1230 Review Article on Pediatric Neuroradiology for Trainees and Fellows: An Updated Practical Guide Clinico-radiological phenotyping and diagnostic pathways in childhood neurometabolic disorders—a practical introductory guide Asthik Biswas1,2, Mukul Malhotra3, Kshitij Mankad4, Olivia Carney4, Felice D’Arco4, Karthik Muthusamy3, Sniya Valsa Sudhakar4 1Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada; 2Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada; 3Department of Neurology, Christian Medical College, Vellore, India; 4Neuroradiology Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK Contributions: (I) Conception and design: A Biswas, K Muthusamy, SV Sudhakar; (II) Administrative support: K Muthusamy, SV Sudhakar; (III) Provision of study materials or patients: A Biswas, K Muthusamy, SV Sudhakar; (IV) Collection and assembly of data: A Biswas, M Malhotra, K Muthusamy, SV Sudhakar; (V) Data analysis and interpretation: A Biswas, M Malhotra, K Muthusamy, SV Sudhakar; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Sniya Valsa Sudhakar. Neuroradiology Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK. Email: [email protected]. Abstract: Inborn errors of metabolism (IEM) although individually rare, together constitute a significant proportion of childhood neurological disorders. Majority of these disorders occur due to deficiency of an enzyme in a specific metabolic pathway, leading to damage by accumulation of a toxic substrate or deficiency of an essential metabolite. Early diagnosis is crucial in many of these conditions to prevent or minimise brain damage. Whilst many of the neuroimaging features are nonspecific, certain disorders demonstrate specific patterns due to selective vulnerability of different structures to different insults. Along with clinical and biochemical profile, neuroimaging thus plays a pivotal role in differentiating metabolic disorders from other causes, in providing a differential diagnosis or suggesting a metabolic pathway derangement, and on occasion also helps make a specific diagnosis. This allows initiation of targeted metabolic and genetic work up and treatment. Familiarity with the clinical features, relevant biochemical features and neuroimaging findings of common metabolic disorders to facilitate a prompt diagnosis cannot thus be overemphasized. In this article, we describe the latest classification scheme, the clinical and biochemical clues and common radiological patterns. The diagnostic algorithm followed in daily practice after clinico-radiological phenotyping is alluded to and illustrated by clinical vignettes. Focused sections on neonatal metabolic disorders and mitochondrial disorders are also provided. The purpose of this article is to provide a brief overview and serve as a practical primer to clinical and radiological phenotypes and diagnostic aspects of IEM. Keywords: Inborn errors of metabolism (IEM); childhood; neuroimaging; brain; magnetic resonance imaging (MRI) Submitted Nov 02, 2020. Accepted for publication Jan 18, 2021. doi: 10.21037/tp-20-335 View this article at: http://dx.doi.org/10.21037/tp-20-335 Introduction partial enzyme deficiencies, or defects in transporters, which lead to clinical manifestations from either accumulation of Disorders of inborn errors of metabolism (IEM), though toxic products or lack of an essential end product. Clinical individually rare, account for a large number of children manifestations are heterogeneous and often non-specific, presenting with a spectrum of neurological manifestations and can result from the involvement of multiple organ in clinical practice. IEMs are usually caused by complete or systems. © Translational Pediatrics. All rights reserved. Transl Pediatr 2021;10(4):1201-1230 | http://dx.doi.org/10.21037/tp-20-335 1202 Biswas et al. Clinico-radiological phenotyping of neurometabolic disorders Even as increasing data from genomics, metabolomics Classification and transcriptomics evolve, the clinico-radiologic Small molecule disorders phenotyping continues to hold a pivotal role in integration Disorders of small molecules in IEMs involve small, and accurate interpretation of the data. The role of diffusible and water soluble molecules. Abnormal neuroimaging is manifold, and includes raising the metabolites in this group of disorders can be easily possibility of a metabolic disease process, narrowing down measured in various body fluids. Most of these disorders the differential diagnoses based on pattern recognition, are amenable to treatment and are divided into two major and occasionally providing a specific diagnosis. Imaging subcategories. also has a role in prognostication and follow-up. The (I) Accumulation of small molecules implications are widespread, encompassing diagnosis and Accumulation of small molecules causes acute or timely management of the metabolic derangement thereby progressive symptoms resulting from the accumulation minimising permanent neurological damage, facilitation of the metabolites proximal to the block. Manifestations of targeted testing and therapy, and initiation of genetic counselling. Role of imaging as a biomarker should also be occur after a varying symptom-free period and are often emphasised as we enter the era of treatment and precision precipitated by intercurrent illness, food intake or fasting. medicine for these disorders. This group of disorders generally do not hamper fetal There are a number of ways to approach a suspected case development. Most disorders are treatable by reducing the of neurometabolic disorder. Pioneering work on pattern toxic metabolites using special formulae, scavengers, and recognition and radiological approach has been performed supplementation of cofactors. Classic IEMs such as amino- by van der Knaap and Valk (1), and Barkovich (2) in this acidurias, organic acidurias and urea cycle defects belong to regard. In this article we provide a comprehensive initial this category. approach to categorize, and summarize the most clinically (II) Deficiency of small molecules and radiologically relevant aspects of this group of diseases. Deficiency of small molecules may occur due to defective We also provide a focused review of antenatal and neonatal synthesis of compounds distal to the metabolic block, or by onset group of disorders, and mitochondrial cytopathies. defects in transport mechanisms. Disorders in this subgroup primarily affect neurodevelopment and may present with developmental malformations and birth defects. This group Definition and classification of disorders share many attributes in common with complex Revolution in molecular diagnostics has led to a paradigm molecule disorders and also mimic chronic genetic non- shift in our approach and definition of IEM. Any disorder metabolic encephalopathies. Defective transport of essential with impairment of specific enzymes or biochemical molecules through cellular membranes, inborn errors pathways intrinsic to the pathomechanism can be labelled of non-essential amino acid and fatty acid synthesis, and as an IEM, and the need for detection of an abnormal neurotransmitter deficiency disorders are included in this metabolite is no longer necessary (3). group. Symptoms of neuro-metabolic disorders usually relate to decreased or abnormal formation of a protein that Complex molecule disorders interferes with the normal function of the brain, either Disorders of complex molecules occur due to defective directly or indirectly. The deficiency or accumulation of metabolism of water insoluble and non-diffusible large these metabolites, or their specific role in signalling, energy complex molecules. This group of disorders can be metabolism or brain development contributes to disease subcategorized into three groups as follows. phenotype. (I) Accumulation of complex molecules To translate the daunting complexity and increasing Defective breakdown of complex molecules leads to storage number of IEMs and increase the bedside clinical of the material proximal to the block in lysosomes or in usability, a classification based on clinical, diagnostic and the cytoplasm leading to clinical manifestations. Clinically, pathophysiological approach has been put forward by these present as progressive disorders with late onset Saudubray et al. (4). It classifies IEM into the following neurodegeneration with or without signs of storage disease. groups. Antenatal manifestations are rare, though hydrops and © Translational Pediatrics. All rights reserved. Transl Pediatr 2021;10(4):1201-1230 | http://dx.doi.org/10.21037/tp-20-335 Translational Pediatrics, Vol 10, No 4 April 2021 1203 malformations may be seen in severe forms. Lysosomal pathway that is compromised. Although neurological storage disorders are amongst the disorders in this group. symptoms comprise the predominant manifestation, these (II) Deficiency of complex molecules are rarely isolated and there are exceptions. Moreover, These disorders occur due to defective synthesis of findings are usually across the spectrum in both severity complex molecules. Neurodevelopmental abnormalities and the systems involved. Age at presentation further and neuroregression are usually seen and antenatal limits the repertoire of clinical manifestation. Other factors malformations are common. Most common disorders in this which influence the clinical presentation include baseline group include cholesterol and bile acid