Genetic background of late onset inherited peripheral neuropathies

Hereditary motor and sensory neuropathies also known as Charcot-Marie-Tooth (CMT) disease are one of the most frequently inherited causes of neurological and orthopaedic disability with an estimated prevalence of 1 in 2500. Hallmark features comprise foot-deformities, slowly progressive weakness in the distal parts of the lower limbs due to considerable muscle wasting which often leads to severe gait disturbances and sometimes even wheelchair dependence. Distal sensory loss, weakness of the small hand muscles and other additional features may also be present to a variable degree. Age at onset is usually within the first two decades but rarely late onset forms after age 35 years have been reported. Molecular genetic studies have shown marked genetic heterogeneity. Our group has found five of these genes (BSCL2, TRPV4, ATL1, FBLN5, REEP1). Still, in many CMT patients and families the underlying gene has to be identified. In particular, the genetic causes of inherited neuropathies with late disease onset (>35 years) remain unknown in the majority of affected individuals. Because family history is often lacking in these cases delineation of acquired inherited neuropathies is frequently challenging and a correct diagnosis may happen late or may even never be made. This research project will focus on the identification of genes involved in the pathogenesis of late onset inherited neuropathies using next generation sequencing methods. These methods (including whole exome sequencing and whole genome sequencing in selected cases) open promising possibilities to find the disease causing gene in small families and sporadic cases. The discovery of genes underlying late onset inherited neuropathies will provide the first step to understand the pathogenesis of these disorders and will enable to elucidate pathways shared by different forms of CMT but also acquired neuropathies. In particular, misclassification and expensive though insufficient treatment of sporadic cases may be avoided once a gene test is available to confirm the genetic cause of the disease. Subsequently, the knowledge of such genes will enable functional and animal studies which may serve to find reasonable therapies for patients with both inherited and acquired forms of neuropathies.

Hereditary neuropathies also known as Charcot-Marie-Tooth (CMT) disease are one of the most frequently inherited causes of neurological and orthopaedic disability. CMT is characterised by distal muscle weakness and wasting, gait disturbances and sensory loss and usually starts within the first two decades. Rarely, late onset forms with disease onset after age 35 years have been reported. In particular, the genetic causes of these late onset inherited neuropathies remain unknown in the majority of patients. Moreover, because family history is often lacking in these cases delineation of acquired inherited neuropathies is frequently challenging and a correct diagnosis may happen late or may even never be made. Even after appropriate and extensive diagnostic work-up, the underlying aetiologies of late onset neuropathies often remain unknown and half of the polyneuropathies are considered idiopathic. This research project focused on the identification of genes involved in the pathogenesis of late onset inherited neuropathies. More than 300 patients with or without family history and late onset peripheral neuropathies have been recruited. By using whole exome sequencing (WES) we identified heterozygous variants in MME encoding the metalloprotease neprilysin as a novel causative gene for late-onset axonal neuropathies. The phenotype was characterized by a severe and rapidly progressive course with predominant manifestation in the lower limbs. Analysis of patient samples with heterozygous MME variants and in vitro studies were consistent with decreased tissue availability and impaired enzymatic activity of the gene product neprilysin. In a follow up study we demonstrated that 21% of individuals studied by WES carried pathogenic or likely pathogenic variants in genes involved in Charcot-Marie-Tooth neuropathy (CMT) or other diseases associated with neuropathies. Among patients without sporadic disease, known monogenic causes accounted for 15% but were twice as high among familial cases. MME was by far the most frequently involved gene. In addition, by studying patients with late onset demyelinating neuropathies (CMT1) we could highlight the significance of mutations in the fibulin 5 (FBLN5) gene. We also demonstrated that FBLN5 mutations lead to a particular and easily recognizable genetic subtype of late onset CMT1. The discovery of genes underlying late onset inherited neuropathies provides the first step to understand the pathogenesis of these disorders and will enable functional and animal studies which may serve to find reasonable therapies for patients with both inherited and acquired forms of neuropathies.