Abstract Details

Title Expanding the Clinical, Pathological, and Molecular Spectrum of HSPB8-Neuromuscular Disorder

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P12 - Poster Session 12 (11:45 AM-12:45 PM)

Poster/Presentation
Number 11-028

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.

Authors/Disclosures
Brendan Putko, MD, MSc PRESENTER	Dr. Putko has nothing to disclose.
Eric J. Sorenson, MD, FAAN (Mayo Clinic)	The institution of Dr. Sorenson has received research support from Biogen.
Teerin Liewluck, MD, FAAN (Department of Neurology, Mayo Clinic)	Dr. Liewluck has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta Therapeutics. Dr. Liewluck has received publishing royalties from a publication relating to health care.
Margherita Milone, MD, FAAN (Mayo Clinic)	Dr. Milone has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cartesian Therapeutics. Dr. Milone has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Genetics, AAN. The institution of Dr. Milone has received research support from Mayo Clinic, CCaTS-CBD. The institution of Dr. Milone has received research support from Mayo Clinic, SGP Award. The institution of Dr. Milone has received research support from MDA for Care Center grant. The institution of Dr. Milone has received research support from Regenerative medicine Minnesota.

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