A French family with Charcot–Marie–Tooth disease related to simultaneous heterozygous MFN2 and GDAP1 mutations

doi:10.1016/j.nmd.2012.04.001

Neuromuscular Disorders

Volume 22, Issue 8, August 2012, Pages 735-741

https://doi.org/10.1016/j.nmd.2012.04.001 Get rights and content

Abstract

Either dominantly inherited mutations in MFN2 encoding mitofusin 2 or GDAP1 encoding ganglioside-induced differentiation associated protein 1 may be associated with mild neuropathy.

The proband, a 41-year-old woman, and her daughter present a severe axonal form of Charcot–Marie–Tooth (CMT) disease. Both are heterozygous for the well-described mild variant p.R120W in GDAP1, which was transmitted by the pauci symptomatic proband’s mother. Given that they had an early onset in the first decade and delayed walking acquisition, the other genes implicated in axonal forms of CMT disease were analyzed. A second mutation truncating MFN2 (p.Val160fsX26) was found in the proband and her daughter. This mutation was transmitted by the proband’s father who has normal neurological examination. The proband underwent two nerve biopsies which showed an axonal degeneration, myelin modifications, and intra-axonal mitochondria with distorted cristae. Such abnormal mitochondria have been reported in cases with autosomal dominant MFN2 mutations and in one patient with an autosomal recessive GDAP1 mutation. Our two cases show that heterozygous truncation of MFN2, which is silent at least until the sixth decade, when combined with the mild p.R120W GDAP1 variant, leads to a severe neuropathy. This supports the emerging hypothesis of cumulative effects of MFN2 and GDAP1 mutation.

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

References (39)

J. Cassereau et al.
Mitochondrial dysfunction and pathophysiology of Charcot–Marie–Tooth disease involving GDAP1 mutations
Exp Neurol
(2011)
A. Niemann et al.
GDAP1 mutations differ in their effects on mitochondrial dynamics and apoptosis depending on the mode of inheritance
Neurobiol Dis
(2009)
I. Banchs et al.
Two Spanish families with Charcot–Marie–Tooth type 2A: clinical, electrophysiological and molecular findings
Neuromuscul Disord
(2008)
M. Luigetti et al.
Clinical, electrophysiological and pathological findings of a patient with CMT2 due to the p.Ala738Val mitofusin 2 mutation
J Neurol Sci
(2011)
A.B. Genari et al.
Characterizing the phenotypic manifestations of MFN2 R104W mutation in Charcot–Marie–Tooth type 2
Neuromuscul Disord
(2011)
D.E. Stickler et al.
Peripheral neuropathy in genetic mitochondrial diseases
Pediatr Neurol
(2006)
M.G. Hanna et al.
Peripheral nerve disease associated with mitochondrial respiratory chain dysfunction
A. Cuesta et al.
The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot–Marie–Tooth type 4A disease
Nat Genet
(2002)
E. Nelis et al.
Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy
Neurology
(2002)
R. Claramunt et al.
Genetics of Charcot–Marie–Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect
J Med Genet
(2005)

K.W. Chung et al.

A novel GDAP1 Q218E mutation in autosomal dominant Charcot–Marie–Tooth disease

J Hum Genet

(2008)

J. Cassereau et al.

Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot–Marie–Tooth disease (CMT2K)

Neurogenetics

(2009)

R. Sivera et al.

Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot–Marie–Tooth disease

J Peripher Nerv Syst

(2010)

M. Zimon et al.

Dominant GDAP1 mutations cause predominantly mild CMT phenotypes

Neurology

(2011)

A. Niemann et al.

Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot–Marie–Tooth disease

J Cell Biol

(2005)

S. Züchner et al.

Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot–Marie–Tooth neuropathy type 2A

Nat Genet

(2004)

V.H. Lawson et al.

Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene

Neurology

(2005)

D. Zhu et al.

Charcot–Marie–Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations

Neurology

(2005)

K. Kijima et al.

Mitochondrial GTPase mitofusin 2 mutation in Charcot–Marie–Tooth neuropathy type 2A

Hum Genet

(2005)

Cited by (31)

Drosophila models to study causative genes for human rare intractable neurological diseases
2021, Experimental Cell Research
Drosophila is emerging as a convenient model for investigating human diseases. Functional homologues of almost 75% of human disease-related genes are found in Drosophila. Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that causes defects in motoneurons. Charcot-Marie-Tooth disease (CMT) is one of the most commonly found inherited neuropathies affecting both motor and sensory neurons. No effective therapy has been established for either of these diseases. In this review, after overviewing ALS, Drosophila models targeting several ALS-causing genes, including TDP-43, FUS and Ubiquilin2, are described with their genetic interactants. Then, after overviewing CMT, examples of Drosophila models targeting several CMT-causing genes, including mitochondria-related genes and FIG 4, are also described with their genetic interactants. In addition, we introduce Sotos syndrome caused by mutations in the epigenetic regulator gene NSD1. Lastly, several genes and pathways that commonly interact with ALS- and/or CMT-causing genes are described. In the case of ALS and CMT that have many causative genes, it may be not practical to perform gene therapy for each of the many disease-causing genes. The possible uses of the common genes and pathways as novel diagnosis markers and effective therapeutic targets are discussed.
Clinical and molecular evidence of possible digenic inheritance for MFN2/GDAP1 genes in Charcot-Marie-Tooth disease
2020, Neuromuscular Disorders
Citation 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 disease (CMT) is a progressive motor and sensory polyneuropathy, it is characterized by a very heterogeneous molecular basis and phenotype. MFN2 and GDAP1 participate in mitochondrial energy metabolism and the rare coinheritance of its pathogenic variants has been associated with a cumulative effect in the observed phenotype. We describe a patient with a severe axonal CMT and inherited heterozygous MFN2 (p.Leu741Val) and GDAP1 (p.Gln163*) variants. In accordance with a possible digenic inheritance, none of the heterozygous carriers in his family were symptomatic or exhibited electrophysiological abnormalities. We also review all of the previously reported patients with coinheritance of variants in these two genes; similar to our patient, all exhibit a predominantly axonal severe CMT phenotype. Our findings expand the genotypic spectrum of CMT and further support that digenic inheritance should be considered for analyzing and counseling CMT patients.
Charcot-Marie-Tooth 2F (Hsp27 mutations): A review
2019, Neurobiology of Disease
Citation 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).
Charcot-Marie-Tooth disease is a commonly inherited form of neuropathy. Although named over 100 years ago, identification of subtypes of Charcot-Marie-Tooth has rapidly expanded in the preceding decades with the advancement of genetic sequencing, including type 2F (CMT2F), due to mutations in heat shock protein 27 (Hsp27). However, despite CMT being one of the most common inherited neurological diseases, definitive mechanistic models of pathology and effective treatments for CMT2F are lacking. This review extensively profiles the published literature on CMT2F and distal hereditary motor neuropathy II (dHMN II), a similar neuropathy with exclusively motor symptoms that is also due to mutations in Hsp27. This includes a review of case reports and sequencing studies detailing disease course. Included are tables listing of all known published mutations of Hsp27 that cause symptoms of CMT2F and dHMN II. Furthermore, pathological mechanisms are assessed. While many groups have established pathologies relating to defective chaperone function, cellular neurofilament and microtubule structure and function, and mitochondrial and metabolic dysfunction, there are still discrepancies in results between different model systems. Moreover, initial mouse models have also produced promising results with similar phenotypes to humans, however discrepancies still exist. Both patient-focused and scientific studies have demonstrated variability in phenotypes even considering specific mutations. Given the clinical heterogeneity in presentation, CMT2F and dHMN II likely result from similar pathological mechanisms of the same general disease process that may present distinctly due to other genetic and environment influences. Determining how these influences exert their effects to produce pathology contributing to the disease phenotype will be a major future challenge ahead in the field.
Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity
2016, Neurobiology of Disease
Citation 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).
Mitochondria are dynamic organelles that continually move, fuse and divide. The dynamic balance of fusion and fission of mitochondria determines their morphology and allows their immediate adaptation to energetic needs, keeps mitochondria in good health by restoring or removing damaged organelles or precipitates cells in apoptosis in cases of severe defects. Mitochondrial fusion and fission are essential in mammals and their disturbances are associated with several diseases. However, while mitochondrial fusion/fission dynamics, and the proteins that control these processes, are ubiquitous, associated diseases are primarily neurological disorders. Accordingly, inactivation of the main actors of mitochondrial fusion/fission dynamics is associated with defects in neuronal development, plasticity and functioning, both ex vivo and in vivo. Here, we present the central actors of mitochondrial fusion and fission and review the role of mitochondrial dynamics in neuronal physiology and pathophysiology. Particular emphasis is placed on the three main actors of these processes i.e. DRP1, MFN1-2, and OPA1 as well as on GDAP1, a protein of the mitochondrial outer membrane preferentially expressed in neurons. This article is part of a Special Issue entitled: Mitochondria & Brain.
MFN2-related neuropathies: Clinical features, molecular pathogenesis and therapeutic perspectives
2015, Journal of the Neurological Sciences
Mitofusin 2 (MFN2) is a GTPase dynamin-like protein of the outer mitochondrial membrane, encoded in the nuclear genome by the MFN2 gene located on the short (p) arm of chromosome 1. MFN2 protein is involved in several intracellular pathways, but is mainly involved in a network that has an essential role in several mitochondrial functions, including fusion, axonal transport, interorganellar communication and mitophagy. Mutations in the gene encoding MFN2 are associated with Charcot–Marie–Tooth disease type 2A (CMT2A), a neurological disorder characterized by a wide clinical phenotype that involves the central and peripheral nervous system. Here, we present the clinical, genetic and neuropathological features of human diseases associated with MFN2 mutations. We also report proposed pathogenic mechanisms through which MFN2 mutations likely contribute to the development of neurodegeneration. MFN2-related disorders may occur more frequently than previously considered, and they may represent a paradigm for the study of the defective mitochondrial dynamics that seem to play a significant role in the molecular and cellular pathogenesis of common neurodegenerative diseases; thus they may also lead to the identification of related therapeutic targets.
Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy
2015, Cell Reports
Citation 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).
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.

View all citing articles on Scopus

View full text

A French family with Charcot–Marie–Tooth disease related to simultaneous heterozygous MFN2 and GDAP1 mutations

Abstract

Introduction

Section snippets

Patients and methods

Peripheral nerve biopsies

Discussion

Exp Neurol

Neurobiol Dis

Neuromuscul Disord

J Neurol Sci

Neuromuscul Disord

Pediatr Neurol

The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot–Marie–Tooth type 4A disease

Nat Genet

Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy

Neurology

Genetics of Charcot–Marie–Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect

J Med Genet

A novel GDAP1 Q218E mutation in autosomal dominant Charcot–Marie–Tooth disease

J Hum Genet

Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot–Marie–Tooth disease (CMT2K)

Neurogenetics

Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot–Marie–Tooth disease

J Peripher Nerv Syst

Dominant GDAP1 mutations cause predominantly mild CMT phenotypes

Neurology

Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot–Marie–Tooth disease

J Cell Biol

Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot–Marie–Tooth neuropathy type 2A

Nat Genet

Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene

Neurology

Charcot–Marie–Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations

Neurology

Mitochondrial GTPase mitofusin 2 mutation in Charcot–Marie–Tooth neuropathy type 2A

Hum Genet