Urogenital dysfunction in male patients with Charcot-Marie-Tooth: a systematic review

Abstract

Introduction

Charcot-Marie-Tooth (CMT) is the most common inherited polyneuropathy. Polyneuropathies are likely to affect the urogenital system. Urogenital dysfunction is rarely investigated and may be underestimated in CMT patients.

Aim

The aim of the present study was to perform a systematic review of the literature to collect all the available evidence on the presence of urogenital dysfunction and in patients with CMT.

Methods

Data sources were MEDLINE, Pubmed, Scopus, and Google Scholar. All types of studies describing the presence of lower urinary tract dysfunction, erectile dysfunction (ED), anejaculation, and other sexual disorders in male patients with CMT were included.

Results

Among 131 records identified, five articles were included in the qualitative synthesis. Lower urinary tract dysfunction, neurogenic bladder, ED, and other sexual dysfunctions have been reported in patients with CMT. One case of anejaculation has been described.

Conclusion

Urogenital dysfunction occurs in patients with CMT. Therefore, uro-andrologic counseling should be performed in the aging male with CMT. This might positively impact on his quality of life.

Keywords:

• Charcot-Marie-Tooth
• anejaculation
• erectile dysfunction
• sexuality

Introduction

Charcot-Marie-Tooth (CMT) is a peripheral polyneuropathy firstly described by Charcot in 1886 [1]. It is the most common inherited disorder of the peripheral nervous system, having a prevalence which range from of 1/2500 [2] to 1/1214 [3]. Different subtypes have been described (CMT1–4 and CMT X), including demyelinating (CMT 1,3,4) and axonal (CMT 2) forms [2,4–6]. More than 50 different genes have been recognized to play a role in the etiology of CMT (www.molgen.ua.ac.be/CMTMutations). Classically, demyelinating forms are characterized by decreased nerve conduction velocity (NCV) in an upper limb motor nerve (<38 m/s), axonal forms by normal or slightly reduced NCV (≥38 m/s) [7].

CMT affects motor and/or sensory nerves, clinically resulting in progressive muscle weakness and atrophy of the distal limb muscles, foot deformities, distal sensory loss, decreased, or absent tendon reflexes [8,9].

CMT severely affects the quality of life (QoL) [8]. The impairment of the autonomic nervous system (ANS) has been documented in CMT [9–12]. Polyneuropathies, particularly those impacting the ANS, can affect the urogenital system, causing lower urinary tract symptoms (LUTS), erectile dysfunction (ED) and ejaculation disorders, bringing to sexual disabilities in both sexes [13]. In CMT, sexuality is likely to be affected [14,15]. Such disturbances could heavily impact on the low QoL of these patients. Unfortunately, disorders of the urogenital system are rarely investigated and may have been underestimated in patients with CMT [14,16,17].

The aim of the present study was to perform a systematic review of the literature to gather all the available evidence regarding urogenital disorders in patients with CMT.

Methods

Sources and study selection

This study was performed using PRISMA guidelines for systematic reviews. Data were extracted by a reviewer (RC). Full-text articles were obtained with the help of a librarian. A systematic search was performed though MEDLINE, Pubmed, Scopus, and Google Scholar databases, from each database inception to 30 April 2018. Our search strategy involved the combination of the following key words: “Charcot-Marie-Tooth”, “ejaculation”, “erectile dysfunction”, “neurogenic bladder”, “fertility”, and “sex”. Additional manual searches were made using the reference lists of relevant studies to retrieve other articles important for this topic. All types of articles describing urogenital dysfunction in patients with CMT were included. Only studies in English language were considered. The authors were contacted for missing data.

Results

A total of 131 records were initially identified though database searching. Among them, nine [11,12,14,16–21] were assessed for eligibility and five were included in the qualitative analysis [11,12,17,19,21]. The flow chart of the study is shown in Figure 1. We considered only the abstract of the study by Nakamura et al. [12] since the full-text was written in Japanese. The study by Vinci et al. [14] was not included because it was a letter to the editor. Both the full-text and the abstract of the study by Crabtree [19] were not available.

Figure 1. Flowchart of the included studies.

Lower urinary tract dysfunction

A case–control study evaluated the urinary system function in 58 CMT patients (22 men and 36 women) and 54 controls (24 men and 30 women), through the International Prostate Symptoms Score (IPSS) and the Consultation on Incontinence Modular (ICIQ) questionnaires. LUTS resulted to be frequent in patients with CMT, since they had higher IPSS scores compared with that of controls. In a deeper detail, compared with sex-matched controls, men with CMT collected significantly higher scores in 3/8 IPSS and in 7/26 ICIQ items. “Frequency”, “Urgency”, “Weak stream”, “Incomplete empting”, “Urge incontinence”, “Post-micturition incontinence”, and “QoL” were the most affected variables from both questionnaires. In this study, CMT 1 A and CMT 2 were the more represented CMT types among the male subjects (Table 1) [17].

Table 1. Number of men with CMT subtypes in the study by Krhut et al. [16].

Type of CMT	Affected men (n)
CMT 1	1
CMT 1A	6
CMT 1B	1
CMT 2	7
CMT X1	3
CMT 4C	3

CMT: Charcot-Marie-Tooth; n: number.

Neurogenic bladder was described in a patient with CMT 1B [12]. The onset was in the third decade of life and required catheterization. Six members of the patient’s family had ANS disorders [12]. Accordingly, bladder dysfunction has been previously reported in CMT patients with mutation in the MPZ gene [12], and in two male members of a single Japanese family with CMT (no mutation were observed in both MPZ and PMP22 genes) [11].

Sexual function assessment

ED has been reported in seven patients with CMT. Its onset ranged from the age of 38 to 55 years (mean age of the ED onset: 45.3 years). None of them had diabetes mellitus and no other cause of ED was found. Most of them had normal or somewhat reduced libido and maintained the ability to obtain the orgasm. A decreased penile sensitivity was found in two patients [18]. Unfortunately, the genetic characterization was described only in one patient, who had a CMT 1 A, was married and had two children. In this patient, the ED arose when he was 38 years old [18]. Among the remaining patients, four had a demyelinating form (NCVs < 38 m/s), one an axonal form (NCV = 46 m/s) of CMT. In one case, the evaluation of NCVs was not performed. ED was also reported in a patient with CMT 1B, carrier of a mutation in the MPZ gene (Thr124Met). The onset was in the third decade of life [12].

Delayed ejaculation or anejaculation have been suggested to occur in patients with CMT [14]. Unfortunately, the literature lacks of studies describing ejaculatory disorders in these patients. The case of a patient with CMT 1B, anejaculation, atony of seminal vesicles, and an abnormal pudendal nerve conduction has been reported [21]. Penile sensitivity was not affected.

A case–control study investigated the sexual function in 58 CMT patients and 54 controls using the ICIQ-FLUTsex validated questionnaire [17]. It was not observed any significant difference among the questionnaire’s scores. In particular, erectile and ejaculation disorders were not registered in 22 men with CMT compared with 24 controls. However, as claimed by the authors, since a questionnaire is not the better modality to evaluate these features, such disorders may have been underestimated in this cohort. Table 2 summarizes the included studies.

Table 2. Summary of the included studies.

Author	n	Type of study	Type of CMT	Diagnostic approach	Uro-andrologic disturbances
Bird et al. [18]	7	Case series	1A (1/7) Demyelinating form (5/7) Axonal form (1/7)	Anamnesis and clinic examination, hormonal evaluation, pudendal nerve SEP, bulbocavernosus reflex study	ED (7/7) (onset: 38–55 years) Reduced penile sensitivity (2/7) The patient with CMT1A was fertile (no available information about the remaining cases) Normal ability to achieve the orgasm (7/7)
Miura et al. [10]	2	Observational study	Not known	Anamnesis and clinic examination, urodynamic studies	Neurogenic bladder (2/2) Sensory disturbance (1/2) No mention of erectile and ejaculation disorders
Nakamura et al. [11]	1	Case report	Mutation of the MPZ gene (p. Thr124Met)	Anamnesis and clinic examination, functional bladder tests, nerve conduction study	ED (onset in the third decade) Neurogenic bladder Sensory impairment in the distal parts of the bilateral lower limbs
Khrut et al. [16]	22	Case–control study	1 (1/21) 1A (6/21) 1B (1/21) 2 (7/21) 2A (1/21) X1 (3/21) 4C (3/21)	Questionnaires (IPSS and ICIQ)	LUTS No mention of erectile and ejaculation disorders
Cannarella et al. [21]	1	Case report	1B	Anamnesis and clinic examination, hormonal evaluation, pudendal nerve SEP, prostate-vesicular ultrasound, penile biothesiometry	Anejaculation Bilateral vesicular atony Decreased pudendal nerve conduction Normal penile sensitivity Normal ability to achieve the orgasm No mention of erectile disorders

CMT: Charcot-Marie-Tooth; ED: erectile dysfunction; ICIQ: Consultation on Incontinence Modular Questionnaire; IPSS: International Prostate Symptoms Score; LUTS: lower urinary tract symptoms; n: number; SEP: somatosensory evocated potentials.

Discussion

CMT is a slowly progressive hereditary degenerative disease and one of the most common neuromuscular disorders [22]. Its prevalence ranges from 1/2500 [2] and 1/1214 [3], depending on the ethnic background and the accuracy of the diagnostic methods adopted.

Disability, sensory impairment, deformities, and pain are the main symptoms which patients complain for [22].

This review provides evidence for urogenital dysfunction in CMT patients. Indeed, LUTS and neurogenic bladder have been described in both male and female CMT patients [17]. Also, ED has been reported in aging males with CMT. Based on the literature survey, its onset might be influenced by CMT type. In fact, among the CMT cohort reported by Krhut et al. [17] showing ED, 28.6% (6/21) had the type 1A and 33.3% (7/21) the type 2. Similarly, Bird et al. [18] reported that the major of patients (5/7) with ED had a demyelinating form of CMT. Therefore, these findings may suggest that demyelinating forms of CMT might differentially affect the onset of ED compared to the axonal forms. However, these data could be affected by the higher prevalence of demyelinating compared to axonal forms [23]. As for ejaculatory function, the occurrence of delayed ejaculation or anejaculation, at least in some CMT types [21], has been previously suggested in CMT patients [14]. Indeed, a delayed nerve conduction may cause ejaculatory disorders due to the control exerted by the ANS on ejaculation [24]. Despite this, such disorders have rarely been reported, probably because of lack of attention to CMT patient’s sexuality and further studies are needed to timely estimate the prevalence of anejaculation in patients with CMT and its association, if any, with CMT types.

CMT patients reach senility due to the slow progression of neurodegeneration [22]. Urogenital and sexual disorders commonly affect the aging male [25,26], due to a variety of pathogenic mechanisms. Indeed, the higher oxidative stress which older men are exposed to, metabolic imbalance, diabetes, endothelial dysfunction, benign prostate hyperplasia negatively impact on erectile function, ejaculation, and LUTS occurrence [27–30]. All these disorders potentially affect also the aging CMT patient, further worsening its sexual and urogenital function.

Therefore, the uro-andrologic counseling should be carried out in aging CMT patients, in the attempt to ameliorate their sexual and urinary disorders and their QoL. In fact, despite the lack of literature data investigating sexuality in CMT patients, this review provides evidence for the occurrence of LUTS, erectile and ejaculation disorders in men affected by this syndrome. However, many studies used questionnaires to evaluate the presence of urogenital dysfunction [16,17], resulting in contradictory data. Therefore, the presence of ED and anejaculation needs to be investigated more in depth and through more objective methods, such as penile Doppler evaluation, basal and post-orgasm prostate vesicular ultrasound examination, and penile biothesiometry. This would help to better understand the prevalence of urogenital dysfunction in men with CMT.

Conclusions

This systematic review provides evidence for the presence of LUTS, anejaculation, neurogenic bladder, and ED in CMT patients. Most of the studies on CMT have not investigated sexuality in these patients, probably due to the difficulty for both physicians and patients to discuss about it. It may also be hypothesized that such problems might not be considered of priority in patients with CMT [13,16]. However, urogenital dysfunction heavily affects the QoL. Therefore, an uro-andrologic counseling should be suggested to CMT patients, especially with aging, in the attempt to improve their QoL.

Ethical approval and consent to participate

All procedures involving human participants were in accordance with the ethical standard of institutional research committee and with Helsinki declaration. This study did not involve animal or human participants.

Disclosure statement

No potential conflict of interest was reported by the authors.