Abstract
Background: Progressive intellectual and neurological deterioration (PIND) is a rare but severe childhood disorder characterized by loss of intellectual or developmental abilities, and requires quick diagnosis to ensure timely treatment to prevent possible irreversible neurological damage. Inborn errors of metabolism (IEMs) constitute a group of more than 1,000 monogenic conditions in which the impairment of a biochemical pathway is intrinsic to the pathophysiology of the disease, resulting in either accumulation of toxic metabolites and/or shortage of energy and building blocks for the cells. Many IEMs are amenable to treatment with the potential to improve outcomes. With this literature review we aim to create an overview of IEMs presenting with PIND in children, to aid clinicians in accelerating the diagnostic process.Methods: We performed a PubMed search on IEMs presenting with PIND in individuals aged 0–18 years. We applied stringent selection criteria and subsequently derived information on encoding genes, pathways, clinical and biochemical signs and diagnostic tests from IEMbase (www.iembase.org) and other sources.Results: The PubMed search resulted in a total of 2,152 articles and a review of references added another 19 articles. After applying our selection criteria, a total of 85 IEMs presenting with PIND remained, of which 57 IEMs were reported in multiple unrelated cases and 28 in single families. For 44 IEMs (52%) diagnosis can be achieved through generally accessible metabolic blood and urine screening tests; the remainder requires enzymatic and/or genetic testing. Treatment targeting the underlying pathophysiology is available for 35 IEMs (41%). All treatment strategies are reported to achieve stabilization of deterioration, and a subset improved seizure control and/or neurodevelopment.Conclusions: We present the first comprehensive overview of IEMs presenting with PIND, and provide a structured approach to diagnosis and overview of treatability. Clearly IEMs constitute the largest group of genetic PIND conditions and have the advantage of detectable biomarkers as well as amenability to treatment. Thus, the clinician should keep IEMs at the forefront of the diagnostic workup of a child with PIND. With the ongoing discovery of new IEMs, expanded phenotypes, and novel treatment strategies, continuous updates to this work will be required.
Highlights
Progressive intellectual and neurological deterioration (PIND) in children is defined as “progressive deterioration for more than 3 months with loss of already attained intellectual or developmental abilities and development of abnormal neurological signs” [1,2,3,4,5,6]
After applying inclusion and exclusion criteria we identified a total of 79 Inborn errors of metabolism (IEMs)
Of these 79 IEMs, 55 (70%) presented with PIND in multiple cases and in multiple families, while the remaining 24 IEMs presented with PIND in single cases or single families (Supplemental Table S1)
Summary
Progressive intellectual and neurological deterioration (PIND) in children is defined as “progressive deterioration for more than 3 months with loss of already attained intellectual or developmental abilities and development of abnormal neurological signs” [1,2,3,4,5,6]. It will urge every pediatrician to find a diagnosis and quickly start treatment in order to halt or even reverse the intellectual decline in the patient. This will provide an opportunity for accurate prognostication and genetic counseling for the family. Inborn errors of metabolism (IEMs) constitute a well-known cause of PIND and intellectual developmental disabilities in general; examples include neuronal ceroid lipofuscinosis (NCL), Niemann-Pick disease type C (NPC), and different types of mucopolysaccharidosis (MPS) [8,9,10]. Progressive intellectual and neurological deterioration (PIND) is a rare but severe childhood disorder characterized by loss of intellectual or developmental abilities, and requires quick diagnosis to ensure timely treatment to prevent possible irreversible neurological damage. With this literature review we aim to create an overview of IEMs presenting with PIND in children, to aid clinicians in accelerating the diagnostic process
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