Charcot-Marie-Tooth 1A (CMT1A) is the most common inherited neuropathy without a known therapy, which is caused by a 1.4 Mb duplication on human chromosome 17, which includes the gene encoding the peripheral myelin protein of 22 kDa (PMP22).
On the whole, the findings of this study indicate that treatment with 4‑ASA reduced the ER stress and SC death caused by 2 different MPZ mutants and suggest that ASA may be a potential therapeutic agent for CMT.
Heterologous expression of the CMT-associated PMP22_L16P variant, which fails to reach the plasma membrane and localizes to the ER, led to larger currents than WT PMP22.
In this review, we summarize the different functions proposed for GDAP1 and focus on the consequences for Ca<sup>2+</sup> homeostasis and mitochondrial energy production linked to CMT disease caused by different <i>GDAP1</i> mutations.
We describe clinical data and detailed pathological analysis mainly by electron microscopy of the sciatic nerves of these animal models conducted in our laboratory; lesions of PMP22 deficient animals (KO and mutated PMP22) and PMP22 overexpressed models are described and compared to ultrastructural anomalies of nerve biopsies from CMT patients due to PMP22 gene anomalies.
A nonsense mutation in myelin protein zero causes congenital hypomyelination neuropathy through altered P0 membrane targeting and gain of abnormal function.
This platform should be useful in clinical trials for CMT1A as a biomarker of target engagement that can be used to optimize dosing, and the same normalization framework is applicable to other types of CMT.ANN NEUROL 2019;85:887-898.
Sixty-three members of a large CMT 1B kindred were assessed for signs of peripheral neuropathy and cranial neuropathies then tested for the G163R mutation in the myelin protein zero (MPZ) gene.
In summary, we demonstrate that inflammation in spinal cord and sciatic nerve, but not in brain and cerebellum, is part of the pathophysiology of axonal GDAP1-related CMT.
Genetic disruption of Schwann cell-derived NRG1 signalling in a mouse model of Charcot-Marie-Tooth Disease 1A (CMT1A), suppresses hypermyelination and the formation of onion bulbs.
A subset of genomic disorders similarly characterized by CNVs between LCRs have been studied epidemiologically, including Williams-Beuren syndrome (7q11.23), Smith-Magenis syndrome (17p11.2), velocardiofacial syndrome (22q11.21), Prader-Willi/Angelman syndromes (15q11.2q12), 17q12 deletion syndrome, and Charcot-Marie-Tooth neuropathy type 1/hereditary neuropathy with liability to pressure palsy (PMP22, 17q11.2).
Duplications or deletions of the dosage-sensitive gene PMP22 mapped to chromosome 17p12 represent the most frequent causes of CMT type 1A and Hereditary Neuropathy with liability to Pressure Palsies (HNPP), respectively.
In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss during adult life.
The early onset of the disease, the distal and proximal weakness and atrophy leading to major disability, along with areflexia, and, most notably, vocal cord and diaphragm paralysis were highly evocative of a GDAP1-related CMT.