Key Genetic Insights and Hypotheses for Research
I’m Not a Doctor, but I’m Driven to Solve Our Family’s Health Challenges
Years ago, a physician told me that if anyone could unravel our family’s medical mystery, it would be me. Since then, I’ve immersed myself in studying my daughters’ test results and genetic data, enrolling us in research programs and connecting with the Rare Disease Community to advance answers. I understand our genetic profiles deeply, but seizures, memory loss, and aphasia have limited my ability to advocate as effectively as before. Now, I rely on technology to share our journey.
Unique Genetic Profile Needs Your Expertise to Unravel New Insights
My family has a rare combination of genetic conditions. My youngest daughter and I both have an MBD5 deletion in non-coding exons, recently found by the Undiagnosed Diseases Network (UDN) to cause a 50% reduction in MBD5 presence—a novel finding in MBD5-associated neurodevelopmental disorder (MAND). My older daughter doesn’t have this deletion, but all three of us share a rare CYTB variant (m.15853C>A, I369M), seen only in our family, suggesting it’s a key driver of our severe health issues.
The CYTB Variant Is Likely Pathogenic, Causing Mitochondrial Dysfunction
The CYTB variant, a non-synonymous change (ATC>ATA, I369M) not found in Mitomap or mtDB, with a near-homoplasmic state (99.6% A). My youngest daughter showed symptoms in utero and is the most impacted, my older daughter’s symptoms began at age 7 with progressive decline, and I developed severe symptoms in my 40s. I’ve also had 12 unexplained miscarriages, likely linked to this variant’s impact on embryonic development. We need researchers to confirm its pathogenicity and explore treatments.
Non-Coding Variants May Amplify Symptoms by Reducing Mitochondrial Function
Our mitochondrial DNA testing identified six non-coding variants in the D-loop and regulatory regions (#236 mtTF1 binding, #263 HV2, #515 OH/CSB2, #520 UR/GabZ, #16362 HV1, #16482 D-Loop), reported in mtDB as polymorphisms. We hypothesize, like the MBD5 non-coding deletion, these may cumulatively reduce mitochondrial gene expression, worsening the energy deficit of the CYTB. This could explain the severity of our symptoms, and we’re eager for researchers to investigate this novel mechanism.
Collaborate to Refine Our Genetic Insights for Breakthroughs
I've listed these critical genetic details for researchers. If you’re a medical professional with insights to refine or challenge these findings, I welcome your expertise to ensure this site presents the most accurate information for future research and treatment.
Metabolic Data Confirms Mitochondrial Dysfunction
Lab results from my youngest daughter show ketosis (UA Ketones 1+, 3-OH butyrate 722, acetoacetate 533, Ref: 0–4) and dicarboxylic aciduria (sebacic 2974, Ref: 0–3; suberic 567, Ref: 0–10; adipic 136, Ref: 0–35; ethylmalonic 20, Ref: 0–15), consistent with the CYTB variant’s effect on Complex III. Low oxygen saturation (O2 Hgb 82.9%, Ref: 94.0–97.0%) and mild hyponatremia suggest multisystem involvement, providing clear metabolic markers for researchers to explore.
Other mtDNA Variants Appear Benign, But Their Role Needs Further Study
Additional mtDNA variants (Segments 2 and 3) in coding regions like ND1 (#3705), ND2 (#4727, #4769), COI (#7202), ATP6 (#8860 T112A), and CYTB (#15326 T194A) are mostly synonymous or known polymorphisms in mtDB. While individually benign, their combined effect in the presence of the CYTB variant and non-coding variants might contribute to our mitochondrial dysfunction, and we’d value research to clarify this.
High ANA & IL-2/IL-10 may be tied to RYR1 Dysfunction from Aunt’s Mutation
My aunt has an RYR1 mutation, Given our muscle-related symptoms, we suspect RYR1 dysfunction might be involved, possibly triggering inflammation. We’re interested in research on how interleukins IL-2 (pro-inflammatory) and IL-10 (anti-inflammatory) with elevated ANA might interact with RYR1-mediated calcium dysregulation, especially since our mitochondrial dysfunction could amplify this inflammatory response. Measuring IL-2 and IL-10 levels in our family could uncover new therapeutic targets.
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