Keiko Shimojima1, Akihisa Okumura2, Mitsuru Ikeno3, Akira Nishimura4, Akira Saito5, Hirotomo Saitsu6, Naomichi Matsumoto6, Toshiyuki Yamamoto7. 1. Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi, Japan; Tokyo Women's Medical University Institute for Integrated Medical Sciences, Tokyo, Japan. 2. Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan; Department of Pediatrics, Aichi Medical University, Nagakute, Japan. 3. Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan. 4. Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan. 5. Statistical Genetics Analysis Division, StaGen Co., Ltd., Tokyo, Japan. 6. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. 7. Tokyo Women's Medical University Institute for Integrated Medical Sciences, Tokyo, Japan. Electronic address: yamamoto.toshiyuki@twmu.ac.jp.
Abstract
OBJECTIVE: Hypomyelinating leukoencephalopathy is a heterogeneous disorder caused by mutations in several-different genes. Clinical entity of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is one of them. METHOD: A male patient showed pendular nystagmus, infantile hypotonia, an abnormal pattern of brain auditory evoked potential, and hypomyelination on brain magnetic resonance imaging, which suggested Pelizaeus-Merzbacher disease (PMD) as the candidate diagnosis; however, no abnormality was found in the proteolipid protein 1 gene (PLP1) that is responsible for PMD. Whole exome sequencing was performed to identify pathogenic mutations in this patient. RESULTS: A de novo mutation was identified in the tubulin 4a gene (TUBB4A), which has been recently reported to be associated with H-ABC. Although the patient did not show any neurological features suggesting H-ABC, such as extrapyramidal or cerebellar signs, radiological findings demonstrated the finding of cerebellar atrophy at the age of 36months. CONCLUSION: This study suggested us the difficulty of clinical diagnosis for H-ABC early in the life of the patient, which makes predication of prognosis and genetic counseling difficult.
OBJECTIVE:Hypomyelinating leukoencephalopathy is a heterogeneous disorder caused by mutations in several-different genes. Clinical entity of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is one of them. METHOD: A male patient showed pendular nystagmus, infantile hypotonia, an abnormal pattern of brain auditory evoked potential, and hypomyelination on brain magnetic resonance imaging, which suggested Pelizaeus-Merzbacher disease (PMD) as the candidate diagnosis; however, no abnormality was found in the proteolipid protein 1 gene (PLP1) that is responsible for PMD. Whole exome sequencing was performed to identify pathogenic mutations in this patient. RESULTS: A de novo mutation was identified in the tubulin 4a gene (TUBB4A), which has been recently reported to be associated with H-ABC. Although the patient did not show any neurological features suggesting H-ABC, such as extrapyramidal or cerebellar signs, radiological findings demonstrated the finding of cerebellar atrophy at the age of 36months. CONCLUSION: This study suggested us the difficulty of clinical diagnosis for H-ABC early in the life of the patient, which makes predication of prognosis and genetic counseling difficult.
Keywords:
Genetic counseling; Hypomyelinating leukoencephalopathy; Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC); Pelizaeus–Merzbacher disease (PMD); TUBB4A