European journal of neurology 2017 10 13() doi 10.1111/ene.13478
Mutations in the small heat shock protein 22 gene (HSPB8) have been associated with Charcot-Marie-Tooth type 2L, distal hereditary motor neuropathy (dHMN) type IIa and, more recently, distal myopathy/myofibrillar myopathy (MFM) with protein aggregates and TDP-43 inclusions.
To report a novel family with HSPB8 (K141E) -related dHMN/MFM and to investigate, in a patient muscle biopsy, whether the presence of protein aggregates was paralleled by altered TDP-43 function.
We reviewed clinical and genetic data. We assessed TDP-43 expression by qPCR and alternative splicing of four previously validated direct TDP-43 target exons in four genes by RT-PCR.
The triplets and their mother presented in the II-III decade of life with progressive weakness affecting distal and proximal lower limb and truncal muscles. Nerve conduction study showed a motor axonal neuropathy. The clinical features, the moderately raised CK levels, the selective pattern of muscle involvement at MRI and the pathological changes on muscle biopsy, including the presence of protein aggregates, supported the diagnosis of a contemporary primary muscle involvement. In affected muscle tissue we observed a consistent alteration of TDP-43-dependent splicing in 3 out of 4 TDP-43-target transcripts (POLDIP3, FNIP1 and BRD8), as well as a significant decrease of TDP-43 mRNA levels.
Our study confirms the role of mutated HSPB8 as a cause of a combined neuromuscular disorder encompassing dHMN and MFM with protein aggregates. We identified impaired RNA metabolism, secondary to TDP-43 loss of function, as a possible pathologic mechanism of HSPB8 (K141E) toxicity, leading to muscle and nerve degeneration. This article is protected by copyright. All rights reserved.