Motor neuropathy / SMN1-negative spinal muscular atrophy panel [38 genes]
Charcot-Marie-Tooth (CMT) disease, or sensorimotor neuropathy, is the most frequent hereditary neuromuscular disease, with a prevalence of 1/2,500 individuals (Suter and Sherer, 2003).
At the molecular level, CMT is a complex disorder, with at least 1,000 associated genetic variants in some 80 genes (Timmerman et al., 2014). In some wide described series, molecular alteration is identified in 60-70% of patients (80% of the demyelinating forms and 25% of the axonal forms) (Rossor et al., 2015). Approximately 90% of abnormalities are distributed in the PMP22, MPZ, GJB1, and MFN2 genes (DiVicenzo et al., 2015), although this value varies between populations, being particularly lower in regions with a high prevalence of recessive hereditary forms. Forty to fifty percent of CMT cases are demyelinating or type 1 (CMT1), of which 70-80% are caused by the duplication of a region of approximately 1,5 Mb which contains the PMP22 gene (CMT1A).
Hereditary motor neuropathy (HMN) comprises 10% of all hereditary neuropathies, with a diagnosis rate of 20-32% (Bansagi et al., 2017).
Priority Genes : Genes where there is sufficient evidence (clinical and functional) to consider them associated with the disease; they are included in the clinical practice guidelines.
Secondary Genes: Genes related to the disease, but with a lower level of evidence or that constitute sporadic cases.
* Candidate Genes: Not enough evidence in humans, but potentially associated with the disease.
- ASAH1: Spinal muscular atrophy with progressive myoclonic epilepsy
- BICD2, DYNC1H1: Spinal muscular atrophy predominantly in lower limbs
- BSCL2: Silver syndrome
- CHCHD10: Spinal muscular atrophy, Jokela type
- HEXB: GM2 gangliosidosis
- SETX: Juvenile amyotrophic lateral sclerosis
- SLC52A2, SLC52A3: Brown-Vialetto-Van Laere / Fazio-Londe syndrome
- UBA1: X-linked spinal muscular atrophy
- VAPB: Spinal muscular atrophy, Finkel type
- Bansagi B, Griffin H, Whittaker RG, Antoniadi T, Evangelista T, Miller J, Greenslade M, Forester N, Duff J, Bradshaw A, Kleinle S, Boczonadi V, Steele H, Ramesh
- V, Franko E, Pyle A, Lochmüller H, Chinnery PF, Horvath R. Genetic heterogeneity of motor neuropathies. Neurology. 2017 Mar 28;88(13):1226-1234.
- DiVincenzo C, Elzinga CD, Medeiros AC, Karbassi I, Jones JR, Evans MC, Braastad CD, Bishop CM, Jaremko M, Wang Z, Liaquat K, Hoffman CA, York MD,
- Batish SD, Lupski JR, Higgins JJ. The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. 2014 Nov;2(6):522-9.
- Rossor AM, Evans MR, Reilly MM. A practical approach to the genetic neuropathies. Pract Neurol. 2015 Jun;15(3):187-98.
- Suter U, Scherer SS. Disease mechanisms in inherited neuropathies. Nat Rev Neurosci. 2003 Sep;4(9):714-26.
- Timmerman V, Strickland AV, Züchner S. Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success. Genes (Basel). 2014 Jan 22;5(1):13-32.