Objective:

To describe 2 patients with HSPB8-neuromuscular disorder, one with childhood-onset and a novel variant, and the other with a novel presentation of a known pathogenic variant.

Background:

HSPB8 is a component of the chaperone-assisted selective autophagy complex, which is crucial to maintain protein homeostasis in muscle and neuronal cells. HSPB8 pathogenic variants are associated with rimmed vacuolar myopathy (RVM) and myofibrillar pathology, Charcot-Marie-Tooth disease (CMT), and distal hereditary motor neuronopathy (dHMN). 

Design/Methods:

Review of clinical history and laboratory data.

Results:

Patient 1 is 61-year-old male with childhood-onset, progressive, distal more than proximal lower limb weakness. Examination showed asymmetric atrophy and weakness predominantly affecting lower limb muscles but sparing quadriceps. CK was normal. EMG detected mixed myopathic and neurogenic changes with the latter being more prominent in lower limbs. Muscle biopsies revealed a RVM in the supraspinatus and neurogenic changes in the tibialis anterior. Patient carries a novel HSPB8 heterozygous variant, c.185G>A (p. Gly62Asp), which is predicted to be disruptive. Patient 2 is a 39-year-old male with distal and asymmetric onset, progressive lower limb weakness and atrophy, followed by fasciculations, since his early 20s. Examination showed moderate generalized lower limb and neck flexor muscle weakness and atrophy, mild proximal upper limb weakness, and fasciculations in the gastrocnemius. CK was mildly elevated. EMG revealed myopathic changes with fibrillation potentials in most muscles and neurogenic changes in the tibialis anterior. Quadriceps biopsy showed a RVM. Patient harbors a de-novo heterozygous pathogenic HSPB8 variant, c.421 A>G (p.Lys141Glu) previously associated with dHMN and myopathy with myofibrillar pathology. Neither patient had cardiac abnormalities by electrocardiogram (patients 1 and 2) or echocardiogram (patient 1).

Conclusions:

HSPB8-neuromuscular disorder can lead to childhood-onset weakness. Myopathy and dHMN can coexist. RVM without myofibrillar aggregates can be a manifestation of HSPB8 c.421A>G, highlighting the spectrum of muscle pathological changes.