Abstract Details

Title Genetic Work Up in a Consanguineous Family with Variable Phenotypes Including Cognitive Regression, Spasticity, and Visual Impairment

Topic Child Neurology and Developmental Neurology

Presentation(s) P8 - Poster Session 8 (5:30 PM-6:30 PM)

Poster/Presentation
Number 8-007

Objective Describe genetic work up in consanguineous Pakistani family with variable severity of visual impairment, abnormal brain imaging, cognitive changes, spasticity, and leg weakness.

Background Newly discovered genetic mutations continue to be described, especially in those beyond European descent. Rare genetic variants in ethnic minorities where consanguinity is practiced may reveal novel, pathogenic variants and disease presentations. Genetic testing in these families may also inform risk to other family members to assist family planning.

Design/Methods NA

Results

A 29-year-old sister and 33-year-old brother from Pakistan with consanguineous parents presented for spasticity and visual changes. The brother was developmentally normal until 8 years old, when he began to develop leg weakness, visual impairment, and developmental regression. Examination demonstrated minimal communication, ability to follow simple commands, and diffuse hyperreflexia greater in the lower extremities. Work up revealed brain atrophy on MRI. Genetic testing with whole exome sequencing (WES) revealed homozygous, likely pathogenic variant in EYS, as well as homozygous VUS’s in FA2H and GRID2.

The sister was developmentally normal. At 20 years of age, she began to develop leg weakness and visual changes. Examination revealed proximal mild leg weakness, loss of ankle dorsiflexion, leg spasticity, and diffuse hyperreflexia worse in the lower extremities. On work up, she was found to have retinitis pigmentosa and cerebellar atrophy with leukodystrophy on MRI. Genetic testing with WES revealed the same homozygous mutations in FA2H and EYS as her brother.

Conclusions Three different autosomal recessive neurologic diseases were identified in this consanguineous family that are likely causing pathological phenotypes in 5 of 6 children. The FA2H variants are observed in homozygous state in those who have features of FA2H-related neurodegeneration within this family. This variant is not found in population databases (gnomAD). We propose this variant is pathologic in this family. The GRID2 variant potentially explains phenotypic differences within the family.

Authors/Disclosures
Matthew J. Woodward, MD PRESENTER	Dr. Woodward has nothing to disclose.
Marrisa M. Lafreniere, MS, CGC (University of Colorado Neurology)	Ms. Lafreniere has nothing to disclose.
Michael Korsmo, MD (University of Colorado)	Dr. Korsmo has nothing to disclose.
Brooke E. Heffernan, MD (University of Colorado School of Medicine (For GME Residents and Faculty))	Dr. Heffernan has nothing to disclose.
Emily L. Forbes, MD (University of Colorado)	The institution of Dr. Forbes has received research support from MJFF. The institution of Dr. Forbes has received research support from Biohaven. The institution of Dr. Forbes has received research support from Neurocrine. The institution of Dr. Forbes has received research support from Biogen. The institution of Dr. Forbes has received research support from BIAL.

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