title: Diffuse central hypomyelination presenting as 4H syndrome caused by compound heterozygous mutations in POLR3A encoding the catalytic subunit of polymerase III.
abstract: We describe a 33-year-old male patient with mental retardation and cerebellar ataxia whose brain magnetic resonance imaging (MRI) showed diffuse central hypomyelination. The associated hypogonadotropic hypogonadism and hypodontia were consistent with the clinical diagnosis of 4H syndrome. Two compound heterozygous mutations in POLR3A were found: p.Met852Val and p.Asn1249His. MRI of the brain showed cerebellar atrophy, atrophy of the corpus callosum, and diffuse hypomyelination extending as far as the U-fibers, with preservation of the basal ganglia. T2 hyperintensity was observed in the bilateral middle cerebellar peduncles. The patient showed almost normal development until 4-5years of age. After 25years of age, the patient showed a gradual but consistent motor and cognitive deterioration. We demonstrated the involvement of the corticospinal tract electrophysiologically, but peripheral nerve conduction was normal. Although this disease may start very early in life, the clinical course in the present case suggests that brains that initially appear to have developed normally may show dysfunction later in life, although the pathophysiological bases for this dysfunction may not be evident on MRIs.
authors: Department of Neurology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. yterao-tky@umin.ac.jp
authors: Yasuo
authors: Y
authors: Terao
authors: Hirotomo
authors: H
authors: Saitsu
authors: Masaya
authors: M
authors: Segawa
authors: Yukiko
authors: Y
authors: Kondo
authors: Kiwako
authors: K
authors: Sakamoto
authors: Naomichi
authors: N
authors: Matsumoto
authors: Shoji
authors: S
authors: Tsuji
authors: Yoshiko
authors: Y
authors: Nomura
mesh_terms: D000328:Adult; D000848:Anodontia / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D001284:Atrophy; D002524:Cerebellar Ataxia / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002531:Cerebellum / Q000473:pathology; D003337:Corpus Callosum / Q000473:pathology; D003711:Demyelinating Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D006801:Humans; D007006:Hypogonadism / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009431:Neural Conduction / Q000502:physiology; D059906:Neuroimaging / Q000379:methods; D011712:Pyramidal Tracts / Q000503:physiopathology*; D012320:RNA Polymerase III / Q000235:genetics*; D013577:Syndrome
chemical_list: D012320:RNA Polymerase III