eP033: COASY-associated pontocerebellar hypoplasia – A possible additional secondary target detectable by expanded newborn screening?


      Carnitine palmitoyl transferase I (CPT I; OMIM: 255120) deficiency is an autosomal recessive disorder that impairs long-chain fatty acid transport into the mitochondria, subsequently leading to isolated elevations in free carnitine and a reduction in long chain fatty acids. CPT I deficient patients typically present with heart failure, hypotonia, hepatic abnormalities, and hypoketotic hypoglycemia during fasting periods. Although clinically similar to other long chain fatty acid oxidation disorders, CPT I deficiency was initially thought to have a unique metabolic derangement. The latter has recently been challenged by individuals presenting with apparently identical biochemical abnormalities, yet without pathogenic variants in the expected gene. Contrarily, these patients harbor variants in the COASY gene which encodes for a dual functioning enzyme responsible for the final steps (4-phosphopantethine adenyl transferase and dephospho-CoA kinase) of coenzyme A synthesis. Biallelic pathogenic variants in COASY may result in severe hypotonia, episodes of dystonia, pontocerebellar hypoplasia, and/or neurodegeneration via iron accumulation in the brain, among other. Considering the heterogenous clinical presentation of previously reported cases, as well as the indistinguishable biochemical presentation of CPT I and COASY-related disorders, these diseases clearly provide a diagnostic challenge.

      Case presentation

      Two female siblings presenting with hyperglycemia, severe hypotonia, and respiratory insufficiency were admitted to the University of Rochester Medical Center neonatal intensive care unit, on two separate occasions. Upon examination, evidence of poor Moro and deep tendon reflexes, along with a resting ‘frog-legged’ appearance, were observed. Initial brain magnetic resonance imaging (MRI) of the siblings revealed symmetric areas of diffusion restriction in the bilateral hippocampi, globus pallida, thalami, and posterior limbs of the internal capsule suggestive of hypoxic injury or metabolic disease. Subsequent MRI in the older sibling revealed progressive atrophy of the cortical and brainstem structures consistent with pontocerebellar hypoplasia. Although the newborn screening and confirmatory plasma acylcarnitines/carnitine results of these patients were suggestive of CPT I deficiency, molecular testing excluded this inborn error of metabolism. Nonetheless, exome sequencing revealed homozygous variants of uncertain significance in the COASY genes of both siblings, suggesting a possible COASY-related disease, even though clinical abnormalities did not correlate with previously reported cases. When comparing the biochemical data of these patients to previously confirmed CPT I patients using Collaborative Laboratory Integrated Reports web application (CLIR;, the ratios of markers not currently considered by standard newborn screening appeared to vary notably between these diseases.


      COASY-related disorders may be indistinguishable from CPT I by newborn screening and conventional post-analytical interpretation. However, utilizing CLIR, we identified metabolite marker ratios that may differentiate between these diseases.