Genetic insights in hereditary neurological and neuromuscular disorders : spectrins bridge neurons to muscles

During my doctoral research, I focused on four primary disease groups: hereditary cerebellar ataxias (HCAs), hereditary motor neuron disorders (HMNDS), inherited peripheral neuropathies (IPNs) and inherited muscle disorders (IMDs). The aim of this thesis was twofold: first, to address the issue of missing genetics, and secondly to enhance our understanding of disease mechanisms within these four groups. To achieve these goals, I employed a deep phenotyping approach, dissecting the multiple layers of a patient’s phenotype. I also studied the impact of a pathogenic variant on phenotype expression, and explored shared disease mechanisms through the lens of overlapping genotype-phenotype associations. The thesis crystallizes into four key themes. First, I describe the problem of missing genetics among these groups and discuss the results of large- and small-scale collaborations. I then go into more detail on repeat expansions and their role in complex inheritance patterns, before concluding with the genotype–phenotype expansion narrative. Next, I characterize the major disease mechanisms underlying IPN, HSP and SCA. The third section is devoted to the spectrinopathy spectrum and the impact of studying SPTAN1 disease mechanisms. Finally, I discuss the growing body of evidence for bidirectional communication between nerves and muscles in disease, describing the genetic overlap between hereditary motor neuropathy (HMN) and distal myopathy (dMYO), and presenting preliminary findings on myopathic abnormalities identified in muscle biopsies from patients with inherited chronic neurogenic disorders.