Does POLG2 Play a Role in Cerebellar Ataxia and Hypogonadotropic Hypogonadism?

Dear Editor, Defects in mitochondrial energy metabolism can lead to multisystem organ dysfunction. Steroid hormones are typically synthesized within mitochondria and the lack of adenosine triphosphate (ATP) from mitochondrial dysfunction can lead to impaired hormone production [ 1 ]. Hypogonadotropic hypogonadism and cerebellar ataxia can be seen in patients with Gordon Holmes syndrome (GHS) and disordered ubiquitination [ 2 ] [ 3 ]. Ubiquitination is an ATP-dependent process [ 4 ]. RNF216 is important for ubiquitin ligase and pathogenic variants in RNF216 can lead to GHS. Variants in RNF216 , STUB1 , PNPLA6 , AARS2 , SIL1 , SETX , POLR3A/3B/1C , CLPP , ERAL1 , HARS , HSD17B4 , LARS2 , TWNK , ATM , WFS1 , PMM2 , FMR1 , and POLG are associated with hypogonadism and ataxia [ 5. ] The nuclear POLG (an official gene symbol, also known as POLG1 ) located on chromosome 15 encodes the mitochondrial DNA polymerase γ, an enzyme located within the inner mitochondrial membrane responsible for replication and repair of the mitochondrial genome (mtDNA). Pathogenic variants in POLG are a prevalent single-gene cause of mitochondrial disease and have been associated with various clinical phenotypes, including endocrine, ophthalmological, audiologic, gastrointestinal, renal, respiratory and neurological disorders, with onset from infancy to late adulthood [ 6 ] [ 7 ] [ 8. ] Double mutant POLG-Akita mice have reduced testosterone levels [ 9 ]. Low testosterone levels and impaired mitochondrial function promote insulin resistance [ 10 ]. Muscle mitochondrial function can be enhanced by growth hormones [ 11 ]. Testosterone administration can increase insulin-like growth factor-1 levels [ 12 ]. We report the first case of cerebellar ataxia and hypogonadotropic hypogonadism with a POLG2 sequence variant of uncertain clinical significance. A 17-year-old boy with cerebellar ataxia was referred for delayed puberty. He had normal development in childhood until he developed progressive ataxia at age 13 years. His physical activity had become limited to swimming and he had no libido and showed no growth spurt. He grew 2.5 cm in 1 year for the last several years. His brother was 173 cm tall at age 19 years with normal development. Family history was positive for type 2 diabetes mellitus. No anosmia, deafness, fatigue, headache, and galactorrhea were present. Physical examination showed a height of 165 cm, a weight of 91 kg, and bilateral gynecomastia. There was no evidence of pectus excavatum, striae, hyperpigmentation, facial hair or acne. His genitalia were notable for small testicles and a small penis (1 cm, flaccid). He had full extraocular movements, an ataxic gait with dysarthritic speech, dysmetria overshoot, and square wave jerks. Laboratory analysis revealed a serum total testosterone level of 16 ng/dL, a free testosterone level of 2.4 pg/dL, an estradiol level of 11 pg/L (normal adult range: 20–50), a luteinizing hormone of 1.5 mIU/mL (normal: 1.8–8.6), a follicle stimulating hormone of 2.0 mIU/mL (normal: 1.5–12.4), a prolactin of 6 ng/mL (normal: