Sisters with rare mitochondrial syndrome kept sharp minds as motor disease progressed

In a finding that challenges long-held assumptions about one of medicine’s rarest mitochondrial disorders, neurologists in Bogotá have documented two adult sisters with genetically confirmed Harel–Yoon syndrome who survived into their third and fourth decades despite profound, progressive motor disability. Both women carry the recurrent ATAD3A p.Arg528Trp variant, a single-letter change in a gene that governs mitochondrial dynamics, yet both completed formal education and scored within the low-average range on adult intelligence testing, with IQ scores of 88 and 82. The case report, published in Frontiers in Genetics, expands the known phenotypic spectrum of this neurometabolic condition and offers the first detailed look at how the disorder unfolds across decades of adult life.

Harel–Yoon syndrome is caused by pathogenic variants in ATAD3A, a nuclear gene encoding a mitochondrial membrane protein central to cellular homeostasis. The gene regulates mitochondrial morphology, content, and turnover, processes that are especially critical in energy-hungry tissues such as brain, muscle, heart, and optic nerve. Since the original description of the syndrome in 2016, reported patients have ranged from infants with lethal neonatal encephalopathy and cardiomyopathy to longer-surviving children with hypotonia, spasticity, optic atrophy, and peripheral neuropathy. What has remained almost entirely unknown is the long-term trajectory: no previously published carrier of the p.Arg528Trp variant had ever been followed into adulthood.

The two sisters, aged 37 and 26 years, were born to first-cousin parents after uneventful pregnancies and normal perinatal periods. Their clinical course followed a familiar mitochondrial pattern. Patient 1 developed hypotonia at 12 months of age, with increased muscle tone and progressive spasticity evident by 3 years. Patient 2 began with hypotonia at 8 months, followed by spasticity from age 2 that ultimately progressed to loss of independent ambulation and permanent wheelchair dependence. Both women exhibited craniofacial dysmorphism, including gingival hypertrophy, a high forehead, mandibular protrusion, and low-set ears, along with optic atrophy confirmed by ophthalmological evaluation. Patient 1 also developed early cataracts.

Neurological examination revealed generalized spasticity, marked lower-limb hypotrophy, bradykinesia, and dysarthria in both patients. Patient 1 showed scanning dysarthria, whereas her sister displayed ataxic dysarthria, subtle differences that reflect the distribution of cerebellar and corticospinal involvement. Brain magnetic resonance imaging demonstrated mild diffuse cerebellar atrophy in both women, notably without supratentorial cortical atrophy, white matter abnormalities, basal ganglia involvement, or structural malformations. Electrophysiological studies showed a chronic sensorimotor polyneuropathy with axonal loss and conduction slowing affecting all four limbs. Electroencephalography revealed no epileptiform activity, echocardiography was unremarkable, and metabolic screening was entirely within normal limits.

The diagnostic journey illustrates the challenges posed by the ATAD3 locus. Clinical duo whole-exome sequencing performed in 2023 initially identified a variant of uncertain significance in COL5A1, a collagen gene associated with connective tissue disorders, along with a heterozygous pathogenic EPM2A variant that represented carrier status for an autosomal recessive condition and could not explain the neurological phenotype. Neither sister showed clinical features of a COL5A1-related disorder, such as skin hyperextensibility, abnormal scarring, or recurrent joint dislocations, so the collagen variant was interpreted as incidental. The known familial ATAD3A variant was not included among the exome findings, a discrepancy the authors describe as not reported rather than not detected, since locus-specific coverage data were unavailable for retrospective review.

Confirmation ultimately came through targeted single-site Sanger sequencing directed specifically at the ATAD3A NM_001170535.3:c.1582C>T variant. Genomic DNA extracted from peripheral blood was sequenced on a SeqStudio Genetic Analyzer, and the variant was confirmed in heterozygosity in both sisters. The authors reassessed pathogenicity using the ACMG/AMP framework, applying criteria for recurrent de novo occurrence, supportive functional evidence, extreme rarity in population databases, and concordant computational evidence. The p.Arg528Trp substitution has been reported as de novo in five unrelated affected individuals, and experimental studies in a Drosophila model demonstrated abnormal mitochondrial morphology, reduced mitochondrial content, and increased mitophagy, together with increased mitophagy in patient fibroblasts. ClinVar lists the variant as pathogenic or likely pathogenic with no conflicting submissions.

Reconciliation of the published literature identifies at least 12 unique individuals with the p.Arg528Trp variant before the present family. Most were children with severe neurodevelopmental disease and variable cardiac, metabolic, epileptic, sensory, or inflammatory involvement. The original Harel cohort described five patients evaluated between 23 months and 9 years of age, four of whom developed spasticity and peripheral neuropathy, three had optic atrophy, and two had hypertrophic cardiomyopathy. Additional patients reported by Lepelley and colleagues included a child with refractory seizures and no useful motor function, another with systemic sclerosis and gastrostomy-dependent feeding, and a third with respiratory-chain deficiency and cerebral lactate elevation. Later reports added infants with cardiac decompensation, metabolic crisis, and early-onset seizures.

What distinguishes the Colombian sisters is the coexistence of severe motor disability with relative cognitive preservation and limited systemic disease. Despite Barthel Index scores of 45/100 and 30/100, indicating moderate-to-severe and severe dependency in activities of daily living respectively, both women survived into adulthood, completed formal education, and achieved low-average IQ scores at single adult assessments. Neither had seizures, cardiomyopathy, lactate elevation, or other detected metabolic abnormalities. The authors emphasize that their phenotype is not globally mild but rather motor-severe while cognitively and systemically attenuated. Age is the most evidence-based explanation for the apparent difference in motor severity compared with pediatric reports, since decades of progressive spasticity and neuropathy could not be revealed by exclusively pediatric follow-up. Age does not, however, explain the comparatively mild cognitive involvement or the absence of cardiac and metabolic abnormalities.

The recurrence of the variant in two sisters requires cautious genetic interpretation. Parental segregation could not be assessed because their father died before genetic evaluation and their mother declined further clinical evaluation and targeted segregation testing. Parental germline or low-level somatic mosaicism remains a plausible explanation for recurrence, but inherited transmission cannot be distinguished without parental data. The extensive homology among ATAD3A, ATAD3B, and ATAD3C also limits conventional short-read detection of copy-number changes and complex rearrangements within the locus. The authors note that targeted copy-number analysis and long-read sequencing in the sisters would help exclude additional contributors, although they would not resolve inheritance without parental samples.

No disease-modifying treatment is established for Harel–Yoon syndrome, and management remains supportive. In these patients, botulinum toxin injections for spasticity, combined with ongoing physical and multidisciplinary rehabilitation, improved passive limb mobilization and facilitated basic caregiving activities including hygiene and positioning, but did not alter disease progression. The authors highlight the importance of comprehensive genetic evaluation in suspected mitochondrial disorders and emphasize that adult survival and relative cognitive preservation do not imply limited neurological severity. These observations carry implications for prognosis, genetic counseling, and clinical management, and they underscore the value of long-term follow-up and patient-level comparison without duplicate counting in the study of rare mitochondrial diseases.

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

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

Article References: Zamudio Soledad, P. N., Montoya, J. S., Poveda-Rodriguez, D. S., King Chio Cho, L. M., Reyes, M. A., & Bernal Pacheco, O. (2026). Case report: Harel–Yoon syndrome (ATAD3A p.Arg528Trp) with relative cognitive preservation despite severe motor impairment. Frontiers in Genetics, 17, Article 1881863. https://doi.org/10.3389/fgene.2026.1881863

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1881863

Keywords: Case, report, Harel, Yoon, syndrome, ATAD3A, Arg528Trp, relative, cognitive, preservation, despite, severe