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

Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterized by abnormal white matter visible by brain imaging. It is estimated that at least 30% to 40% of individuals remain without a precise diagnosis despite extensive investigations. We mapped tremor-ataxia with central hypomyelination (TACH) to 10q22.3-23.1 in French-Canadian families and sequenced candidate genes within this interval. Two missense and one insertion mutations in five individuals with TACH were uncovered in POLR3A, which codes for the largest subunit of RNA polymerase III (Pol III). Because these families were mapped to the same locus as leukodystrophy with oligodontia (LO) and presented clinical and radiological overlap with individuals with hypomyelination, hypodontia and hypogonadotropic hypogonadism (4H) syndrome, we sequenced this gene in nine individuals with 4H and eight with LO. In total, 14 recessive mutations were found in 19 individuals with TACH, 4H, or LO, establishing that these leukodystrophies are allelic. No individual was found to carry two nonsense mutations. Immunoblots on 4H fibroblasts and on the autopsied brain of an individual diagnosed with 4H documented a significant decrease in POLR3A levels, and there was a more significant decrease in the cerebral white matter compared to that in the cortex. Pol III has a wide set of target RNA transcripts, including all nuclear-coded tRNA. We hypothesize that the decrease in POLR3A leads to dysregulation of the expression of certain Pol III targets and thereby perturbs cytoplasmic protein synthesis. This type of broad alteration in protein synthesis is predicted to occur in other leukoencephalopathies such as hypomyelinating leukodystrophy-3, caused by mutations in aminoacyl-tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1). Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Osteoporosis is a worldwide disease characterized by reduction of bone mass and alteration of bone architecture resulting in increased bone fragility and increased fracture risk. Causes of osteoporosis include increasing age, female sex, postmenopausal status, hypogonadism or premature ovarian failure, low body mass index, ethnic background, rheumatoid arthritis, low bone mineral density (BMD), vitamin D deficiency, low calcium intake, hyperkyphosis, current smoking, alcohol abuse, immobilization, and long-term use of certain medications. The diagnosis of osteoporosis is established by measurement of BMD of the hip and spine using dual energy X-ray absorptiometry. According to the World Health Organization criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviation or more below the average value for young healthy women. Bone turnover biomarker detection may be useful in monitoring osteoporosis treatment and assessing fracture risk but not for diagnosis of osteoporosis. Management of osteoporosis consists of nonpharmacological interventions, which are recommended for all subjects, and pharmacological therapy in all postmenopausal women who have had an osteoporotic fracture or have BMD values consistent with osteoporosis.

To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B. We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the common c.1568T>A POLR3B mutation on one allele, homozygosity for which causes a mild phenotype. Systematic MRI review revealed that the combination of hypomyelination with relative T2 hypointensity of the ventrolateral thalamus, optic radiation, globus pallidus, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum suggests the diagnosis. 4H is a well-recognizable clinical entity if all features are present. Mutations in POLR3A are associated with a more severe clinical course. MRI characteristics are helpful in addressing the diagnosis, especially if patients lack the cardinal non-neurologic features. © 2014 American Academy of Neurology.