AUTOSOMAL RECESSIVE PERIPHERAL NEUROPATHY WITH NEUROMYOTONIA (ARAN-NM): DESCRIPTION OF A CLINICAL CASE CONFIRMED BY A MUTATION IN THE HINT1 GENE

Autosomal recessive  peripheral neuropathy with neuromyotonia  (ARAN-NM)  is a relatively newly described  disease associated  with mutations  in the HINT1 gene.  It accounts  for a significant  part of the poorly  differentiated  forms  of axonal polyneuropathies.  We present the first in Russia description of the genetically confirmed case of ARAN-NM in a boy aged 14 years and 11 months without the hereditary-tainted anamnesis. On presentation,  the patient experienced  progressive  distal muscular weakness, asymmetric foot deformity,  gait disorders  and minimal manifestations  of neuromyotonia  (stiffness  in the fingers).  During examination,  we detected an increase in the level of creatine phosphokinase up to 635 U/l, a disturbance of conduction of motor and, to a lesser extent, sensory fibers  of  the  peripheral  nerves  (according  to  the  stimulation  electromyography,  EMG),  denervation-reinnervation  changes,  single positive acute waves, fibrillation potentials, complex repeated discharge (according to the data of needle EMG). In the study of exome, a homozygous mutation c.110G>C, p.R37P was determined in exon 01 of the HINT1 gene, which confirmed the presence of ARAN-NM. A molecular-genetic  examination of the patient's immediate relatives was carried out. The described case is compared with literature data. An overview of currently available information on ARAN-NM is provided. Diagnostic criteria of the disease are presented.

1. Говбах И.А. Современные подходы диагностики наследственных мото-сенсорных нейропатий // ScienceRise. — 2015. — Т. 3. — № 4 — С. 43–53. [Govbakh IA. Modern approaches to diagnostics of hereditary motor-sensory neuropathy. ScienceRise. 2015;3(4)43–53. (In Russ).] doi: 10.15587/2313-8416.2015.39134

2. Reilly MM, Murphy SM, Laura M. Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2011;16(1):1–14. doi: 10.1111/j.1529-8027.2011.00324.x.

3. Saporta ASD, Sottile SL, Miller LJ, et al. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol. 2011;69(1):22–33. doi: 10.1002/ana.22166.

4. Lassuthova P, Brozkova DS, Krutova M, et al. Mutations in HINT1 are one of the most frequent causes of hereditary neuropathy among Czech patients and neuromyotonia is rather an underdiagnosed symptom. Neurogenetics. 2015;16(1):43–54. doi: 10.1007/s10048-014-0427-8.

5. Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009; 8(7):654–667. doi: 10.1016/S1474-4422(09)70110-3

6. Reilly MM, Shy ME. Diagnosis and new treatments in genetic neuropathies. J Neurol Neurosurg Psychiatry. 2009;80(12): 1304–1314. doi: 10.1136/jnnp.2008.158295.

7. Zhao H, Race V, Matthijs G, et al. Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy. Eur J Hum Genet. 2014;22(6):847–850. doi: 10.1038/ejhg.2013.231.

8. Rossor AM, Kalmar B, Greensmith L, Reilly MM. The distal hereditary motor neuropathies. J Neurol Neurosurg Psychiatry. 2012;83(1):6–14. doi: 10.1136/jnnp-2011-300952.

9. Zimon M, Baets J, Almeida-Souza L, et al. Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nat Genet. 2012;44(10):1080–1083. doi: 10.1038/ng.2406.

10. Aminkeng F. HINT1 mutations define a novel disease entity — autosomal recessive axonal neuropathy with neuromyotonia. Clin Genet. 2013;83(1):31–32. doi: 10.1111/cge.12030.

11. Mertens HG, Zschocke S. [Neuromyotonia. (In German).] Klin Wochenschr. 1965;43(17):917–925. doi: 10.1007/BF01712058

12. Lance JW, Durke D, Pollard J. Neuromyotonia in the spinal form of Charcot-Marie-Tooth disease. Clin Exp Neurol. 1979;16:49–56.

13. Peeters K, Chamova T, Tournev I, Jordanova A. Axonal neuropathy with neuromyotonia: there is a HINT. Brain. 2017;140:868–877. doi: 10.1093/brain/aww301.

14. Hahn AF, Parkes AW, Bolton CF, Stewart SA. Neuromyotonia in hereditary motor neuropathy. J Neurol Neurosurg Psychiatry. 1991;54(3):230–235. doi: 10.1136/jnnp.54.3.230.

15. Black JT, Garcia-Mullin R, Good E, Brown S. Muscle rigidity in a newborn due to continuous peripheral nerve hyperactivity. Arch Neurol. 1972;27(5):413–425. doi: 10.1001/archneur.1972.00490170045007

16. Auger RG, Daube JR, Gomez MR, Lambert EH. Hereditary form of sustained muscle activity of peripheral nerve origin causing generalized myokymia and muscle stiffness. Ann Neurol. 1984;15(1): 13–21. doi: 10.1002/ana.410150104.

17. Mcguire SA, Tomasovic JJ, Ackerman N. Hereditary Continuous Muscle-Fiber Activity. Arch Neurol. 1984;41(4):395–396. doi: 10.1001/archneur.1984.04050160057016

18. Grund G. [Zur Frage des Vorkommens erworbener Myotonie. (In German).] Dtsch Z Nervenheilkd. 1911;42(1–2):110–127. doi: 10.1007/bf01649723.

19. Grund G. [Uber genetische Beziehungen zwischen Myotonie, Muskelkrampfen und Myokymie. (In German).] Dtsch Z Nervenheilkd. 1938;146(1–2):3–14. doi: 10.1007/bf01762426.

20. Gamstorp I, Wohlfart G. A syndrome characterized by myokymia, myotonia, muscular wasting and increased perspiration. Acta Psychiatr Scand. 1959;34(2):181–194. doi: 10.1111/j.1600-0447.1959.tb07573.x.

21. Vasilescu C, Alexianu M, Dan A. Neuronal type of Charcot-Marie-Tooth Disease with a syndrome of contrinuous motor unit activity. J Neurol Sci. 1984;63(1):11–25. doi: 10.1016/0022-510x(84)90105-9.

22. Zimon M, Battaloglu E, Parman Y, et al. Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach. Neurogenetics. 2014;16(1):33–42. doi: 10.1007/s10048-014-0422-0.

23. Мальмберг С.А., Куренков А.Л. Аксональная моторная полиневропатия с гиперактивностью двигательных единиц // Неврологический журнал. — 2002. — Т. 7. — № 6 — С. 28–33. [Mal’mberg SA, Kurenkov AL. Aksonal’naya motornaya polinevropatiya s giperaktivnost’yu dvigatel’nykh edinits. Journal of neurology. 2002;7(6):28–33. (In Russ).]

24. Никитин С.С., Куренков А.Л. Методические основы транскраниальной магнитной стимуляции в неврологии и психиатрии. — М.: «ИПЦ Маска»; 2006. — С. 160–166. [Nikitin SS, Kurenkov AL. Metodicheskie osnovy transkranial’noi magnitnoi stimulyatsii v nevrologii i psikhiatrii. Moscow: Maska; 2006. p. 160–166. (In Russ).]

25. Barbier E, Zapata A, Oh E, et al. Supersensitivity to amphetamine in protein kinase-C interacting protein/HINT1 knockout mice. Neuropsychopharmacology. 2007;32(8):1774–1782. doi: 10.1038/sj.npp.1301301.

26. Liu Q, Puche AC, Wang JB. Distribution and expression of protein kinase c interactive protein (PKCI/HINT1) in mouse central nervous system (CNS). Neurochem Res. 2008;33(7):1263–1276. doi: 10.1007/s11064-007-9578-4.

27. Caetano JS, Costa C, Baets J, et al. Autosomal recessive axonal neuropathy with neuromyotonia: a rare entity. Pediatr Neurol. 2014;50(1):104–107. doi: 10.1016/j.pediatrneurol. 2013.08.028.

28. Jerath NU, Shy ME, Grider T, Gutmann L. A case of neuromyotonia and axonal motor neuropathy: a report of a HINT1 mutation in the United States. Muscle Nerve. 2015;52(6):1110-1113. doi: 10.1002/mus.24774.

29. Rauchenzauner M, Fruhwirth M, Hecht M, et al. A novel variant in the HINT1 gene in a girl with autosomal recessive axonal neuropathy with neuromyotonia: thorough neurological examination gives the clue. Neuropediatrics. 2016;47(2):119–122. doi: 10.1055/s-0035-1570493.

30. Boaretto F, Cacciavillani M, Mostacciuolo ML, et al. Novel loss-of-function mutation of the HINT1 gene in a patient with distal motor axonal neuropathy without neuromyotonia. Muscle Nerve. 2015;52(4):688–689. doi: 10.1002/mus.24720.

31. Вавилов М.А., Бландинский В.Ф., Громов И.В. и др. Артродезирующие операции у детей старше 10 лет с деформациями стоп различной этиологии // Гений ортопедии. — 2016. — № 3 — С. 35–38. [Vavilov MA, Blandinskii VF, Gromov IV, et al. Arthrodesing surgeries in children above 10 years of age with feet deformities of various etiologies. Genij ortopedii. 2016;(3):35–38. (In Russ).] doi: 10.18019/1028-4427-2016-3-35-38.