Jordan Klein
University of Virginia School of Medicine
Charlottesville, VA
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.jpg "Michael Spaeder, MD, MS, FCCM photo")
Michael Spaeder, MD, MS, FCCM
Associate Professor/Fellow Director
University of Virginia School of Medicine
Charlottesville, VA
Disclosure information not submitted.
Title: Homozygous nonsense mutation in ARL6IP1 leads to severe phenotype of hereditary spastic paraplegia.
Case Report Body
Introduction: Hereditary spastic paraplegia is a heterogenous disease with over 70 responsible mutations described thus far in the literature. We present a case of a rare, homozygous nonsense mutation c.346 >T (p.Arg116*) in ADP ribosylation factor like GTPase 6 interacting protein 1 (ARL6IP1) gene with a more severe phenotype than generally described for non-null mutations in ARL6IP1.
Description: A 3-month-old male with failure to thrive presented to the pediatric intensive care unit with acute hypoxemic respiratory failure. He was born at term and starting at one month of life was noted to have progressive fatigue, choking and increased work of breathing with feeds. During admission he required intubation with full ventilatory support and developed seizures treated with levetiracetem. He failed a trial of extubation with immediate gasping respirations, tachycardia, and hypoxia. Magnetic resonance imaging of the brain demonstrated an immature sulcation pattern, hypoplastic vermis and corpus callosum and a normal myelination pattern. Preliminary genetic testing revealed a mutation in ARL6IP1 gene which is associated with motor and sensory neuropathy with normal cognition. Final results, however, indicated he had a homozygous nonsense mutation c.346 >T (p.Arg116*) which has been reported in only two cases with respiratory failure resulting in death for one patient at age 3 months and tracheostomy/ventilator and gastrostomy tube feed dependence in the second patient. Additionally our patient had an older sibling who presented with a similar course and died of respiratory failure at age 3 months with similar neuroimaging findings as well as a sural nerve biopsy with amyelination. With this information the family decided against tracheostomy and gastrostomy and requested a final trial of extubation. The patient, however, developed Modified Bell Stage II necrotizing enterocolitis. Despite treatment with broad spectrum antibiotics and bowel rest, he progressed to necrotizing enterocolitis totalis and was transitioned to comfort care prior to death.
Discussion: This case adds one confirmed and one suspected case to the reports of nonsense mutation c.346 >T (p.Arg116*) in ARL6IP1 with a severe phenotype and a poor prognosis. This information can be used moving forward to inform care as well as our counseling of families.