Novel variants broaden the phenotypic spectrum of PLEKHG5‐associated neuropathies

Abstract

Background and purpose Pathogenic variants in PLEKHG5 have been reported to date to be causative in three unrelated families with autosomal recessive intermediate Charcot‐Marie‐Tooth disease (CMT) and in one consanguineous family with spinal muscular atrophy (SMA). PLEKHG5 is known to be expressed in the human peripheral nervous system, and previous studies have shown its function in axon terminal autophagy of synaptic vesicles, lending support to its underlying pathogenetic mechanism. Despite this, there is limited knowledge of the clinical and genetic spectrum of disease. Methods We leverage the diagnostic utility of exome and genome sequencing and describe novel biallelic variants in PLEKHG5 in 13 individuals from nine unrelated families originating from four different countries. We compare our phenotypic and genotypic findings with a comprehensive review of cases previously described in the literature. Results We found that patients presented with variable disease severity at different ages of onset (8–25 years). In our cases, weakness usually started proximally, progressing distally, and can be associated with intermediate slow conduction velocities and minor clinical sensory involvement. We report three novel nonsense and four novel missense pathogenic variants associated with these PLEKHG5‐associated neuropathies, which are phenotypically spinal muscular atrophy (SMA) or intermediate Charcot‐Marie‐Tooth disease. Conclusions PLEKHG5‐associated neuropathies should be considered as an important differential in non‐5q SMAs even in the presence of mild sensory impairment and a candidate causative gene for a wide range of hereditary neuropathies. We present this series of cases to further the understanding of the phenotypic and molecular spectrum of PLEKHG5‐associated diseases.

PLEKHG5: Merging phenotypes and disease mechanisms in Charcot‐Marie‐Tooth neuropathy and lower motor neuron disease

“…Of note, these patients presented with intermediate Charcot‐Marie‐Tooth neuropathy (OMIM #615376), a neurological phenotype with different, but partly overlapping, characteristics of a sensorimotor neuropathy affecting Schwann cells as well as motor and sensory axons [2,3] In this issue of the European Journal of Neurology , Chen and colleagues combined precise phenotyping, comprehensive genetic screening, and worldwide data sharing and collaboration. Their research has resulted in the identification of several additional PLEKHG5 missense and loss‐of‐function mutations and a little more than a tripling of the total number of reported families [4] Consistent with previous reports, some of their families can be classified as spinal muscular atrophy or intermediate Charcot‐Marie‐Tooth neuropathy, whereas others are probably best categorised as pure distal motor neuropathy. In essence, their work demonstrates that PLEKHG5 mutations are probably less rare than previously anticipated and not confined to a particular phenotype, but rather cause a continuum of related conditions ranging from lower motor neuron disease over motor neuropathies to sensorimotor neuropathies.…”

Leukoencephalopathy and conduction blocks in PLEKHG5-associated intermediate CMT disease

“…Rapid progress in molecular genetics, including the increasing availability of nextgeneration sequencing has allowed to identify over 100 genes associated to CMT [1,12] and has unveiled a striking genetic and clinical overlap between CMT, distal hereditary motor neuropathies (HMN) and lower motor neuron syndromes [13,14]. Such is the case for PLEKHG5, associated with both proximal SMA, intermediate CMT and HMN [3][4][5][6].…”

“…More recently, cases with either pure lower motor neuron disease (LMND), distal and proximal neuropathy with mild sensory involvement or intermediate-CM have been documented [6][7][8]. Here, we report two additional families carrying novel PLEKHG5 mutations presenting with an intermediate CMT phenotype associated with atypical findings, including leukoencephalopathy, conduction blocks on electrophysiological studies and highly elevated creatine kinase (CK), thus expanding the phenotypical spectrum of the disease.…”

Expanding the genotype-phenotype spectrum of autosomal recessive Charcot-Marie-Tooth disease: A novel PLEKHG5 gene mutation

“…In the present case, intermediate polyneuropathy was detected with moderately but predominantly demyelinating features of the sensory and motor nerves at first examination, while later axonal features became evident with active and chronic denervation findings. 5,9 Kim et al reported the involvement of anterior and lateral compartment muscles predominantly on hip MRI. 3 However, in the current study, the lower-limb MRI of the patient showed Goutallier classification of 1 degree of fatty changes in both the anterior and medial compartment muscles.…”

“…Motor and sensory neuropathy in electrophysiological studies and neurological examination are characterized by progressive distal > proximal symmetric muscle atrophy and weakness, initially presenting as distal muscle weakness of the lower limbs, and foot and spine deformity were observed in almost all of the patients. [3][4][5] In this report, the case of a Turkish girl who was diagnosed with autosomal recessive (AR) intermediate CMT disease type-C (AR-CMTRIC) with a novel homozygous mutation in the PLEKHG5 gene is presented. This is a case report of a female patient in clinical follow-up at the Department of Pediatric Neurology, University of Health Sciences (SBU), Dr. Sami Ulus Training and Research Hospital, Ankara, Turkey.…”