By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports he is a consultant for Merck Sharp & Dohme Corp.
SYNOPSIS: The neuromuscular syndromes caused by BSCL2 gene mutations may mimic several other disorders, including Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis.
SOURCE: Fernandez-Eulate G, Fernandez-Torron R, Guisasola A, et al. Phenotypic correlations in a large single-center cohort of patients with BSCL2 nerve disorders: A clinical, neurophysiological and muscle magnetic resonance imaging study. Eur J Neurol 2020;27:1364-1373.
Distal hereditary motor neuropathy (dHMN), or distal spinal muscular atrophy, comprises a genetically and phenotypically heterogeneous group of disorders, characterized by almost exclusive degeneration of motor nerve fibers, predominantly in the distal parts of the limbs. Several forms are linked to the Berardinelli-Seip congenital lipodystrophy (BSCL2) gene, of which two mutations comprise a majority of the patients. In this study, 26 patients from five families carrying the p.N88S mutation were studied to form a description of the full phenotypic spectrum of this entity.
Electronic medical records provided clinical data, including age of onset, age at diagnosis, mutation, phenotype, and limb onset. Muscle strength was graded using the Medical Research Council (MRC) scale and disability was ranked using the modified Rankin Scale (mRS) score. Nineteen patients had undergone nerve conduction studies, and 18 underwent whole body muscle magnetic resonance imaging (MRI), including the hands and feet. Patients underwent either whole-exome sequencing for diagnosis (n = 2) (which also excluded other genetic causes of distal weakness, such as Charcot-Marie-Tooth [CMT] disease) or Sanger-sequencing of exon 3 of the BSCL2 gene, with mutation carriers identified using BigDye chemistry in AB13130 (Life Technologies) equipment. Statistical analysis included the mean and standard deviation of symmetric quantitative variables, and the median and interquartile range of asymmetric quantitative variables, with parametric and non-parametric tests applied as needed, and statistical significance considered at P < 0.05.
All patients came from a small region on the coast of the Basque Country in northern Spain and were confirmed carriers of the p.N88S mutation. Ages ranged from 20 to 99 years, males comprised 53.8% of the patient group (n = 26), the mean age of onset was 24.4 years, and the mean age of diagnosis was 51.4 years. Pure dHMN was the most common presentation, seen in 13 patients (50%), with spastic paraplegia 17 (Silver syndrome) present in five patients (19%), and CMT2 in three patients (11%). Five patients (19%) remain asymptomatic. Limb onset was seen in 18 patients (68%), affecting the legs in 12, the arms in four, and both arms and legs in two. Sensory symptoms were present in only three (11%), and respiratory insufficiency in two (8%), but pes cavus and pyramidal signs were present in 46% and 50%, respectively. Slow progression was seen in all patients, with low mean disability — two patients walked with aid, one required help with activities of daily living, and none used a wheelchair. Axonal neuropathy was seen in 17 of 19 patients, with slowing of nerve conduction velocities rare and mild if present, but dispersed compound muscle action potentials in the legs were found in seven patients (37%). Of eight patients who underwent cervical spine MRI, one showed disc herniation with signs of myelopathy, which resolved with surgery. No signs of myelopathy were appreciated otherwise.
Whole body MRI in 18 patients showed generally symmetric proximal to distal gradient fat replacement in each muscle in 15, with the most frequently affected muscles being the soleus, tibialis anterior, and thenar eminence (61%, 56%, and 50%, respectively), followed by the extensor digitorum longus, medial gastrocnemius, peroneus, and flexor digitorum longus (in 44%, 39%, 33%, and 33%, respectively). Proximal limb and axial muscle abnormalities were unusual. Patients with the p.N88S BSCL2 mutation can be phenotypically variable, but most frequently present as a slowly progressive dHMN. However, all phenotypes demonstrate a consistent muscle MRI pattern of fat replacement, which may be helpful in differential diagnosis and as an outcome measure in future clinical trials.
Among 407 Japanese patients clinically suspected of having CMT disease, but screened for BSCL2 mutations by exome sequencing, five were identified with heterozygous BSCL2 mutations, of which three had known mutations (p.N88S and p.S90l) and two had novel mutations (p.N88T and p.S141A). Early onset and significant vocal cord paresis were present in the p.N88T mutation, and the p.S141A mutation showed features typical of CMT type 1 based on electrodiagnostic studies. BSCL2 mutation may rarely mimic the demyelinating form of CMT.1
- Ishihara S, Okamoto Y, Tanabe H, et al. Clinical features of inherited neuropathy with BSCL2 mutations in Japan. J Peripher Nerv Syst 2020;25:125-131.