Continuum of phenotypes in hereditary motor and sensory neuropathy with proximal predominance and Charcot–Marie–Tooth patients with TFG mutation

Abstract

Charcot-Marie-Tooth (CMT) is a common neuropathy, and hereditary motor and sensory neuropathy with proximal predominance (HMSN-P) is a recently described rare neuromuscular disease. Although many genes have been implicated for CMT, TFG is the only known HMSN-P-causing gene. Within the framework of diagnostic criteria, clinical variation is evident among CMT-diagnosed and also HMSN-P-diagnosed individuals. Mutations that cause p.(Pro285Leu) and p.(Gly269Val) in TFG were earlier reported as cause of HMSN-P in two Iranian pedigrees. Here, we report the identification of p.(Gly269Val) in TFG as cause of CMT in a large Iranian pedigree. The clinical features of patients of the three pedigrees are presented and critically compared. Similarities between the two HMSN-P-diagnosed pedigrees with different TFG mutations, and differences between the two differentially diagnosed pedigrees with the same p.(Gly269Val) mutation were evident. The clinical features of the HMSN-P pedigree with the p.(Pro285Leu) and the CMT pedigree with the p.(Gly269Val) mutation were clearly congruent with the respective diagnoses, whereas the features of the HMSN-P-diagnosed pedigree with the p.(Gly269Val) were intermediate between the other two pedigrees. It is therefore suggested that the clinical features of the three Iranian pedigrees with TFG mutations and diagnosed with HMSN-P or CMT represent a continuum.

A novel TFG c.793C>G mutation in a Chinese pedigree with Charcot‐Marie‐Tooth disease 2

“…It seems that the clinical features of our patients had an overlap between CMT2 and HMSN‐P. Actually, patients carrying TFG p.Gly269Val have been reported in patients with either CMT2 or HMSN‐P (Khani, Shamshiri, Alavi, Nafissi, & Elahi, 2016; Khani et al., 2019; Tsai et al., 2014) This implied a continuum of phenotypes in HMSN‐P and CMT patients with TFG mutations (Fabrizi et al., 2020; Khani et al., 2019).…”

“…Previous studies revealed that TFG mutations were associated with hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), (Alavi, Shamshiri, & Nafissi, 2015;Ishiura, Sako, & Yoshida, 2012) which is characterized by predominantly proximal muscle weakness and atrophy, widespread fasciculations, cramps, and late-onset distal sensory deficit. It seems that the clinical features of our patients had an overlap between CMT2 and HMSN-P. Actually, patients carrying TFG p.Gly269Val have been reported in patients with either CMT2 or HMSN-P (Khani, Shamshiri, Alavi, Nafissi, & Elahi, 2016;Khani et al, 2019;Tsai et al, 2014) This implied a continuum of phenotypes in HMSN-P and CMT patients with TFG mutations (Fabrizi et al, 2020;Khani et al, 2019).…”

“…Functional study showed that TFG p.Gly269Val mutation increased the propensity of TFG proteins to form aggregates, resulting in sequestration of mutant and wild TFG protein and thus compromising the protein secretory process. Recently, Khani et al found TFG p.Gly269Val mutation in an Iranian pedigree with CMT2 (Khani, Taheri, & Shamshiri, 2019). Of note, only few CMT2 pedigrees with TFG mutations were documented so far.…”

Genetic disorders of cellular trafficking

“…YIF1B causes a progressive encephalopathy with movement disorders, microcephaly, and epilepsy with Golgi and primary cilium alterations [65]. (ii) Late-onset presentations (from late childhood to adulthood) are related with motor dysfunctions such spastic paraparesis (i.e., TANGO2, SLC33A1 defects), and Charcot-Marie-Tooth (CMT) disease (i.e., TFG, CNPNY3 defects) [66].…”

Identification of UBA1 as the causative gene of an X‐linked non‐Kennedy spinal–bulbar muscular atrophy

“…This possibility is negated by observation of sensory indications in the MND‐227 patients and the absence of sensory indications in all forms of SMA. All in all, the clinical and genetic findings pertaining to MND‐227 patients are yet another indication of the complexities and overlaps amongst various neurological diseases [7, 50–53]. Here, these issues are imperfectly resolved by designating the name “non‐Kennedy SBMA” to the disease MND‐227.…”