Knowledge and experiences of healthcare workers in managing children with neurometabolic disorders in a developing country: a cross-sectional study.

OBJECTIVE: To evaluate the knowledge and experiences of healthcare workers in the management of neurometabolic disorders. METHODS: A cross-sectional study was carried out among the 132 participants of a continued medical education program conducted in the Department of Pediatrics at a tertiary-care teaching hospital. A questionnaire-based feedback form was circulated among the participants, and their responses were analyzed. RESULTS: Ninety-three responses were analyzed. The most common pediatric illnesses identified were infections (91%), nutritional (91%), birth-related injuries (44.4%) and metabolic disorders (44.4%). Consanguinity (81.5%) and genetic heterogeneity (42.4%) were recognized as most important causes of neurometabolic disorders. Important steps identified for prevention were prenatal testing (65.6%) and newborn screening at birth (61%); while for improving the diagnosis were routine availability of metabolic investigations (65.3%) and screening at birth (46.6%). Most respondents (58.7%) expressed discomfort in managing a case with inherited metabolic defect due to a lack of knowledge (46.8%) and diagnostic facilities (44.6%). Despite access to testing in the majority, a high cost of testing was noticed for biochemical and genetic investigations. The majority of participants (73%) considered some of the inherited metabolic disorders as treatable. Dietary substitution (89.3%), enzyme replacement (69%), cofactor replacement (53.6%), gene therapy (35.7%) and regular dialysis (16.7%) were considered the treatment options. CONCLUSION: In spite of growing awareness of inherited metabolic disorders, there are still gaps in knowledge among healthcare workers. It is challenging to diagnose and manage these disorders. Cost-reduction of diagnostic tests, routine newborn screening and increased educational activities are key challenges to be addressed.

Neurodegeneration and Early Infantile Epilepsy Associated with ITPA Variants: A Case Series and Review of Literature.

BACKGROUND: Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency associated with mutations in the ITPA gene is a recently characterized purine pathway defect that presents with early infantile epileptic encephalopathy and lethal course. This disorder is rare, and only 12 cases are reported worldwide. METHODS: We report two additional cases of ITPA-associated neurodegeneration and two pathogenic compound heterozygous variants. We also reviewed the previously published cases of ITPA-associated encephalopathy. RESULTS: Both cases presented with progressive infantile-onset encephalopathy, severe developmental delay, microcephaly, facial dysmorphism, and epilepsy. Together with the presented two cases, 14 cases were available for analysis. The mean age of presentation was 16.7 ± 12.4 months (range 3-48 m). The most common clinical features at presentation were developmental delay, seizures, microcephaly, and hypotonia, seen in all 14 (100%) patients. The mean age of seizure onset was 4.75 months (range 2-14 m). Cardiomyopathy was noted in 42% of patients where it was explicitly evaluated (n = 5/12). Consanguinity was reported in 77% of the cases. The cardinal neuroradiological features are T2-signal abnormalities and diffusion restriction in the long tracts, especially the posterior limb of the internal capsule and the optic radiation. The majority of the patients died before 4 years of age (85.7%). CONCLUSION: ITPA-related encephalopathy presents with infantile-onset neurodegeneration, progressive microcephaly, and epilepsy. Progressive brain atrophy and diffusion restriction in the white matter tracts are important radiological clues.

Antibiotic-resistant Enterobacteriaceae in healthy gut flora: A report from north Indian semiurban community.

Background & objectives: Rampant use of ß-lactam antibiotics in both community and hospitals has transformed the human healthy intestinal gut flora into a reservoir of antibiotic-resistant organisms. This study was conducted to find the faecal presence of antibiotic-resistant Enterobacteriaceae in faecal samples in the community in north India. Methods: In this prospective study, 207 stool samples were collected from apparently healthy individuals residing in a semiurban community in Chandigarh, India, from August to October, 2015. Isolates belonging to family Enterobacteriaceae were identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), and antibiotic susceptibility was determined using Clinical Laboratory Standard Institute disc diffusion method. Detection of extended spectrum ß-lactamases (TEM, SHV, OXA-1, CTXM 1, CTXM 2, CTXM 9 and CTXM 8/25), carbapenemases (IMP, VIM and KPC) and New Delhi metallo-ß-lactamase was done by multiplex PCR. Results: Of the population studied, 55.5 per cent were females and 60 per cent were illiterate or had only primary education; 43.4 per cent individuals were aged <20 yr. Overall, 70.5 per cent of stool samples had antibiotic-resistant isolates. Maximum resistance was seen for cephalosporins (60.4%) followed by fluoroquinolones (41.5%). The multidrug-resistant (MDR) isolates were 2.4 per cent. The most commonly detected genes were TEM, SHV, OXA-1, CTXM-1, CTXM-2, CTXM-9 and CTXM-8/25 ß-lactamases. Escherichia coli was the most common resistant isolate, and TEM was the most common gene detected. Interpretation & conclusions: Overall, 70.5 per cent members of Enterobacteriaceae had antibiotic resistance in the community and 2.4 per cent were MDR. Higher resistance rates were observed for most commonly used drugs such as cephalosporins and fluoroquinolones. High rate of antibiotic-resistant Enterobacteriaceae in gut of healthy individuals points towards the need for active screening and prevention of dissemination.

Identification of novel pathogenic variants in the GCDH gene and assessment of neurodevelopmental outcomes in 24 children with glutaric aciduria type 1.

AIM: To evaluate the pathogenic variants in GCDH gene and to assess the neurodevelopmental outcomes in children with Glutaric aciduria type 1 (GA-1). METHOD: Cross-sectional observational study between January 2019 and June 2020 in consecutive North Indian children with a clinical and biochemical suspicion of GA-1. Variants in the coding regions of GCDH gene were identified through Sanger sequencing. Neurodevelopmental and quality of life assessment was done using standardized scales. RESULTS: 24 children with GA-1 were identified. The median age at diagnosis was 12 months and the median delay in diagnosis was 3 months. Genetic analysis was done in 14 cases. It revealed 12 variants (11 missense and one nonsense) from 13 patients. Most of the pathogenic variants were in exon 9 and exon 5. Three novel variants were identified in three patients: two missense variants c.169G > A (p.Glu57Lys), c.1048T > C (p.Cys350Arg) and one nonsense variant c.331C > T (p.Lys111Ter). On neurodevelopmental assessment, majority of children with GA-1 were non ambulatory (62.5%), had limited hand skills (58.3%) and impaired communication (58.3%). Overall, poor global development was noted in 43.7%. A pre-existing developmental delay was significantly associated with impaired communication skills (p = 0.03), and the number of episodes of encephalopathy were significantly associated with impaired gross motor skill (p = 0.02). Presence of encephalopathy was significantly associated with poor performance in social emotional (p = 0.01) and cognitive (p = 0.03) domains of Developmental Profile-III scale and development of severe dystonia (p = 0.01). CONCLUSION: Our findings highlight the clinical, biochemical, radiological and genetic spectrum of GA-1 in children in North India and report the presence of novel pathogenic variations.

Detection of IEMs by Mass Spectrometry Techniques in High-Risk Children: A Pilot Study.

OBJECTIVES: To determine the incidence and types of inborn errors of metabolism (IEMs) in high-risk children using mass spectrometry techniques. METHODS: Children considered high-risk for IEM were screened for metabolic diseases during a 3-y period. Dried blood spots and urine samples were analyzed by tandem mass spectrometry (LC-MS/MS) and gas chromatograph-mass spectrometry (GCMS). Samples with abnormal amino acids were confirmed by high-performance liquid chromatography (HPLC). RESULTS: Eight hundred and twenty-two suspected cases were evaluated; of which, 87 possible cases of IEMs were identified. Homocystinuria (n = 51) was the most common IEM detected followed by biotinidase deficiency (n = 7), glutaric aciduria type 1 (n = 7), and carnitine uptake defect (n = 6). Overall, there were 45 (51.7%) cases of organic acidemia, 31 cases (35.6%) of amino acid defect, 9 (10.3%) cases of fatty-acid oxidation disorders, and 2 (2.3%) cases of probable mitochondrial disorder. CONCLUSION: IEMs are common in India, with a hospital-based incidence of 1 in approximately 6642 among high-risk children. Screening of high-risk children by mass spectrometry techniques is a valuable strategy for early diagnosis of IEMs where universal newborn screening is not yet available.

ADSL Deficiency - The Lesser-Known Metabolic Epilepsy in Infancy.

Adenylosuccinate lyase deficiency is a rare inherited disorder of purine metabolism causing severe neurological impairment ranging from early-onset neonatal epileptic encephalopathy to progressive psychomotor retardation and autism in later life. Diagnostic workup involves the measurement of toxic succinyl purines in body fluids and gene sequencing. The authors describe a 13-mo-old girl with compound heterozygous variants in the ADSL gene, presenting as early-onset seizures, severe neurological impairment, development delay, and hypotonia. Neuroimaging revealed cerebral atrophy, delayed myelination and diffusion restriction in bilateral basal ganglia, thalamus and periventricular white matter. The present case highlights ADSL deficiency as a rare cause of metabolic epilepsy that needs timely recognition and prevention of unnecessary investigations.

Bone density and bone health alteration in boys with Duchenne Muscular Dystrophy: a prospective observational study.

OBJECTIVES: Boys with Duchenne Muscular Dystrophy (DMD) are at increased risk for compromised bone health, manifesting as low-impact trauma long bone fractures and vertebral compression fractures. METHODS: In a prospective observational study, we studied bone health parameters in North Indian boys with DMD. We consecutively enrolled ambulatory boys with DMD on glucocorticoid therapy. Bone health was evaluated with X-ray spine, Dual-energy X-ray absorptiometry (DXA), serum calcium, vitamin D3 (25[OH]D), 1,25-dihyroxyvitamin D3 (1,25[OH]2D3), serum osteocalcin, osteopontin, and N terminal telopeptide of type 1 collagen (Ntx) levels. RESULTS: A total of 76 boys with DMD were enrolled. The median age was 8.5 (interquartile range [IQR] 7.04-10.77) years. Among these, seven (9.2%) boys had long bone fractures, and four (5.3%) had vertebral compression fractures. Fifty-four (71%) boys underwent DXA scan, and among these 31 (57%) had low bone mineral density (BMD, ≤-2 z-score) at the lumbar spine. The mean BMD z-score at the lumbar spine was -2.3 (95% confidence interval [CI] = -1.8, -2.8), and at the femoral neck was -2.5 (95% CI = -2, -2.9). 25(OH)D levels were deficient in 68 (89.5%, n=76) boys, and 1,25(OH)2D3 levels were deficient in all. Mean serum osteocalcin levels were 0.68 ± 0.38 ng/mL (n=54), serum osteopontin levels were 8.6 ± 4.6 pg/mL (n=54) and serum Ntx levels were 891 ± 476 nmol/L (n=54). Boys with low BMD received glucocorticoids for longer duration, in comparison to those with normal BMD (median, IQR [16.9 (6-34) months vs. 7.8 (4.8-13.4) months]; p=0.04). CONCLUSIONS: Bone health is compromised in North Indian boys with DMD. BMD at the lumbar spine is reduced in more than half of boys with DMD and nearly all had vitamin D deficiency on regular vitamin D supplements. Longer duration of glucocorticoid therapy is a risk factor for low BMD in our cohort.