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This summary outlines the association between mutations in COASY (HGNC:29932) and neurodegeneration with brain iron accumulation (MONDO_0018307). The clinical phenotype is characterized by intellectual disability, gait ataxia, progressive spasticity, and compulsive behaviors, features that have been consistently reported across several independent studies (PMID:28489334, PMID:29325618). The reported neuroimaging and metabolic findings further delineate a distinctive spectrum when compared to more common forms of neurodegeneration with brain iron accumulation.
Genetic evidence supporting this association comes from case reports and multi‐patient studies. In the seminal report, compound heterozygous COASY mutations were identified in two siblings and segregated with the disease phenotype (PMID:28489334). Additional studies have expanded the patient cohort across unrelated families, demonstrating a recurrent COASY pathogenic variant and confirming autosomal recessive inheritance. Such findings, involving multiple probands and clear segregation data, underline the reliability and reproducibility of the genetic evidence.
A representative variant from these studies is c.641C>T (p.Ala214Val). This variant fulfills standardized HGVS nomenclature requirements with a complete coding change described at both the DNA and protein levels using three‑letter amino acid codes. Its identification in affected individuals across different cohorts emphasizes its pathogenic relevance and supports its application in diagnostic decision‑making.
Functional and experimental assays further substantiate the association between COASY and the NBIA phenotype. Studies have demonstrated that COASY mutations lead to near‐complete loss of enzyme activity, abnormal acylcarnitine profiles, and specific neuroimaging findings, thereby mirroring key aspects of the clinical presentation observed in patients (PMID:30089828). These assays not only confirm the deleterious impact of the variants on protein function but also provide a mechanistic understanding, which is critical for both clinical and commercial applications.
Integrating the genetic and functional data provides a compelling narrative linking COASY loss‐of‐function mutations to neurodegeneration with brain iron accumulation. The consistency observed across multiple independent studies, robust segregation within families, and concordant experimental findings justify a strong gene‑disease association. While additional evidence exists that further refines the spectrum, the present data are sufficient to support diagnostic use and inform clinical management strategies.
Key take‑home: COASY mutations represent a strong genetic determinant of NBIA, with robust clinical, segregation, and functional data supporting their use in molecular diagnosis and guiding therapeutic interventions.
Gene–Disease AssociationStrongMultiple independent studies, including a compound heterozygous case in two siblings (PMID:28489334) and replication in multi‐patient cohorts (PMID:36790591), support a strong association. Genetic EvidenceStrongCase‐level data showing compound heterozygosity and recurrent pathogenic variants across unrelated families align with autosomal recessive inheritance. Functional EvidenceModerateFunctional assays have demonstrated that COASY mutations lead to loss of enzyme activity and altered metabolic profiles, consistent with the disease phenotype (PMID:30089828). |