Abstract
<title>Abstract</title> <p>Background The central nervous system (CNS) is disproportionately susceptible to the biochemical derangements that characterise inborn errors of metabolism (IEM), owing to its elevated energy requirements, dependence on regulated metabolic homeostasis, and limited regenerative capacity. Neurological features therefore constitute among the earliest and most clinically disabling manifestations of these conditions. The considerable clinical heterogeneity of IEM presentations and their overlap with common neurodevelopmental disorders compound diagnostic uncertainty, resulting in delayed confirmatory diagnosis. This study aimed to characterise the spectrum of CNS manifestations and associated genotypes among patients with molecularly confirmed IEM attending a tertiary referral centre in Kenya, and to identify clinical features that may guide selective investigation. Methods This retrospective cross-sectional study enrolled patients aged 25 years or younger, together with their biological relatives, who presented with CNS manifestations and underwent genetic evaluation for clinically suspected IEM between January 2018 and February 2026. Inclusion was restricted to individuals with pathogenic or likely pathogenic variants confirmed on molecular analysis. Clinical, demographic, and genomic data were extracted from medical records. Associations between clinical features and an IEM diagnosis were assessed using the appropriate measures of association including a regression analysis. Results The study included 92 patients with CNS manifestations and confirmed pathogenic variants; 51 (55.4%) received a diagnosis of IEM and 41 (44.6%) were assigned non-IEM inherited conditions. Motor delay, intellectual impairment, and cognitive impairment were the most prevalent neurodevelopmental features(x(%). A positive family history of similar illness, dysmorphic features, hemizygous variant status, and X-linked inheritance were each associated with an IEM diagnosis. On multivariable logistic regression, hemizygous variant status (adjusted OR 31.2, 95% CI 5.97–250; p < 0.001) and use of a targeted metabolic gene panel rather than whole-exome sequencing (adjusted OR 9.32, 95% CI 1.58–73.5; p = 0.020) emerged as the strongest independent predictors of IEM. Conclusion Inborn errors of metabolism accounted for more than half of genetically confirmed diagnoses among patients presenting with CNS manifestations at this Kenyan tertiary centre. Structured clinical assessment combined with targeted molecular genetic testing can improve diagnostic accuracy, shorten diagnostic delay, and facilitate timely institution of therapeutic interventions.</p>