Charcot-Marie-tooth Disease type 2G redefined by a new mutation in LRSAM1

Charcot-Marie-Tooth disease (CMT) is the most frequent hereditary neuropathy, with a prevalence in Cantabria of 28 cases per 100,000 inhabitants (Combarros et al, Acta Neurol Scand 1987; 75: 9-12). Under the acronym CMT2 are included the axonal forms with autosomal dominant inheritance. The IDIVAL Neurodegenerative Diseases Group, based on the Neurology Service of the Hospital Universitario Marqués de Valdecilla, in 1986, described the clinical, neurophysiological and neuropathological study of an extensive Cantabrian strain that allowed the definition of the phenotype as a sensory-motor lumbosacral neuronopathy with Distance-dependent axonal degeneration (dying-back phenomenon) (Berciano et al, Brain 1986; 109: 897-914). Clinically it is manifested by foot cavus, and syndrome of peroneal muscular atrophy of varying degree.

Almost two decades later, in collaboration with the Neurogenetic Group of the University of Antwerp (Belgium) and through linkage analysis, the locus of the disease was located at cr12q12-q13.3 (Nelis et al, J Med Genet 2004; : 193-7), entering OMIM under catalog number 608591. In the following years the localization was refined, and the study of candidate genes (Peeters K, Doctoral thesis, Antwerp University, Belgium, 2014) was unsuccessful.

In the last five years, the aforementioned group has carried out a clinical re-evaluation on the available members of the third and fourth generation. Dr. Antonio García (Clinical Neurophysiology Service of the University Hospital Marqués de Valdecilla) repeated electrophysiological studies protocolized according to the requirements of the CMTNS scale (Shy et al, Neurology 2005; 64: 1209-1214); And Dr. Elena Gallardo (Radiological Diagnostic Service of the University Hospital Marqués de Valdecilla) underwent MRI examination of the leg muscles, with the protocol she had introduced in the CMT1A study with duplication (Gallardo et al, Brain 2006; 129 : 426-37). At this point, it was established that in CMT2G there is incomplete penetrance, a very rare phenomenon in any other CMT syndrome, which greatly complicates any linkage study. In any case, muscular MRI has been an excellent biomarker, detecting an evident and constant fat atrophy of the intrinsic musculature of the feet and to a lesser extent of the muscles of the posterior superficial compartment of the legs. Together with the clinical, neurophysiological and muscular MRI we were able to discriminate affected subjects, potential carriers of a subclinical pathogenic mutation (incomplete penetrance), and subjects at risk but healthy.

With a better phenotypic definition, the next step was to retake the genetic linkage analysis and then go on a “hunt” for a pathogenic mutation. The new locus was redefined in the cr9q31.3-q34.2 region. Using high throughput sequencing techniques, a novel pathogen mutation was identified in LRSAM1, p.Cyst694Tyr, which codes for the enzyme ligase of the ubiquitin E3 protein. Other punctate mutations of this gene have been associated with CMT2P. In patient lymphoblasts, the mutation did not influence the levels of LRSAM1 or those of its ubiquitinated target TSG101. The mutation is associated, however, with several transcriptional modifications including up-regulation of other ligases, NEDD4L and TNFRSF21 (Peeters et al, Ann Neurol 2016 Sep 30. doi: 10.1002 / ana.24775. [Epub ahead of Print]; PMID: 27686364).

Our work concludes that CMT2G is caused by a misconception of LRSAM1, so it should be reclassified as CMT2P. MRI of the leg muscles can be used to detect minimal signs of the disease. Transcriptomic analysis in the cells of several patients has allowed the identification of new factors associated with LRSAM1 dysfunction, which offer new therapeutic targets shared with amyotrophic lateral sclerosis and Alzheimer's disease.

Reference: Peeters K, Palaima P, Pelayo-Negro AL, García A, Gallardo E, García-Barredo R, Mateiu L, Baets J, Menten B, De Vriendt E, De Jonghe P, Timmerman V, Infante J, Berciano J, Jordanova A. Charcot-Marie-Tooth disease type 2G redefined by a novel mutation in LRSAM1. Ann Neurol. 2016 Sep 30. doi: 10.1002/ana.24775.