PBD Project Summary

• PBD Project is a non-profit organization that is funding medical research with the objective to provide meaningful positive clinical impact for patients with Peroxisome Biogenesis Disorders (PBD), with a focus on Zellweger Spectrum Disorder (ZSD) caused by mutations to PEX10 gene.

• PBD Project is inspired by Diego, who was born October 2017 and was diagnosed in late 2019 with autosomal recessive Zellweger Spectrum Disorder (a Peroxisome Biogenesis Disorder) via PEX10 gene. Current clinical manifestation is cerebellar ataxia that has impeded gross motor development.

• Potential research projects include drug repurposing efforts, chemical library screens, in silico screens, chaperone therapies, gene replacement therapy, gene editing, ASO/mRNA therapies, cellular therapies, associated cell / animal models, and basic research to support translational work

• PBD Project would like to connect with interested:

  1. Industry / biotech partners

  2. Medical / academic researchers

  3) Individuals who are similarly funding / coordinating medical research for genetic diseases

• Please email DiegoZSDResearch@gmail.com if you are interested to participate

An Introduction to Diego

• Diego loves trains, buses, airplanes, construction equipment, and Halloween. He enjoys singing along to many of his favorite songs, including Wheels on the Bus, Cielito Lindo, and of course Baby Shark. Diego's favorite foods are quesadillas, fruit, and oat milk.
• He likes to show off counting to 20 (in both English and Spanish), his mastery of the alphabet, building Lego sets, puzzles, drawing, and games on his tablet.
• Diego is working hard on his walking skills and enjoys celebrating every small step (and will call you out if you are not actively celebrating hard enough with him!)

Diego Summary

• Diego born in October 2017

• Gross motor delay (walking) with mild hypotonia in lower extremities (e.g., ligamentous laxity of ankle); aside from walking, all developmental milestones met at age-appropriate times

• No currently observed issues/delays with cognitive, speech, fine motor skills, sight, hearing, etc.

• Exome Sequencing indicates autosomal recessive Zellweger Spectrum Disorder (a Peroxisome Biogenesis Disorder) via PEX10 gene

  Boosted Exome Results (LINK)

  • One "Variant of Uncertain Significance" (VUS): PEX10 gene, Exon 5, c.928C>G (His290Asp in shorter isoform, His310Asp in longer isoform)
    • This missense mutation replaces C>G at sequence 928, resulting in replacing histidine (CAU/CAC) with aspartic acid (GAU/GAC) at codon 290 of the shorter PEX10 protein isoform (codon 310 of the longer PEX10 protein isoform). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid.
    • ClinVar indicates prior case of specific mutation (also supplement here) via Steinberg et al 2004 (note shorter isoform nomenclature of "H290D")
    • Also note a different mutation at same codon (H290Q) was identified in Warren et al 1998
  • One pathogenic variant: PEX10 gene, Exon 1, c.28dup (p.Glu10Glyfs*41)
    • This duplication mutation duplicates sequence 28 (inferred to be G), replacing glutamic acid (GAA/GAG) with glycine (GGA) at codon 10, causing frameshift mutation in the rest of the gene, resulting in a premature translational stop signal at sequence 41 ("p.Glu10Glyfs*41"). It is expected to result in an absent or disrupted protein product

• ZSD-specific tests are "indicative of a peroxisomal disorder"

• Baseline testing (e.g., visual, auditory, dental, metabolic testing, abdominal ultrasounds) show function within normal range