Phenotypic characterization of the ECHS1 pathogenic variant c.476A>G (p.Q159R): a review of 9 cases

Background: ECHS1 deficiency is caused by decreased activity of mitochondrial short-chain enoyl-CoA hydratase. It manifests as a clinical spectrum with three phenotypes: neonatal encephalopathy, infantile regression and delay; and isolated paroxysmal dystonia. The earlier the presentation, the greater risk for severe impairment or a fatal outcome. Except for the A173V variant that manifests as paroxysmal dystonia when compound heterozygous, there is no clear genotype – phenotype correlation. Here, we look to provide a characterization of the c.476A>G (p.Q159R) variant, identified in 9 cases.

Case Study/Methods: We identified a 10-month-old male born to a consanguineous Pakistani couple with a history of hearing loss, hypotonia, spasticity and developmental delay. After suggestive biochemical testing (including 3-methylglutaconate, 2-methyl-dihydroxybutyrate), he was found homozygous for Q159R. We then performed a literature search by using the terms “ECHS1”, “c.476A>G” and “p.Gln159Arg”. Seven papers describing 9 cases were identified. One paper was excluded as it described a previous case. Therefore, 6 papers with 8 distinct patients were reviewed.

Results: Out of the 9 affected individuals with the Q159R variant, 4 were homozygous, 2 from Pakistani ancestry, 1 from Lebanon. These 3 cases were from consanguineous families. All patients manifested either at birth (3/9) or early infancy (6/8). While the outcome of these cases was not reported, there is only one surviving individual who reached adulthood. This patient was compound heterozygous for the variant E77Q. This patient had milder neurologic problems than the other cases, but still presented visual and hearing impairment.

Discussion/Conclusions: It appears that when homozygous, a moderate to severe phenotype is expected. Tetreault et al 2015, had considered that the variant could be common for various ethnic groups. This is supported by its higher frequency in Middle East and South Asian patients.