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A compound heterozygous mutation in HADHB gene causes an axonal Charcot-Marie-tooth disease

Young Bin Hong1, Ja Hyun Lee2, Jin-Mo Park3, Yu-Ri Choi4, Young Se Hyun2, Bo Ram Yoon2, Jeong Hyun Yoo5, Heasoo Koo6, Sung-Chul Jung4, Ki Wha Chung2* and Byung-Ok Choi1*

Author Affiliations

1 Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong Gangnam-Gu, Seoul 135-710, Korea

2 Department of Biological Science, Kongju National University, 182 Sinkwan-dong, Gongju 314-701, Korea

3 Department of Neurology, School of Medicine, Ewha Womans University, Seoul, Korea

4 Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Korea

5 Department of Radiology, School of Medicine, Ewha Womans University, Seoul, Korea

6 Department of Pathology, School of Medicine, Ewha Womans University, Seoul, Korea

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BMC Medical Genetics 2013, 14:125  doi:10.1186/1471-2350-14-125

Published: 5 December 2013



Charcot-Marie-Tooth disease (CMT) is a heterogeneous disorder of the peripheral nervous system. So far, mutations in hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), beta subunit (HADHB) gene exhibit three distinctive phenotypes: severe neonatal presentation with cardiomyopathy, hepatic form with recurrent hypoketotic hypoglycemia, and later-onset axonal sensory neuropathy with episodic myoglobinuria.


To identify the causative and characterize clinical features of a Korean family with motor and sensory neuropathies, whole exome study (WES), histopathologic study of distal sural nerve, and lower limb MRIs were performed.


WES revealed that a compound heterozygous mutation in HADHB is the causative of the present patients. The patients exhibited an early-onset axonal sensorimotor neuropathy without episodic myoglobinuria, and showed typical clinical and electrophysiological features of CMT including predominant distal muscle weakness and atrophy. Histopathologic findings of sural nerve were compatible with an axonal CMT neuropathy. Furthermore, they didn’t exhibit any other symptoms of the previously reported HADHB patients.


These data implicate that mutation in HADHB gene can also cause early-onset axonal CMT instead of typical manifestations in mitochondrial trifunctional protein (MTP) deficiency. Therefore, this study is the first report of a new subtype of autosomal recessive axonal CMT by a compound heterozygous mutation in HADHB, and will expand the clinical and genetic spectrum of HADHB.

Charcot-Marie-Tooth disease (CMT); Whole exome sequencing (WES); HADHB; Mitochondrial trifunctional protein (MTP)