Abstract
RNA polymerase III (POLR3)-related leukodystrophy is an autosomal recessive form of leukodystrophy caused by homozygous or compound heterozygous mutations of the RNA polymerase III subunit genes, including subunit A (POLR3A). With respect to the manifestation triad, hypomyelination, hypodontia, and hypogonadotropic hypogonadism, it is also known as 4H leukodystrophy. Here, we report a 41-year-old woman of POLR3-related leukodystrophy by carrying compound heterozygous pathogenic variants of c.2554A>G (p.M852V) and c.2668G>T (p.V890F) in the POLR3A gene. She was amenorrheic and became a wheelchair user from the age of 15 years and suffered from multiple episodes of pathologic fractures, starting with a subtrochanteric fracture of the right femur after a tonic seizure at age 30 years. Head magnetic resonance imaging demonstrated hypomyelination and atrophies of the cerebellum, brainstem, and corpus callosum. Laboratory examination revealed a marked decrease of gonadotropins and estrogen, low bone density, and high bone resorption markers. Administration of anti-receptor activator of nuclear factor kappa-B ligand monoclonal antibody restored bone resorption markers to a normal level and prevented further pathological bone fractures. Our case emphasizes that osteoporosis should be recognized as a potential but serious complication in POLR3-related leukodystrophy. It may be feasible to prevent pathologic fractures by intensive osteoporosis therapy after endocrinological examinations and evaluation of bone metabolism.
Highlights
RNA polymerase III (POLR3) consists of 17 subunits, including two major subunits, RPC1 and RPC2, encoded by the POLR3A and 3B genes, respectively
A majority of female patients lack secondary sex characteristics and menstruation caused by hypogonadotropic hypogonadism [5]
Severe osteoporosis has not been emphasized in patients with POLR3-related leukodystrophy
Summary
RNA polymerase III (POLR3) consists of 17 subunits, including two major subunits, RPC1 and RPC2, encoded by the POLR3A and 3B genes, respectively. She had primary amenorrhea with no menarche in puberty Due to her progressive gait disturbance along with cerebellar ataxia and limb spasticity, she became a wheelchair user at the age of 15 years. As her motor functions deteriorated, she became bedridden and required total assistance. Her parents had different POLR3A gene mutations with paternal heterozygous of c.2554A>G (p.M852V) and maternal heterozygous of c.2668G>T (p.V890F) Her elder sister was healthy at birth, but limb spasticity and walking impairment appeared at age 2 years. Pathological fractures have no longer occurred since the initiation of the treatment with RANKL mAb against bone resorption
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