Abstract Details

Title Distal Agrin (AGRN) Congenital Myasthenic Syndrome With Mitochondrial Dysfunction

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P3 - Poster Session 3 (5:00 PM-6:00 PM)

Poster/Presentation
Number 9-008

Objective To report myopathological evidence of mitochondrial dysfunction in a patient with agrin (AGRN)-congenital myasthenic syndrome (CMS).

Background

AGRN-CMS is a rare, phenotypically heterogeneous genetic disorder of the neuromuscular transmission, which can affect pre-synaptic and post-synaptic sites of the neuromuscular junction. It can present with progressive distal weakness, mimicking a distal myopathy. Muscle biopsy findings are variable, ranging from normal to non-specific myopathic changes, rimmed vacuoles, myofibrillar network disarray, tubular aggregates, and neurogenic changes, posing additional diagnostic challenges. To date, mitochondrial dysfunction has not been reported in AGRN-CMS.

Design/Methods NA

Results A 47-year-old male presented at age 18 with sudden onset of eyelid ptosis, weakness and fatigue, followed by dysphagia and dyspnea on exertion. More recently he developed exercise-induced myalgia. Three sisters have similar symptoms. Neurological examination showed diffuse lower limb weakness predominantly affecting calf muscles with associated atrophy. Tendon reflexes were normal but absent at the ankles. Creatine kinase was normal. EMG demonstrated myopathic changes in distal and paraspinal muscles with fibrillation potentials in the gastrocnemius. 2Hz-Repetitive nerve stimulation of fibular nerve revealed a 32% decrement in the extensor digitorum brevis without facilitation. Tibialis anterior biopsy showed non-specific myopathic changes, neurogenic features, and evidence of mitochondrial dysfunction, as suggested by the frequent cytochrome-c-oxidase-negative fibers. A trial of treatment with pyridostigmine was of no benefit. Pulmonary tests showed a restrictive pattern. Cardiac findings were normal. Whole exome sequencing (WES) detected an AGRN homozygous pathogenic variant (c.5012G>A, p.Arg1671Gln) and a heterozygous TTN variant (c.41480delG, p.Ser13827fs). Mitochondrial DNA analysis showed a homoplasmic VUS (m. 9157G>A, p.A211Thr).

Conclusions We describe a case of AGRN-CMS with myopathological evidence of mitochondrial dysfunction which could be part of the phenotype. Myopathological and electromyographic myopathic changes can occur in CMS. Therefore, low-frequency repetitive nerve stimulation is crucial for differentiating myopathies from CMS, especially in the setting of distal weakness.

Authors/Disclosures
Mariana Hiromi M. Oku, MD PRESENTER	Dr. Oku has nothing to disclose.
Zhiyv Niu, PhD, FACMG (Mayo Clinic)	Zhiyv Niu has nothing to disclose.
William J. Litchy, MD, FAAN	Dr. Litchy has nothing to disclose.
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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