Hereditary Ulceromutilating Sensory Neuropathy – Clinical, Electrophysiological and Molecular Genetic Study of Three Families

Czech version

Authors: D. Šafka Brožková ¹; R. Mazanec ²; J. Böhm ³; O. Vyšata ⁴; M. Auer-Grumbach ⁵; Ch. Windpassinger ⁶; J. Neupauerová ¹; L. Baránková ¹; S. Nevšímalová ³; P. Seeman ¹
Authors‘ workplace: DNA laboratoř Kliniky dětské neurologie 2. LF UK a FN v Motole, Praha ¹; Neurologická klinika 2. LF UK a FN v Motole, Praha ²; Neurologická klinika 1. LF UK a VFN v Praze ³; Neurologická klinika LF UK a FN Hradec Králové ⁴; Department of Orthopaedics, Medical University Vienna ⁵; Institute of Human Genetics, Medical University of Graz ⁶
Published in: Cesk Slov Neurol N 2014; 77/110(4): 479-486
Category: Short Communication

Grantová podpora: IGA MZ ČR NT 14348-3, MZ ČR - RVO, FN v Motole 00064203 a grant PRVOUK- P26/LF1/4.

Overview

Aim:
The goal was to clinically and electrophysiologically characterize two types of ulceromutilating hereditary neuropathy CMT2B and HSN1 in three Czech families where molecular genetic cause was confirmed.

Patients:
We describe three families, overall 16 affected patients, with hereditary sensory neuropathy.

Methods:
The diagnosis of sensory, predominantly axonal neuropathy was done on the basis of neurological and electrophysiological examination. Sequencing of the SPTLC1 and RAB7 genes was done in families A, B, C and 24 unrelated patients with clinical suspicion for HSN.

Results:
Hereditary sensory neuropathy type 1 (HSN1) caused by the p.C133Y mutation in the SPTLC1 gene was confirmed in family B and the Charcot-Marie-Tooth type 2B (CMT2B) caused by p.L129F and p.V162M mutations in the RAB7 gene was confirmed in families A and C. All three mutations have been previously described. DNA examination of 24 unrelated patients did not reveal the cause of their disease.

Conclusion:
As in other countries, ulceromutilating hereditary neuropathies CMT2B and HSN1 are rare in the Czech population. However, clinical manifestations are clearly recognizable if correctly obtained genealogical data – family history – is properly taken into account. The three families described here are the only known families with hereditary neuropathies caused by mutations in RAB7 and SPTLC1 in the Czech Republic. Clarification of the cause of ulceromutilating sensory neuropathy is crucial for genetic and clinical prognosis, including targeted genetic prevention, but possibly also for an L-serin therapy in SPTLC1 mutation patients to be tested in a clinical study (Boston, USA).

Key words:
hereditary sensory neuropathy – HSN1 – CMT2B – RAB7 gene – SPTLC1 gene

Sources

1. Dyck PJ. Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF (eds). Peripheral Neuropathy. 3rd ed. Philadelphia: W.B. Saunders 1993: 1065– 1093.

2. Harding AE, Thomas PK. The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 1980; 103(2): 259– 280.

3. Dawkins JL, Hulme DJ, Brahmbhatt SB, Auer‑ Grumbach M, Nicholson GA. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit‑ 1, cause hereditary sensory neuropathy type I. Nat Genet 2001; 27(3): 309– 312.

4. Bejaoui K, Wu C, Scheffler MD, Haan G, Ashby P, Wu L et al. SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet 2001; 27(3): 261– 262.

5. Verhoeven K, De Jonghe P, Coen K, Verpoorten N,Auer‑ Grumbach M, Kwon JM et al. Mutations in the small GTP‑ ase late endosomal protein RAB7 cause Charcot‑ Marie‑ Tooth type 2B neuropathy. Am J Hum Genet 2003; 72(3): 722– 727.

6. Rotthier A, Auer‑ Grumbach M, Janssens K, Baets J,Penno A, Almeida‑ Souza L et al. Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I.Am J Hum Genet 2010; 87(4): 513– 522. doi: 10.1016/ j.ajhg.2010.09.010.

7. Nielsen E, Severin F, Backer JM, Hyman AA, Zerial M. Rab5 regulates motility of early endosomes on microtubules. Nat Cell Biol 1999; 1(6): 376– 382.

8. Echard A, Jollivet F, Martinez O, Lacapere JJ, Rousselet A, Janoueix‑ Lerosey I et al. Interaction of a Golgi‑associated kinesin‑like protein with Rab6. Science 1998; 279(5350): 580– 585.

9. Seeman P, Mazanec R, Zidar J, Hrusakova S, Ctvrteckova M, Rautenstrauss B. Charcot‑ Marie‑ Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP): reliable detection of the CMT1A duplication and HNPP deletion using 8 microsatellite markers in 2 multiplex PCRs. Int J Mol Med 2000; 6(4): 421– 426.

10. Auer‑ Grumbach M, Mauko B, Auer‑ Grumbach P, Pieber TR. Molecular genetics of hereditary sensory neuropathies. Neuromolecular Med 2006; 8(1– 2): 147– 158.

11. Auer‑ Grumbach M, De Jonghe P, Verhoeven K, Timmerman V, Wagner K, Hartung HP et al. Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations: a review. Arch Neurol 2003; 60(3): 329– 334.

12. Houlden H, King R, Blake J, Groves M, Love S, Woodward C et al. Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I). Brain 2006; 129(2): 411– 425.

13. Manganelli F, Pisciotta C, Provitera V, Taioli F, Iodice R,Topa A et al. Autonomic nervous system involvement in a new CMT2B family. J Peripher Nerv Syst 2012; 17(3): 361– 364. doi: 10.1111/ j.1529‑ 8027.2012.00415.x.

14. Gable K, Gupta SD, Han G, Niranjanakumari S, Harmon JM, Dunn TM. A disease‑ causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity. J Biol Chem 2010; 285(30): 22846– 22852. doi: 10.1074/ jbc.M110.122259.

15. Penno A, Reilly MM, Houlden H, Laura M, Rentsch K, Niederkofler V et al. Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem 2010; 285(15): 11178– 11187. doi: 10.1074/ jbc.M109.092973.

16. Garofalo K, Penno A, Schmidt BP, Lee HJ, Frosch MP,von Eckardstein A et al. Oral L‑ serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest 2011; 121(12): 4735– 4745. doi: 10.1172/ JCI57549.