Identificatie van nieuwe causale genen voor autosomaal recessieve Charcot-Marie-Tooth neuropathie├źn

Datum: 15 juni 2018

Locatie: UAnwerpen, Campus Drie Eiken, Gebouw Q, Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk (Antwerpen) (route: UAntwerpen, Campus Drie Eiken)

Tijdstip: 16 - 18 uur

Promovendus: Derek Atkinson

Promotor: Albena Jordanova

Korte beschrijving: Doctoraatsverdediging Derek Atkinson - Departement Biomedische Wetenschappen


Charcot-Marie-Tooth neuropathies (CMT) as a group represent the most common inherited disorder of the peripheral nervous system (PNS), affecting 1/2500 individuals worldwide. The disease is characterized by a length-dependent degeneration of motor and sensory peripheral neurons and is clinically divided into demyelinating (CMT1), axonal (CMT2) or intermediate (I-CMT) forms. CMT patients develop progressive distal muscle weakness and wasting, sensory loss and have walking difficulties or become wheelchair dependent early in life. Despite this classical clinical presentation, there are huge intra- and interfamilial differences in phenotype expression. All modes of inheritance are documented in CMT, accompanied by an extensive genetic and allelic heterogeneity.

Autosomal recessive CMT forms (ARCMT) represent <10% of patients in the European CMT population. Due to the small size of sibships, however, many recessive forms remain unrecognized and are considered to be sporadic. In populations with a high degree of consanguinity, ARCMT represents 30-50% of all CMT patients. ARCMT forms are generally distinguished by an earlier onset and a more severe disease course.

The aim of my doctoral thesis was to contribute to the knowledge on inherited neuropathies, more particularly ARCMT. I was able to identify a novel disease gene, SGPL1, causing  a distinct form of CMT disease in humans, hereby extending the clinical and genetic spectrum of inherited peripheral neuropathies. Additionally, this finding emphasizes the importance of sphingolipid metabolism for neuronal function. I have also identified novel genetic causes for ARCMT in already established CMT genes. For NDRG1 I’ve uncovered several novel mutations within different populations, underscoring the impact of mutations in the whole gene in the general CMT population. To facilitate the search for novel causes in ARCMT, and other recessive disorders, I helped developing a tool to perform homozygosity mapping using whole exome sequencing data (HOMWES) in an accurate and automated way, enabling the identification of candidate regions. Through the combined use of HOMWES and next generation sequencing technologies, I was able to identify these novel genetic causes for ARCMT disease.