Case report: Harel–Yoon syndrome (ATAD3A p.Arg528Trp) with relative cognitive preservation despite severe motor impairment

Abstract

Harel–Yoon syndrome (HAYOS) is a rare neurometabolic disorder caused by pathogenic variants in the ATAD3A gene, a key regulator of mitochondrial dynamics and cellular homeostasis. Although a broad phenotypic spectrum has been described, the relationship between genotype and long-term functional outcomes remains incompletely understood. We report two adult sisters with genetically confirmed HAYOS who exhibited early-onset hypotonia progressing to spasticity, craniofacial dysmorphism, optic atrophy, and sensorimotor polyneuropathy. Neuroimaging revealed mild cerebellar atrophy, and electrophysiological studies showed a chronic sensorimotor polyneuropathy with axonal loss and conduction slowing. Initial exome sequencing revealed a variant of uncertain significance in COL5A1 , whereas subsequent targeted familial Sanger sequencing confirmed the heterozygous ATAD3A NM_001170535.3:c.1582C>T (p.Arg528Trp) variant in both sisters. Parental segregation could not be assessed because their father died before genetic evaluation and their mother declined further clinical evaluation and targeted segregation testing for the familial ATAD3A variant. Despite severe progressive motor impairment leading to wheelchair dependence, both patients completed formal education and had low-average IQ scores (88 and 82) at single adult assessments. These cases expand the phenotypic spectrum of HAYOS by demonstrating that severe progressive motor disability may coexist with relative cognitive preservation at adult assessment, limited cardiac or metabolic involvement, and long-term survival. Our findings highlight the diagnostic challenges posed by the ATAD3 locus and underscore the importance of comprehensive genetic evaluation in suspected mitochondrial disorders. Rather than representing a globally mild phenotype, these patients show a motor-severe but cognitively and systemically attenuated presentation, with implications for prognosis, genetic counseling, and clinical management.