Clinical, biochemical and genetic spectra of carnosinemia: a systematic review of case reports and case series

Abstract Carnosinemia, also referred to as carnosinase 1 (CNDP1) deficiency, is an ultra-rare inborn error of metabolism characterized by impaired CNDP1 activity and carnosine degradation. The clinical significance and phenotypic spectrum of this condition remain poorly defined, with highly heterogeneous neurological and developmental manifestations reported in the literature. This systematic review aims to characterize the clinical, biochemical, and genetic spectra of carnosinase deficiency based on published case reports. Following PRISMA guidelines, case reports and case series were identified through PubMed (MEDLINE), Embase (OVID), and Web of Science from inception to 2025. Eligible studies included cases with biochemical evidence of serum carnosinase deficiency and available genetic or cytogenetic investigations. Data on demographic characteristics, clinical presentation, biochemical findings, genetic variants, management, and outcomes were extracted and synthesized qualitatively. A total of 9 articles were included. Most patients presented in infancy or early childhood, although asymptomatic or mildly affected individuals were also reported. Neurological manifestations were the most frequent clinical features, including developmental delay, hypotonia, seizures, and ataxia, while a subset of cases showed minimal or no overt neurological impairment. Biochemically, elevated plasma and urinary carnosine (carnosinuria) levels with reduced or absent serum carnosinase activity were consistently observed. Management strategies were largely supportive and heterogeneous, including dietary restriction of carnosine-rich foods in some cases, with no standardized therapeutic approach. Long-term follow-up data were limited; however, outcomes ranged from stable neurological function to persistent neurodevelopmental impairment. The available case reports highlight marked clinical heterogeneity in carnosinemia, ranging from severe neurodevelopmental phenotypes to asymptomatic biochemical abnormalities. The absence of consistent genotype–phenotype correlations and standardized management strategies underscores the need for improved phenotypic characterization, systematic follow-up, and international case registries. Future studies are required to clarify the true clinical relevance of carnosinemia and to define evidence-based diagnostic and management pathways.