Clinicobiochemical Profile and Outcome of Children with Small Molecule Neurometabolic Disorders: A Tertiary Care Hospital Experience from India

Abstract

Inborn Errors of Metabolism (IEM), though heterogenous, are not uncommon. Neurologic manifestations predominate. Without universal newborn screening, early diagnosis and treatment may lessen neuromorbidity. Hence, this study was done to understand small molecule neurometabolic disorders' presentation, diagnostic clues, and outcome. Small molecule neurometabolic disorder was diagnosed in 45 children (postneonatal onset) over 14 years (2008–2022) in a tertiary care hospital. Clinical and laboratory data were retrospectively analyzed. There were 26 boys and 19 girls. The median age at diagnosis was 19 months (interquartile range [IQR]: 8–38 months). The median diagnostic delay was 12 months in chronic encephalopathy (IQR: 1–24 months) and 1 month (IQR: 0.2–5.5 months) in the acute encephalopathy group (p ≤ 0.01). The presentation mode was chronic encephalopathy/myopathy in 29 (64.4%) and acute encephalopathy in 11 (24.4%). Diagnostic clues included unexplained developmental delay (n = 27, 60%), tone abnormalities (n = 26, 57.7%), movement disorder and ataxia (n = 16, 35.5%), acute encephalopathy (n = 11, 24.4%), neuroregression (n = 10, 22.2%), macrocephaly (n = 10, 22.2%), and alopecia (n = 4, 8.9%). Diagnostic/suggestive blood-spot tandem mass spectrometry (TMS) was seen in 34/38 (89.5%) children. Neuroimaging helped clinch the diagnosis in 17 (47%) children. Diagnostic categories were organic acidemias (n = 25, 55.6%), urea cycle disorders (n = 11, 24.4%), aminoacidopathies (n = 5, 11.1%), and fatty acid oxidation disorders (n = 4, 8.9%). The neurodevelopmental outcome was normal in 13 (28.8%), mild delay in 12 (26.6%), severe delay in 11 (24.4%), 3 deaths (6.6%), and 6 (13.3%) children being lost to follow-up. Overall, the outcome was favorable in 55% of cases. Unexplained developmental delay with tone abnormalities with or without movement disorders is a joint presentation of late-onset neurometabolic diseases. Neuroimaging studies and laboratory tests like blood-spot TMS help identify many small molecule disorders.

Keywords

encephalopathy - inborn errors of metabolism - neuroimage - neurometabolic - tandem mass spectrometry

Authors' Contributions

S.S. was responsible for data curation and statistical analysis. B.B. was responsible for conceptualization, data curation, and supervision of the study. R.C. was responsible for conceptualization and investigation. U.A. was responsible for data curation and investigation.

All authors have read and agreed to the published version of the manuscript.

Publikationsverlauf

Eingereicht: 06. Juli 2023

Angenommen: 17. Dezember 2023

Artikel online veröffentlicht:
01. März 2024

• References

• 1 Christopher R, Sankaran BP. An insight into the biochemistry of inborn errors of metabolism for a clinical neurologist. Ann Indian Acad Neurol 2008; 11 (02) 68-81
• 2 Ferreira CR, Rahman S, Keller M, Zschocke J. ICIMD Advisory Group. An international classification of inherited metabolic disorders (ICIMD). J Inherit Metab Dis 2021; 44 (01) 164-177
• 3 Nagaraja D, Mamatha SN, De T, Christopher R. Screening for inborn errors of metabolism using automated electrospray tandem mass spectrometry: study in high-risk Indian population. Clin Biochem 2010; 43 (06) 581-588
• 4 Waters D, Adeloye D, Woolham D, Wastnedge E, Patel S, Rudan I. Global birth prevalence and mortality from inborn errors of metabolism: a systematic analysis of the evidence. J Glob Health 2018; 8 (02) 021102
• 5 Saudubray JM, Garcia-Cazorla A. An overview of inborn errors of metabolism affecting the brain: from neurodevelopment to neurodegenerative disorders. Dialogues Clin Neurosci 2018; 20 (04) 301-325
• 6 AlObaidy H. Patterns of inborn errors of metabolism: a 12 year single-center hospital-based study in Libya. Qatar Med J 2013; 2013 (02) 57-65
• 7 Altimimi HA, Aljawadi HF, Ali EA. Inborn errors of metabolism in children with unexplained developmental delay in Misan, Iraq. Oman Med J 2019; 34 (04) 297-301
• 8 Kamate M, Chetal V, Kulgod V, Patil V, Christopher R. Profile of inborn errors of metabolism in a tertiary care centre PICU. Indian J Pediatr 2010; 77 (01) 57-60
• 9 Romão A, Simon PEA, Góes JEC. et al. Initial clinical presentation in cases of inborn errors of metabolism in a reference children's hospital: still a diagnostic challenge. Rev Paul Pediatr 2017; 35 (03) 258-264
• 10 Papavasiliou AS, Bazigou H, Paraskevoulakos E, Kotsalis C. Neurometabolic testing in developmental delay. J Child Neurol 2000; 15 (09) 620-622
• 11 Engbers HM, Berger R, van Hasselt P. et al. Yield of additional metabolic studies in neurodevelopmental disorders. Ann Neurol 2008; 64 (02) 212-217
• 12 Cleary MA, Green A. Developmental delay: when to suspect and how to investigate for an inborn error of metabolism. Arch Dis Child 2005; 90 (11) 1128-1132
• 13 Montaut S, Tranchant C, Drouot N. et al; French Parkinson's and Movement Disorders Consortium. Assessment of a targeted gene panel for identification of genes associated with movement disorders. JAMA Neurol 2018; 75 (10) 1234-1245
• 14 Ferreira CR, Hoffmann GF, Blau N. Clinical and biochemical footprints of inherited metabolic diseases. I. Movement disorders. Mol Genet Metab 2019; 127 (01) 28-30
• 15 Abdel Maksoud M, ELsayed SM, Shatla RH. et al. Frequency of inborn errors of metabolism screening for children with unexplained acute encephalopathy at an emergency department. Neuropsychiatr Dis Treat 2018; 14: 1715-1720
• 16 Narayanan MP. Inborn errors of metabolism: Indian Scenario. Acta Scientific Paediatrics 2019; 2 (11) 50-52
• 17 Hampe MH, Panaskar SN, Yadav AA, Ingale PW. Gas chromatography/mass spectrometry-based urine metabolome study in children for inborn errors of metabolism: an Indian experience. Clin Biochem 2017; 50 (03) 121-126
• 18 Raghuveer TS, Garg U, Graf WD. Inborn errors of metabolism in infancy and early childhood: an update. Am Fam Physician 2006; 73 (11) 1981-1990
• 19 Narayanan MP, Kannan V, Vinayan KP, Vasudevan DM. Diagnosis of major organic acidurias in children: two years experience at a tertiary care centre. Indian J Clin Biochem 2011; 26 (04) 347-353
• 20 Kumta NB. Inborn errors of metabolism (IEM) - an Indian perspective. Indian J Pediatr 2005; 72 (04) 325-332
• 21 van Karnebeek CD, Stockler S. Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Mol Genet Metab 2012; 105 (03) 368-381
• 22 Ibrahim M, Parmar HA, Hoefling N, Srinivasan A. Inborn errors of metabolism: combining clinical and radiologic clues to solve the mystery. AJR Am J Roentgenol 2014; 203 (03) W315-27
• 23 Bijarnia-Mahay S, Kapoor S. Testing modalities for inborn errors of metabolism - what a clinician needs to know. Indian Pediatr 2019; 56 (09) 757-766
• 24 Auger N, Nelson C, Brousseau É, Bilodeau-Bertrand M, Dewar R, Arbour L. Extended risk of mortality in children with inborn errors of metabolism: a longitudinal cohort study. J Pediatr 2023; 252: 16-21.e2
• 25 Jouvet P, Touati G, Lesage F. et al. Impact of inborn errors of metabolism on admission and mortality in a pediatric intensive care unit. Eur J Pediatr 2007; 166 (05) 461-465
• 26 Sahai I, Zytkowicz T, Rao Kotthuri S, Lakshmi Kotthuri A, Eaton RB, Akella RR. Neonatal screening for inborn errors of metabolism using tandem mass spectrometry: experience of the pilot study in Andhra Pradesh, India. Indian J Pediatr 2011; 78 (08) 953-960