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Horm Metab Res
DOI: 10.1055/a-2773-6627
Letter to the Editor

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

Authors

  • Christian A. Koch 

    1   Medicine, University of Florida College of Medicine – Jacksonville, Jacksonville, USA
    2   Medicine, The University of Tennessee Health Science Center, Memphis, USA

  • Frank Tüttelmann 

    3   Institute of Reproductive Genetics, Centre of Medical Genetics, University of Münster, Münster, Germany (Ringgold ID: RIN9185)

  • Vetta Vedanarayanan

    4   Pediatric Neurology, The University of Texas at Austin, Austin, USA
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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: <20), a thyroid stimulating hormone of 2.7 mIU/L (normal: 0.4–4.0), a free T4 of 1.3 ng/dL (normal: 0.8–1.8), an insulin-like growth factor-1 of 308 ng/mL (normal range: 113–566), and a hemoglobin A1c of 5.1% (normal).

Brain magnetic resonance imaging showed cerebellar atrophy, no pituitary or sellar pathology and no white matter lesions (such lesions would typically be seen in patients with GHS).

Sequencing analysis of the mitochondrial genes POLG, POLG2, ANT1, and the DNA helicase twinkle gene was negative for known (likely) pathogenic variants. However, POLG2 harbored a heterozygous intronic variant c.1191_+8insT close to the invariant splicing site, which is a variant of unknown significance. Genetic testing for KAL1, FGFR1, PROK2, and PROKR2, known to be involved in hypogonadotropic hypogonadism, was negative.

The patient received transdermal testosterone therapy (with total testosterone serum levels between 400 and 800 ng/dL and estradiol levels between 20 and 32 pg/mL) which resulted in marked improvement in his development. At follow-up visits, he developed axillary and pubic hair consistent with his age. His physical activity (swimming) and muscle mass increased, gynecomastia regressed, and he achieved a growth spurt to a current height of 175 cm with a weight of 83 kg at age 23 years ([Fig. 1]). Despite the improvements in his sexual maturity, he remains functionally limited due to his ataxia.

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Fig. 1 (a) Age 17 years. Bilateral gynecomastia and increased “excess” abdominal and body fat. (b) Age 18 years. Regressed gynecomastia and declining “excess” body fat. (c) Age 23 years. Full virilization, more muscle mass on lower extremities.

This case suggests to consider mitochondrial gene alterations such as POLG2 variants and other molecular mechanisms in the pathogenesis of cerebellar ataxia combined with hypogonadotropic hypogonadism. Neurological impairment in childhood can lead to osteoporosis due to multiple risk factors including reduced mobility, weight-bearing, poor nutrition, and certain medications. Children with conditions like ataxia, cerebral palsy, spina bifida, and Duchenne muscular dystrophy often have low bone mineral density and an increased risk of fragility fracture [13] [14] [15] [16]. Timely diagnosis and treatment of central hypogonadism in such neurologically impaired patients may help prevent secondary osteoporosis and metabolic syndrome.

Endocrine dysfunction can be the presenting feature of a mitochondrial disease and can precede neurological symptomatology [17]. Pathogenic variants in POLG have not yet been implicated in congenital hypogonadotropic hypogonadism but are associated with premature mitochondrial ovarian insufficiency due to the proposed disease mechanism of impaired mitochondrial DNA maintenance [18] [19]. A clinical guide for the diagnosis of mitochondrial endocrine disease has recently been published [17]. Fatigue can be a symptom of a primary mitochondrial disease but is often reported in patients with obesity which can also be considered a multisystemic disease with potentially multiple endocrine abnormalities. Overfeeding induces the adipose tissue release of distinct mitochondria favoring de novo lipogenesis and obesity can lead to mitochondrial dysfunction [20] [21]. Weight loss including the one achieved with semaglutide can increase skeletal muscle mitochondrial efficiency [22]. For a long time, over the counter supplements including Coenzyme Q10 and antioxidants have been very popular, especially considering the increasing population of people feeling tired and trying to grasp for any help to increase their energy level and physical performance. Levels of Coenzyme Q10 drop with ageing and with certain conditions including heart disease and obesity. Lower levels of Coenzyme Q10 are also found in processed foods compared with unprocessed foods. Thermal processing including boiling and frying can destroy Coenzyme Q10 or reduce its levels. In patients with chronic fatigue syndrome, the intake of Coenzyme Q10 showed significant reductions in fatigue but the evidence does not allow firm conclusions[23]. To tackle the problem of the obesity epidemic with all its multisystem health problems including fatigue and reduced mental and physical performance, societies have to decide if they are willing to resist the ever increasing temptations of hedonism in favor of more asceticism [3] [24].



Publication History

Received: 02 December 2025

Accepted: 16 December 2025

Article published online:
30 January 2026

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