A TRPV4 mutation caused Charcot-Marie-Tooth disease type 2C with scapuloperoneal muscular atrophy overlap syndrome and scapuloperoneal spinal muscular atrophy in one family: a case report and literature review

doi:10.21203/rs.3.rs-2485021/v1

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Case Report

A TRPV4 mutation caused Charcot-Marie-Tooth disease type 2C with scapuloperoneal muscular atrophy overlap syndrome and scapuloperoneal spinal muscular atrophy in one family: a case report and literature review

https://doi.org/10.21203/rs.3.rs-2485021/v1

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published 30 Jun, 2023

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Background

Charcot-Marie-Tooth disease 2C (CMT2C) and scapuloperoneal spinal muscular atrophy (SPSMA) are different clinical phenotypes of TRPV4 gene mutation. The mutation of p.Arg316Cys has been previously found to cause CMT2C and SPSMA separately.

Case presentation

Here, we reported a Chinese family harboring the same p.Arg316Cys variant but with overlap syndrome and different clinical manifestations. A 58-year-old man presented with severe scapula muscle atrophy as hanger-like shoulders. Distinct muscle atrophy also presented in his four limbs especially in the lower limbs. Sural nerve biopsy of the father indicated severe loss of myelinated nerve fibers with scattered regenerating clusters and pseudo-onion bulbs. Nerve conduction study indicated axon damage in both motor and sensory nerves. Sensory nerve action potentials could not be evocated in bilateral sural or superficial peroneal nerves. He was diagnosed with Charcot-Marie-Tooth disease type 2C and scapuloperoneal muscular atrophy overlap syndrome. While his 27-year-old son was born with club foot and clinodactyly. Electromyogram examination indicated chronic neurogenic changes and anterior horn cells involvement. He complained of no obvious weakness or sensory symptoms currently. Early SPSMA could be considered for him.

Conclusion

A literature review of the clinical characteristics in CMT2C and SPSMA patients with TRPV4 gene mutation suggested that our case was distinct for his overlap syndrome. Altogether, this case broadened the phenotype spectrum and supplied the nerve biopsy pathological characters of TRPV4 gene mutation related neuropathy.

CMT2C

p. Arg316Cys mutation

SPSMA

Sural nerve biopsy

TRPV4

Transient receptor potential vanilloid type 4 (TRPV4) is a nonselective Ca²⁺ permeable cation channel and is mainly involved in the regulation of systemic osmotic pressure. The TRPV4 protein is composed of six transmembrane domains, a characteristic N-terminal ankyrin repeat domain (ARD) and C-terminal intracellular tails[1]. Transmembrane domains 5, 6 and the interconnecting loop form the central cation conductivity pore. Four subunits assemble to form the functional cation channel[2]. The TRPV4 gene is located on 12q24.11. The mutations in this gene have been identified in skeletal dysplasia, arthropathy and neuromuscular disorders. Different sites of mutation from the N- to C-terminus can lead to diverse clinical manifestations[3]. It is particularly associated with a broad spectrum of neuropathies like scapuloperoneal spinal muscular atrophy (SPSMA), congenital distal spinal muscular atrophy (CDSMA), distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease type 2C (CMT2C)[4–8]. Clinically, the phenotypes of neuropathy could vary in a single family with same gene mutation. These different phenotypes sometimes may occasionally overlap in one person[9]. Herein, we reported a family harboring the TRPV4 R316C mutation manifesting a distinct clinical phenotype between the father and his son. The father had CMT2C and scapuloperoneal muscular atrophy overlap syndrome, while his son had SPSMA. Furthermore, we performed a literature review on the clinical characteristic of CMT2C and SPSMA.

Patient 1

This patient was a 58-year-old male, born to non-consanguineous parents after an uneventful pregnancy and delivery. He presented with difficulty in playing sports since childhood but with normal developmental milestones of motion. At the age of 48, he began to experience weakness in his four limbs without any obvious cause and had difficulty holding objects and walking upstairs. Starting from the age of 55, he went through numbness in both hands and feet accompanied by the feeling of wearing gloves and socks. The muscle weakness of limbs was progressively aggravated with atrophy. He had to walk with external help and made a significant effort in holding chopsticks and writing. He has been diagnosed with diabetes for more than twenty years.

The neurologic exam found severe scapula muscle atrophy as hanger-like shoulders (Fig. 1A). Distinct muscle atrophy was also present in the thenar (Fig. 1B) and the lower limbs (Fig. 1C). Muscle strength was bilateral 4/5 in elbow extension, 2/5 in finger extension, 2/5 in hip extension and 0/5 in ankle dorsiflexion. Deep tendon reflexes were absent in both the upper and lower extremities without Babinski sign. Pinprick and vibration sensation were absent in the feet and moderately reduced in the hands. The pyramidal sign was negative.

Laboratory testing showed that his creatine kinase was 56U/L, within normal range. His glucose level was slightly elevated at 7.1 mmol/L and his glycated hemoglobin was 7.1% (normal below 5.7%). Echocardiography manifested a thick interventricular septum with a normal contraction function. Magnetic resonance imaging (MRI) indicated mild atrophy of bilateral thigh muscles. Quadriceps and biceps femoris muscles were involved, while the semitendinosus muscle was partially spared (Fig. 1D). The calf muscle was also atrophic with fat infiltration (Fig. 1E). Electrophysiology presented that the amplitudes of compound muscle action potentials (CMAPs) were reduced in ulnar nerves and were absent in bilateral peroneal nerves. Sensory nerve action potentials (SNAPs) were not evocated in right median, ulnar, sural or superficial peroneal nerves. Electromyogram (EMG) showed fibrillation and positive sharp waves in partial muscles. Increased duration and large amplitude of motor unit potentials (MUPs) were found in bilateral calf muscles.

Sural nerve biopsy was performed in this patient. The semi-thin section showed a severe reduction in the density of myelinated fibers. The scattered pseudo-onion bulbs formed by regenerating clusters were visible, which were probably a reflection of axonal regeneration. Immunohistochemical staining was negative. Ultrastructural examination represented denervated Schwann cell bands, scattered myelinated axons, and numerous unmyelinated fibers regeneration. There were collections of concentric Schwann cell processes which enclosed unmyelinated axons. More or less Schwann cells sprouted within the fields (Fig. 2)

Genetic analysis indicated that this patient had a hemizygous c.946C > T mutation in the TRPV4 gene, leading to amino acid substitutions of arginine to leucine (p.R316C). This mutation was absent in his wife but was heterozygous in his son (Fig. 3A).

Patient 2

This 27-year-old patient was the son of the patient 1. He was born with club foot and received corrective surgery at the age of seven. Clinodactyly could be found on the left foot. He complained of thigh muscles twitching after exertions. Currently, the weakness is not apparent. He denied any sensory symptoms. In nerve conduction study, The CMAPs of right common fibular nerve were not evocated, while the sensory nerves were normal. EMG examination indicated chronic neurogenic changes. Muscles of limbs and trapezius muscle were affected with increased duration and large amplitude MUPs. The anterior horn cells involvement can be considered.

Herein, we reported a Chinese family with different phenotypes of neuropathy caused by a TRPV4 R316C mutation. Patient 1 was diagnosed with CMT2C and scapulopeoneal muscular atrophy overlap syndrome. It was remarkable that the clinical phenotype of patient 1 differed from his son (Patient 2). This 27-year-old son presented no obvious weakness but show chronic neurogenic damage in EMG, and can be considered for early SPSMA currently. However, his clinical phenotype may change over time as the weakness of his father started in his forties.

Our case indicated the dynamic and complicated phenotypes of TRPV4-related neuropathy in one family. The phenotypic spectrum of TRPV4-related neuropathy was identified from ventral horn to peripheral nerves, in terms of affected sites (Fig. 3E), CDSMA (congenital and sometimes accompanied by arthrogryposis), SPSMA (scapulopeoneal muscular atrophy), CMT2C (muscle weakness and sensory involvement) and dHMN (length-dependent condition and no sensory involvement) separately. Furthermore, a literature review of the clinical characteristics of CMT2C patients[3, 4, 7, 10–17] (Table 1) and SPSMA [3, 9, 13, 18–21] were performed (Table e-1). In the summary table, we showed that CMT2C might also have other manifestations in addition to nervous system involvement, such as vocal cord paralysis (37/48, 77%), hearing loss (12/42, 29%), and scoliosis (10/37, 27%). The distal and lower limbs are more likely to be affected than the proximal and upper limbs by axon damage. Besides, the skeletal dysplasia leading short stature was only caused by the mutations on the transmembrane region(S542Y and V620I)[3, 16]. As for SPSMA patients, scapuloperoneal weakness manifesting hanger-like shoulders and calf muscle atrophy should be noted. Scoliosis and vocal cord paralysis may also be observed. Consistent with patient 2, the club foot was also identified in some SPSMA patients.

Table 1

Clinical characteristics of CMT2C patients and a review of the literature
Case number	1	2	3	4	5	6	7	8	9		10
Study	Deng et al.	Sullivan et al.	Evangelista et al.	Echaniz-Laguna et al.	Klein et al.	Landoure et al.	Auer-Grumbach et al.	Landoure et al.	Chen et al.		Zimoń et al.
Referrence	[10]	[12]	[13]	[4]	[11]	[14]	[7]	[14]	[16]		[3]
Year	2020	2015	2015	2014	2011	2012	2010	2010	2010		2010
Number(male)	2(2)	4(2)	1(0)	1	4(2)	3(1)	9	17(6)	3(1)	6(2)	1
Mean age at onset	Childhood	33	40	Childhood	39	5	15	16	26/1^†	7^†	6
Family history	Incomplete penetrance	AD	de novo	de novo	AD/ de novo	AD	AD	AD	AD	AD	de novo
Mutation site	R316C /269C	R237G /R237L	D62N	R232S	R232C /R316H	R186Q	R316C /R315W	R269C /R269H	R315W	S542Y	V620I
Sensory involvement	2/2	4/4	1/1	1/1	4/4	3/3	5/9	16/17	3/3	2/6	0/1
Proxiaml UL weakness	0/2	2/4	1/1	0/1	0/4	0/3	6/7	8/17	0/3	0/6	0/1
Proxiaml LL weakness	0/2	1/4	1/1	0/1	0/4	1/3	NA	8/17	2/3	0/6	0/1
Distal UL weakness	1/2	3/4	1/1	1/1	2/4	3/3	8/9	17/17	3/3	4/6	0/1
Distal LL weakness	2/2	4/4	1/1	1/1	2/4	3/3	9/9	17/17	3/3	4/6	1/1
Areflex	2/2	2/4	0/1	NA	4/4	3/3	9/9	NA	3/3	6/6	NA
Scoliosis	0/2	0/4	0/1	1/1	0/4	2/3	4/7	2/5	0/3	0/6	1/1
Vocal cord paralysis	1/2	2/4	0/1	1/1	2/4	3/3	7/9	15/15	2/3	4/6	0/1
Hearing loss	1/2	0/4	0/1	0/1	0/4	1/3	NA	10/17	0/3	0/6	0/1
Pes cavus	2/2	NA	0/1	1/1	1/4	NA	NA	3/7	NA	1/6	NA
Other features	Pes cavus			Tremor	Shortness of breath		Respiratory failure	Bladder incontinence	Congenital III CN palsy	Short stature/ Dolichocephaly	Short stature
AD, autosomal dominant; NA, not available; CN, central nervous
† the onset age of Hoarse voice/wheezing

The clinical phenotypes are typically variable and have overlapping features between syndromes. For example, scapulopeoneal muscular atrophy, a typical manifestation of SPSMA can also occur in CMT2C patients. A clinical diagnosis can also evolve into another over time. It is possible that dHMN may shift to CMT2C later with sensory nerves involvement[16]. More attention should be paid to this clinical feature along with time-dependent changes.

As for the crystal structure model of the human TRPV4 protein, we marked the mutations related to CMT2C and SPSMA with colors (Fig. 3B). These arginine sites were located on the convex face of the domain. All neuropathy-related arginine mutations were in ARD region, located in the connecting finger loop between inner and outer helices of the ankyrin repeats (Fig. 3C). They mainly involved D62 in the N-terminal cytoplasmic domain and R186, R232, R237, R269, R315, and R316 in ARD as well as S542 and V620 in the transmembrane domains where skeletal dysplasia was more commonly seen. Neuropathy was more commonly seen with mutations in the ARD region which was normally responsible for protein-protein interactions[22] (Fig. 3D). The gain-of-function mutations of R232C, R269H, and R316H have been noted with increased basal and maximum Ca²⁺ channel activities compared to wild-type TRPV4[11]. It was remarkable that disease-associated TRPV4 mutations, which caused a gain-of-function phenotype, abolished PI(4,5)P2 binding to TRPV4 ARD. This binding sensitivity could negatively regulate the channel activity[23]. Increased channel activity and subsequent Ca²⁺ overload resulted in impaired axonal mitochondrial transport and axonal degeneration[24]. Recent studies demonstrated that neuropathy mutations but not skeletal dysplasia mutations disrupted TRPV4-RhoA binding and cytoskeletal outgrowth[25]. The CMT2C patients with transmembrane region mutation S542Y showed short stature because of mild metaphyseal dysplasia. The other transmembrane site V620I exhibited a brachyolmia phenotype with scoliosis and short stature. These facts indicated that the transmembrane region mutation was more associated with skeletal dysplasia (Fig. 3D). In addition, the R316C mutation was the most commonly change and was observed in dHMN[4], SPSMA[4, 7, 18] and CMT2C[7, 10, 11] patients. Only two patients with R316H mutation have been reported so far, manifesting CMT2C and dHMN, respectively. The phenotypic variability of the R316 mutation was well documented in the literature. However, only few reports explained the pathology of nerve biopsy in TRPV4-related neuropathy. Our case further supplied the pathological characters.

In conclusion, TRPV4-related neuropathy spectrum showed considerable phenotypic heterogeneity. Recognizing such striking phenotypic variation is crucial to defining the proper clinical diagnosis. Mutations detected in the TRPV4 ARD region and matched neuropathy features may aid in earlier diagnosis. Extra-nerve manifestations of vocal cord paralysis, scoliosis, and hearing loss should be highlighted, too. More studies are still needed to elucidate the pathogenic mechanism of TRPV4-related neuropathy. From this, appropriate therapies can be anticipated.

CMT2C Charcot-Marie-Tooth disease 2C

SPSMA scapuloperoneal spinal muscular atrophy

TRPV4 transient receptor potential vanilloid type 4

CMAPs compound muscle action potentials

SNAPs sensory nerve action potentials

EMG electromyogram

MUPs motor unit potentials

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent for publication has been obtained from the study participant. Under the obtained consent, it is allowed to Share (copy and redistribute the material in any medium or format) and Adapt (remix, transform, and build upon the material for any purpose, even commercially) any information and details provided in this publication.

Availability of data and materials

There are no associated datasets for this manuscript. All data generated or analyzed during this study are included in this published article. Related queries can be directed to the corresponding author.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported by Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01) and ZJLab.

Authors’ contributions

All authors have read and approved the manuscript. HFC: Collecting the clinical data and writing the original draft. CS, YSZ, JXY: Collecting the clinical data. CS, MSG: Collecting the pathological data. CBZ: Conceptualization. JL: Conceptualization, Reviewing and Editing.

Acknowledgements

We would like to extend our appreciation to the patient and his son for their cooperation.

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A TRPV4 mutation caused Charcot-Marie-Tooth disease type 2C with scapuloperoneal muscular atrophy overlap syndrome and scapuloperoneal spinal muscular atrophy in one family: a case report and literature review

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