The fourth family in the world with a novel variant in the ATP5MK gene: four siblings with complex V (ATP synthase) deficiency.

Mitochondrial Complex V (ATP synthase) deficiency nuclear type 6 (MC5DN6) is a progressive neurodegenerative disorder characterized by autosomal recessive inheritance and developmental regression, particularly in gross motor skills, which manifests in early childhood. This study aims to present the discovery of a novel variant in four male siblings aged 13 years 9 months to 25 years, making this the fourth family reported globally, while also raising awareness of rare mitochondrial diseases. Four individuals from the same family were retrospectively evaluated based on their demographic, clinical, laboratory, and molecular genetic data. The mutation in the ATP5MK gene was analyzed using the exome sequencing (ES) method. The detected variation was classified according to the criteria American College of Medical Genetics. Four cases, aged between 13 years 9 months and 25 years, were analyzed. All individuals were male. While all four cases had a history of neurodegenerative disease, they also exhibited intellectual disability, muscle weakness, increased deep tendon reflexes in the lower extremities, spasticity, scoliosis, pes cavus deformity, positive Babinski reflex, abnormal gait patterns due to foot deformities, and normal cerebellar tests. Additional findings included geographic tongue (n = 2), strabismus (n = 2), nystagmus (n = 1), ophthalmoplegia (n = 2), hypertrophic upper extremity muscle body build (n = 2), keloid tissue (n = 1), and short stature (n = 3). ES of the first case identified a homozygous splice donor variant (c.87 + 1G > A) in the ATP5MK gene as a novel variant, and family screening revealed the same variant in a biallelic state in the other three siblings. The parents were confirmed as heterozygous carriers, consistent with autosomal recessive inheritance. Mitochondrial diseases can mimic a wide range of neurological disorders. They should be considered as a potential underlying cause when treatment for suspected differential diagnoses proves ineffective.