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Available from: Juan J Vílchez, Oct 06, 2015
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    • "Within 10 years over 100 patients harboring mutations in the GDAP1 gene have been reported all over the world (Cassareau et al., 2011). In 2005 Claramunt and colleagues reported on the Arg120Trp mutation in the GDAP1 gene inherited as an autosomal dominant trait (Claramunt et al., 2005). The Arg120Trp mutation segregates with a phenotype of a mild axonal neuropathy with a wide spectrum of clinical features (Siviera et al., 2010). "
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    ABSTRACT: Charcot-Marie-Tooth (CMT) disease caused by mutations in the GDAP1 gene has been shown to be inherited via traits that may be either autosomal recessive (in the majority of cases) [CMT4A] or autosomal dominant [CMT2K]. CMT4A disease is characterized by an early onset, and a severe clinical course often leading to a loss of ambulation, whereas CMT2K is characterized by a mild clinical course of benign axonal neuropathy beginning even in the 6th decade of life. Clinical data from a GDAP1 mutated patient suggests that the presence of a particular mutation is associated with a certain trait of inheritance. The association of a particular GDAP1 gene mutation and a dominant or recessive trait of inheritance is of special importance for genetic counseling and the prenatal diagnostics as regards severe forms of CMT. In the present study we report on two CMT families in which a newly identified Glu222Lys mutation within the GDAP1 gene segregates both in autosomal dominant and recessive traits. Our study shows that at least some GDAP1 gene mutations may segregate with the CMT phenotype as both dominant and recessive traits. Thus, genetic counseling for CMT4A/CMT2K families requires more extensive data on GDAP1 phenotype-genotype correlations.
    Acta biochimica Polonica 10/2014; 61(4). · 1.15 Impact Factor
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    • "Both slow and normal NCVs have been reported in patients, and many of the cases show a severe phenotype and have their onset in childhood. However, mild forms segregating as an autosomal dominant phenotype have also been reported [61]. Mutations have been described in every exon and include missense, nonsense, splicing site, short deletions, and insertion mutations. "
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    ABSTRACT: In the peripheral nervous system disorders plasticity is related to changes on the axon and Schwann cell biology, and the synaptic formations and connections, which could be also a focus for therapeutic research. Charcot-Marie-Tooth disease (CMT) represents a large group of inherited peripheral neuropathies that involve mainly both motor and sensory nerves and induce muscular atrophy and weakness. Genetic analysis has identified several pathways and molecular mechanisms involving myelin structure and proper nerve myelination, transcriptional regulation, protein turnover, vesicle trafficking, axonal transport and mitochondrial dynamics. These pathogenic mechanisms affect the continuous signaling and dialogue between the Schwann cell and the axon, having as final result the loss of myelin and nerve maintenance; however, some late onset axonal CMT neuropathies are a consequence of Schwann cell specific changes not affecting myelin. Comprehension of molecular pathways involved in Schwann cell-axonal interactions is likely not only to increase the understanding of nerve biology but also to identify the molecular targets and cell pathways to design novel therapeutic approaches for inherited neuropathies but also for most common peripheral neuropathies. These approaches should improve the plasticity of the synaptic connections at the neuromuscular junction and regenerate cell viability based on improving myelin and axon interaction.
    Neural Plasticity 06/2012; 2012(2):171636. DOI:10.1155/2012/171636 · 3.58 Impact Factor
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    • "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]. "
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    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.
    Neuromuscular Disorders 04/2012; 22(8):735-41. DOI:10.1016/j.nmd.2012.04.001 · 2.64 Impact Factor
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