Abstract
Inherited metabolic disorders (IMD) can disrupt brain development and functioning, leading to cognitive and behavioral abnormalities. This systematic review aims to provide a comprehensive synthesis of the evidence regarding neurocognitive impairments in intoxication IMD due to the accumulation of small molecule disorders and energy-related IMD. A search was conducted in the PubMed database until August 2024, using the term "cognition" and up to 421 energy-related IMD and 196 intoxication IMD. Reviews, animal models, studies with non-standardized measures, and studies that focused on complex molecule disorders, small molecule deficiencies, and phenylketonuria were excluded. In total, 163 studies were included in the final analysis. The cognitive domains assessed were executive functions, attention, processing speed, language, speech, visual performance, fine motor dexterity, memory, behavioral and emotional regulation, and social cognition. Most available evidence focused on intoxication IMD (83%), which exhibited better global cognitive functioning than energy defects. The cognitive domains most frequently reported as impaired were fine motor dexterity (80.9%), behavioral and emotional regulation (80%), executive functions (73.3%), attention (72.4%), and social cognition (65.6%). After applying the chi-square test with a 95% confidence level, no statistically significant differences were found between intoxication and energy-related IMD. However, language impairments were slightly more pronounced in intoxication disorders, while visuospatial deficits were more common in energy disorders. Individuals with IMD are at a higher risk of neurodevelopmental disorders, which can persist despite early detection and treatment. Although the number of cognitive studies has increased in recent years, further research with standardized measures is necessary to understand the underlying pathophysiology of neurocognitive impairments.