Paeds · genetics-dysmorphology-and-metabolism
Inborn errors presenting with neurological regression
Also known as Inborn errors presenting with neurological regression · Metabolic causes of developmental regression · Neuroregression from inborn errors of metabolism · Progressive encephalopathy of metabolic origin · Treatable intellectual disability
A fellowship approach to the inborn errors of metabolism that present with neurological regression: recognise loss of previously acquired milestones as a red flag, distinguish true progressive neurodegeneration from plateau and static loss, group the disorders by affected pathway (intoxicating small molecule, energy/mitochondrial, storage/lysosomal, lipid-traffic and metal), deploy a tiered metabolic-and-genomic investigation strategy, and crucially identify the treatable subset before labelling a child degenerative or palliative.
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Target exams
Red flags
- A child who loses previously acquired motor or language milestones has neurological regression until proved otherwise - and a progressive, potentially treatable cause must be sought
- Regression with hepatosplenomegaly, coarse facies, or a cherry-red spot points to a lysosomal storage disorder - send urine glycosaminoglycans and an enzyme panel without delay
- Regression with epilepsy, ataxia, or a movement disorder, and raised lactate, points to a mitochondrial or energy disorder - consider the ketogenic diet if GLUT1 deficiency is possible
- A boy with new seizures, school decline, behavioural change, and adrenal insufficiency on a parieto-occipital white-matter MRI lesion has cerebral X-linked adrenoleukodystrophy - a transplant emergency
- Acute or subacute regression with vomiting, encephalopathy, and metabolic acidosis or hyperammonaemia is a late-onset small-molecule disorder in decompensation - start the emergency stop-the-regression protocol
- Progressive dystonia with iron in the globus pallidus on brain MRI is a neurodegeneration with brain iron accumulation such as PKAN - some subtypes are treatable
- Never label a regressing child 'degenerative' or 'palliative' until the treatable inborn errors of metabolism have been excluded by a tiered metabolic-and-genomic workup
Life stages
Care settings
Clinical exam formats
Board mappings
- General and Community Paediatrics
- Growth and Development
- Genetics and Metabolism
- Neurology
- Neurology - recognise and investigate developmental regression and neurodegenerative disorders
- Metabolic Medicine - diagnose and manage the inborn errors of metabolism presenting with neurological regression
- Genetics - request and interpret chromosomal microarray, exome and genome sequencing in neuroregression
- Metabolic Medicine 1-3
- Neurology 13-15
- Clinical Applications
- Long Cases
- Short Cases
- 2. Genetics: chromosomal and multi-system disorders
- 8. Metabolic medicine: inborn errors of metabolism
- 9. Neurology: neurodegenerative disorders and developmental regression
- Foundation of Practice (FOP)
- Theory and Science (TAS)
- Applied Knowledge in Practice (AKP)
- Clinical
- Development
- Communication
- History
- General Pediatrics Content Outline - D19 Genetics (6%)
- General Pediatrics Content Outline - D21 Metabolic Disorders (3%)
- General Pediatrics Content Outline - D15 Neurology (6%)
- Patient Care 4: Clinical Reasoning
- Patient Care 5: Patient Management
- Medical Knowledge 1: Congenital and Genetic Disorders
- Systems-Based Practice 1: Patient Safety
- Medical Expert
- Pediatrics: Metabolic Medicine
- Pediatrics: Neurology - neurodegenerative disease and developmental regression
A toddler who was speaking in two-word phrases and running stops talking and begins to stumble, and a school-age boy whose teacher notices falling grades and new seizures turns out to have inflammatory white-matter disease on his scan. In both rooms the unifying question is the same: is this loss of milestones a progressive metabolic disorder, and is there a therapy whose window is closing right now. The fellowship task is to convert that bedside worry into a structured, time-aware workup that does not forfeit a treatable cause to a comforting but wrong label such as cerebral palsy or autism. [5] [8]
Anchor the whole topic with REGRESS - Recognise true loss of previously acquired skills (distinguish from plateau and static deficit), Exclude non-metabolic mimics (Rett, autism, subacute sclerosing panencephalitis), Group by pathway (small-molecule, energy, storage, lipid/metal), Run a tiered metabolic screen then targeted assays then trio exome, Emergency protocol for acute decompensation (stop feeds, dextrose, halt catabolism), Specific disease-modifying therapy matched to CNS involvement, and Surveillance with structured transition to adult care. [1] [8]
Overview & Definition
The clinician's first act is to confirm what kind of developmental problem this is, because the word "regression" is used loosely and the distinction changes everything. Developmental delay means milestones are not being met on time. A plateau means the child has stopped gaining new skills but has not lost old ones. Neurological regression - the entity this page owns - means the child has lost previously acquired skills. Only regression carries the weight of a presumed progressive process, and only regression mandates the search for a neurodegenerative cause at speed. [8]
An inborn error of metabolism is a monogenic disorder in which a deficient enzyme, transporter, cofactor, or structural protein disrupts a biochemical pathway, and the accumulating substrate or the energy deficit injures the cell. When the affected pathway runs through the central nervous system, the injury declares itself as neurological regression - a slide from a higher to a lower level of function. The slide may be rapid, over days to weeks, as in acute decompensation of a late-onset small-molecule disorder; or insidious, over months to years, as in a leukodystrophy or a lysosomal storage disorder. Reading the tempo is part of reading the disease. [5] [13]
What makes the IEM group worth knowing as a cause of regression is that a meaningful subset is treatable, and that treatment works best - or only - when it is begun before the brain injury becomes irreversible. The systematic work of van Karnebeek, Stockler, Saudubray and others reframed the field around this idea: among the IEM that cause intellectual disability and regression, a defined fraction respond to a disease-modifying intervention, and missing them is the cardinal avoidable error in paediatric neurology. [1] [2] [3]
References13ShowHide
- [1]van Karnebeek CD, Stockler S. Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Mol Genet Metab, 2012.PMID 22212131
- [2]van Karnebeek CD, Shevell M, Zschocke J, Moeschler JB, Stockler S. The metabolic evaluation of the child with an intellectual developmental disorder: diagnostic algorithm for identification of treatable causes and new digital resource. Mol Genet Metab, 2014.PMID 24518794
- [3]Hoytema van Konijnenburg EMM, Wortmann SB, Koelewijn MJ, et al. Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app. Orphanet J Rare Dis, 2021.PMID 33845862
- [4]Sedel F, Lyon-Caen O, Saudubray JM. Therapy insight: inborn errors of metabolism in adult neurology--a clinical approach focused on treatable diseases. Nat Clin Pract Neurol, 2007.PMID 17479075
- [5]Saudubray JM, Sedel F, Walter JH. Clinical approach to treatable inborn metabolic diseases: an introduction. J Inherit Metab Dis, 2006.PMID 16763886
- [6]Leonard JV, Morris AA. Diagnosis and early management of inborn errors of metabolism presenting around the time of birth. Acta Paediatr, 2006.PMID 16373289
- [7]Lake NJ, Compton AG, Rahman S, Thorburn DR. Leigh syndrome: One disorder, more than 75 monogenic causes. Ann Neurol, 2016.PMID 26506407
- [8]Moeschler JB, Shevell M Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics, 2014.PMID 25157020
- [9]Williams RE, Mole SE. New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses. Neurology, 2012.PMID 22778232
- [10]Hogarth P, Kurian MA, Gregory A, et al. Consensus clinical management guideline for pantothenate kinase-associated neurodegeneration (PKAN). Mol Genet Metab, 2017.PMID 28034613
- [11]Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, Aubourg P, Poll-The BT. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis, 2012.PMID 22889154
- [12]Pearson TS, Akman C, Hinton VJ, Engelstad K, De Vivo DC. Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS). Curr Neurol Neurosci Rep, 2013.PMID 23443458
- [13]Saudubray JM, Garcia-Cazorla A. Inborn Errors of Metabolism Overview: Pathophysiology, Manifestations, Evaluation, and Management. Pediatr Clin North Am, 2018.PMID 29502909