Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Apr 1;140(4):868-877.
doi: 10.1093/brain/aww301.

Axonal Neuropathy With Neuromyotonia: There Is a HINT

Affiliations
Free PMC article
Review

Axonal Neuropathy With Neuromyotonia: There Is a HINT

Kristien Peeters et al. Brain. .
Free PMC article

Abstract

Recessive mutations in the gene encoding the histidine triad nucleotide binding protein 1 (HINT1) were recently shown to cause a motor-predominant Charcot-Marie-Tooth neuropathy. About 80% of the patients exhibit neuromyotonia, a striking clinical and electrophysiological hallmark that can help to distinguish this disease and to guide diagnostic screening. HINT1 neuropathy has worldwide distribution and is particularly prevalent in populations inhabiting central and south-eastern Europe. With 12 different mutations identified in more than 60 families, it ranks among the most common subtypes of axonal Charcot-Marie-Tooth neuropathy. This article provides an overview of the present knowledge on HINT1 neuropathy with the aim to increase awareness and spur interest among clinicians and researchers in the field. We propose diagnostic guidelines to recognize and differentiate this entity and suggest treatment strategies to manage common symptoms. As a recent player in the field of hereditary neuropathies, the role of HINT1 in peripheral nerves is unknown and the underlying disease mechanisms are unexplored. We provide a comprehensive overview of the structural and functional characteristics of the HINT1 protein that may guide further studies into the molecular aetiology and treatment strategies of this peculiar Charcot-Marie-Tooth subtype.

Keywords: CMT; HINT1; clinical characteristics; neuromyotonia; neuropathy.

Figures

Figure 1
Figure 1
Worldwide distribution of HINT1 mutations. Pie chart size represents the number of patients identified per country and colours indicate which founder HINT1 mutations they are carrying. Dashed lines point out the country of origin of the identified patients. Enlarged panel below shows the regions in Europe where most patients are clustered. Note the gradient of distribution for the most common HINT1 mutation (R37P), increasing in central and south-eastern Europe.
Figure 2
Figure 2
Clinical presentation of HINT1 patients. (A–E) A 29-year-old male patient (genotype R37P/R37P) showing bilateral calf muscle atrophy (A and B), flexion contractures of the fingers (C), intrinsic hand muscle wasting (D), and pes cavus (E). (F) Neuromyotonic discharges, recorded with a concentric needle electrode in the right m. rectus femoris of a 27-year-old female patient (genotype R37P/R37P). (G) Diagnostic guidelines for HINT1 neuropathy.
Figure 3
Figure 3
HINT1 structure and known mutations. (A) Reaction scheme for cleavage of AMP-linked compounds by the HINT1 enzyme, adapted from Krakowiak et al. (2014). (B and C). Position of the 12 known HINT1 mutations on the cDNA and protein structures, respectively. (D) 3D representation of the HINT1 dimer, highlighting the eight amino acid residues targeted by missense mutations. HINT1 monomers are shown in blue and yellow.

Similar articles

See all similar articles

Cited by 3 articles

References

    1. Ajit SK, Ramineni S, Edris W, Hunt RA, Hum WT, Hepler JR. et al. RGSZ1 interacts with protein kinase C interacting protein PKCI-1 and modulates mu opioid receptor signaling. Cell Signal 2007; 19: 723–30. - PubMed
    1. Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ. et al. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am J Hum Genet 2003; 72: 1293–9. - PMC - PubMed
    1. Barbier E, Wang JB. Anti-depressant and anxiolytic like behaviors in PKCI/HINT1 knockout mice associated with elevated plasma corticosterone level. BMC Neurosci 2009; 10: 132. - PMC - PubMed
    1. Barbier E, Zapata A, Oh E, Liu Q, Zhu F, Undie A. et al. Supersensitivity to amphetamine in protein kinase-C interacting protein/HINT1 knockout mice. Neuropsychopharmacology 2007; 32: 1774–82. - PubMed
    1. Beyoglu D, Krausz KW, Martin J, Maurhofer O, Dorow J, Ceglarek U. et al. Disruption of tumor suppressor gene Hint1 leads to remodeling of the lipid metabolic phenotype of mouse liver. J Lipid Res 2014; 55: 2309–19. - PMC - PubMed

MeSH terms

Feedback