Autosomal recessive MFN2‐related Charcot‐Marie‐Tooth disease with diaphragmatic weakness: Case report and literature review

Abstract

Pathogenic variants in the mitofusin 2 gene (MFN2) are the most common cause of autosomal dominant Charcot-Marie-Tooth (CMT2) disease, which is typically characterized by axonal sensorimotor neuropathy. We report on a 7-month-old white female with hypotonia, motor delay, distal weakness, and motor/sensory axonal neuropathy in which next-generation sequencing analysis identified compound heterozygous pathogenic variants (c.2054_2069_1170del and c.392A>G) in MFN2. A review of the literature reveals that sporadic and familial cases of compound heterozygous or homozygous pathogenic MFN2 variants have been infrequently described, which indicates that MFN2 can also be inherited in a recessive manner. This case highlights several clinical findings not typically associated with MFN2 pathogenic variants, including young age of onset and rapidly progressing diaphragmatic paresis that necessitated tracheostomy and mechanical ventilation, and adds to the growing list of features identified in autosomal recessive MFN2-related CMT2. Our patient with MFN2-related CMT2 expands the clinical and mutational spectrum of individuals with autosomal recessive CMT2 and identifies a new clinical feature that warrants further observation. © 2016 Wiley Periodicals, Inc.

Phrenic nerve involvement and respiratory muscle weakness in patients with Charcot‐Marie‐Tooth disease 1A

“…Given that capnographic data from sleep studies in CMT1A patients are not yet available, sleep‐related breathing has only been systematically evaluated with regard to intermittent upper airway collapse, that is, obstructive sleep apnea . Thus, current evidence suggests that severe diaphragm weakness is rare in CMT1A, which is in clear contrast with other genetic subtypes that may be associated with respiratory failure already in childhood . However, phrenic nerve involvement with variable impact on diaphragm function may be present as outlined above.…”

“…22 We observed that mean dCMAP amplitude did not significantly differ between [51][52][53] Thus, current evidence suggests that severe diaphragm weakness is rare in CMT1A, which is in clear contrast with other genetic subtypes that may be associated with respiratory failure already in childhood. 54 However, phrenic nerve involvement with variable impact on diaphragm function may be present as outlined above.…”

Role of the Ca2+-Calcineurin-Nuclear Factor of Activated T cell Pathway in Mitofusin-2-Mediated Immune Function of Jurkat Cells

“…[ 39 ] Thus, MFN2 may be involved in different pathophysiological processes in different systems. [ 40 41 42 ] Further studies are necessary to determine if this effect is present in other types of immune cells. Second, MFN2 may mediate different effects in T cells under different stimuli.…”

Mitochondrial Dynamics: Molecular Mechanisms, Related Primary Mitochondrial Disorders and Therapeutic Approaches

“…Other clinical findings included hearing loss, lipodystrophy, vocal cord palsy, tongue hypertrophy, and facial and respiratory muscle weakness. Heterozygous carrier parents showed no or minimal symptoms [157,[161][162][163][164][165][166][167][168][169][170][171][172].…”