Clinical and genetic characteristics of Charcot–Marie–Tooth disease type 4D (type Lom) in Russia

Introduction. Charcot–Marie–Tooth disease type 4D is a hereditary demyelinating neuropathy, that occurs with the high frequency in patients of Roma origin. It is characterized by early onset at the age of 2–10 years and hearing impairment, manifested by the 3rd decade of life.

Aim of the study. To describe the clinical and genetic characteristics of Charcot–Marie–Tooth disease type 4D in Russian patients of Roma origin.

Materials and methods. For 14 probands from unrelated families of Roma origin with a clinical diagnosis of Charcot–Marie–Tooth disease, genetic tests for the pathogenic variants c. 442C>T in the NDRG1 gene and c. 3325C>T in the SH3TC2 gene was carried out. For 8 patients with Charcot–Marie–Tooth disease type 4D, detailed clinical and electrophysiological examination was performed.

Results. In 11 families of Roma origin, the c. 442C>T pathogenic variant in the NDRG1 gene in a homozygous state was detected, which accounted for 79 % all observed Roma patients with Charcot–Marie–Tooth disease. There are 12 of the 14 tested families live in the European part of Russia, 7 of them are from nearby regions. The average age of onset was 3.3 years. The first symptom in 7 of 8 patients was gait disturbances. At the time of examination (age range 6–19 years), all patients showed marked hypotrophy and weakness of the feet, lower leg, hands muscles, feet deformities, reduction or loss of tendon reflexes.

Discussion. Due to the detection of only one pathogenic variant in most Russian patients of Roma origin with Charcot–Marie–Tooth disease, the knowledge of the ethnicity of a proband with early myelinopathy can significantly simplify the confirmation of the diagnosis on the molecular level.

1. Barreto L.C., Oliveira F.S., Nunes P.S. et al. Epidemiologic study of Charcot–Marie– Tooth disease: a systematic review. Neuroepidemiology 2016;46(3):157–65. DOI: 10.1159/000443706. PMID: 26849231.

2. Sevilla T., Martínez-Rubio D., Márquez C. et al. Genetics of the Charcot-MarieTooth disease in the Spanish Gypsy population: the hereditary motor and sensory neuropathy-Russe in depth. Clin Genet 2013;83(6):565–70. DOI: 10.1111/cge.12015. PMID: 22978647.

3. Šafka Brožková D., Haberlová J., Mazanec R. et al. HSMNR belongs to the most frequent types of hereditary neuropathy in the Czech Republic and is twice more frequent than HMSNL. Clin Genet 2016;90(2):161–5. DOI: 10.1111/cge.12745. PMID: 26822750.

4. Kalaydjieva L., Gresham D., Gooding R. et al. N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. Am J Hum Genet 2000;67(1):47–58. DOI: 10.1086/302978. PMID: 10831399.

5. Claramunt R., Sevilla T., Lupo V. et al. The p.R1109X mutation in SH3TC2 gene is predominant in Spanish Gypsies with Charcot-Marie-Tooth disease type 4. Clin Gene 2007;71(4):343–9. DOI: 10.1111/j.1399-0004.2007.00774.x. PMID: 17470135.

6. Smirnova-Seslavinskaya M.V., Tsvetkov G.N. Anthropology of sociocultural development of the gypsy population of Russia. M.: Federal Institute for the Development of Education, 2011. 128 p. (In Russ.).

7. Federal state statistics service. (In Russ.). URL: https://www.gks.ru/free_doc/new_site/perepis2010/croc/perepis_itogi1612.htm.

8. Kalaydjieva L., Hallmayer J., Chandler D. et al. Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24. Nat Genet 1996;14(2):214–7. DOI: 10.1038/ng1096-214. PMID: 8841199.

9. The Human Gene Mutation Database. URL: http://www.hgmd.cf.ac.uk/ac/index.php.

10. Morar B., Gresham D., Angelicheva D. et al. Mutation history of the roma/ gypsies. Am J Hum Genet 2004;75(4):596– 609. DOI: 10.1086/424759. PMID: 15322984.

11. Chandler D., Angelicheva D., Heather L. et al. Hereditary motor and sensory neuropathy – Lom (HMSNL): refined genetic mapping in Romani (Gypsy) families from several European countries. Neuromuscul Disord 2000;10(8):584–91. DOI: 10.1016/s0960-8966(00)00148-6. PMID: 11053686.

12. King R.H., Chandler D., Lopaticki S. et al. Ndrg1 in development and maintenance of the myelin sheath. Neurobiol Dis 2011;42(3):368–80. DOI: 10.1016/j.nbd.2011.01.030. PMID: 21303696.

13. Echaniz-Laguna A., Degos B., Bonnet C. et al. NDRG1-linked Charcot-MarieTooth disease (CMT4D) with central nervous system involvement. Neuromuscul Disord 2007;17(2):163–8. DOI: 10.1016/j.nmd.2006.10.002. PMID: 17142040.

14. Luigetti M., Taroni F., Milani M. et al. Clinical, electrophysiological and pathological findings in a patient with Charcot–Marie–Tooth disease 4D caused by the NDRG1 Lom mutation. J Neurol Sci 2014;345(1–2):271–3. DOI: 10.1016/j.jns.2014.07.042. PMID: 25108819.