Thread by @MParfyonov

I've seen two patients in my training with ring chromosome 20 associated epilepsy, which inspired my recent talk at #CleClinicNeuro Peds Epilepsy GR, so I decided to distill it to a #neurogenetics #epilepsy #tweetorial 🤓 🧬
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what is a 💍 chromosome? Rather than having a full complement of rod-shaped chromosomes like this:

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affected individuals have at least one chromosome with circular formation, due to fusion of distal chromosome regions:

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Mechanisms of 💍 chromosome formation - double strand breaks (results in loss of genetic material), telomere fusion (no loss), or complex rearrangements

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💍 chromosomes have been reported in all human chromosomes, 99% sporadic, prevalence between 1 in 30-60,000 live births. Often asymptomatic, and mosaicism is common
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💍 Chromosomes associated with epilepsy: r(14), r(17) and r(20). We'll focus on the latter.

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r(20) syndrome core phenotype: intractable epilepsy, frequent non convulsive status epileptics, cognitive/behavioral decline following seizure onset, characteristic EEG findings (frontal discharges, high voltage slow waves, frontotemporal theta)

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❗DIAGNOSIS - is often missed on routine genetic investigations including microarray. So you MUST to ask for a KARYOTYPE, and specifically indicate your suspicion for ring chromosome! The lab should analyze more metaphases to increase chance of detection

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Treatment - limited data, most patients remain medically refractory. Some anecdotal data that combination of Lamotrigine and Valproic acid, VNS, and KD may be useful. Caution with pursuing aggressive treatment. Epilepsy surgery generally not helpful
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Pathogenesis - not well understood, but three main theories from my reading: (1) haploinsufficiency, (2) altered gene expression, (3) ring instability

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(1) Haploinsufficiency - double strand breaks cause loss of genetic material. Two known epilepsy genes CHRNA4 and KCNQ2 are found at end of chrom 20. So, deletion of these causes epilepsy?

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That would be a neat and tidy explanation, but unfortunately things are not so simple… multiple patients with r(20) syndrome with intact subtelomeric regions [figure - FISH testing for CHRNA4 in red and KCNQ2 in green in r20 patient]

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(2) Altered gene expression. Telomere position effect - genes near the ends of chromosomes tend to get turned off. Could ring formation cause change in gene expression near fusion points?

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@kenmyers123 et al studied transcriptome of r20 patients compared to unaffected relatives, with differential expression of 97 genes including known epilepsy gene, NPRL3. However, not statistically significant on quantitative PCR confirmatory testing
tinyurl.com/42k95vhm
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(3) Ring instability - rings are not stable within cells, and with cell division multiple products can be created. This impairs cell viability and function, which could lead to epileptogenesis

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To summarize - suspect r(20) in patients with cognitive decline in the setting of treatment resistant epilepsy with frequent non convulsive status epilepticus. Ask for a karyotype! Treatment is difficult, and more research is needed on this devastating condition

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Further #tweetorials on the way!

Please add in your own experience/offer corrections if I made mistakes!

References/Resources:
tinyurl.com/yjfhv75f
tinyurl.com/2vkr5hpw
tinyurl.com/betv38bf

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@AMoosaMD @bowtieneuro @OligoclonalBand @TheNotoriousEEG @isaherman85
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