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Journal of Peking University (Health Sciences) ›› 2021, Vol. 53 ›› Issue (5): 957-963. doi: 10.19723/j.issn.1671-167X.2021.05.025

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Clinical, pathological and genetic characteristics of 8 patients with distal hereditary motor neuropathy

LIU Mei-ge1,FANG Pu2,WANG Yan1,CONG Lu1,FAN Yang-yi1,YUAN Yuan1,XU Yan1,ZHANG Jun1,HONG Dao-jun1,2,△()   

  1. 1. Department of Neurology, Peking University People’s Hospital, Beijing 100044, China
    2. Department of Neurology, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
  • Received:2019-10-14 Online:2021-10-18 Published:2021-10-11
  • Contact: Dao-jun HONG E-mail:hongdaojun@hotmail.com
  • Supported by:
    National Natural Science Foundation of China(81870996)

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Abstract:

Objective: Distal hereditary motor neuropathy (dHMN) comprises a heterogeneous group of inherited disorders associated with neurodegeneration of motor nerves and neurons, mainly charac-terized by progressive atrophy and weakness of distal muscle without clinical or electrophysiological sensory abnormalities. To improve the recognition and diagnosis of the disease, we summarized the clinical manifestations, electrophysiological, pathological, and genetic characteristics in eight patients with dHMN. Methods: Eight probands from different families diagnosed with dHMN were recruited in this study between June 2018 and April 2019 at Peking University People’s Hospital. Eight patients underwent complete neurological examination and standard electrophysiological examinations. The clinical criteria were consistent with the patients presenting with a pure motor neuropathy with no sensory changes on electrophysiology. The detailed clinical symptoms, neurophysiological examinations, pathological features and gene mutations were analyzed retrospectively. Genetic testing was performed on the eight patients using targeted next-generation sequencing panel for inherited neuromuscular disorder and was combined with segregation analysis. Results: The age of onset ranged between 11 and 64 years (median 39.5 years) in our dHMN patients. All the cases showed a slowly progressive disease course, mainly characterized by distal limb muscle weakness and atrophy. The motor nerve conduction revealed decreased compound muscle action potential amplitude and velocity, while the sensory nerve conduction velocities and action potentials were not affected. Needle electromyography indicated neurogenic chronic denervation in all patients. Muscle biopsy performed in two patients demonstrated neurogenic skeletal muscle damage. Sural nerve biopsy was performed in one patient, Semithin sections shows relatively normal density and structure of large myelinated fibers, except very few fibers with thin myelin sheaths, which suggested very mild sensory nerve involvement. Eight different genes known to be associated with dHMN were identified in the patients by next-generation sequencing, pathogenic dHMN mutations were identified in three genes, and the detection rate of confirmed genetic diagnosis of dHMN was 37.5% (3/8). Whereas five variants of uncertain significance (VUS) were identified, among which two novel variants co-segregated the phenotype. Conclusion: dHMN is a group of inherited peripheral neuropathies with great clinical and genetic heterogeneity. Next-generation sequencing is widely used to discover pathogenic genes in patients with dHMN, but more than half of the patients still remain genetically unknown.

Key words: Distal hereditary motor neuropathy, Clinical manifestations, Electromyography, Pathology, Gene

CLC Number: 

  • R596

Table 1

Clinical features and laboratory findings of 8 patients with dHMN"

Pt Gender AAD/
years		 AAO/
years		 Distal limb atrophy Foot deformities Deep tendon
reflexes UL/LL		 Sensory loss CK/(U/L) Needle EMG Muscle biopsy
1 M 63 60 Yes No +/- No 400-700 Neurogenic No
2 F 36 33 Yes Yes +++/+ No 189 Neurogenic Neurogenic
3 M 45 27 Yes No +/- No 700-987 Neurogenic No
4 M 65 64 Yes No +++/+++ Yes Normal Neurogenic No
5 M 29 24 Yes Yes +/+ No 428 Neurogenic Neurogenic
6 F 47 46 Yes No -/- No Normal Neurogenic No
7 F 16 11 Yes Yes +/+++ No 189-217 Neurogenic No
8 F 51 49 Yes No -/+ No Unknown Neurogenic No

Table 2

Overview of nerve conduction studies of 8 patients with dHMN"

Pt MCV SCV
Median nerve
(wrist)		 Ulnar nerve
(wrist)		 Peroneal nerve
(ankle)		 Tibial nerve
(ankle)		 Median nerve
(wrist)		 Ulnar nerve
(wrist)		 radial nerve
(forearm)		 Sural nerve
(lower leg)
Amp/
mV		 CV/
(m/s)		 Amp/
mV		 CV/
(m/s)		 Amp/
mV		 CV/
(m/s)		 Amp/
mV		 CV/
(m/s)		 Amp/
μV		 CV/
(m/s)		 Amp/
μV		 CV/
(m/s)		 Amp/
μV		 CV/
(m/s)		 Amp/
μV		 CV/
(m/s)
1 L - - - - NR NR - - - - - - 7.0 43.0
R 13.2 56.0 8.4 47↓ 1.6↓ 36.0↓ 0.4↓ 41↓ 24.0 55.0 34.0 56.0 24.0 55.0 12.0 44.0
2 L 17.9 58.3 14.8 63.6 * 6.6↓ 49.2 74.6 63.6 62.8 59.7 41.0 54.5 *
R 11.9 66.0 9.4 62.0 0.2↓ 39.4↓ 5.8↓ 50.4 31.9 58 53.2 63.7 36.1 63.6 19.7 48.3
3 L 6.5 52.4 7.0 39.6 2.7 43.1 3.1↓ 37.5↓ 7.6 48.3 5.8 40.0 - - 3.9 50.0
R 7.3 40.2 8.5 52.4 3.9 30↓ 3.7↓ 37.6↓ 10.0 46.7 6.7 44.6 - - 1.9 46.7
4 L 13.1 56.0 19.9 56.0 5.2 41↓ 23.6 46.0 30.0 58.0 16.0 52.0 31.0 57.0 1.0 50.0
R 11.6 55.0 14.9 54.0 3.0 41↓ 24.1 44.0 39.0 60.0 27.0 57.0 26.0 59.0 3.0 43.0
5 L 19.9 56.0 21.6 55.0 3.9 43.0 2.0↓ 44.0 60.0 59.0 34.0 57.0 16.0 59.0 9.0 53.0
R 26.3 58.0 20.3 57.0 3.6 43.0 3.4↓ 44.0 37.0 58.0 42,0 54.0 23.0 53.0 11.0 50.0
6 L 18.2 56.0 14.7 56.4 7.4 43.5 15.0 46.7 85.5 60.8 38.4 54.7 15.9 57.8 19.1 50.0
R 14.6 60.6 14.7 65.0 10.6 49.2 16.7 46.7 32.2 60.4 22.2 50.0 15.9 57.8 24.4 50.0
7 L 9.2 60.0 6.5↓ 55.5 NR 0.7↓ 44.1 68.4 61.3 40.0 51.4 24.8 54.7 7.8 47.6
R 0.4↓ 52.3 0.8↓ 55.5 NR 0.9↓ 48.1 51.2 59.0 20.4 55.0 18.7 61.7 17.7 48.4
8 L 17.9 60.7 13.2 71.0 6.1 50.0 19.3 49.3 50.4 56 19 52.1 35.8 56.8 4.6 59.4
R 21.5 57.6 13.1 73.6 5.0 54.4 19.7 48.7 28.8 59 29.1 58.2 38.3 58.8 5.8 57.0

Figure 1

Muscle biopsy from pathological changes of patient 2 A, a group of small horny angular atrophic muscle myofibers distributed in groups or in slices (HE ×100); B, target or target-like fibers (NADHTR ×200); C and D, the group distribution of type Ⅰ and type Ⅱ fibers, atrophic muscle fibers involve type Ⅰ and type Ⅱ fibers (pH4.5 ×100, pH 10.5 ×100)."

Figure 2

Sural nerve biopsy results of patient 2 A, normal nerve bundle and its accessory structure (HE ×100); B, the morphology and density of myelinated/unmyelinated fibers were normal (NF immunostaining ×100); C, semithin section revealed relatively normal density and structure of nerve fibers (toluidine blue stain ×200); D, a magnification of figure C showed a few fibers with thin myelin sheaths (toluidine blue stain ×1 000)."

Table 3

Overview of genetic findings in 8 patients with dHMN"

Pt Gene cDNA change AA change Inheritance Haplotype Function ACMG class
1 HSPB1 c.379C>T p.Arg127Trp AD het Chaperone protein P
2 AARS c.2177+1G>A - AD het tRNA Synthetase VUS
3 SETX c.3631C>T p.Arg1211Cys AD het RNA/DNA metabolism VUS
4 DYNC1H1 c.12823A>C p.Thr4275Pro AD het Cytoskeleton VUS
5 DNAJB2 c.184C>T p.Arg62Trp AR hoz Chaperone protein VUS
6 HSPB8 c.137C>A p.Ala46Asp AD het Chaperone protein VUS
7 BSCL2 c.269C>T p.Ser90Leu AD het ER protein P
8 BICD2 c.1823C>T p.Ser608Leu AD het Cytoskeleton P

Figure 3

Pedigree and sanger sequencing of patient 3 and patient 5 A, pedigree and chromatograms of the mutation sites confirmed by Sanger sequencing patient 3 with SETX mutation and his family; B, pedigree and chromatograms of the mutation sites confirmed by Sanger sequencing patient 5 with DNAJB2 and his family. Square, male; circle, female; black filled symbol, clinically and electromyogram confirmed affected individual; empty symbol, clinically healthy individual."

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