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Charcot-Marie-Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges.

ABSTRACT: INTRODUCTION:This study analyzes and describes atypical presentations of Charcot-Marie-Tooth disease type 4C (CMT4C). METHODS:We present clinical and physiologic features of 5 patients with CMT4C caused by biallelic private mutations of SH3TC2. RESULTS:All patients manifested scoliosis, and nerve conduction study indicated results in the demyelinating range. All patients exhibited signs of motor impairment within the first years of life. We describe 2 or more different genetic diseases in the same patient, atypical presentations of CMT, and 3 new mutations in CMT4C patients. DISCUSSION:A new era of unbiased genetic testing has led to this small case series of individuals with CMT4C and highlights the recognition of different genetic diseases in CMT4C patients for accurate diagnosis, genetic risk identification, and therapeutic intervention. The phenotype of CMT4C, in addition, appears to be enriched by a number of features unusual for the broad CMT category. Muscle Nerve 57: 749-755, 2018.

SUBMITTER: Jerath NU

PROVIDER: S-EPMC5886823 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Charcot-Marie-Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges.

Jerath Nivedita U NU Mankodi Ami A Crawford Thomas O TO Grunseich Christopher C Baloui Hasna H Nnamdi-Emeratom Chioma C Schindler Alice B AB Heiman-Patterson Terry T Chrast Roman R Shy Michael E ME

Muscle & nerve 20171024 5

<h4>Introduction</h4>This study analyzes and describes atypical presentations of Charcot-Marie-Tooth disease type 4C (CMT4C).<h4>Methods</h4>We present clinical and physiologic features of 5 patients with CMT4C caused by biallelic private mutations of SH3TC2.<h4>Results</h4>All patients manifested scoliosis, and nerve conduction study indicated results in the demyelinating range. All patients exhibited signs of motor impairment within the first years of life. We describe 2 or more different gene ...[more]

PMID: 28981955

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Project description:Charcot-Marie-Tooth disease type 4C is the most common recessively inherited demyelinating neuropathy that results from loss of function mutations in the SH3TC2 gene. Sh3tc2-/- mice represent a well characterized disease model developing early onset progressive peripheral neuropathy with hypo- and demyelination, slowing of nerve conduction velocities and disturbed nodal architecture. The aim of this project was to develop a gene replacement therapy for treating Charcot-Marie-Tooth disease type 4C to rescue the phenotype of the Sh3tc2-/- mouse model. We generated a lentiviral vector LV-Mpz.SH3TC2.myc to drive expression of the human SH3TC2 cDNA under the control of the Mpz promoter specifically in myelinating Schwann cells. The vector was delivered into 3-week-old Sh3tc2-/- mice by lumbar intrathecal injection and gene expression was assessed 4-8 weeks after injection. Immunofluorescence analysis showed presence of myc-tagged human SH3TC2 in sciatic nerves and lumbar roots in the perinuclear cytoplasm of a subset of Schwann cells, in a dotted pattern co-localizing with physiologically interacting protein Rab11. Quantitative PCR analysis confirmed SH3TC2 mRNA expression in different peripheral nervous system tissues. A treatment trial was initiated in 3 weeks old randomized Sh3tc2-/- littermate mice which received either the full or mock (LV-Mpz.Egfp) vector. Behavioural analysis 8 weeks after injection showed improved motor performance in rotarod and foot grip tests in treated Sh3tc2-/- mice compared to mock vector-treated animals. Moreover, motor nerve conduction velocities were increased in treated Sh3tc2-/- mice. On a structural level, morphological analysis revealed significant improvement in g-ratios, myelin thickness, and ratios of demyelinated fibres in lumbar roots and sciatic nerves of treated Sh3tc2-/- mice. Finally, treated mice also showed improved nodal molecular architecture and reduction of blood neurofilament light levels, a clinically relevant biomarker for axonal injury/degeneration. This study provides a proof of principle for viral gene replacement therapy targeted to Schwann cells to treat Charcot-Marie-Tooth disease type 4C and potentially other similar demyelinating inherited neuropathies.

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Charcot-Marie-Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges.

Publications

Charcot-Marie-Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges.

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