBARS), superoxide dismutase (S-SOD)] and antioxidant levels [vitamin C, selenium, total antioxidant capacity-ferric reducing ability of plasma (FRAP)]. Matched healthy controls were assessed for OS and antioxidant levels. Good response was defined as ≥ 50% reduction in number of painful days/month. RESULTS: 48 CP children (25 boys, age 13 years) and 14 controls were enrolled. 38/48 cases completed 6 months of therapy. CP cases had higher OS [TBARS (7.8 vs 5.2 nmol/mL; p < 0.001)] and lower antioxidant levels [FRAP (231 vs. 381.3 µmol/L; p = 0.003), vitamin C (0.646 vs. 0.780 mg/dL; p < 0.001)] than controls. Significant reduction in TBARS and S-SOD and increase in FRAP, vitamin C, and selenium occurred after 6 months. 10.5% cases had minor side effects. 26(68%) cases had a good response, with 9(24%) becoming pain-free. Subjects with severe ductal changes had lower median BMI (- 0.73 vs 0.10; p = 0.04) and responded less often than those with mild changes (17/29 vs 9/9; p = 0.036). CONCLUSION: CP children have higher OS than healthy controls. Antioxidant therapy is safe. Pain response is seen in 68% cases, less often in patients with severe ductal changes.

Effect of chelation therapy in pediatric Wilson's disease: Liver and endoscopic outcome.

BACKGROUND: As there is paucity of exclusive literature on pediatric hepatic Wilson's disease (WD), this study was undertaken to evaluate the efficacy of chelation on hepatocellular function and portal hypertension in WD. METHODS: Wilson's disease patients with ≥9 months of follow-up were evaluated for response to chelation therapy in the following categories: (a) complete remission, (b) partial remission (c) progression of disease; (d) drug toxicity. Pediatric end-stage liver disease (PELD), Nazar and New Wilson Index scores were compared. Hemodynamically stable patients underwent esophagogastroduodenoscopy (baseline and surveillance) and received prophylaxis (primary or secondary). Endoscopic outcome was assessed at follow-up. RESULTS: Of the 111 WD children (aged 9 [3-15] years; PELD score 16 [-11 to 60]), 65 with follow-up of 3.6 (0.8-12) years on chelation (83% D-penicillamine monotherapy, 17% D-penicillamine and zinc) were analyzed. 81% had severe disease at presentation. Favorable outcome (complete and or partial remission), progression of disease and drug toxicity were seen in 71%, 29% and 10.8%, respectively. Two-thirds had esophageal varices which did not show progression. Large esophageal varices (16%) were effectively downgraded in 3 (2-6) therapeutic endoscopic sessions. Nazar score and PELD score at baseline were independent predictors of outcome with favorable correlation with each other (r = .864, P < .001). PELD cutoff 9.45 (AUC: 71%, sensitivity: 87%, specificity: 50%; P = .009) and Nazar score cut off 3.5 (AUC: 68%, sensitivity: 83%, specificity: 50%; P = .02) were associated with poor prognosis. CONCLUSIONS: Despite severe liver disease, the majority of hepatic WD can be managed on D-penicillamine monotherapy. PELD score and Nazar score effectively determine the outcome.

Chronic vomiting in children: A prospective study reveals rumination syndrome is an important etiology that is underdiagnosed and untreated.

BACKGROUND: The diagnosis of rumination syndrome is frequently overlooked, and under-recognized; children are subjected to unnecessary testing and inappropriate treatment for a condition which can be diagnosed clinically and managed easily. In the first ever systematic exploration of this condition from India, we present a prospective study on children with chronic vomiting in which rumination emerged as the predominant cause. METHODS: This was a prospective study in which all consecutive children (5-18 years) presenting with chronic or recurrent vomiting of at least 2-month duration were enrolled. Clinical history was assessed by a physician-administered questionnaire. All subjects underwent standard testing followed by additional investigations as required. The ROME III criteria were used. RESULTS: Fifty children (28 boys, age 12.2 + 3 years) were enrolled. Diagnosis was rumination syndrome 30, cyclical vomiting 8, functional vomiting 6, intestinal tuberculosis 4, intestinal malrotation 1, and superior mesenteric artery syndrome 1. Children with rumination syndrome had a relapsing and remitting (12, 40%) or a chronically symptomatic course (18, 60%). These children received incorrect diagnoses (26, 87%) or no diagnosis (3, 10%) and extensive investigation before referral. Before referral, children with rumination syndrome were treated with a median of four drugs (range 1 to 9); two underwent surgery (appendectomy) for their symptoms while one child was subjected to electroconvulsive therapy. Overall, resolution after treatment was seen in 26 (87%) with a relapse in 8 (27%) children. CONCLUSION: The diagnosis of rumination syndrome is delayed and these children are often inappropriately treated. Therapy in the form of diaphragmatic breathing has a good success rate.

Solitary Rectal Ulcer Syndrome in Children: A Report of 140 Cases.

OBJECTIVES: Solitary rectal ulcer syndrome (SRUS) is said to be rare in children (largest series so far; 55 in children, 116 in adults). We analyzed our experience to look at its clinical presentations, endoscopic appearance, and treatment outcome in a large cohort of children. METHODS: Clinical and endoscopic data were collected between 2000 and 2018. Children (18 years or younger) diagnosed to have SRUS on colonoscopy and confirmed by histopathology were included. All children with SRUS were treated with behavioral modification, bulk laxative. Most with ulcer received steroid enema and some sulfasalazine or sucralfate enema. RESULTS: The median age of 140 children was 12 (interquartile range [IQR]: 10-14) years, 79% were boys. The median symptom duration was 21 (IQR: 9-36) months. Rectal bleeding was the presenting feature in 131 (93.6%); constipation in 38 (27%); and small, frequent stools in 79 (56%). Most children had features of dyssynergic defecation such as prolonged sitting in the toilet (131, 93.6%), excessive straining (138, 98.6%), a feeling of incomplete evacuation (130, 92.8%), and rectal digitation (71, 50.7%). Rectal prolapse was noted in 24 (17%) cases. Colonoscopy documented rectal ulcer in 101 (72%) [Single: 84]. Over a median follow-up of 6 (IQR: 4-18) months, 27 patients were lost to follow-up and of the remaining 113 cases, 71 (62.8%) showed clinical improvement (healing of ulcer documented in 36/82, 44%). CONCLUSIONS: The majority of cases of SRUS presented in second decade with rectal bleeding and features of dyssynergic defecation. Ulcer was noted in three fourths of cases. The outcome of medical treatment with behavioral modification and local therapy was modest.

Management of Childhood Functional Constipation: Consensus Practice Guidelines of Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition and Pediatric Gastroenterology Chapter of Indian Academy of Pediatrics.

JUSTIFICATION: Management practices of functional constipation are far from satisfactory in developing countries like India; available guidelines do not comprehensively address the problems pertinent to our country. PROCESS: A questionnaire-based survey was conducted among selected practising pediatricians and pediatric gastroenterologists in India, and the respondents agreed on the need for an Indian guideline on the topic. A group of experts were invited to present the published literature under 12 different headings, and a consensus was developed to formulate the practice guidelines, keeping in view the needs in Indian children. OBJECTIVE: To formulate practice guidelines for the management of childhood functional constipation that are relevant to Indian children. RECOMMENDATIONS: Functional constipation should be diagnosed only in the absence of red flags on history and examination. Those with impaction and/or retentive incontinence should be disimpacted with polyethylene glycol (hospital or home-based). Osmotic laxatives (polyethylene glycol more than 1 year of age and lactulose/lactitol less than 1 year of age) are the first line of maintenance therapy. Stimulant laxatives should be reserved only for rescue therapy. Combination therapies of two osmotics, two stimulants or two classes of laxatives are not recommended. Laxatives as maintenance therapy should be given for a prolonged period and should be tapered off gradually, only after a successful outcome. Essential components of therapy for a successful outcome include counselling, dietary changes, toilet-training and regular follow-up.

Mucuna pruriens (L.) DC chemo sensitize human breast cancer cells via downregulation of prolactin-mediated JAK2/STAT5A signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Mucuna pruriens (L.) DC (MP) is an ancient Indian medicinal plant traditionally used to treat Parkinson's disease. L-Dopa (LD), precursor of dopamine is abundantly found in the seeds of MP. L-dopa is a natural inhibitor of prolactin (PRL) hormone which is required to maintain lactation in women but it's over production (hyperprolactinemia) plays critical role in advancement of breast cancer. AIM OF THE STUDY: We aim to examine the pharmacological effect of LD and MP on this hyperprolactinemia associated breast cancer and related signaling for effective management of the disease. We also investigated chemo-sensitizing effect of MP on hyperprolactinemia-mediated cisplatin resistance. MATERIALS AND METHODS: Methanolic seed extract of MP were prepared and analysed using HPLC. Effect of LD and MP on the cellular viability of breast cancer cells (T47D, MCF-7, MDA-MB-468 and MDA-MB-231) were evaluated using MTT assay. Further, effect of LD and MP on colony forming potential, DNA damage, cell cycle distribution and apoptosis was determined using agar/agarose method, comet assay and annexin and PI method followed by FACS analysis. To reveal the molecular mechanism involved in the anti-cancer activity of MP, transcriptional and translational level analysis of the key proteins involved in the PRL-mediated signaling, was performed using RT-PCR and western blot analysis. The effect of MP extract on PRL-mediated signaling was validated using dopaminergic agonist bromocriptine. MP extract and cisplatin was given in different combination with appropriate controls to check their effect on chemo-resistivity of breast cancer cells. RESULTS: Our results demonstrated that MP seed extract has the potential to inhibit cellular proliferation of PRL expressing T47D and MCF-7 breast cancer cells via induction of DNA damage, G1 phase of cell cycle arrest and apoptosis more effectively as compare to LD. Further, MP-mediated anti-cancerous effect was associated with the downregulation of PRL expression, further suppressing the JAK2/STAT5A/Cyclin D1 signaling pathway which has been validated using dopaminergic agonist bromocriptine. Cancer-related hyperprolactinemia confers cisplatin resistance, we observed that MP via PRL inhibition, enhances cisplatin efficacy after their combinatorial treatment in breast cancer cells. CONCLUSIONS: Collectively, our study suggests that MP could be recommended as dietary supplement along with the chemotherapeutic agents against breast cancer.

Infant with hepatomegaly and hypoglycemia: A setting for fatty acid oxidation defects.

Fatty acid oxidation defects (FAOD) are one of the commonest metabolic liver diseases (MLDs) that can have varied presentations in different age groups. An infant presented with short history of jaundice and irritability, examination showed soft hepatomegaly. Investigations revealed non-ketotic hypoglycemia suggesting FAOD which was later confirmed as carnitine uptake defect with gas chromatography and mass spectrometry and mutation analysis. Patient improved with acute management of metabolic crisis, carnitine supplementation and corn starch therapy with reversal of encephalopathy, reduction in hepatomegaly, maintenance of euglycemia and improvement in liver function tests and creatine phosphokinase on follow up. Non-ketotic hypoglycemia is a characteristic finding in FAODs. Early diagnosis and appropriate management can result in excellent outcomes in patients with FAODs.

Child with Jaundice and Pruritus: How to Evaluate?

Jaundice with pruritus is a manifestation of cholestasis. The defective biliary drainage causes accumulation of substances that are usually excreted in bile, which in turn causes pruritus. The exact nature of the pruritogen is under evaluation. However, lysophosphatidic acid is the current favourite. The causes of cholestasis can be broadly classified as intra or extrahepatic, with intrahepatic disorders being more often associated with pruritus. Cholestatic phase of acute viral hepatitis, progressive familial intrahepatic cholestasis, syndromic and non-syndromic paucity of intralobular bile ductules, drug induced cholestasis and sclerosing cholangitis (SC) are the common causes in children. An algorithmic approach facilitates early etiological diagnosis by careful clinical evaluation combined with investigations including gamma glutamyl transpeptidase, radiological imaging (ultrasonography, magnetic resonance cholangiopancreatography), liver biopsy and genetic analysis. Management is largely supportive and includes nutritional rehabilitation with supplement of fat soluble vitamins and calcium, stepwise therapy of pruritus with drugs (ursodeoxycholic acid, rifampicin, bile acid sequestrants and/or opioid antagonists) and biliary diversion surgery. Complications of advanced liver disease and portal hypertension need to be addressed. Liver transplantation is required in children with refractory pruritus affecting the quality of life or those with end stage liver disease. Relief of biliary obstruction by endoscopy or surgery and treatment of diseases associated with SC like histiocytosis may be rewarding. Long-term follow-up for development of complications of liver disease and hepatocellular/ cholangiocarcinoma is essential. Thus, an early diagnosis and stepwise treatment with an understanding of the pathogenesis of pruritus in cholestatic disorders may decrease morbidity and mortality.

Progressive familial intrahepatic cholestasis.

Progressive familial intrahepatic cholestasis (PFIC) is a group of rare disorders which are caused by defect in bile secretion and present with intrahepatic cholestasis, usually in infancy and childhood. These are autosomal recessive in inheritance. The estimated incidence is about 1 per 50,000 to 1 per 100,000 births, although exact prevalence is not known. These diseases affect both the genders equally and have been reported from all geographical areas. Based on clinical presentation, laboratory findings, liver histology and genetic defect, these are broadly divided into three types-PFIC type 1, PFIC type 2 and PFIC type 3. The defect is in ATP8B1 gene encoding the FIC1 protein, ABCB 11 gene encoding BSEP protein and ABCB4 gene encoding MDR3 protein in PFIC1, 2 and 3 respectively. The basic defect is impaired bile salt secretion in PFIC1/2 whereas in PFIC3, it is reduced biliary phospholipid secretion. The main clinical presentation is in the form of cholestatic jaundice and pruritus. Serum gamma glutamyl transpeptidase (GGT) is normal in patients with PFIC1/2 while it is raised in patients with PFIC3. Treatment includes nutritional support (adequate calories, supplementation of fat soluble vitamins and medium chain triglycerides) and use of medications to relieve pruritus as initial therapy followed by biliary diversion procedures in selected patients. Ultimately liver transplantation is needed in most patients as they develop progressive liver fibrosis, cirrhosis and end stage liver disease. Due to the high risk of developing liver tumors in PFIC2 patients, monitoring is recommended from infancy. Mutation targeted pharmacotherapy, gene therapy and hepatocyte transplantation are being explored as future therapeutic options.

Refeeding syndrome in children in developing countries who have celiac disease.

OBJECTIVES: The clinical presentations of celiac crisis and refeeding syndrome in celiac disease are almost similar, but information about refeeding syndrome is scarce. We are reporting for the first time 5 cases of refeeding syndrome in children with celiac disease that could have otherwise been labeled as celiac crisis. METHODS: From January to December 2010, a chart review of hospital records of all celiac disease cases was performed, and refeeding syndrome was ascribed in those celiac patients who deteriorated clinically after initiation of a gluten-free diet and had biochemical parameters suggestive of refeeding syndrome such as hypophosphatemia, hypokalemia, hypocalcemia, and hypoalbuminemia. RESULTS: Of the total 35 celiac disease patients, 5 (median age 6.5 [range 2.2-10] years, 3 boys) were identified as having refeeding syndrome. All 5 children were severely malnourished (body mass index <14 kg/m) and all of them had anemia, hypophosphatemia, hypokalemia, hypoalbuminemia, and hypocalcemia, meaning that they had the perfect setting for developing refeeding syndrome. At the same time, their clinical features fulfilled the criteria for celiac crisis except that their symptoms have worsened after the introduction of a gluten-free diet. Nevertheless, instead of using steroids, they were managed as refeeding syndrome in terms of correction of electrolytes and gradual feeding, and that led to a successful outcome in all of them. CONCLUSIONS: Severely malnourished patients with celiac disease are at risk of developing potentially life-threatening refeeding syndrome, which may mimic celiac crisis, especially in developing countries. Early recognition and appropriate treatment are the keys to a successful outcome.