title: More than hypomyelination in Pol-III disorder.
abstract: The 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism) is a newly recognized leukodystrophy. The classical form is characterized by the association of hypomyelination, abnormal dentition, and hypogonadotropic hypogonadism, but the recent identification of 2 genes responsible for the syndrome demonstrates that these 3 main characteristics can be variably combined among "Pol-III (polymerase III)-related leukodystrophies." The pathophysiology of this group of diseases is still to be elucidated, and there are no neuropathologic descriptions of brain tissue. We report the clinical, neuroradiologic, and neuropathologic findings of a patient affected by 4H syndrome with confirmed POLR3A mutations. We found a marked loss of oligodendrocytes, varying in severity in different brain regions, and accompanied by severe loss of myelin, moderately severe loss of axons, and patchy perivascular regions of better preserved white matter. There was relatively mild white matter astrogliosis and microgliosis. A macrophage reaction involving viable normal-appearing oligodendroglia suggests the possibility of an immunologic process in this disorder. Cortical laminar astrogliosis and mineralization of Layers I and II in particular were present. Thus, despite the uniformly hypomyelinating pattern seen on magnetic resonance imaging, neuropathologic examination reveals a complex heterogeneous leukodystrophy with prominent neuroaxonal and glial involvement in this disorder.
authors.affiliation: Center for Genetic Medicine, Children's National Medical Center, Washington, District of Columbia 20010-2970, USA. avanderv@childrensnational.org
authors.forename: Adeline
authors.initials: A
authors.lastname: Vanderver
authors.forename: Davide
authors.initials: D
authors.lastname: Tonduti
authors.forename: Genevieve
authors.initials: G
authors.lastname: Bernard
authors.forename: Jinping
authors.initials: J
authors.lastname: Lai
authors.forename: Christopher
authors.initials: C
authors.lastname: Rossi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Carosso
authors.forename: Martha
authors.initials: M
authors.lastname: Quezado
authors.forename: Kondi
authors.initials: K
authors.lastname: Wong
authors.forename: Raphael
authors.initials: R
authors.lastname: Schiffmann
mesh_terms: D000328:Adult; D000848:Anodontia / Q000175:diagnosis* / Q000235:genetics*; D001259:Ataxia / Q000175:diagnosis* / Q000235:genetics*; D004258:DNA Polymerase III / Q000235:genetics*; D017809:Fatal Outcome; D006801:Humans; D007006:Hypogonadism / Q000175:diagnosis* / Q000235:genetics*; D056784:Leukoencephalopathies / Q000175:diagnosis* / Q000235:genetics*; D008297:Male
chemical_list: C074904:DNA polymerase III, alpha subunit; D004258:DNA Polymerase III