Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum

Department of Child Neurology, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.
Brain & development (Impact Factor: 1.88). 11/2008; 31(8):582-7. DOI: 10.1016/j.braindev.2008.09.003
Source: PubMed


Three unrelated Japanese patients who presented with ataxia and mild mental retardation were examined in this study. Early development was normal in two patients and slightly delayed in one. All could walk independently, but were unstable due to cerebellar ataxia. They had mild intellectual retardation and displayed slow, progressive, and mild clinical courses. Two patients lost the ability to walk at 12 and 25 years of age. Brain MRI of the three patients revealed diffuse cerebral hypomyelination, moderate cerebellar cortical atrophy, and hypoplasia of the corpus callosum, which were seen in other diffuse hypomyelination syndrome. No known abnormalities were found in biochemical and genetic studies. Auditory brainstem responses and nerve conduction studies were normal. A definite diagnosis could not be made because of the lack of hypodontia, hypogonadism, cataracts, or basal ganglia atrophy. Based on common MRI findings and the relatively mild clinical courses, we believe that these patients may have another subset form of diffuse hypomyelination syndrome involving the cerebral white matter and cerebellum.

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    • "4H leukodystrophy is one of five overlapping leukodystrophies that have been associated with mutations in the POLR3A and POLR3B genes, which encode the two largest subunits of RNA polymerase III (Pol III) [1] [2] [3] [4] [5] [6]. The 4H leukodystrophy is characterized by hypomyelination, with or without hypodontia (or other dental abnormalities), and hypogonadotropic hypogonadism [7] [8]. "
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    ABSTRACT: Introduction. 4H leukodystrophy is an autosomal recessive RNA polymerase III-related leukodystrophy, characterized by hypomyelination, with or without hypodontia (or other dental abnormalities) and hypogonadotropic hypogonadism. Case Presentation. We describe a 28-year-old female who presented with primary amenorrhea at the age of 19. She had a history of very mild neurological and dental abnormalities. She was found to have hypogonadotropic hypogonadism, and magnetic resonance imaging of the brain showed hypomyelination. The diagnosis of 4H leukodystrophy was made. She was subsequently found to have mutations in the POLR3B gene, which encodes the second largest subunit of RNA polymerase III. She wished to become pregnant and failed to respond to pulsatile GnRH but achieved normal follicular growth and ovulation with subcutaneous gonadotropin therapy. Discussion. Patients with 4H leukodystrophy may initially present with hypogonadotropic hypogonadism, particularly if neurological and dental manifestations are subtle. Making the diagnosis has important implications for prognosis and management. Progressive neurologic deterioration is expected, and progressive endocrine dysfunction may occur. Patients with 4H leukodystrophy should be counseled about disease progression and about this disease’s autosomal recessive inheritance pattern. In those who wish to conceive, ovulation induction may be achieved with subcutaneous gonadotropin therapy, but pulsatile GnRH does not appear to be effective.
    Full-text · Article · Jun 2015 · Case Reports in Endocrinology
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    • "Hypomyelinating disorders are numerous, and the growing list of these disorders includes Pelizaeus–Merzbacher disease, Pelizaeus–Merzbacher-like disease , hypomyelination with atrophy of the basal ganglia and cerebellum, and hypomyelination with congenital cataracts. Recently, mutations of POLR3A and POLR3B, which encode the largest and second largest subunits of RNA polymerase III (Pol III), have been reported to cause allelic Pol III-related hypomyelinating disorders [2] [3] [4], including hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome ) [5], leukodystrophy with oligodontia [6], tremor-ataxia with central hypomyelination [7], and diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC) [8]. MRI in patients with clinically diagnosed 4H syndrome revealed cerebellar atrophy in addition to hypomyelination [1]. "
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    ABSTRACT: Background: Mutations of POLR3A and POLR3B have been reported to cause several allelic hypomyelinating disorders, including hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome). Patients and methods: To clarify the difference in MRI between the two genotypes, we reviewed MRI in three patients with POLR3B mutations, and three with POLR3A mutations. Results: Though small cerebellar hemispheres and vermis are common MRI findings with both types of mutations, MRI in patients with POLR3B mutations revealed smaller cerebellar structures, especially vermis, than those in POLR3A mutations. MRI also showed milder hypomyelination in patients with POLR3B mutations than those with POLR3A mutations, which might explain milder clinical manifestations. Conclusions: MRI findings are distinct between patients with POLR3A and 3B mutations, and can provide important clues for the diagnosis, as these patients sometimes have no clinical symptoms suggesting 4H syndrome.
    Full-text · Article · May 2013 · Brain & development
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    • "However, the peripheral nerve involvement is sometimes seen in PMD with null mutations of the PLP1 gene [3], and also in some cases of PMLD caused by GJC2 mutations [4]. In addition, there has been a recent report of three cases of diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum [5], which should be included in the latter group. On the other hand, congenital cataracts are a diagnostic feature in HCC, which was ruled out in our patient because FAM126A gene analysis revealed no mutation in the open reading frame and promoter region. "
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    ABSTRACT: Hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) is a rare disease, characterized by both central and peripheral hypomyelination. We describe a 21-year-old male with mildly progressive ataxia, mental retardation, pituitary hypogonadotropic hypogonadism, delayed dentition, and cataract. Brain magnetic resonance imaging showed hypomyelinated white matter, cerebellar atrophy, and a thin corpus callosum. The literature suggests that abnormal findings upon sural nerve biopsy may indicate peripheral hypomyelination, even in the absence of clinically and physiologically evident peripheral neuropathy. A sural nerve biopsy of this patient was normal, and this finding is further discussed. Taken together with previous reports, this case suggests that 4H syndrome can be regarded as a spectrum disorder, the cardinal signs of which may be central hypomyelination, ataxia, hypogonadotropic hypogonadism, and hypodontia.
    Full-text · Article · Sep 2010 · Journal of the neurological sciences
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