Congenital Myasthenic Syndrome Due to Novel GFPT1 Variant Presenting with Head Drop and Visual Impairment: A Case Report
Katharine Torrey1, Emmanuelle Tiongson6, Rachel Logan7, John Dennison2, Andrew Fischer3, Nieraj Jain3, Matthew Schniederjan4, Ricardo Maselli8, Sumit Verma5
1Neurology, 2Departments of Pediatrics and Radiology, 3Department of Ophthalmology, 4Department of Pathology and Pediatrics, 5Departments of Pediatrics and Neurology, Emory University School of Medicine, 6Division of Neurology, Childrens Hospital Los Angeles, 7Neurology, Children's Healthcare of Atlanta, 8Neurology, University of California
Objective:
Our objective is to describe a novel GFPT1 variant causing congenital myasthenic syndrome (CMS), expanding the clinical, pathologic, neurophysiological and genetic understanding of GFPT1-related CMS and emphasizing the importance of deep phenotyping a novel genotype.
Background:
GFPT1 gene variants are a known cause of CMS, typically presenting with fatigable limb-girdle weakness and characteristic tubular aggregates on muscle biopsy, though recent reports have broadened the clinical spectrum. GFPT1 encodes for glutamine-fructose-6-phosphate transaminase 1, an enzyme that catalyzes the initial and rate-determining step of the hexosamine biosynthetic pathway regulating the glycosylation of key neuromuscular junction (NMJ) proteins including acetylcholine receptor subunits. The pathogenic GFPT1 variants result in decreased NMJ acetylcholine receptor expression and impaired signaling.
Design/Methods:
We describe a 5-year-old boy presenting with hypotonia, progressive muscle weakness with head drop, cognitive delay, and visual impairment, found to have a novel homozygous missense variant in GFPT1 (c.1154G>A, p.R385Q). Upon further workup, neuroimaging showed white matter abnormalities with atrophy of corpus callosum and cerebellum, electromyography showed myopathic motor unit potentials, and muscle biopsy showed non-specific changes.
Results:
A stimulated jitter analysis (stim-JA) of the right orbicularis oculi muscle was performed. The Twenty apparent single fiber action potentials (ASFAPs) were recorded with mean jitter value of 69 µs (normal < 24 µs). 95% of ASFAPs (n=19) showed increased jitter and 55% (n=8) were blocked. The NMJ transmission defect on the stim-JA study confirmed the clinical and genetic suspicions of CMS.
Conclusions:
CMS can present broadly and can be diagnostically challenging due to its clinical overlap with other neuromuscular disorders. The index case underscores the importance of deep phenotyping a genotype based on suspected clinical presentation. The case also highlights glycosylation-related CMS and a muscle-eye-brain connection.
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.