CMT Peripheral neuropathy 2DD axonal type, associated with ATP1A1 c.620C>A (p.Ser20Tyr) in heterozygosity, presentation of a case and review of the literature.

Peripheral neuropathy 2DD axonal type,

Abstract

Title: Peripheral neuropathy 2DD axonal type, associated with ATP1A1 c.620C>A (p.Ser20Tyr) in heterozygosity: case presentation and literature review.
Leyva García N, Magaña JJ, Rosas Méndez D, Meza Bravo B, Zarco Ordoñez K, Bautista Tirado MT.
Introduction: Peripheral neuropathies, also known as Charcoth Marie Tooth (CMT) disease, are a group of genetically heterogeneous diseases in which more than 50 associated genes have been reported. Their incidence is 1 in 2,500 patients with CMT. They are clinically characterized by lower limb weakness, generally beginning in the first decade of life, and a cavus varus deformity, sometimes with a claw-like hand deformity. Electromyographic studies have classified them as demyelinating and axonal with abnormal conduction velocities <38 m/s and normal, respectively. Through human genome analysis, the etiology of the condition has been determined, providing appropriate counseling and management.
Objective: To evaluate the importance of exome analysis in the investigation of hereditary peripheral neuropathies that do not present with PMP22-CMT1A duplication.
Case Presentation and Results: A 22-year-old male patient was referred for clinical symptoms of neuromuscular diseases. Physical examination revealed muscle weakness in the lower extremities, which he had presented since the age of 3, with slow progression. Currently, his overall muscle strength is 3/3, with moderate deficiency. He was evaluated by cardiology and reported an electrocardiographic trace with sinus arrhythmia. He was evaluated by psychology for anxiety disorders and depression, and had personal sessions. Laboratory tests revealed hyperlipidemia, elevated CPK (770 UL) (33-220), and vitamin D deficiency. The electromyographic study reported: Mixed axonal polyneuropathy in all four limbs. A whole-exome analysis was requested, reporting ATP1A1 c.620C>A (p.Ser20Tyr) and MARS c.491-3C>T (Intronic), both in heterozygosity.
Conclusions: CMT2DD disease is an autosomal dominant axonal neuropathy caused by mutations in the ATP1A1 gene located at 1p13.1, OMIM 618036, Genomic coordinates (GRCh38): 1:116,373,244-116,404,774 (from NCBI). The ATP1A1 gene encodes the alpha-1 isoform of Na(+),K(+)-ATPase, an integral membrane protein responsible for establishing and maintaining electrochemical gradients of Na and K ions across the plasma membrane. The initial report of the mutation was an association, however, the variant found in the ATP1A1 gene in this case was reclassified as probably pathogenic, according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). By having a variant in this classification with a picture compatible with the associated diseases, the diagnosis of an entity can be made, thus reaffirming the diagnosis of CMT 2DD. In this case, the MARS c.491-3C>T (Intronic) gene is also involved in heterozygosity. We observed a deterioration in the patient's clinical progression than expected, perhaps causing a dominant negative effect of his pathology, since it is a gene that encodes for a methionyl-tRNA synthetase enzyme, which can cause CMT type 2U, so this possibility should be considered.