COASY – COASY protein-associated neurodegeneration (CoPAN)

COASY encodes a bifunctional enzyme catalyzing the final steps of coenzyme A (CoA) biosynthesis. Biallelic variants in COASY have been linked to a novel subtype of neurodegeneration with brain iron accumulation (NBIA), termed COASY protein-associated neurodegeneration (CoPAN) (MONDO:0014290). This autosomal recessive (AR) disorder features early-onset motor and cognitive decline.

Genetic evidence for COASY in CoPAN includes compound heterozygous missense variants identified in two siblings with intellectual disability, gait ataxia, progressive spasticity, and obsessive–compulsive behavior (2 probands; 1 family) (PMID:28489334). A subsequent study reported an additional individual with classical CoPAN features carrying novel COASY variants, bringing the total to 3 unrelated probands (PMID:38750253). No additional affected relatives were described.

Clinically, patients present with progressive spasticity (HP:0002191), intellectual disability (HP:0001249), gait ataxia (HP:0002066), and compulsive behaviors (HP:0000722). MRI reveals bilateral hyperintensity and swelling of the caudate, putamen, and thalamus without the characteristic “eye-of-the-tiger” sign seen in pantothenate kinase–associated NBIA.

Functional studies demonstrate impaired fatty acid metabolism and mitochondrial dysfunction. Metabolic profiling showed elevated free carnitine and decreased acylcarnitines in dried blood spots, linking COASY deficiency to disrupted CoA-dependent lipid metabolism (PMID:28489334). Transcriptomic and bioenergetic analyses of patient fibroblasts revealed dysregulated oxidative phosphorylation genes, reduced mitochondrial oxygen consumption, and decreased levels of mitochondrial phosphopantetheinylated proteins, confirming a loss-of-function mechanism (PMID:38750253).

Mechanistically, COASY haploinsufficiency leads to deficient CoA biosynthesis, neurometabolic dysfunction, and iron accumulation in basal ganglia. The spectrum extends to pontocerebellar hypoplasia type 12 in near–complete loss-of-function alleles, indicating a continuum of COASY-related neurodegeneration.

In summary, biallelic COASY variants cause AR CoPAN with a consistent clinical and neuroimaging phenotype, supported by genetic segregation and concordant functional data. Early recognition of the metabolic and MRI signatures enables timely diagnosis and genetic counseling. Key take-home: COASY testing is clinically useful for patients with unexplained early-onset spasticity, ataxia, and basal ganglia abnormalities.

References

• American journal of medical genetics. Part A • 2017 • Diagnosis of CoPAN by whole exome sequencing: Waking up a sleeping tiger's eye. PMID:28489334
• Molecular Genetics and Metabolism • 2024 • Transcriptomic and bioenergetic insights into COASY-related neurodegeneration. PMID:38750253

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