Charcot-Marie-Tooth Disease 4G Caused by Homozygous Deletion of Exon 4 in HK1 Gene due to Inbreeding: A Case Report and Literature Review

Review Article

J Pediatr & Child Health Care. 2022; 7(1): 1054.

Charcot-Marie-Tooth Disease 4G Caused by Homozygous Deletion of Exon 4 in HK1 Gene due to Inbreeding: A Case Report and Literature Review

Xu H#, Ying G#, Qian H#, Wang S, Huang T, Chen J, Zhu X, Guo H, Zheng G and Zhang G*

Department of Neurology, Children’s Hospital of Nanjing Medical University, China

#These authors contributed equally to this article

*Corresponding author: Gang Zhang, Department of Neurology, Children’s Hospital of Nanjing Medical University, No.72 Guangzhou Road, Nanjing, Jiangsu, China

Received: July 13, 2022; Accepted: August 08, 2022; Published: August 15, 2022


Objectives: The objective is to investigate the clinical and genotypic characteristics of Charcot-Marie-Tooth disease, caused by HK1 gene mutation.

Methods: The detailed medical history of the child was collected and the clinical symptoms were summarized. The genomic DNA was extracted from the 2ml of peripheral blood of child and their parents, and the whole exome sequencing was performed, and the related literatures were reviewed.

Results: A 7-year-old girl with unstable walking for 7 months, left claudication, obvious valgus of left foot, unable to squate , unable to jump on one foot, grade IV of muscle strength of lower extremity and slight limitation of dorsal extension of left foot. Electromyography showed multiple peripheral neurogenic lesions (motor and sensory nerve demyelination with axonal damage, more severe in lower limbs than in upper limbs). Whole exome sequencing and PCR verification indicated that the patient had a homozygous deletion in exon 4 of HK1 gene, and the variation site was located in the range of chr10:71048499-71048526, which had not been reported before, and the associated disease was peroneal muscular atrophy type 4G.

Conclusion: This study expands the number of reported cases of CMT4G and the mutation spectrum of HK1 gene, and provides reference for prenatal diagnosis and genetic counseling.

Keywords: Charcot-Marie-Tooth disease; HK1; Clinical phenotype; Gene detection; CMT4G; 0020HMSN


Charcot-Marie-Tooth disease (CMT), also known as Hereditary Motor Sensory Neuropathy (HMSN), is a group of the most common peripheral nerve single gene genetic diseases, with a high degree of clinical and genetic heterogeneity, the prevalence rate is about 1max 2500 [1]. Its clinical features include: the average age of onset is about 12 years, progressive symmetrical muscle weakness and atrophy with sensory disorders in the distal extremities (lower limbs are more commonly involved than upper limbs), typical “crane leg-like” changes, in addition, some patients may have arched feet, spinal deformities and other manifestations [2]. The genetic mode of the disease includes autosomal dominant inheritance, autosomal recessive inheritance and x-linked inheritance, with autosomal dominant inheritance being the most common [3]. Since the discovery of the first case of CMT in 1991, with the clinical application of Whole Exon Sequencing (WES), the research of CMT has turned to the field of molecular biology. More than 100 genes have been found to be associated with CMT [4]. Due to the differences in pathological features and pathogenic genes, dozens of genotypes have been found in CMT studies, including CMT1, CMT2, CMT3, CMT4, CMT5, CMT6, CMTDI, CMTRI, CMTX and so on [5]. Of all the known pathogenic genes, the PMP22 gene that causes CMT1 is the most common, accounting for about 60.5% of all confirmed CMT cases, followed by the GBJ1 gene that can cause CMTX (about 16.7%), the MPZ gene that can cause CMT1 and CMT2 (about 9.4%), and the MFN2 gene that can cause CMT2A (about 4.4%) [6,7]. Studies have found that in patients who have been diagnosed with CMT, the positive rate of these four genes can even reach 96% [6]. It can be said that CMT4G is a rare disease among the rare diseases. CMT4G is an autosomal recessive CMT, or AR-CMT, and its pathogenic gene is HK1. A case of CMT4G caused by HK1 gene mutation is reported. The clinical data of the child is as following.

Clinical data the child, a 7-year-old girl, came to our hospital on July 10, 2021 because of “more than 7 months of unstable gait”. The child developed normally in terms of language and intelligence, lagged behind in motor development since childhood, sat steadily at more than 8 months of age, at 16 months walked independently, running, jumping and other major movements lagged behind for the same age, the left foot valgus was obvious, the left foot could not squat & the left foot jump could not be completed (Figure 1A-C). There was no numbness in the limbs or any other sensory abnormalities, and denied the history of foot trauma. While pregnant with this child, the mother was G2P2 with normal term delivery and no abnormality during pregnancy and perinatal period. Parents were healthy, had consanguineous marriage; father’s grandmother and mother’s grandmother are cousins (Figure 1D). Physical examination upon admission: the child was well oriented with normal mental status, language expression & memory. Neck supple, unremarkable cardiopulmonary & abdominal examination, equal length of both lower limbs, no obvious limitation of hip and knee movement, normal muscle tension, normal muscle strength of both the upper limbs, lower limb muscle strength of grade IV. The lateral side of the left foot is slightly swollen, the dorsal extension is slightly limited, and both arches are high. Bilateral knee reflexes were not elicited, Kirschner’s sign and Brinell’s sign were negative, and bilateral Pap’s sign was also negative. Auxiliary examination: the pelvic radiograph is normal. No obvious abnormality was found in MRI of skull and spinal cord. Electromyography and nerve conduction: the amplitudes of CMAP waves in most of the examined nerves was grossly decreased or slightly decreased, bilateral tibial nerves had conduction block, the motor nerve MCV significantly slowed down (> 3SD), the shortest latency of F wave in the right median, ulnar nerve and bilateral tibial motor nerve was prolonged, and the H-reflex latency of bilateral tibial nerves was prolonged with waveform difference (Figure 2). The amplitudes of SNAP waves of sensory nerves decreased or did not elicit, with SCV slowing down. EMG: when the tested muscle was relaxed, some of the tested muscle showed positive spontaneous potential; when the muscle contracted slightly, the MUP shape of some of the tested muscle was broadened, and the oligo-set of heavy contraction of some of the tested muscles was slightly reduced. It is suggested that the comprehensive examination results of myoelectric changes of multiple peripheral neurogenic damage (motor and sensory nerve demyelination with axonal damage, lower limbs are more severe than upper limbs) suggest peripheral neuropathy.