TY - JOUR
T1 - Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations
AU - Wolf, Nicole I.
AU - Vanderver, Adeline
AU - van Spaendonk, Rosalina M. L.
AU - Schiffmann, Raphael
AU - Brais, Bernard
AU - Bugiani, Marianna
AU - Sistermans, Erik
AU - Catsman-Berrevoets, Coriene
AU - Kros, Johan M.
AU - Pinto, Pedro Soares
AU - Pohl, Daniela
AU - Tirupathi, Sandya
AU - Strømme, Petter
AU - de Grauw, Ton
AU - Fribourg, Sébastien
AU - Demos, Michelle
AU - Pizzino, Amy
AU - Naidu, Sakkubai
AU - Guerrero, Kether
AU - van der Knaap, Marjo S.
AU - Bernard, Geneviève
AU - AUTHOR GROUP
AU - Benko, William
AU - Boltshauser, Eugen
AU - Bonkowsky, Joshua
AU - Brouwer, Oebele F.
AU - Brozova, Klara
AU - Champaigne, Neena L.
AU - Cimas, Icíar
AU - Clough, Christopher
AU - Cohen, Ana
AU - Collins, Abigail
AU - Corenblum, Bernard
AU - Dai, Lanlan
AU - Dolan, Gail
AU - Faletra, Flavio
AU - Fernandez, Raymond
AU - Eugenia Garcia Garcia, Maria
AU - Gasparini, Paolo
AU - Gburek-Augustat, Janina
AU - Gibson, William
AU - Gonzalez Moron, Dolores
AU - Guo, Yiran
AU - Hakonarson, Hakon
AU - Hamati, Aline
AU - Harms, Nils
AU - Harting, Inga
AU - Hertzberg, Christoph
AU - Hill, Alan
AU - Hobson, Grace
AU - Poll-Thé, Bwee-Tien
AU - Stromme, P.
PY - 2014
Y1 - 2014
N2 - 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
AB - 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
U2 - https://doi.org/10.1212/WNL.0000000000001002
DO - https://doi.org/10.1212/WNL.0000000000001002
M3 - Article
C2 - 25339210
SN - 0028-3878
VL - 83
SP - 1898
EP - 1905
JO - Neurology
JF - Neurology
IS - 21
ER -