Juvenile ALS masquerading as an acquired inflammatory neuropathy

Topic:

Clinical Management

Poster Number: P264

Author(s):

Ameya Walimbe, MD, PhD, MSE, Baylor College of Medicine, Chrissie Massrey, MD, Baylor College of Medicine, Abhijit Das, MD, Baylor College of Medicine, Zurisadai Gonzalez Castillo, MD, UT Southwestern, Sofia Babool, UT Southwestern, Sreenivas Avula, MD, Department of Neurology, Baylor College of Medicine, Susan Iannaccone, MD, UT Southwestern, Kaitlin Batley, MD, UT Southwestern, Timothy Lotze, MD, Baylor College of Medicine

Background: Juvenile Amyotrophic Lateral Sclerosis-6 (JALS-6, MIM# 608030) is a rare, progressive motor neuron disorder caused by pathogenic variants in Fused in Sarcoma (FUS, MIM #137070), a ubiquitously expressed pre-mRNA splicing factor. The classic phenotype includes upper and lower motor neuron signs, early bulbar dysfunction, cognitive impairment, tremor, and myoclonus. However, findings are variable and may mimic other conditions.

Objectives: Report an unusual clinical presentation of JALS-6.

Results: Here, we describe a 16-year-old female with intellectual disability who presented with seven months of painless progressive proximal muscle weakness and worsening tremors. She had preserved reflexes, but CSF showed albumino-cytologic dissociation. A spine MRI demonstrated peripheral nerve root enhancement, suggesting an acquired inflammatory neuropathy. However, IVIG, steroids, and PLEX were ineffective. An EMG demonstrated fibrillation potentials, severely decreased motor amplitudes, and prolonged motor latencies, consistent with axonal neuropathy. A muscle biopsy corroborated these findings. Chromosomal Microarray (CMA) and duo-whole exome sequencing (WES) reported no pathogenic variants related to a phenotype of chronic, progressive weakness with neuropathic features. With non-diagnostic genetic studies, an inflammatory neuropathy remained a consideration, and rituximab and monthly IVIG were started. She presented to our institution in acute respiratory failure with flaccid quadriplegia, areflexia, tongue atrophy, fasciculations, and polyminimyoclonus. WES re-analysis, with an updated phenotype concerning for motor neuron disease, revealed a de novo heterozygous likely pathogenic variant in FUS (c.1573C>T, p.P525S), consistent with JALS-6. She was subsequently started on Riluzole, but without significant clinical improvement. She was not a candidate for the IONIS trial, and her condition was too advanced for jacifusen. Currently, she has minimal finger and facial movements, can vocalize, and communicates with eye gaze.

Conclusions: We highlight a case of JALS-6 that began with subacute progressive weakness accompanied by CSF albumino-cytologic dissociation, nerve root enhancement on MRI, and an initially non-diagnostic genetic work-up mimicking an acquired inflammatory neuropathy. Our study suggests that features of JALS-6 can mimic an inflammatory neuropathy, and WES re-analysis may be beneficial when the clinical phenotype has evolved.