A French family with Charcot–Marie–Tooth disease related to simultaneous heterozygous MFN2 and GDAP1 mutations
Introduction
Most of the families affected by Charcot–Marie–Tooth (CMT) disease, due to mutations in GDAP1 encoding ganglioside-induced differentiation associated protein 1, display an autosomal recessive inheritance (CMT4A), with an early onset and severe disability [1], [2], [3]. Alternatively, a few families with autosomal dominant mutations in GDAP1 have been reported in Spain [3], Korea [4], various European countries [5], [6], [7], [8], [9], [10], the United States [7], and were classified as CMT2K characterized by juvenile-onset and a slow rate of progression. A mitochondrial dysfunction associated with abnormalities in organelle dynamics have been emphasized [8], [9], [10]. The mode of inheritance of GDAP1 mutations influences such abnormalities [10]. Mutations in another mitochondrial nuclear gene, MFN2, encoding the mitochondrial fusion protein mitofusin 2, lead to axonal CMT which may also be dominantly (CMT2A) [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], or more rarely recessively [20], [21] inherited.
Characteristic intra-axonal modified mitochondria with distorted cristae were reported in seven unrelated cases with CMT2A [21], [24], [25], [32] and in a patient with CMT4A [33]. Very recently, three other cases of CMT2A have been reported, without characteristic mitochondrial abnormalities on nerve biopsy [28], [29], [30]. We report histological features on nerve biopsies from a patient carrying simultaneously heterozygous dominant MFN2 and GDAP1 mutations.
Section snippets
Patients and methods
The family under investigation originated from the South-West of France, and the pedigree is shown (Fig. 1). Available clinical and neurophysiological data are given in Table 1.
The proband (IV.1), a 41-year-old woman, presented a typical CMT phenotype with abnormal gait noted at age 3. The course was slowly progressive leading to involvement of the arms since age 13. At age 41, examination revealed distal amyotrophy and weakness of the four limbs, limited walking, dysesthesia in both feet and
Peripheral nerve biopsies
Both nerve biopsies showed similar modifications. There were a few features of hypermyelination characterized by a too thick myelin sheath wrapping a normal axon (Fig. 2a). There was a moderate loss of myelinated fibers, with presence of numerous clusters of regenerating small myelinated fibers, a few features of axonopathy, and also onion bulb-like formations composed of concentric Schwann cell processes surrounding clusters of regenerating fibers (Fig. 2b). Several enlarged mitochondria with
Discussion
Nerve biopsy results in a case with CMT2K [4] and in our case showed similar lesions with myelin modifications, myelinated fiber loss and onion bulb-like formations surrounding clusters of regenerating nerve fibers. In our case, there were also features of hypermyelination and intra-axonal modified mitochondria. Fiber loss was associated with onion bulb-like formations composed of Schwann cell processes surrounding clusters of regenerating nerve fibers. GDAP1 is located in the mitochondrial
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2020, Neuromuscular DisordersCitation Excerpt :True DI has been defined as the coinheritance of two non-allelic mutations, both necessary and sufficient to elicit the phenotype [9]. A probable DI has been suggested for several genes known to cause CMT [10], and the coinheritance of variants for the MFN2 and GDAP1 genes has already been published, however, a synergistic effect has been deemed as causal and a true DI has not been proved [3,11–14]. Herein, we report a 10-year-old boy with a severe CMT phenotype due to the coinheritance of two familial MFN2/GDAP1 non-allelic variants, and summarize similar published cases.
Charcot-Marie-Tooth 2F (Hsp27 mutations): A review
2019, Neurobiology of DiseaseCitation Excerpt :Multiple groups have discovered patients with mutations of both MFN2 and GDAP1. As both of these genes influence mitochondrial dynamics, mitochondrial function may be a common mechanistic of CMT2 (Cassereau et al., 2011; Vital et al., 2012). Moreover, specific mutations that typically lead to mild disease alone present with severe symptomatology when inherited together, suggesting a synergistic or additive effect of mutation burden (Vital et al., 2012).
Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity
2016, Neurobiology of DiseaseCitation Excerpt :We will concentrate on CMT2A, an axonal autosomal dominant CMT associated to MFN2 mutations (Feely et al., 2011; Zuchner et al., 2004) and to recessive or dominant CMTs (CMT4A, AR-CMT2, CMTK) linked to mutations of GDAP1 (see for review Cassereau et al., 2011b). In this respect, it is interesting to note that some patients with severe CMT symptoms carry simultaneous heterozygous MFN2 and GDAP1 mutations that, separately, are either linked to a mild form of CMT or not associated to CMT (Cassereau et al., 2011a; Vital et al., 2012). On the other hand, it was recently reported that mutations in the SLC25A46 gene cause both CMT2 and optic atrophy, thus increasing the number of mitochondrial neurodegenerative diseases associated with mitochondrial dynamics (Abrams et al., 2015).
MFN2-related neuropathies: Clinical features, molecular pathogenesis and therapeutic perspectives
2015, Journal of the Neurological SciencesExome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy
2015, Cell ReportsCitation Excerpt :We identified a patient with mutations in both MFN2 and GDAP1, both of which are involved in mitochondrial dynamics. Concurrent mutations in these genes have been reported, suggesting the possibility of epistasis or modifying effects (Cassereau et al., 2011; Vital et al., 2012). In a family with three generations affected by autosomal dominant intermediate CMT, we sequenced two individuals and identified a novel variant in YARS affecting a residue previously reported to be mutated in disease (Jordanova et al., 2006) (Figure 1B).