Clinical, pathological and genetic characteristics of 8 patients with distal hereditary motor neuropathy / 北京大学学报(医学版)

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.

Progress of clinical and genetic research on distal hereditary motor neuropathy / 中华医学遗传学杂志

Distal hereditary motor neuropathy (dHMN) is a group of clinically and genetically heterogeneous disorders characterized by progressive distal weakness and atrophy. The onset of dHMN is at mid-adulthood or early childhood, and the symptoms are mainly present in the lower limbs. Besides weakness and atrophy of distal limb muscles, some patients may develop bulbar paralysis, and some may also present with mild sensory disturbance. Decreased or absent tendon reflexes may be discovered. Electromyography may show neurogenic damages. Muscular biopsy may reveal neurogenic amyotrophy. An increasing number of genes have been associated with dHMN. Pathogenesis of dHMN may include formation of protein aggregates, impairment of autophagy pathway, RNA processing, translation synthesis, axonal transport, endoplasmic reticulum stress, calcium channel and neuroprotection. A review for recent progress made on clinical characterization and molecular genetics of dHMN is provided.

Distal Hereditary Motor Neuropathy Type V (dHMN-V) With N88S Mutation in BSCL2 Gene

Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene is known to be associated with different clinical phenotypes; Silver syndrome, Charcot-Marie-Tooth type 2 with a dominant hand involvement and distal hereditary motor neuropathy type V (dHMN-V). Up to now, only two heterozygous mutations (N88S and S90L) in BSCL2 have been reported. We identified a N88S BSCL2 mutation in a dHMN-V family with a spastic gait by whole-exome sequencing. To our knowledge, this is the first report of a N88S BSCL2 mutation in Korean patient.

Chinese patients with distal hereditary motor neuropathy: An analysis of clinical characteristics / 第二军医大学学报

Objective: To evaluate the clinical characteristics of Chinese patients with distal hereditary motor neuropathy (dHMN). Methods: The clinical data on patients with dHMN collected from literatures published in China and from the patients treated in our hospital were retrospectively analyzed. Results: The male to female ratio of patients was 1.32 : 1. The age of onset was from 13 to 60 years old, with a mean of (38.2±10.4) years old. The incidences of onset from the lower limbs, the upper limbs, and the four limbs were 84.7% 5.6%, and 9.7%, respectively. The incidences of decreased tendon reflexes, lost tendon reflexes in the upper limbs, decreased tendon reflexes and lost tendon reflexes in the upper limbs were 30.4% 65.3%, 13.0%, and 87.0%, respectively. The incidences of grade 3-4, grade 2, and grade 0-1 muscle strength of the upper limbs, grade 3-4, grade 2, and grade 0-1 muscle strength of the lower limbs were 55.4%, 37.5%, 7.1%, 50.0%, 37.5%, and 12.5%, respectively. No sensory disturbance was found in the patients. Electromyography (EMG) of 26 patients showed neurogenic damages; the motor and sensory nerve conduction velocities were all normal. Eight patients showed neurogenic amyotrophy in muscular biopsy. Conclusion: The onset of dHMN is mainly at middle-age and mainly in the lower limbs. The major manifestations include weakness and atrophy of distal limb muscles, decreased or lost tendon reflexes without sensory loss. Electrophysiology and pathology examinations play an important role in the diagnosis of dHMN.