Clinical characteristics.

SH3TC2-related hereditary motor and sensory neuropathy (SH3TC2-HMSN) is a demyelinating neuropathy characterized by severe spine deformities (scoliosis or kyphoscoliosis) and foot deformities (pes cavus, pes planus, or pes valgus) that typically present in the first decade of life or early adolescence. Other findings can include cranial nerve involvement (most commonly tongue involvement, facial weakness/paralysis, hearing impairment, dysarthria) and respiratory problems.

Diagnosis/testing.

The diagnosis of SH3TC2-HMSN is established in a proband with suggestive findings and biallelic pathogenic variants in SH3TC2 identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment is symptomatic. Affected individuals are often managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, physical and occupational therapists, audiologists/otolaryngologists, speech and language therapists, and pulmonologists.

Surveillance: Routine follow up of motor and sensory manifestations, foot care, spine deformities, occupational and physical therapy needs, hearing, speech, and language therapy needs, and nutrition and growth.

Agents/circumstances to avoid: Obesity, which makes walking more difficult; medications that are toxic or potentially toxic to persons with hereditary motor and sensory neuropathy.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual in order to identify as early as possible those who would benefit from early detection and treatment of scoliosis as well as awareness of agents/circumstances to avoid.

Genetic counseling.

SH3TC2-HMSN is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SH3TC2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic SH3TC2 pathogenic variants and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Because the carrier frequency for SH3TC2-HMSN in certain populations (e.g., individuals of Spanish Roma heritage) is relatively high and the onset of SH3TC2-HMSN may be late, some individuals who undergo carrier testing may be identified as being homozygous. Once the SH3TC2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for SH3TC2-HMSN are possible.

Suggestive Findings

SH3TC2-HMSN should be suspected in individuals with the following clinical manifestations, nerve conduction velocities, neuropathology, and family history [Kessali et al 1997, Gabreëls-Festen et al 1999, Azzedine et al 2006].

Clinical manifestations

• Early and severe scoliosis, the presenting sign in most individuals
• Neuropathy, usually developing in the first decade or adolescence, but occasionally manifesting as delay in onset of independent ambulation in early childhood
• Slowly progressive neuropathy, with some individuals becoming wheelchair dependent because of involvement of the proximal lower limbs

Motor nerve conduction velocities (MNCV) are in the range observed in demyelinating disease:

• MNCV of the median nerve is typically 4-37 m/sec, with a mean of 22 m/sec.
• MNCV is not correlated with disease duration.
• In some cases, electroneuromyographic examination is incomplete or does not allow measurement of MNCVs because of the severity of the secondary axonal loss.

Neuropathology. Neuropathologic findings are no longer required to raise suspicion of SH3TC2-HMSN. If nerve biospy was performed in the past, see Clinical Description, Histopathology for characteristic findings.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of SH3TC2-HMSN is established in a proband with Suggestive Findings and biallelic pathogenic (or likely pathogenic) variants in SH3TC2 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic SH3TC2 variants of uncertain significance (or identification of one known SH3TC2 pathogenic variant and one SH3TC2 variant of uncertain significance) does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) (Option 1) and comprehensive genomic testing (exome sequencing, genome sequencing) (Option 2). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not.

Clinical Description

SH3TC2-related hereditary motor and sensory neuropathy (SH3TC2-HMSN) is a demyelinating neuropathy characterized by early-onset severe scoliosis. Scoliosis as well as foot deformities were the presenting findings in most individuals with SH3TC2-HMSN. Other findings include cranial nerve involvement, respiratory involvement, and sensory ataxia (Table 2).

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified: to date, intra- and interfamilial variability is consistently observed [Azzedine et al 2006].

Nomenclature

Hereditary motor and sensory neuropathy is most commonly referred to by the eponymous name "Charcot-Marie-Tooth (CMT) neuropathy" or "Charcot-Marie-Tooth disease."

Based on an older classification system in which subtypes were defined by clinical findings, the mode of inheritance, neuropathy type (defined by electrophysiologic findings), pathologic finding (when available), and involved gene, SH3TC2-HMSN is also referred to as "Charcot-Marie-Tooth disease type 4C (CMT4C)."

For further review of nomenclature, see the Charcot-Marie-Tooth Hereditary Neuropathy Overview.

Prevalence

SH3TC2-HMSN (caused by biallelic pathogenic variants in SH3TC2) is a relatively frequent cause of the autosomal recessive demyelinating neuropathy (also known as CMT4). On the basis of cumulative data available in 2013, the prevalence of SH3TC2-HMSN among those with CMT4 was approximately 18% (53/299) [Senderek et al 2003, Azzedine et al 2006, Houlden et al 2009, Fischer et al 2012, Iguchi et al 2013].

Three more recent studies revealed the following:

• Testing for 14 genes (EGR2, FIG4, GARS, GDAP1, GJB1, HSPB1, LITAF, MFN2, MPZ, NEFL, PMP22, PRX, RAB7A, and SH3TC2) in a large cohort of 17,880 individuals with neuropathy identified SH3TC2 pathogenic variants in 0.8% [DiVincenzo et al 2014].
• Evaluation of 612 index cases with a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a panel of 80 genes associated with autosomal recessive, autosomal dominant, and X-linked neuropathy identified SH3TC2-HMSN as the cause in 9.9% of all individuals (representing the third most involved gene of the cohort) and in 29.3% of individuals with neuropathy inherited in an autosomal recessive manner [Dohrn et al 2017].
• In a cohort of 50 Greek individuals with autosomal recessive demyelinating CMT, Kontogeorgiou et al [2019] identified SH3TC2 pathogenic variants in 26%.
• Dohrn et al [2017] and Kontogeorgiou et al [2019] confirm the high prevalence of SH3TC2-HMSN among autosomal recessive demyelinating CMTs (CMT4).

SH3TC2-HMSN has been found in diverse geographic origins: Europe, Mediterranean Basin, Asia, North America; and diverse countries, including: Albania, Algeria, Austria, Belgium, Bosnia, Canada, China, Czech Republic, England, France, Germany, Greece Hungary, Iran, Italy, Japan, Morocco, Spain, Sweden, the Netherlands, Turkey, and the United States.

SH3TC2-HMSN occurs in diverse ethnic groups:

• Romani from Spain and Turkey [LeGuern et al 1996, Gabreëls-Festen et al 1999, Guilbot et al 1999, Senderek et al 2003, Azzedine et al 2005a, Azzedine et al 2005b, Azzedine et al 2006, Colomer et al 2006, Houlden et al 2009, Baets et al 2011, Fischer et al 2012]
• The SH3TC2 pathogenic variant p.Arg954Ter is recurrent in several populations, including people who originated from the Mediterranean basin, Europe, and America [Azzedine et al 2005a, Azzedine et al 2005b, Azzedine et al 2006]. This founder effect leads to an increase in the occurrence of the disease in those populations [Azzedine et al 2005a, Azzedine et al 2005b, Gosselin et al 2008].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SH3TC2-HMSN, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment is symptomatic. Affected individuals are often managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, physical and occupational therapists, audiologists/otolaryngologists, speech and language therapists, and pulmonologists (Table 6).

Surveillance

Agents/Circumstances to Avoid

Obesity is to be avoided because it makes walking more difficult.

Medications that are toxic or potentially toxic to persons with Charcot-Marie-Tooth (CMT) disease comprise a range of risks ranging from definite high risk to negligible risk [Salih & Azzedine 2020]. See www.cmtausa.org for an up-to-date list.

Anesthesia. Relatively few studies reported in the literature address risks of anesthesia in patients with CMT. No complications were observed after anesthesia in a large cohort followed in specialized consultation, but the advice of the anesthesiologist should be followed. See also CMT Overview.

• Although it had no adverse effects in 41 persons with CMT [Antognini 1992], use of succinylcholine for general anesthesia is usually contraindicated.
• Blockers of the neuromuscular junction should be used with caution.
• Local/regional anesthesia, especially epidural analgesia at childbirth, has been used without problems in CMT. This use of anesthesia should be discussed on a case-by-case basis with the anesthesiologist.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual in order to identify as early as possible those who would benefit from awareness of agents/circumstances to avoid and early detection and treatment of scoliosis.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There are no guidelines for pregnancy management in CMT of any type; the following general statements are offered as possible considerations.

CMT appears to be an independent risk factor for complications during pregnancy and delivery.

• The symptoms of CMT can worsen during pregnancy; in particular: cramps, subjective sensitivity (e.g., paresthesias), difficulty walking, and fatigue.
• In rare instances, crises occurring during pregnancy do not subside post partum.
• A retrospective study in Norway between 1967 and 2002 comparing 108 births to mothers with CMT with 2.1 million births to mothers without CMT determined that mothers with CMT more frequently needed interventions during delivery [Hoff et al 2005]. Bleeding post partum was also more common in mothers with CMT.
• It has been postulated that fetal presentation tends to be abnormal because of the combination of CMT in the mother and fetus [Rayl et al 1996, Hoff et al 2005].

Note: Because SH3TC2-HMSN is an autosomal recessive type of CMT typically associated with early onset and severe manifestations, management of pregnancy in affected females is rarely an issue; however, an affected mother with late-onset disease who gave birth before becoming symptomatic has been reported [Gooding et al 2005].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder

Mode of Inheritance

SH3TC2-related hereditary motor and sensory neuropathy (SH3TC2-HMSN) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are typically heterozygotes (i.e., carriers of one SH3TC2 pathogenic variant).
• In families in which the parents are of the same ethnic origin, where endogamy is frequent, a parent of the proband may have signs of SH3TC2-HMSN and be found to have homozygous SH3TC2 pathogenic variants.
  • The carrier frequency of SH3TC2-HMSN is relatively high in certain populations. For example, the carrier frequency in individuals of Spanish Roma heritage is approximately 4% (see Prevalence).
  • Because a parent with biallelic SH3TC2 pathogenic variants may have a late age of onset [Gooding et al 2005, Colomer et al 2006], their clinical status may not be apparent or recognized until their child is diagnosed with SH3TC2-HMSN.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SH3TC2 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent of a proband with SH3TC2-HMSN, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband.
  • One of the pathogenic variants identified in the proband was inherited from a mosaic parent [Jónsson et al 2017].
  • The proband inherited a chromosome or a particular chromosomal region from only one of the proband's parents (if the chromosome or the chromosomal region encompasses an SH3TC2 pathogenic variant, the child will be homozygous for this pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an SH3TC2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic SH3TC2 pathogenic variants and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Intrafamilial clinical variability may be observed in sibs who inherit biallelic SH3TC2 pathogenic variants [Azzedine et al 2006].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing SH3TC2-HMSN.

Offspring of a proband. Unless an affected individual's reproductive partner also has SH3TC2-HMSN or is a carrier (e.g., in a consanguineous union and/or in a union between two individuals of the same ethnic origin), offspring will be obligate heterozygotes (carriers) for a pathogenic variant in SH3TC2 (see Prevalence).

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SH3TC2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SH3TC2 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the SH3TC2 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for SH3TC2-HMSN are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The SH3TC2 protein has been reported to contain Src homology-3 (SH3) domains and tetratricopeptide repeat (TPR) domains (see Roberts et al [2010] for more information about possible pathogenic mechanisms). The spectrum of possible functions mediated by the TPR and SH3 domains is large.

• SH3 domains are highly conserved in eukaryotes, prokaryotes, and viruses, and mediate interactions with enzymes (tyrosine kinases, phospholipases cγ [PLCγ], and PLCγ, phosphoinositide 3-kinase, and the NADPH-oxidase complex), cytoskeleton molecules (spectrin and nebulin), and myosins. They play important roles in cell-to-cell communication and signal transduction from the cell surface to the nucleus [Whisstock & Lesk 1999].
• Proteins with TPR domains are involved in many cellular processes through protein-protein interactions: in mitosis and RNA synthesis by their association in multi-protein complexes controlling cell-cycle or transcription machinery, in protein transport, and in chaperone functions [Blatch & Lassle 1999].

Mechanism of disease causation. Most pathogenic variants in SH3TC2 lead to loss or truncation of the protein, compatible with loss of function in an autosomal recessive disorder.

Author Notes

For more than two decades, our work has been mainly devoted to peripheral neuropathies and related disorders, especially the autosomal recessive forms. We intended to identify the genetic basis of these disorders, to establish genotype-phenotype correlations, if any, and to better characterize each clinical phenotype. We are also interested in the pathophysiology underlying the different phenotypes encountered in this highly variable genetic disorder. This work leads to a better knowledge of the disease and paves the way for therapeutic research.

Contact: Dr Hamid Azzedine
Email: rf.oohay@dimah.enidezza

Acknowledgments

This work was supported by the Association Française contre les Myopathies (AFM).

Author History

Hamid Azzedine, PhD (2008-present)
Luc Bontoux, MD; Centre Hospitalier Universitaire d'Angers (2008-2015)
Eric LeGuern, MD, PhD; La Pitié-Salpêtrière Hospital (2008-2021)
Mustafa A Salih, MD, Dr Med Sci, FRCPCH, FAAN (2015-present)

Revision History

• 11 March 2021 (bp) Comprehensive update posted live
• 15 October 2015 (me) Comprehensive update posted live
• 6 July 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
• 31 March 2008 (me) Review posted live
• 10 February 2006 (ha) Original submission

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