Abstract Details

Title Severe adolescent-onset limb-girdle muscular dystrophy due to a novel homozygous nonsense BVES mutation

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) Neuromuscular and Clinical Neurophysiology (EMG) Posters (7:00 AM-5:00 PM)

Poster/Presentation
Number 011

Objective To describe a severe phenotype of adolescent-onset autosomal recessive limb-girdle muscular dystrophy 25 (LGMDR25) due to a novel truncating BVES mutation.

Background LGMDR25 is a recently defined adult-onset muscular dystrophy due to loss-of-function mutations in the blood vessel epicardial substance (BVES) gene. BVES encodes Popeye domain–containing 1 (POPDC1), a transmembrane protein prominently expressed in plasma membrane of skeletal and cardiac muscle, which plays a role in skeletal muscle membrane trafficking and cardiac pacemaking and cardiomyocyte survival after ischemia, respectively. POPDC1 binds cyclic 3’,5’-adenosine monophosphate (cAMP), and loss of popdc1 expression in zebrafish leads to atrioventricular (AV) block and abnormal skeletal muscle development. Nine patients with LGMDR25 have been described to date, characterized by AV block with or without late adult-onset progressive proximal lower limb weakness.

Design/Methods Case report.

Results A 38 year-old male presented with slowly progressive weakness in the proximal right lower extremity at age 16. By age 25, bilateral scapular winging and severe right greater than left humeral-pectoral and left proximal lower extremity weakness had developed. Creatine kinase was elevated at 4054 U/L. Nerve conduction studies, including repetitive nerve stimulation, were normal. Electromyography revealed a diffuse myopathy with occasional fibrillation potentials. MRI demonstrated diffuse fatty atrophy of the thigh, lateral gastrocnemius and soleus, with relative, asymmetric sparing of rectus femoris and medial gastrocnemius. Right quadriceps biopsy was consistent with chronic myopathy. Electrocardiogram revealed sinus bradycardia and 1^st degree AV block. Echocardiogram was normal. Next generation sequencing identified a novel homozygous c.427A>T (p.Arg143Ter) variant in exon 4 of BVES, which is absent in the general population and is predicted to result in protein truncation or nonsense mediated mRNA decay.

Conclusions This relatively severe phenotype of scapular winging and prominent humeral-pectoral weakness, with the earliest age of onset to date, expands the clinical spectrum of LGMDR25.

Authors/Disclosures
Grayson B. Beecher, MD (University of Alberta) PRESENTER	Dr. Beecher has nothing to disclose.
Connie G. Tang, MD (Lehigh Valley Health Network)	Dr. Tang has nothing to disclose.
Teerin Liewluck, MD, F�鶹��ýӳ�� (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.

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