Two Cases of Charcot-Marie-Tooth Disease Diagnosed in a 53-Year-Old Mother and a 24-Year-Old Daughter

Abstract

Case series

Patients: Female, 24-year-old • Female, 53-year-old

Final Diagnosis: CMT1E

Symptoms: Peroneal muscular atrophy and others

Clinical Procedure: —

Specialty: Neurology

Objective: Rare disease

Background

Charcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy, affecting an estimated 17.7–40 per 100 000 population. CMT exhibits diverse clinical manifestations, including gradually progressive bilateral atrophy, weakness of the lower-extremity muscles, sensory abnormalities, and abnormal nerve conduction velocities or amplitudes. It is important to note that other complications tend to occur during the progression of CMT disease. This report describes the late diagnosis of CMT in a 53-year-old mother and her 24-year-old daughter to highlight the risk of CMT patients complicated with respiratory and digestive diseases.

Case Reports

In this report, we describe the late diagnosis of CMT1E in 2 patients who carried the same missense point mutation in the peripheral myelin protein 22 gene {PMP22; [c.117G>C; p.(Trp39Cys)]}. Case 1 (daughter), in addition to CMT1E, was also diagnosed with respiratory disorders, hiatal hernia, gastroesophageal reflux disease (GERD), and chronic atrophic gastritis. Similarly, Case 2 (mother), who was diagnosed with CMT1E, also had a hiatal hernia, GERD, and chronic atrophic gastritis. Our report emphasized a potential association between CMT and digestive diseases and provides new insights into the prognosis of CMT.

Conclusions

This report presents 2 cases of respiratory dysfunction and multiple digestive diseases in a 53-year-old mother and her 24-year-old daughter, with the late diagnosis of CMT. These findings emphasize the importance of comprehensive patient care and provide a reference for future research into multidisciplinary approaches to the diagnosis and treatment of CMT.

Introduction

Charcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy, affecting an estimated 17.7–40 per 100 000 population [1,2]. This disease’s classification is complex and currently relies primarily on electrophysiological examinations, including electromyography and nerve conduction velocity (NCV), along with genetic testing [3–5]. CMT is characterized by gradually progressive bilateral atrophy, weakness of the lower-extremity muscles, sensory abnormalities, and abnormal nerve conduction velocities or amplitudes [6]. Point mutations in PMP22 are rare, accounting for less than 5% of CMT1 cases, and have a wide range of clinical phenotypes, presenting as dysmyelinating neuropathy, mechanical pressure-sensitive neuropathy, and the mild-to-severe CMT1E subtype [7,8]. Although studies have observed other complications in patients with CMT, such as respiratory disorders [9,10], there has been limited exploration of the potential links between CMT and digestive system diseases.

Diaphragmatic atrophy and weakness associated with respiratory dysfunction are significant factors contributing to the development of hiatal hernia, which can further promote the onset and progression of gastroesophageal reflux disease (GERD) [11]. Furthermore, researchers have noted that patients with autosomal dominant hereditary sensory neuropathy, a disease very similar to CMT, often have GERD [12], and the development of GERD has been suspected to be associated with genetic factors [13]. These findings suggest that CMT patients are at risk of developing digestive system complications, yet related evidence has rarely been reported [14].

To raise awareness of respiratory and digestive system disorder risks in CMT patients, this report presents the late diagnosis of CMT in a 53-year-old mother and her 24-year-old daughter. We hope these cases will raise awareness of the risk of other system disorders in CMT patients and promote future multidisciplinary research into the diagnosis and treatment of CMT, thereby contributing to comprehensive patient care.

Case Reports

Case 1

The proband was a 24-year-old woman, born to a non-consanguineous Chinese couple. The results of the next-generation sequencing panel for peripheral neuropathies and hereditary spastic paraplegia (Beijing Kangso Medical Inspection, China) revealed a missense point mutation in peripheral myelin protein 22 gene {PMP22; [c.117G>C; p.(Trp39Cys)]} (Figure 1), which was inherited from her mother (Figure 1). This variant has been previously reported as CMT1E. The results of genetic testing also revealed a heterozygote for a point mutation in the SH3 domain and tetratricopeptide repeats 2 gene {SH3TC2; [c.830C>T; p.(Thr277Met)]}, which was inherited from her father (Figure 1). Specific sequencing peak profiles are presented in Figures 2 and 3. It is important to note that the patient’s father did not have any neurological diseases.

Figure 1.

Family tree for the proband. ‘Square’ – male; ‘circle’ – female; ‘open symbol’ – unaffected carriers; ‘filled symbol’ – affected individual; ‘WT’ – wild-type allele; ‘+/−’ – heterozygous; ‘bold text’ – carrying mutation; PMP22 – peripheral myelin protein 22 gene; SH3TC2 – SH3 domain and tetratricopeptide repeats 2 gene.

Figure 2.

Identification of the peripheral myelin protein 22 gene (PMP22) mutation. (A, B) Direct sequencing analysis revealed a G-to-C transversion in Case 1 and her mother (Case 2), which alters the amino acid sequence from tryptophan (Trp) to cysteine (Cys) at codon 39 [c.117G>C; p.(Trp39Cys)]. (C) The c.117G>C mutation in PMP22 was not detected in the patient’s father.

Figure 3.

Identification of the SH3 domain and tetratricopeptide repeats 2 gene (SH3TC2) mutation. (A, C) Direct sequencing analysis revealed a C-to-T transversion in Case 1 and her father, which alters the amino acid sequence from threonine (Thr) to methionine (Met) at codon 277 [c.830C>T; p.(Thr277Met)]. (B) The c.830C>T mutation in SH3TC2 was not detected in the patient’s mother (Case 2).

She had poorer exercise capacity than her peers since childhood. Muscle atrophy of the distal extremities, bilateral talipes equinovarus, severe flexion contractures of both hands, and mild scoliosis became evident as she grew up (Figure 4). The neurosonographic findings revealed mild compression of the bilateral median nerves and localized thickening of the bilateral posterior tibial nerves (Table 1). In the electrophysiological study, severe impairment of nerve conduction was confirmed, as evidenced by the inability to measure motor and sensory NCV of the bilateral median, ulnar, and radial nerves, as well as motor NCV of the bilateral tibial and peroneal nerves, and sensory NCV of the bilateral sural and superficial peroneal nerves. Additionally, the distal latency and amplitudes of compound action potentials of the above-tested nerves could not be elicited. Improvements in talipes equinovarus occurred after the proband undergoing osteotomy of bilateral talipes equinovarus, anterior tibial muscle transfer, and surgical fixation with cast immobilization (The 359^th Hospital of Chinese People’s Liberation Army, Jiangsu Province, China). Images comparing foot deformity and postoperative results are shown in Figure 5.

Figure 4.

Dysmorphia in hands, feet, and spine. (A) Severe flexion contractures of both hands and bilateral talipes equinovarus, and mild scoliosis of the proband with Charcot-Marie-Tooth disease type 1E (CMT1E). (B) Flexion contractures of both hands of the proband’s mother with CMT1E.

Table 1.

Cross-sectional area (mm²) of nerves in Case 1 (24 years, female).

Nerve	Left	Right
Median nerve	8.50	11.21
Fibular nerve	18.29	16.00
Tibial nerve	37.80	44.10

Figure 5.

Comparison images of feet before and after corrective surgery. (A) Bilateral talipes equinovarus of Case 1 with Charcot-Marie-Tooth disease type 1E (CMT1E). (B) Improvements in foot deformity after corrective surgery.

The proband has been experiencing dyspnea and daytime sleepiness for a long time and had been having nocturnal awakening and cough since she was 22 years old. A diaphragm ultrasound examination revealed impaired diaphragm function, characterized by reduced diaphragmatic mobility (China-Japan Friendship Hospital, Beijing, China). The pulmonary function test results demonstrated a restrictive ventilatory impairment, characterized by a decreased actual forced expiratory volume in 1 s. Furthermore, the polysomnography report showed that she had severe obstructive sleep apnea. Previously, she had anemia, nausea, melena, and indigestion. Given that the proband presented with these digestive symptoms, and her conditions of scoliosis and diaphragmatic dysfunction could play important roles in promoting the development and progression of digestive complications, she underwent further gastrointestinal examinations at The First Affiliated Hospital of Kunming Medical University (Yunnan Province, China). The upper-gastrointestinal contrast radiography showed that the esophagus was shortened, and the cardia had moved above the diaphragm. A pouch-like protrusion was observed on the left side of the lower end of the esophagus, and barium reflux occurred in the middle and lower segments of the esophagus. Additionally, her gastric fundus had herniated into the chest (Figure 6). Based on these findings, the presence of a mixed hiatal hernia with GERD was confirmed.

Figure 6.

Hiatal hernia and scoliosis. The upper-gastrointestinal contrast radiography demonstrates marked curvature of the spine and hiatal hernia of the proband with Charcot-Marie-Tooth disease type 1E (CMT1E).

Case 2

The proband’s mother was found to have a missense mutation in PMP22 (Figures 1, 2) when she was 48-years-old. At the age of 2 years, she had abnormal gait, talipes equinovarus, and distal weakness. She underwent corrective surgery for foot and ankle deformities when she was 6 and 14 years old, respectively. Unfortunately, progressive worsening of bilateral hand paresthesia and weakness, and muscle atrophy in both hands and contracture deformities in the fingers became evident as she grew up. Nerve conduction studies confirmed the inability to measure the motor and sensory nerve conduction velocity of both upper-and lower-limb nerves (Table 2).

Table 2.

Neurophysiological findings in Case 2 (53 years, female).

Nerve	DL (ms)	Amp (M, mV; S, μV)	NCV (m/s)
L & R median (M)	NR	NR	NR
L & R median (S)	NR	NR	NR
L & R peroneal (M)	NR	NR	NR
L & R radial (M)	NR	NR	NR
L & R radial (S)	NR	NR	NR
L & R superficial peroneal (S)	NR	NR	NR
L & R sural (S)	NR	NR	NR
L & R tibial (M)	NR	NR	NR
L & R ulnar (M)	NR	NR	NR
L & R ulnar (S)	NR	NR	NR

Amp – amplitudes of compound motor (M) action potentials or sensory (S) nerve action potentials; DL – distal latency; L – left; NCV – nerve conduction velocity; NR – no response; R – right.

It is noteworthy that, like her daughter, the proband’s mother also presented with restrictive ventilatory dysfunction and multiple gastrointestinal disorders, including hiatal hernia with GERD and chronic atrophic gastritis. Although there were no diaphragm function results available for the proband’s mother, we speculated that the respiratory dysfunction and gastrointestinal disorders observed in both the mother and daughter were closely associated with CMT-related diaphragm dysfunction.

Discussion

This report describes the late diagnosis of CMT in a 53-year-old mother and her 24-year-old daughter, complicated with respiratory and digestive diseases, highlighting the risk of CMT patients, expanding the clinical phenotypic spectrum of CMT, and emphasizing the importance of comprehensive patient care. CMT is one of the most common inherited disorders that affects the peripheral nervous system. It is a highly heterogeneous condition, meaning that there are many different subtypes of CMT with varying clinical presentations and genetic causes. CMT1E is a rare subtype of CMT1 (1–5% of all CMT1 cases) that is caused by various point mutations in PMP22, causing similar or different clinical manifestations in CMT patients [7]. Although CMT is generally considered a single-gene disorder, some studies have reported that in some CMT subtypes caused by concomitant variants, the pathogenetic interaction of the concomitant mutations can have a double effect of causing milder or more severe phenotypic features [15]. Although no phenotype associated with the point mutation in SH3TC2 was observed in the proband and her father, further research is necessary to clarify the impact of each variant on disease severity.

Our 2 consanguineous CMT1E patients exhibited respiratory symptoms similar to those observed in previous reports in CMT patients [10]. Interestingly, diaphragmatic dysfunction can also be a contributing factor for digestive diseases. Atrophy and weakness of the diaphragm can allow organs of the abdominal cavity, most commonly the stomach, to herniate through the esophageal hiatus of the diaphragm and into the mediastinum, causing hiatal hernia [16]. In patients with scoliosis, greater intra-peritoneal pressure than intra-thoracic pressure due to a reduced intra-abdominal volume, and progressive laxity of the diaphragmatic hiatal sling musculature, can lead to hiatal hernia [17]. Patients with hiatal hernia often also have GERD due to the presence of the hiatal sphincter and impaired esophageal emptying [11]. Hence, CMT patients are at risk of experiencing digestive complications. However, to our knowledge, only a few studies have reported digestive system disorders in CMT patients [14].

Both of our CMT patients had hiatal hernia with GERD. Most mutations in CMT1E result in a de-/dysmyelinating electrophysiological pattern, which is associated with Schwann cell dysfunction. In addition to their role in the peripheral nervous system, Schwann cells are also the glial cells of the extrinsic innervation of the digestive system and are involved in the physiology and disorders of the digestive system [18]. Cases of digestive system disorders in patients with dysmyelinating neuropathies have been reported. In a previous report [19], all 7 patients with severe congenital hypomyelinating neuropathy were found to have severe GERD, and most of them required a gastrostomy. These facts and our report suggest that developing phrenic nerve paralysis and/or diaphragmatic dysfunction may be involved in the neuropathy of some forms of CMT, and except for respiratory system disorders, digestive complications might be more frequent than expected in CMT patients.

The present report has several limitations: (1) the small sample size (only 2 CMT1E cases) limits the generalizability of our findings to broader patient populations; (2) some information was based on patient recall, which may have caused recall bias; and (3) our conclusions were drawn solely from clinical observations and lacked supporting evidence from in vivo or in vitro functional studies. Therefore, future research should include larger-cohort studies encompassing CMT patients of both sexes and diverse geographic origins, ages, and genotypes to provide more robust and generalizable evidence regarding the CMT–digestive complication link. Additionally, experimental studies are needed to investigate the underlying mechanisms of these associations.

Conclusions

We report the presence of respiratory dysfunction and multiple digestive system complications in a daughter–mother pair of patients with CMT who carried an abnormal PMP22. In addition to respiratory system diseases, it is also important to be aware of the risk of developing and progressively worsening hiatal hernia and GERD in CMT patients with diaphragm dysfunction and/or scoliosis. When these symptoms are observed in CMT patients, a thorough examination of the digestive system should be performed, including an assessment of diaphragm function, to prevent the development and progression of hiatal hernia and GERD. Our cases emphasize the importance of comprehensive patient care and provide a reference for future research into multidisciplinary approaches to the diagnosis and treatment of CMT. However, this study is limited by including only 2 CMT1E patients. To provide more evidence, enhance the generalizability of results, and develop personalized treatment approaches, future studies involving patients with different regions, sexes, ages, and genotypes are urgently needed to further clarify the association between CMT and digestive complications and their underlying mechanisms.