Abstract
Neurofilament heavy chain (NEFH) gene was recently identified to cause autosomal dominant axonal Charcot-Marie-Tooth disease (CMT2cc). However, the clinical spectrum of this condition and the physio-pathological pathway remain to be delineated. We report 12 patients from two French families with axonal dominantly inherited form of CMT caused by two new mutations in the NEFH gene. A remarkable feature was the early involvement of proximal muscles of the lower limbs associated with pyramidal signs in some patients. Nerve conduction velocity studies indicated a predominantly motor axonal neuropathy. Unique deletions of two nucleotides causing frameshifts near the end of the NEFH coding sequence were identified: in family 1, c.3008_3009del (p.Lys1003Argfs*59), and in family 2 c.3043_3044del (p.Lys1015Glyfs*47). Both frameshifts lead to 40 additional amino acids translation encoding a cryptic amyloidogenic element. Consistently, we show that these mutations cause protein aggregation which are recognised by the autophagic pathway in motoneurons and triggered caspase 3 activation leading to apoptosis in neuroblastoma cells. Using electroporation of chick embryo spinal cord, we confirm that NEFH mutants form aggregates in vivo and trigger apoptosis of spinal cord neurons. Thus, our results provide a physiological explanation for the overlap between CMT and amyotrophic lateral sclerosis (ALS) clinical features in affected patients.
Highlights
Charcot-Marie-Tooth disease (CMT) refers to a heterogeneous group of chronic inherited motor and sensory disorders of the peripheral nervous system
We further show that this type of mutations induces neuronal apoptosis, both in neuroblastoma cells and in vivo in spinal cord neurons using in ovo chick spinal cord electroporation
There was distal and proximal muscle wasting in the lower limbs, and distal muscle wasting in the upper limbs
Summary
Charcot-Marie-Tooth disease (CMT) refers to a heterogeneous group of chronic inherited motor and sensory disorders of the peripheral nervous system. CMT are classified according to their axonal or demyelinating feature on nerve conduction studies, and their mode of inheritance [10]. The autosomal dominant axonal forms are termed CMT2. The number of genes associated with CMT is progressively expanding, since the development of next-generation sequencing. Several of these genes are expressed in both the central and peripheral nervous system, such as neurofilaments, which. NEFH mutations have been identified as a rare cause of autosomal dominant CMT, with two Jacquier et al Acta Neuropathologica Communications (2017) 5:55 families reported to date [27]. The two mutations (c.3010_3011delGA and c.3017_3020dup) cause the loss of the stop codon and the translation of 40 additional amino acids which encode a cryptic amyloidogenic element (CAE) and cause protein aggregation [27]
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