Genetics results: Anyone with AOA4 in UK?

[AbbeysAtaxia]

Hi,

After many years without a diagnosis, I finally got Whole Gene Sequencing done myself (with Nebula Genomics). In my data I screened ~1300+ neurology genes, but only found three Ataxia-causing gene candidates needing more tests for confirmation. I repeated the test, exposed some glitches and false leads, but got basic confirmation for these three.

Top of the list is actually very rare:

- AOA4 (My History: Microcephaly but no seizures, adult onset Ataxia with normal MRI, CMT like neuropathy, Dystonia, complex movement disorders such as choreoathetosis at onset but which later faded, normal albumin, raised cholesterol but other genes for this, unknown alpha-fetoprotein. Genetics: known and new PNKP gene variants). However, I have other symptoms not usually seen with this but currently have no other genetic or other explanations for them, e.g. (1) Parkinsons-like rigidity with slow movement, onset before age 40, responds to low dose levodopa, and has sleep benefit (retained, even after many years), and (2) telangiectasias on whites of eyes since childhood (like A-T or AOA2, but no gene variants for those).

My other Ataxia candidates are currently:

- EA2 (2 new CACNA1A variants, potentially harmful).

- Auto-Immune, Gluten Ataxia/Neuropathy (genetic DQ2.2+ predicted, plus my history of IgG4 anti-gliadin etc) or other HLA variants for auto-immune conditions like Hashimoto's Thyroiditis (but currently have normal thyroid tests), and these usually cause cerebellar atrophy, but my MRI (2012) and CT (2021) were normal.

But none of those come with Microcephaly, and EA2 doesn't cause CMT etc, and I have no other known gene variants for Parkinsons, DRD or other similar disorders, nor microcephaly or metabolic ataxias with microcephaly etc, so PNKP seems the only explanation - but if so, Parkinsonism would be a new discovery for PNKP disorders...

So I'm just wondering if anyone else has PNKP gene variants causing AOA4/MCSZ/CMT, and unexpected symptoms or conditions not otherwise explained, especially Parkinsons like symptoms...

Further confirmation to come and possible new discoveries: I am awaiting long-read results (PacBio HiFi Reads) to confirm PNKP variants are on seperate long-read strands (recessive condition) and not on same strands from one parent (so still just a carrier), since my parents passed away and siblings are unavailable so they can't get tested. Plus I want to confirm and define some longer deletions in CACNA1A etc, as well as rule out SCA repeat expansion ataxias, gene silencing (epigenetics) as seen in Friedreich's Ataxia, then with T2T aligment done later to look at the 99 newly discovered genes and 2000 new potential genes or modifiers. Plus other cool stuff!

Once that's done, if results are positive, maybe it's worth returning to the London Ataxia Clinic - I was last there in 2012 with "still unexplained ataxia", but now I can see that may simply be "Because AOA4 and it's gene weren't discovered until three years later in 2015"! 😂

Thanks for reading.

[wobblybee]

🙂 Sorry I don’t have a link with AOA4……...but I have had Whole Genome Sequencing results recently…via my Neurologist and the NHS.

Previously..I had negative results to routine NHS testing..and specific testing for Episodic Ataxias - Gluten Ataxia - CANVAS (Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome)

But..I have had a 70% link with SYNE1 gene.

I have a long history of Vestibular issues, and at one point was told my link may be Recessive because of no family history.

But after Whole Genome Sequencing I was told I had no link with any genetic Ataxias.

[penelope2]

Hi I admire your tenacity but balanced with cost and labelling is it worth it?Many of us do not have a diagnosis of what type and so label, so "self fulfilling prophecy" comes to mind?

If you are younger and want to start a family or already have children then that would explain it but otherwise my thoughts are your energy is better spent looking after yourself and your general health. If we have to wait for science to come up with answers then probably ataxia will be towards the bottom of the list. Numbers dictate this. Good luck with your search.