EGR2 gene-linked hereditary neuropathies present with a bimodal age distribution at symptoms onset

• Published in: Journal of the peripheral nervous system 2023-09, Vol.28 (3), p.359-367
• Main Authors: Echaniz-Laguna, Andoni, Cauquil, Cécile, Chanson, Jean-Baptiste, Tard, Céline, Guyant-Marechal, Lucie, Kuntzer, Thierry, Ion, Ioana Maria, Lia, Anne-Sophie, Bouligand, Jérôme, Poinsignon, Vianney
• Format: Article
• Language: English
• Subjects: Age composition; Atrophy; Children; Demyelination; Egr-2 protein; Immunosuppressive agents; Inflammation; Limbs; Mutation; Myotonic dystrophy; Nerve conduction; Neuropathy; Scoliosis; Sensorimotor system
• ISSN: 1085-9489; 1529-8027
• DOI: 10.1111/jns.12572

Mutations in the Early-Growth Response 2 (EGR2) gene cause various hereditary neuropathies, including demyelinating Charcot-Marie-Tooth (CMT) disease type 1D (CMT1D), congenital hypomyelinating neuropathy type 1 (CHN1), Déjerine-Sottas syndrome (DSS), and axonal CMT (CMT2). In this study, we identified 14 patients with heterozygous EGR2 mutations diagnosed between 2000 and 2022. Mean age was 44 years (15-70), ten patients were female (71%), and mean disease duration was 28 years (1-56). Disease onset was before age 15 years in 9 cases (64%), after age 35 years in 4 cases (28%), and 1 patient aged 26 years was asymptomatic (7%). All symptomatic patients had pes cavus and distal lower limbs weakness (100%). Distal lower limbs sensory symptoms were observed in 86% of cases, hand atrophy in 71%, and scoliosis in 21%. Nerve conduction studies showed a predominantly demyelinating sensorimotor neuropathy in all cases (100%), and 5 patients needed walking assistance after a mean disease duration of 50 years (47-56) (36%). Three patients were misdiagnosed as inflammatory neuropathy and treated with immunosuppressive drugs for years before diagnosis was corrected. Two patients presented with an additional neurologic disorder, including Steinert's myotonic dystrophy and spinocerebellar ataxia (14%). Eight EGR2 gene mutations were found, including 4 previously undescribed. Our findings demonstrate EGR2 gene-related hereditary neuropathies are rare and slowly progressive demyelinating neuropathies with 2 major clinical presentations, including a childhood-onset variant and an adult-onset variant which may mimic inflammatory neuropathy. Our study also expands the genotypic spectrum of EGR2 gene mutations.