Hypomyelinating Leukodystrophy 7
HLD7

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Description from OMIM

Hypomyelinating leukodystrophy-7 is an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive motor decline manifest as spasticity, ataxia, tremor, and cerebellar signs, as well as mild cognitive regression. Other features may include hypodontia or oligodontia and hypogonadotropic hypogonadism. There is considerable inter- and intrafamilial variability (summary by Bernard et al., 2011). See also HLD8 (614381), which has similar features and is caused by mutation in the POLR3B gene (614366) on chromosome 12q23. The POLR3A and POLR3B genes encode the 2 largest subunits of RNA polymerase III. For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080.



Prevalence of clinical parameters (%)







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List of symptoms



Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
Psychomotor regression nervous 100 % 21855841 2015-01-09
Pyramidal signs nervous 100 % 21855841 2015-01-09
Ataxia nervous 100 % 21855841 2015-01-09
Leukodystrophy nervous 100 % 24105487 2015-01-09
Hypomyelination nervous 95 % 25339210 2015-01-09
Cerebellar atrophy nervous 92 % 24105487 2015-01-09
Myopia nervous 87 % 25339210 2015-01-09
Hypogonadism endocrine 81 % 25339210 2015-01-09
Hypodontia skeletal 72 % 25339210 2015-01-09
Wheelchair use nervous 63 % 21855841 2015-01-09
Tremor nervous 58 % 21855841 2015-01-09
Developmental delay nervous 52 % 25339210 2015-01-09
Short stature skeletal 51 % 25339210 2015-01-09
Developmental delay nervous 37 % 21855841 2015-01-09
Dysphagia nervous 37 % 21855841 2015-01-09
Hypogonadism endocrine 37 % 21855841 2015-01-09
Hypersalivation digestive 32 % 21855841 2015-01-09
Optic atrophy nervous 21 % 21855841 2015-01-09
Seizures nervous 19 % 25339210 2015-01-09
Seizures nervous 16 % 21855841 2015-01-09
Nystagmus nervous 16 % 21855841 2015-01-09



List of references:


Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy.
Geneviève Bernard, Eliane Chouery, Maria Lisa Putorti, Martine Tétreault, Asako Takanohashi, Giovanni Carosso, Isabelle Clément, Odile Boespflug-Tanguy, Diana Rodriguez, Valérie Delague, Joelle Abou Ghoch, Nadine Jalkh, Imen Dorboz, Sebastien Fribourg, Martin Teichmann, André Megarbane, Raphael Schiffmann, Adeline Vanderver, Bernard Brais,

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).

American journal of human genetics - Sep 2011



Brain magnetic resonance imaging (MRI) pattern recognition in Pol III-related leukodystrophies.
Roberta La Piana, Davide Tonduti, Heather Gordish Dressman, Johanna L Schmidt, Jonathan Murnick, Bernard Brais, Genevieve Bernard, Adeline Vanderver,

Pol III-related leukodystrophies are caused by mutations in POLR3A and POLR3B genes and all share peculiar imaging and clinical features. The objectives of this study are (1) to define the neuroradiologic pattern in a cohort of POLR3A and POLR3B subjects and (2) to compare the neuroradiologic pattern of Pol III-related leukodystrophies with other hypomyelinating disorders. The magnetic resonance imaging (MRI) examinations of 13 patients with POLR3A and POLR3B mutations and of 14 patients with other hypomyelinating disorders were analyzed. All the subjects with Pol III-related leukodystrophies presented hypomyelination associated with T2 hypointensity of the thalami and/or the pallida. Twelve subjects (92%) presented T2 hypointensity of the optic radiations. Cerebellar atrophy was observed in most patients (92%). The combination of the analyzed criteria identified patients with Pol III-related leukodystrophies with a sensitivity of 84.6% and a specificity of 92.9%.

Journal of child neurology - Feb 2014



Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations.
Nicole I Wolf, Adeline Vanderver, Rosalina M L van Spaendonk, Raphael Schiffmann, Bernard Brais, Marianna Bugiani, Erik Sistermans, Coriene Catsman-Berrevoets, Johan M Kros, Pedro Soares Pinto, Daniela Pohl, Sandya Tirupathi, Petter Strømme, Ton de Grauw, Sébastien Fribourg, Michelle Demos, Amy Pizzino, Sakkubai Naidu, Kether Guerrero, Marjo S van der Knaap, Geneviève Bernard, ,

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.

Neurology - Nov 2014