Heterozygous loss-of-function variants in SPTAN1 cause a novel early childhood onset distal myopathy with chronic neurogenic features
Authors: De Winter Jonathan , Van de Vondel Liedewei , Ermanoska Biljana , Monticelli Alice , Isapof Arnaud , Cohen Enzo , Stojkovic Tanya , Hackman Peter , Johari Mridul , Palmio Johanna , Waldrop Megan A. , Meyer Alayne P. , Nicolau Stefan , Flanigan Kevin M. , Töpf Ana , Diaz-Manera Jordi , Straub Volker , Longman Cheryl , McWilliam Catherine A. , Orbach Rotem , Verma Sumit , Laine Regina , Donkervoort Sandra , Bonnemann Carsten G. , Rebelo Adriana , Züchner Stephan , Grider Tiffany , Shy Michael E. , Maystadt Isabelle , Demurger Florence , Cairns Anita , Beecroft Sarah , Folland Chiara , De Ridder Willem , Ravenscroft Gina , Bonne Gisèle , Udd Bjarne , Baets Jonathan 
Published: September 2024

ABSTRACTBackgroundNeurogenetic disorders caused by pathogenic variants in four genes encoding non-erythrocytic spectrins (SPTAN1, SPTBN1, SPTBN2, SPTBN4)range from peripheral and central nervous system involvement to complex syndromic presentations. Heterozygous pathogenic variants inSPTAN1are exemplary for this diversity with phenotypes spanning almost the entire spectrum.MethodsThrough international collaboration we identified 14 families with genetically unsolved distal weakness and unreported heterozygousSPTAN1loss-of-function variants including frameshift, nonsense and splice-acceptor variants. Clinical data, electrophysiology, muscle CT or MRI and muscle biopsy findings were collected and standardized.SPTAN1protein, mRNA expression analysis and cDNA sequencing was performed on muscle tissue from two patients.ResultsAll 20 patients presented with early childhood onset distal weakness. The severity varied both within families and between different families. Foot abnormalities ranged from hammer toes and pes cavus to distal arthrogryposis. Electrophysiology showed mixed myogenic and neurogenic features. Muscle MRI or CT in 10 patients showed fatty infiltration of the distal lower limb anterior compartment and/or selective involvement of the extensor hallucis longus muscle. Muscle biopsy revealed myopathic changes with mild dystrophic and chronic neurogenic changes in 7 patients. Finally, we provide proof for nonsense mediated decay in tissues derived from two patients.ConclusionsWe provide evidence for the association ofSPTAN1loss-of-function variants with childhood onset distal myopathy in 14 families. This finding extends the phenotypic spectrum ofSPTAN1loss-of-function variants ranging from intellectual disability to distal weakness with a predominant myogenic cause.KEY MESSAGES⋄SPTAN1loss-of-function variants, including frameshift, nonsense and splice site variants cause a novel childhood onset distal weakness syndrome with primarily skeletal muscle involvement.⋄Hereditary motor neuropathies and distal myopathic disorders present a well-known diagnostic challenge as they demonstrate substantial clinical and genetic overlap. The emergence ofSPTAN1loss-of-function variants serves as a noteworthy example, highlighting a growing convergence in the spectrum of genotypes linked to both hereditary motor neuropathies and distal myopathies.