Case Report: Severe Osteoporosis and Preventive Therapy in RNA Polymerase III-Related Leukodystrophy

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.

Knockdown NRPC2, 3, 8, NRPABC1 and NRPABC2 Affects RNAPIII Activity and Disrupts Seed Development in Arabidopsis

“…Several mutant RNAPIII subunits have been reported in previous studies. RNAPIII-related leukodystrophy, caused by variation in NRPC1, NRPC2, NRPC10, and NRPAC1, often impairs the normal assembly, or biogenesis, of RNAPIII and causes a retention of the unassembled subunits in the cytoplasm [ 16 , 17 ]. A rare homozygous mutation (D40H) in NRPC5 impairs the assembly of RNAPIII initiation complexes and causes an innate immune deficiency state in humans [ 18 ].…”