Original article| Volume 23, ISSUE 2, P254-261, March 2019

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Characteristic clinical and ultrastructural findings in nesprinopathies

Published:December 29, 2018DOI:


      • Thumb abnormalities in patients with SYNE1 mutations.
      • Lobulated myonuclei were a consistent ultrastructural feature.
      • Nuclear envelope pathology not only in myonuclei but also in Schwann cells nuclei.
      • Schwann cell nuclei are affected, indicating the neurodegenerative phenotype.



      To define the neurological and neuropathological alterations caused by SYNE1 mutations.


      We describe 5 patients (3 males, 2 females; age 3–24 years) from 3 families. The diagnostic work-up included three muscle biopsies and two nerve biopsies in three of the cases.


      Three different phenotypes were discerned. Two patients showed progressive ataxia, mental retardation, neuropathy and radially deviated thumbs (spinocerebellar ataxia, SCAR, type 8 phenotype). Two patients had mild congenital myopathy with restrictive lung disease, clubfeet and thumb anomalies (myopathic arthrogryposis). One patient had congenital myopathy with dilated cardiomyopathy and adducted thumbs (Emery-Dreifuss Muscular Dystrophy, EDMD, type 4). Light microscopy of the three muscle biopsies revealed chronic non-necrotizing myopathy without rimmed vacuoles in all cases combined with neurogenic atrophy in one case. The two nerve biopsies showed predominantly axonal neuropathy with demyelinating features. Nuclear alterations, most notably lobulation and focal widening of the space between inner and outer leaflet of the nuclear envelope, were a prominent consistent feature of myonuclei and Schwann cell nuclei in each of the three muscle specimens and one nerve specimen that could be examined by electron microscopy.


      Thumb abnormalities and nuclear envelope alterations are characteristic for SYNE 1 mutations. Schwann cell nuclei are affected, indicating that such nuclear envelope changes in glial cells contribute to the neurodegenerative phenotype in human nesprinopathies.


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