Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy

Abstract

Objective: To report novel disease and pathology due to HSPB8 mutations in 2 families with autosomal dominant distal neuromuscular disease showing both myofibrillar and rimmed vacuolar myopathy together with neurogenic changes.Methods: We performed whole-exome sequencing (WES) in tandem with linkage analysis and candidate gene approach as well as targeted next-generation sequencing (tNGS) to identify causative mutations in 2 families with dominant rimmed vacuolar myopathy and a motor neuropathy. Pathogenic variants and familial segregation were confirmed using Sanger sequencing.Results: WES and tNGS identified a heterozygous change in HSPB8 in both families: c.421A . G p.K141E in family 1 and c.151insC p.P173SfsX43 in family 2. Affected patients had a distal myopathy that showed myofibrillar aggregates and rimmed vacuoles combined with a clear neurogenic component both on biopsy and neurophysiologic studies. MRI of lower limb muscles demonstrated diffuse tissue changes early in the disease stage progressing later to fatty replacement typical of a myopathy. Conclusion:We expand the understanding of disease mechanisms, tissue involvement, and phenotypic outcome of HSPB8 mutations. HSPB8 is part of the chaperone-assisted selective autophagy (CASA) complex previously only associated with Charcot-Marie-Tooth type 2L (OMIM 60673) and distal hereditary motor neuronopathy type IIa. However, we now demonstrate that patients can develop a myopathy with histologic features of myofibrillar myopathy with aggregates and rimmed vacuoles, similar to the pathology in myopathies due to gene defects in other compounds of the CASA complex such as BAG3 and DNAJB6 after developing the early neurogenic effects. Mutations in the small heat shock protein 22 gene (HSPB8, also called HSP22) located on chromosome 12q24.23 are associated with Charcot-Marie-Tooth type 2L (CMT2L) (OMIM 60673) 1 and distal hereditary motor neuronopathy type IIa (dHMN2A). 2 HSPB8 is part of the chaperone-assisted selective autophagy (CASA) complex, a vital part of the cellular protein quality control system in mechanically strained cells and tissues such as skeletal muscle, heart, and lung.3-5 HSPB8 has not been previously associated with a myopathy. The CASA complex comprises the molecular chaperones HSPA8 and HSPB8 and the cochaperones BAG3 and STUB1. 5 In muscle, CASA has a specific role in maintenance of the Z-disk and protein turnover.6,7 CASA mediates degradation of the actin cross-linking protein

Novel HSPB1 mutation causes both motor neuronopathy and distal myopathy

“…It is also interesting that a similar pattern of muscle and nerve involvement was recently reported in 2 families with distal weakness caused by mutation in the related protein encoded by HSPB8 . 8 …”

Neurological disorders, genetic correlations, and the role of exome sequencing

“…In the latter study, the researchers found clinically, electrophysiologically, and via neuroimagery, that "the p.R158H PDK3 mutation [findings from a second CMTX6 family] were similar to the axonal neuropathy reported in the [original] Australian family," even though the phenotype and genotype results indicated that the two families had mutations of a different haplotype [24]. Whole -exome sequencing research expanded HSPB8 mutations knowledge, which had previously only associated with either CMT type 2L or distal hereditary motor neuronopathy type IIa [25]. These researchers were also able to demonstrate that the eventual outcomes, when early neurogenic effects of HSPB8 mutations were present, were no longer limited to the aforementioned two diseases [25].…”

“…The latter study's authors concluded that the finding "differs from demyelinating CMT1A patients and is similar to axonal CMT2A patients" [24]. Autosomal dominant distal neuromuscular disease research on HSPB8 mutations as the causal factor that resulted in myofibrillar aggregates and rimmed vacuolar myopathy combined with neurogenic changes revealed by MRI that the lower limb diffuse tissue alterations in the early disease stages eventually progressed in later stages to myopathy with a typical fatty deposition [45].…”

“…Whole -exome sequencing research expanded HSPB8 mutations knowledge, which had previously only associated with either CMT type 2L or distal hereditary motor neuronopathy type IIa [25]. These researchers were also able to demonstrate that the eventual outcomes, when early neurogenic effects of HSPB8 mutations were present, were no longer limited to the aforementioned two diseases [25].…”

Evolving neuromuscular phenotype in a patient with a heterozygous CHCHD10 p.G66V mutation

“…Because detailed long-term follow-up studies of patients with neuromuscular disorders are not frequently published, it is unclear if the phenotypic heterogeneity reported in the literature actually means the existence of distinct phenotypes, or if it, in some cases, reflects the accumulation of additional abnormalities in the same individual over time, as recently shown for the HSPB8 mutation p.K141E [3] causing a distal hereditary motor neuropathy and a myopathy. Based on our clinical experience with more than 60 patients, in some cases, over a 30-year time period, the phenotype caused by the p.G66V mutation in CHCHD10 is relatively uniform and recognizable, and the expansion of the phenotype to include typical CMT2 and ALS, although recently reported in the literature, has not been well substantiated.…”