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Case Reports
. 2016 Jan 26;86(4):391-8.
doi: 10.1212/WNL.0000000000002324. Epub 2015 Dec 30.

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

Roula Ghaoui  1 , Johanna Palmio  1 , Janice Brewer  1 , Monkol Lek  1 , Merrilee Needham  1 , Anni Evilä  1 , Peter Hackman  1 , Per-Harald Jonson  1 , Sini Penttilä  1 , Anna Vihola  1 , Sanna Huovinen  1 , Mikaela Lindfors  1 , Ryan L Davis  1 , Leigh Waddell  1 , Simran Kaur  1 , Con Yiannikas  1 , Kathryn North  1 , Nigel Clarke  1 , Daniel G MacArthur  1 , Carolyn M Sue  2 , Bjarne Udd  2
Affiliations
Case Reports

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

Roula Ghaoui et al. Neurology. .

Erratum in

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.

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Figures

Figure 1
Figure 1. Pedigrees of 2 unrelated families with HSPB8 mutations causing a distal myopathy
Pedigrees of family 1 and family 2. The blue symbols represent unaffected members and red symbols represent affected members. *Patients with available DNA samples.
Figure 2
Figure 2. Muscle MRI of the affected patients with HSPB8 variants
(A) In patient III-2 (family 1), early diffuse degenerative changes are seen in the distal thigh muscles and in the lower legs, specifically in the gastrocnemius and peroneal muscles. (B) In patient II-2 (family 1), there is severe fatty degenerative replacement in the quadriceps muscles and milder in sartorius, gracilis, semimembranosus, and long head of biceps femoris. In the lower legs, there is generalized fatty replacement, although to a lesser extent in the left soleus and extensor digitorum longus. (C) In patient III-2 (family 2), fatty degenerative changes are present in the gluteus minimus and medius on the pelvic level, in the anterior compartment of the lower legs, and with more diffuse involvement in the thigh muscles.
Figure 3
Figure 3. Scapular winging and muscle atrophy in proband of family 2 (III-2)
Asymmetrical upper limb proximal muscle atrophy was evident with scapular winging more pronounced on the left compared to the right.
Figure 4
Figure 4. Muscle histochemistry and immunohistochemistry of HSPB8-associated distal myopathy
Panel shows histochemical and immunohistochemical analyses of patient III-2 (family 1): (A) Herovici, (B) α-B-crystallin, (C) LC3b, (D) HSPB8 (green)/TAR DNA-binding protein 43 (TDP-43) (red) double stain, (E) DNAJB6 (green)/TDP-43 (red), (F) myotilin (green)/TDP-43 (red), (G) p62 (green)/TDP-43 (red), (H) BAG3 (green)/TDP-43 (red); and patient III-2 (family 2): (I) Herovici, (J) α-B-crystallin, (K) LC3b, (L) myotilin, (M) SMI-31, (N) TDP-43, (O) DYS2, (P) p62. Magnification ×20 in 3,3'-diaminobenzidine/immunohistochemistry stainings (A–C, I–P) and ×40 in immunofluorescence stainings (D–H).
Figure 5
Figure 5. The K141E mutation alters the aggregation score compared to wild-type
Transient cotransfection of an aggregation prone protein (GFP-120Q-HTT) and HSPB8 constructs results in a loss of ability to prevent aggregation in the mutant HSPB8 protein.
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