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SDHB-linked Paraganglioma

Rijken, J.A.

2020

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Rijken, J. A. (2020). SDHB-linked Paraganglioma.

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Summary and conclusion

Summary

Conclusion

Future perspectives

9.1

SUMMARY

Chapter 1ĐŽŶƐŝƐƚƐŽĨĂŶŽǀĞƌǀŝĞǁŽĨĐƵƌƌĞŶƚŝŶƐŝŐŚƚƐŝŶƚŚĞĐůŝŶŝĐĂůĐŚĂƌĂĐƚĞƌŝƐƟĐƐ͕ ŐĞŶĞƟĐƐĂŶĚŵĂŶĂŐĞŵĞŶƚŽĨƉĂƌĂŐĂŶŐůŝŽŵĂĂŶĚƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂƉĂƟĞŶƚƐ͘ In chapter 2͕ƚŚĞĐůŝŶŝĐĂůĐŚĂƌĂĐƚĞƌŝƐƟĐƐĂŶĚƚƌĞĂƚŵĞŶƚƐƚƌĂƚĞŐŝĞƐŽĨϭϰϳƉĂƟĞŶƚƐ ǁŝƚŚ Ă ƚŽƚĂů ŽĨ Ϯϴϵ ŚĞĂĚ ĂŶĚ ŶĞĐŬ ƉĂƌĂŐĂŶŐůŝŽŵĂƐ ƚƌĞĂƚĞĚ Ăƚ ƚŚĞ ŵƐƚĞƌĚĂŵ hŶŝǀĞƌƐŝƚLJ DĞĚŝĐĂů ĞŶƚƌĞƐ͕ sƌŝũĞ hŶŝǀĞƌƐŝƚĞŝƚ ŵƐƚĞƌĚĂŵ͕ ĂƌĞ ĞǀĂůƵĂƚĞĚ͘ sĂƌŝĂ-ďůĞ ĐůŝŶŝĐĂů ŵĂŶŝĨĞƐƚĂƟŽŶƐ͕ ƐƵĐŚ ĂƐ ŵƵůƟĨŽĐĂůŝƚLJ ;ϱϰйͿ͕ ĂƐƐŽĐŝĂƚĞĚ ƐLJŵƉĂƚŚĞƟĐ ƉĂƌĂŐĂŶŐůŝŽŵĂ;ϭйͿ͕ĐŽŶĐƵƌƌĞŶƚƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂ;ϯйͿ͕ŚLJƉĞƌƐĞĐƌĞƟŽŶŽĨĐĂƚ-ĞĐŚŽůĂŵŝŶĞƐ;ϯϬйͿĂŶĚͬŽƌŵĞƚĂƐƚĂƟĐĚŝƐĞĂƐĞ;ϮйͿǁĞƌĞĞŶĐŽƵŶƚĞƌĞĚ͘^ŝdžƚLJͲĮǀĞ ƉĞƌĐĞŶƚŽĨEƚĞƐƚĞĚƉĂƟĞŶƚƐĐĂƌƌŝĞĚĂƉĂƚŚŽŐĞŶŝĐǀĂƌŝĂŶƚŝŶSDHD͕ϭϬйŝŶSDHB ĂŶĚϭйŝŶSDHAF2. None of the SDHBǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐƉƌŽǀĞĚƚŽŚĂƌďŽƵƌŵĞƚĂƐ-ƚĂƐƟĐĚŝƐĞĂƐĞŽƌĚĞǀĞůŽƉĞĚĂƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂŽƌƐLJŵƉĂƚŚĞƟĐƉĂƌĂŐĂŶŐůŝŽŵĂ͘ KǀĞƌ Ă ϲϬͲLJĞĂƌ ƉĞƌŝŽĚ Ă ĚĞĐƌĞĂƐŝŶŐ ŶƵŵďĞƌ ŽĨ ŚĞĂĚ ĂŶĚ ŶĞĐŬ ƉĂƌĂŐĂŶŐůŝŽŵĂƐ ǁĞƌĞƐƵƌŐŝĐĂůůLJƌĞƐĞĐƚĞĚ͘ŽŶǀĞƌƐĞůLJ͕ĂĐƟǀĞƐƵƌǀĞŝůůĂŶĐĞŚĂƐďĞĐŽŵĞĂŵŽƌĞƉƌĞǀ-ĂůĞŶƚƚƌĞĂƚŵĞŶƚƐƚƌĂƚĞŐLJĂŶĚŝƐŶŽǁŽŌĞŶƚŚĞŝŶŝƟĂůŵĂŶĂŐĞŵĞŶƚŽƉƟŽŶŽĨĐŚŽŝĐĞ͘ dŚĞŐƌŽǁŝŶŐƵŶĚĞƌƐƚĂŶĚŝŶŐŽĨƚŚĞŐĞŶĞƟĐƉƌĞĚŝƐƉŽƐŝƟŽŶ͕ƚŚĞĂƐƐŽĐŝĂƚĞĚĐůŝŶŝĐĂů ƌŝƐŬƉƌŽĮůĞƐ;ƉŚĞŶŽƚLJƉĞͿŽĨŚĞĂĚĂŶĚŶĞĐŬƉĂƌĂŐĂŶŐůŝŽŵĂƉĂƟĞŶƚƐƵďŐƌŽƵƉƐ͕ĂŶĚ ďĞƩĞƌƵŶĚĞƌƐƚĂŶĚŝŶŐŽĨƚŚĞŶĂƚƵƌĂůĐŽƵƌƐĞŚĂƐƌĞƐƵůƚĞĚŝŶĂŵŽƌĞĐŽŶƐĞƌǀĂƟǀĞ ŵĂŶĂŐĞŵĞŶƚŽĨŚĞĂĚĂŶĚŶĞĐŬƉĂƌĂŐĂŶŐůŝŽŵĂƉĂƟĞŶƚƐ͘ In chapter 3ĂŶŽǀĞůSDHBŐĞŶĞǀĂƌŝĂŶƚŝƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚƚŚĞĨŽƌŵĂƟŽŶŽĨŚĞĂĚ ĂŶĚŶĞĐŬƉĂƌĂŐĂŶŐůŝŽŵĂ͘/ŶƚŚŝƐĨĂŵŝůLJͲďĂƐĞĚƐƚƵĚLJ͕ƚŚĞEŽĨϭϴĨĂŵŝůLJŵĞŵ- ďĞƌƐǁĂƐƚĞƐƚĞĚ͕ƌĞƐƵůƟŶŐŝŶƚŚĞŝĚĞŶƟĮĐĂƟŽŶŽĨϭϬĐĂƌƌŝĞƌƐŽĨĂŶĞdžŽŶϭͲϯĚĞůĞ-ƟŽŶŝŶƚŚĞSDHBŐĞŶĞ͘KŶĞƉĂƟĞŶƚŚĂĚĂ;ƉƌĞƐLJŵƉƚŽŵĂƟĐͿĐĂƌŽƟĚďŽĚLJƚƵŵŽƌ͕ ĞůĞǀĂƚĞĚĐĂƚĞĐŚŽůĂŵŝŶĞůĞǀĞůƐĂŶĚŚŝŐŚďůŽŽĚƉƌĞƐƐƵƌĞ͕ǁŚŝĐŚŶŽƌŵĂůŝnjĞĚĂŌĞƌ ƐƵƌŐŝĐĂů ƌĞƐĞĐƟŽŶ ŽĨ ƚŚĞ ƚƵŵŽƌ͘ EĞŐĂƟǀĞ SDHB ŝŵŵƵŶŽƐƚĂŝŶŝŶŐ ŽĨ ƚŚĞ ĐĂƌŽƟĚ ďŽĚLJƉĂƌĂŐĂŶŐůŝŽŵĂĐŽƌƌŽďŽƌĂƚĞĚƚŚĞŚLJƉŽƚŚĞƐŝƐƚŚĂƚŝƚǁĂƐĐĂƵƐĞĚďLJƚŚĞSDHB ǀĂƌŝĂŶƚ͘dŚƵƐ͕ƚŚŝƐĚĞůĞƟŽŶŽĨĞdžŽŶϭͲϯŝŶƚŚĞSDHBŐĞŶĞŝƐĂŶŽǀĞůŐĞƌŵůŝŶĞǀĂƌŝ-ĂŶƚĂƐƐŽĐŝĂƚĞĚǁŝƚŚƚŚĞĨŽƌŵĂƟŽŶŽĨŚĞƌĞĚŝƚĂƌLJƉĂƌĂŐĂŶŐůŝŽŵĂ͘ In chapter 4͕ĂŶĞdžƚĞŶĚĞĚĨĂŵŝůLJǁŝƚŚĂĨŽƵŶĚĞƌĞdžŽŶϯĚĞůĞƟŽŶŝŶƚŚĞSDHB gene ŝƐƐƚƵĚŝĞĚ͘^ĞǀĞŶƚĞĞŶǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐǁĞƌĞŝĚĞŶƟĮĞĚ͕ŽĨǁŚŽŵϲǁĞƌĞĐůŝŶŝĐĂůůLJ ĂīĞĐƚĞĚƉĂƌĂŐĂŶŐůŝŽŵĂƉĂƟĞŶƚƐ͘dŚĞĞƐƟŵĂƚĞĚƉĞŶĞƚƌĂŶĐĞĨŽƌƚŚŝƐSDHBĞdžŽŶϯ ĚĞůĞƟŽŶĂƚƚŚĞĂŐĞƐŽĨϰϬ͕ϱϬ͕ϲϬĂŶĚϳϬǁĂƐϰй͕ϵй͕ϭϱйĂŶĚϮϭйƌĞƐƉĞĐƟǀĞůLJ͘ dŚĞůŽǁƉĞŶĞƚƌĂŶĐĞĨŽƵŶĚŝŶƚŚŝƐƐƚƵĚLJŵŝŐŚƚƌĞŇĞĐƚĂĐůŝŶŝĐĂůĐŚĂƌĂĐƚĞƌŝƐƟĐŽĨ ƚŚŝƐƐƉĞĐŝĮĐƵƚĐŚSDHBĨŽƵŶĚĞƌŵƵƚĂƟŽŶ͕ŽƌƚŚĞŝŶŇƵĞŶĐĞŽĨĂƐŚĂƌĞĚŐĞŶĞƚ-ŝĐŽƌĞŶǀŝƌŽŶŵĞŶƚĂůŵŽĚŝĮĞƌŽĨƉĞŶĞƚƌĂŶĐĞŝŶƚŚŝƐĨĂŵŝůLJ͘,ŽǁĞǀĞƌŝƚŵŝŐŚƚĂůƐŽ ƌĞŇĞĐƚĂŶŽǀĞƌĞƐƟŵĂƟŽŶŽĨSDHBͲůŝŶŬĞĚƉĞŶĞƚƌĂŶĐĞŝŶƉƌĞǀŝŽƵƐƌĞƉŽƌƚƐĚƵĞƚŽ 162 Chapt er 9

ǀĂƌŝŽƵƐĨŽƌŵƐŽĨďŝĂƐ͘WƌĞǀŝŽƵƐƉĞŶĞƚƌĂŶĐĞĐĂůĐƵůĂƟŽŶƐǁĞƌĞƉƌŽŶĞƚŽŽǀĞƌĞƐƟ-ŵĂƟŽŶďĞĐĂƵƐĞŽĨƚŚĞůŝŵŝƚĞĚŝŶĐůƵƐŝŽŶŽĨƵŶĂīĞĐƚĞĚǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐĂŶĚďĞĐĂƵƐĞ ƚŚĞǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐĂƌĞŝĚĞŶƟĮĞĚǀŝĂŝŶĚĞdžƉĂƟĞŶƚƐ͘dŚŝƐŵŝŐŚƚƌĞƐƵůƚŝŶĂŚŝŐŚĞƌ ĐŚĂŶĐĞŽĨƐĞůĞĐƟŶŐŽƚŚĞƌǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐǁŝƚŚƚŚĞĚŝƐĞĂƐĞ;ĂƐĐĞƌƚĂŝŶŵĞŶƚďŝĂƐͿ͘/Ŷ ƚŚĞĐƵƌƌĞŶƚƐƚƵĚLJ͕ǁĞŝŶĐůƵĚĞĚĂƌĞůĂƟǀĞůLJůĂƌŐĞŶƵŵďĞƌŽĨƵŶĂīĞĐƚĞĚǀĂƌŝĂŶƚĐĂƌ-ƌŝĞƌƐĂŶĚĐŽƌƌĞĐƚĞĚĨŽƌĂƐĐĞƌƚĂŝŶŵĞŶƚďŝĂƐ͘dŚŝƐƌĞƐƵůƚĞĚŝŶƌĞĚƵĐĞĚĞƐƟŵĂƚĞƐŽĨ SDHBͲůŝŶŬĞĚƉĞŶĞƚƌĂŶĐĞ͕ĂŶŝŵƉŽƌƚĂŶƚĮŶĚŝŶŐĨŽƌĂĚĞƋƵĂƚĞ;ŐĞŶĞƟĐͿĐŽƵŶƐĞůŝŶŐ of SDHB- variant carriers. In chapter 5͕ ƚŚĞ ƉŚĞŶŽƚLJƉŝĐĂů ĐŚĂƌĂĐƚĞƌŝƐƟĐƐ ŽĨ Ă ŶĂƟŽŶǁŝĚĞ ĐŽŚŽƌƚ ŽĨ SDHB ǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐĂƌĞĚĞƚĞƌŵŝŶĞĚĂŶĚĚŝīĞƌĞŶĐĞƐŝŶĐůŝŶŝĐĂůƉŚĞŶŽƚLJƉĞƐƌĞůĂƚĞĚƚŽ ƐƉĞĐŝĮĐ SDHB ǀĂƌŝĂŶƚƐ ǁĞƌĞ ĂƐƐĞƐƐĞĚ͘ /Ŷ Ă ƌĞƚƌŽƐƉĞĐƟǀĞ͕ ĚĞƐĐƌŝƉƟǀĞ ƐƚƵĚLJ ϭϵϰ SDHBǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐǁĞƌĞŝŶĐůƵĚĞĚŝŶƐĞǀĞŶĐůŝŶŝĐĂůŐĞŶĞƟĐƐĐĞŶƚĞƌƐ͘dŚŝƐĐŽŚŽƌƚ ĐŽŶƐŝƐƚĞĚŽĨϴϯ;ϰϮ͘ϴйͿĚŝƐĞĂƐĞͲĂīĞĐƚĞĚǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐĂŶĚϭϭϭ;ϱϳ͘ϮйͿƵŶĂĨ-ĨĞĐƚĞĚǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐ͘&ŝŌLJͲĨŽƵƌĐĂƌƌŝĞƌƐ;Ϯϳ͘ϴйͿǁĞƌĞĐůŝŶŝĐĂůůLJĂīĞĐƚĞĚǁŝƚŚŽŶĞ ŽƌŵŽƌĞŚĞĂĚĂŶĚŶĞĐŬƉĂƌĂŐĂŶŐůŝŽŵĂƐ͘KŶůLJĨŽƵƌƉĂƟĞŶƚƐ;Ϯ͘ϭйͿǁĞƌĞĐůŝŶŝĐĂůůLJ ĂīĞĐƚĞĚǁŝƚŚĂƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂĂŶĚϮϲ;ϭϯ͘ϰйͿǁŝƚŚŽŶĞŽƌŵŽƌĞƐLJŵƉĂƚŚĞƟĐ ƉĂƌĂŐĂŶŐůŝŽŵĂƐ͘dŚĞƌĂƟŽƐĨŽƌƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂĂŶĚƐLJŵƉĂƚŚĞƟĐƉĂƌĂŐĂŶŐůŝ-ŽŵĂƐĨŽƵŶĚŝŶŽƵƌƐƚƵĚLJǁĞƌĞůŽǁĞƌƚŚĂŶƉƌĞǀŝŽƵƐůLJƌĞƉŽƌƚĞĚŝŶĐŽŚŽƌƚƐŽĨSDHB ǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐ͘dŚĞŶƵŵďĞƌŽĨƉĂƟĞŶƚƐĂīĞĐƚĞĚǁŝƚŚĂƚůĞĂƐƚŽŶĞŚĞĂĚĂŶĚŶĞĐŬ ƉĂƌĂŐĂŶŐůŝŽŵĂǁĂƐƌĞůĂƟǀĞůLJŚŝŐŚ;Ϯϳ͘ϴйͿĐŽŵƉĂƌĞĚǁŝƚŚŽƚŚĞƌƐƚƵĚŝĞƐ;ϯͲϯϭйͿ͘ LJƚŚĞŝŶĐůƵƐŝŽŶŽĨĂůĂƌŐĞŶƵŵďĞƌŽĨƵŶĂīĞĐƚĞĚǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐƚŚƌŽƵŐŚĐůŝŶŝĐĂů ŐĞŶĞƟĐƐĐĞŶƚĞƌƐƌĂƚŚĞƌƚŚĂŶƚŚƌŽƵŐŚŵĞĚŝĐĂůĐĞŶƚĞƌƐ͕ƚŚĞƌŽůĞŽĨĂƐĐĞƌƚĂŝŶŵĞŶƚ ďŝĂƐǁĂƐƌĞĚƵĐĞĚ͘dŚĞĐĂƐĐĂĚĞƚĞƐƟŶŐŽĨƌĞůĂƟǀĞƐĂŶĚƐƚƌƵĐƚƵƌĞĚĨŽůůŽǁͲƵƉƉƌŽƚŽ-ĐŽůƐŽĨSDHBǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐŝŶƚŚĞEĞƚŚĞƌůĂŶĚƐŝĚĞŶƟĮĞƐĂƌĞůĂƟǀĞůLJŚŝŐŚŶƵŵďĞƌ ŽĨĂƐLJŵƉƚŽŵĂƟĐǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐ͕ǁŝƚŚŽƌǁŝƚŚŽƵƚĂƐƐŽĐŝĂƚĞĚƚƵŵŽƌƐ͕ĂůůŽǁŝŶŐĨŽƌ ĂŵŽƌĞĂĐĐƵƌĂƚĞƌĞƉƌĞƐĞŶƚĂƟŽŶŽĨƚŚĞƉŚĞŶŽƚLJƉĞŽĨSDHBŵƵƚĂƟŽŶĐĂƌƌŝĞƌƐ͘KŶůLJ ĮŌĞĞŶƉĂƟĞŶƚƐ;ϳ͘ϳйͿĚĞǀĞůŽƉĞĚŵĞƚĂƐƚĂƟĐĚŝƐĞĂƐĞĂŶĚϭϳƉĂƟĞŶƚƐ;ϴ͘ϴйͿĚĞǀĞů-ŽƉĞĚŶŽŶͲƉĂƌĂŐĂŶŐůŝŽŶŝĐƚƵŵŽƌƐ͕ŝŶĐůƵĚŝŶŐϱƌĞŶĂůĐĞůůĐĂƌĐŝŶŽŵĂƐĂŶĚϮŐĂƐƚƌŝĐ ŐĂƐƚƌŽŝŶƚĞƐƟŶĂůƐƚƌŽŵĂůƚƵŵŽƌƐ͘^ƚĂƟƐƟĐĂůĂŶĂůLJƐĞƐƐŚŽǁĞĚŶŽƐŝŐŶŝĮĐĂŶƚĚŝīĞƌ-ĞŶĐĞƐďĞƚǁĞĞŶƚŚĞĐĂƌƌŝĞƌƐŽĨƚŚĞƚǁŽŵŽƐƚƉƌĞǀĂůĞŶƚĨŽƵŶĚĞƌŵƵƚĂƟŽŶƐŝŶSDHB ;ĞdžŽŶϯĚĞůĞƟŽŶĂŶĚĐ͘ϰϮϯнϭ'хͿĨŽƌƚŚĞŶƵŵďĞƌĂŶĚůŽĐĂƟŽŶŽĨŚĞĂĚĂŶĚŶĞĐŬ ƉĂƌĂŐĂŶŐůŝŽŵĂƐ͕ƐLJŵƉĂƚŚĞƟĐƉĂƌĂŐĂŶŐůŝŽŵĂƐŽƌƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂƐ͕ŶŽƌŝŶƚŚĞ ŽĐĐƵƌƌĞŶĐĞŽĨŵĞƚĂƐƚĂƟĐĚŝƐĞĂƐĞŽƌŶŽŶͲƉĂƌĂŐĂŶŐůŝŽŶŝĐƚƵŵŽƌƐ͘dŚŝƐƐƚƵĚLJƵŶĚĞƌ-ůŝŶĞƐƚŚĞŝŵƉŽƌƚĂŶĐĞŽĨƚŚĞŝŶĐůƵƐŝŽŶŽĨƵŶĂīĞĐƚĞĚǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐŝŶƐƚƵĚŝĞƐƚŚĂƚ ĂƐƐĞƐƐƚŚĞƉŚĞŶŽƚLJƉĞƐŽĨƉĂƚŚŽŐĞŶŝĐŐĞƌŵůŝŶĞǀĂƌŝĂŶƚƐ͘/ŶĐůƵĚŝŶŐĂƐLJŵƉƚŽŵĂƟĐ ĐĂƌƌŝĞƌƐƉƌŽǀŝĚĞƐĂŵŽƌĞĂĐĐƵƌĂƚĞŝŶƐŝŐŚƚŝŶƚŽƚŚĞƚƌƵĞƐƉĞĐƚƌƵŵŽĨĚŝƐĞĂƐĞ͘dŚĞ ƌĞƐƵůƚƐĨƌŽŵƚŚŝƐƐƚƵĚLJĂƌĞŝŵƉŽƌƚĂŶƚƚŽĐŽŶƐŝĚĞƌŝŶƚŚĞĐůŝŶŝĐĂůŵĂŶĂŐĞŵĞŶƚĂŶĚ ŐĞŶĞƟĐĐŽƵŶƐĞůŝŶŐŽĨĨĂŵŝůŝĞƐĂīĞĐƚĞĚďLJSDHBͲůŝŶŬĞĚƉĂƌĂŐĂŶŐůŝŽŵĂͬƉŚĞŽĐŚƌŽ-ŵŽĐLJƚŽŵĂƐLJŶĚƌŽŵĞƐ͘ Summary and c onclusion 163

Chapter 6 ĨŽĐƵƐĞƐ ŽŶ ƚŚĞ ĐůŝŶŝĐĂů ĐŚĂƌĂĐƚĞƌŝƐƟĐƐ ĂŶĚ ŽƵƚĐŽŵĞ ŽĨ ƚƌĞĂƚŵĞŶƚ ŽĨ ϱϰŚĞĂĚĂŶĚŶĞĐŬƉĂƌĂŐĂŶŐůŝŽŵĂƉĂƟĞŶƚƐĐĂƌƌLJŝŶŐĂƉĂƚŚŽŐĞŶŝĐǀĂƌŝĂŶƚŝŶSDHB ;ƐĞůĞĐƚĞĚ ĨƌŽŵ ƚŚĞ ŶĂƟŽŶǁŝĚĞ ĐŽŚŽƌƚ ĚĞƐĐƌŝďĞĚ ŝŶ ĐŚĂƉƚĞƌ ϱͿ͘  KŶůLJ ϴ ƉĂƟĞŶƚƐ ;ϭϱйͿ ŚĂĚ ŵƵůƟƉůĞ ƉĂƌĂŐĂŶŐůŝŽŵĂƐ͕ ĐŽŶƚƌĂƐƟŶŐ ƚŽ ǁŚĂƚ ŝƐ ŬŶŽǁŶ ĨƌŽŵ SDHD-ůŝŶŬĞĚƉĂƟĞŶƚƐ͕ǁŚŽƐƵīĞƌĨƌŽŵŵƵůƟƉůĞƉĂƌĂŐĂŶŐůŝŽŵĂƐŵƵĐŚŵŽƌĞĨƌĞƋƵĞŶƚůLJ ;ŝŶϲϬʹϳϵйͿ͘KŶĞƉĂƟĞŶƚ;ϮйͿŚĂƌďŽƌĞĚĂĐŽŶĐƵƌƌĞŶƚƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂĂŶĚϯ ;ϲйͿĚĞǀĞůŽƉĞĚŵĞƚĂƐƚĂƟĐĚŝƐĞĂƐĞ͘dǁĞŶƚLJͲƐĞǀĞŶƉĂƟĞŶƚƐ;ϱϬйͿŚĂĚĂŶŽƉĞƌĂ-ƟŽŶĨŽƌƚŚĞŝƌŚĞĂĚĂŶĚŶĞĐŬƉĂƌĂŐĂŶŐůŝŽŵĂĂŶĚϭϱ;ϮϴйͿƌĞĐĞŝǀĞĚƌĂĚŝŽƚŚĞƌĂƉLJ͘ ůƚŚŽƵŐŚƚŚĞŵĞĂŶĂŐĞĂƚĚŝĂŐŶŽƐŝƐŝŶƚŚŝƐĐŽŚŽƌƚǁĂƐƌĞůĂƟǀĞůLJŚŝŐŚ;ϰϱ͘ϵLJĞĂƌƐͿ͕ ƚŚĞLJŽƵŶŐĞƐƚƉĂƟĞŶƚĚĞǀĞůŽƉĞĚĂŚĞĂĚĂŶĚŶĞĐŬƉĂƌĂŐĂŶŐůŝŽŵĂĂƚƚŚĞĂŐĞŽĨϭϭ LJĞĂƌƐ͕ ĂŶĚ ĂŶ ϭϴͲLJĞĂƌͲŽůĚ ƉĂƟĞŶƚ ŚĂĚ ĂůƌĞĂĚLJ ĚĞǀĞůŽƉĞĚ ŵĞƚĂƐƚĂƟĐ ĚŝƐĞĂƐĞ͘ /Ŷ ĂŐƌĞĞŵĞŶƚ ǁŝƚŚ ƚŚĞƐĞ ĮŶĚŝŶŐƐ͕ ƚƵŵŽƌ ƐĐƌĞĞŶŝŶŐ ŝŶ SDHBͲůŝŶŬĞĚ ĨĂŵŝůŝĞƐ ŝŶ ƚŚĞ EĞƚŚĞƌůĂŶĚƐŶŽǁĂĚĂLJƐƐƚĂƌƚƐĂƚƚŚĞĂŐĞŽĨϭϬLJĞĂƌƐ͘/ĨĂŶSDHBǀĂƌŝĂŶƚŝƐŝĚĞŶƟĮĞĚ ŝŶĂŚĞĂĚĂŶĚŶĞĐŬƉĂƌĂŐĂŶŐůŝŽŵĂƉĂƟĞŶƚ͕ƚŚĞĐůŝŶŝĐŝĂŶƐŚŽƵůĚďĞĂǁĂƌĞŽĨƚŚĞ ǀĂƌŝĂďůĞŵĂŶŝĨĞƐƚĂƟŽŶƐŽĨƚŚĞSDHBͲůŝŶŬĞĚƚƵŵŽƌƐLJŶĚƌŽŵĞ͕ƚŚĞƌŝƐŬŽĨŚLJƉĞƌƐĞ-ĐƌĞƟŽŶŽĨĐĂƚĞĐŚŽůĂŵŝŶĞƐ͕ĐŽŶĐƵƌƌĞŶƚƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂ͕ĂŶĚƚŚĞĂƐƐŽĐŝĂƟŽŶ ǁŝƚŚŶŽŶͲƉĂƌĂŐĂŶŐůŝŽŶŝĐƚƵŵŽƌƐ͘ĚĞƋƵĂƚĞƐƵƌǀĞŝůůĂŶĐĞŽĨSDHBŐĞƌŵůŝŶĞǀĂƌŝĂŶƚ ĐĂƌƌŝĞƌƐŝƐŵĂŶĚĂƚŽƌLJĂŶĚƐŚŽƵůĚŝŶĐůƵĚĞƐĐƌĞĞŶŝŶŐĨŽƌĐĂƚĞĐŚŽůĂŵŝŶĞƐŽƌƚŚĞŝƌ ŵĞƚĂďŽůŝƚĞƐ͕ĂůŽŶŐǁŝƚŚƉĞƌŝŽĚŝĐƌĂĚŝŽůŽŐŝĐĂůŝŶǀĞƐƟŐĂƟŽŶŽĨƚŚĞĂďĚŽŵĞŶ͕ƚŚĞ ƉĞůǀŝĐƌĞŐŝŽŶ͕ƚŚŽƌĂdž͕ĂŶĚŚĞĂĚĂŶĚŶĞĐŬƌĞŐŝŽŶ͘ In chapter 7ƚŚĞƉĞŶĞƚƌĂŶĐĞŽĨƉĂƌĂŐĂŶŐůŝŽŵĂĂŶĚƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂŝŶSDHB ǀĂƌŝĂŶƚ ĐĂƌƌŝĞƌƐ ŝƐ ĐĂůĐƵůĂƚĞĚ ŝŶ ƚŚĞ ŶĂƟŽŶǁŝĚĞ ĐŽŚŽƌƚ͕ ƵƐŝŶŐ Ă ŶŽǀĞů ŵĂdžŝŵƵŵ ůŝŬĞůŝŚŽŽĚ ĞƐƟŵĂƚŽƌ͘ dŚŝƐ ĞƐƟŵĂƚŽƌ ĂĚĚƌĞƐƐĞƐ ĂƐĐĞƌƚĂŝŶŵĞŶƚ ďŝĂƐ ĂŶĚ ŵŝƐƐŝŶŐ ĚĂƚĂ ŽŶ ƉĞĚŝŐƌĞĞ ƐŝnjĞ ĂŶĚ ƐƚƌƵĐƚƵƌĞ͘  ƚŽƚĂů ŽĨ ϭϵϱ SDHB variant carriers were ŝŶĐůƵĚĞĚ͕ĐĂƌƌLJŝŶŐϮϳĚŝīĞƌĞŶƚSDHBŵƵƚĂƟŽŶƐ͘dŚĞϮŵŽƐƚƉƌĞǀĂůĞŶƚSDHB ge-ŶĞƟĐǀĂƌŝĂŶƚƐǁĞƌĞŬŶŽǁŶƵƚĐŚĨŽƵŶĚĞƌŵƵƚĂƟŽŶƐ͗ĂĚĞůĞƟŽŶŝŶĞdžŽŶϯ;ϯϭйŽĨ ŵƵƚĂƟŽŶĐĂƌƌŝĞƌƐͿĂŶĚƚŚĞĐ͘ϰϮϯнϭ'хŵƵƚĂƟŽŶ;ϮϰйŽĨŵƵƚĂƟŽŶĐĂƌƌŝĞƌƐͿ͘KŶĞ ŚƵŶĚƌĞĚĂŶĚƚǁĞůǀĞĐĂƌƌŝĞƌƐ;ϱϳйͿƐŚŽǁĞĚŶŽƉŚLJƐŝĐĂů͕ƌĂĚŝŽůŽŐŝĐĂůŽƌďŝŽĐŚĞŵ-ŝĐĂůĞǀŝĚĞŶĐĞŽĨƉĂƌĂŐĂŶŐůŝŽŵĂŽƌƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂ͘&ŝŌLJͲĨŽƵƌƉĂƟĞŶƚƐŚĂĚĂ ŚĞĂĚĂŶĚŶĞĐŬƉĂƌĂŐĂŶŐůŝŽŵĂ;ϮϴйͿ͕ϰƉĂƟĞŶƚƐŚĂĚĂƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂ;ϮйͿ͕ ϮϲƉĂƟĞŶƚƐĂŶƐLJŵƉĂƚŚĞƟĐƉĂƌĂŐĂŶŐůŝŽŵĂ;ϭϯйͿ͘hƐŝŶŐƚŚĞŶŽǀĞůĞƐƟŵĂƚŽƌ͕ƚŚĞ ŽǀĞƌĂůůƉĞŶĞƚƌĂŶĐĞŽĨSDHBǀĂƌŝĂŶƚƐŝƐĞƐƟŵĂƚĞĚƚŽďĞϮϭйĂƚĂŐĞϱϬĂŶĚϰϮйĂƚ ĂŐĞϳϬ͘dŚĞƐĞĞƐƟŵĂƚĞƐĂƌĞůŽǁĞƌƚŚĂŶƉƌĞǀŝŽƵƐůLJƌĞƉŽƌƚĞĚƉĞŶĞƚƌĂŶĐĞĞƐƟŵĂƚĞƐ of SDHBͲůŝŶŬĞĚĐŽŚŽƌƚƐ͕ĂŶĚĐŽŶĮƌŵƚŚĞƉĞŶĞƚƌĂŶĐĞĞƐƟŵĂƚĞƐĨŽƵŶĚŝŶĐŚĂƉƚĞƌϰ͘ ^ŝŵŝůĂƌĚŝƐĞĂƐĞƌŝƐŬƐĂƌĞĨŽƵŶĚĨŽƌĚŝīĞƌĞŶƚSDHBŐĞƌŵůŝŶĞǀĂƌŝĂŶƚƐĂƐǁĞůůĂƐĨŽƌ ŵĂůĞĂŶĚĨĞŵĂůĞSDHB variant carriers.

In chapter 8ƚŚĞŵŽƌƚĂůŝƚLJŽĨĂŶĂƟŽŶǁŝĚĞĐŽŚŽƌƚŽĨSDHB variant carriers and ƚŚĂƚŽĨĂůĂƌŐĞĐŽŚŽƌƚŽĨSDHDǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐŝƐĞƐƟŵĂƚĞĚĂŶĚĐŽŵƉĂƌĞĚƚŽƚŚĞ

164

Chapt

ŵŽƌƚĂůŝƚLJ ŽĨ Ă ŵĂƚĐŚĞĚ ĐŽŚŽƌƚ ŽĨ ƚŚĞ ŐĞŶĞƌĂů ƵƚĐŚ ƉŽƉƵůĂƟŽŶ͘  ƚŽƚĂů ŽĨ ϭϵϮ

SDHB variant carriers and 232 SDHDǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐǁĞƌĞŝŶĐůƵĚĞĚŝŶƚŚŝƐƐƚƵĚLJ͘

dŚĞ^ƚĂŶĚĂƌĚDŽƌƚĂůŝƚLJZĂƟŽ;^DZͿĨŽƌSDHBŵƵƚĂƟŽŶĐĂƌƌŝĞƌƐŝƐϭ͘ϴϵ͕ŝŶĐƌĞĂƐ-ŝŶŐƚŽϮ͘ϴϴŝŶĐĂƌƌŝĞƌƐĂīĞĐƚĞĚďLJƉĂƌĂŐĂŶŐůŝŽŵĂĂŶĚͬŽƌƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂ͘&Žƌ SDHDǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐƚŚĞ^DZŝƐϬ͘ϵϯ͕ĂŶĚϭ͘ϬϲŝŶĂīĞĐƚĞĚĐĂƌƌŝĞƌƐ͘ŽŵƉĂƌĞĚ ƚŽƚŚĞŐĞŶĞƌĂůƉŽƉƵůĂƟŽŶ͕ŵŽƌƚĂůŝƚLJƐĞĞŵƐƚŽďĞŝŶĐƌĞĂƐĞĚŝŶSDHB variant car-ƌŝĞƌƐ͕ĞƐƉĞĐŝĂůůLJŝŶƚŚŽƐĞĂīĞĐƚĞĚďLJƉĂƌĂŐĂŶŐůŝŽŵĂĂŶĚͬŽƌƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂ͘ In SDHDǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐ͕ƚŚĞŵŽƌƚĂůŝƚLJŝƐĐŽŵƉĂƌĂďůĞƚŽƚŚĂƚŽĨƚŚĞŐĞŶĞƌĂůƵƚĐŚ ƉŽƉƵůĂƟŽŶ͕ ĞǀĞŶ ŝĨ ƚŚĞLJ ĂƌĞ ĂīĞĐƚĞĚ ďLJ ƉĂƌĂŐĂŶŐůŝŽŵĂ ĂŶĚͬŽƌ ƉŚĞŽĐŚƌŽŵŽĐLJ- ƚŽŵĂ͘dŚŝƐĮŶĚŝŶŐŝƐĂŶƉŽŝŐŶĂŶƚĞdžĂŵƉůĞŽĨƚŚĞĚŝīĞƌĞŶĐĞƐŝŶĐůŝŶŝĐĂůƌŝƐŬƐĐŽŶ-ĨĞƌƌĞĚďLJĚŝīĞƌĞŶƚSDHxŐĞŶĞƐ͘/ƚĞŵƉŚĂƐŝnjĞƐƚŚĞƐŝŐŶŝĮĐĂŶĐĞŽĨEͲƚĞƐƟŶŐŝŶĂůů ƉĂƌĂŐĂŶŐůŝŽŵĂĂŶĚƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂƉĂƟĞŶƚƐ͕ĂŶĚŵĂLJǁĂƌƌĂŶƚŐĞŶĞͲƐƉĞĐŝĮĐ management strategies.

9.2

CONCLUSION

^ŝŶĐĞƚŚĞLJĞĂƌϮϬϬϬǁĞŚĂǀĞǁŝƚŶĞƐƐĞĚĂŶĞǀŽůƵƟŽŶŝŶƚŚĞĐĂƌĞŽĨƉĂƟĞŶƚƐǁŝƚŚ ƉĂƌĂŐĂŶŐůŝŽŵĂĂŶĚƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂ͘ŶĞdžƉĂŶĚŝŶŐŶƵŵďĞƌŽĨŐĞŶĞǀĂƌŝĂŶƚƐ ĂƌĞŶŽǁĂƐƐŽĐŝĂƚĞĚǁŝƚŚƉĂƌĂŐĂŶŐůŝŽŵĂĂŶĚƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂĚĞǀĞůŽƉŵĞŶƚ͕ ĂŶĚƚŚĞŐĞŶĞƟĐŚĞƚĞƌŽŐĞŶĞŝƚLJŝŶƉĂƌĂŐĂŶŐůŝŽŵĂƐŝƐƵŶƌŝǀĂůĞĚďLJĂŶLJŽƚŚĞƌŚƵŵĂŶ ŶĞŽƉůĂƐŵ͘ dŚĞ ĚŝīĞƌĞŶƚ ƉĂƌĂŐĂŶŐůŝŽŵĂ ƐƵƐĐĞƉƟďŝůŝƚLJ ŐĞŶĞƐ Ăůů ĐĂƵƐĞ ŝĚĞŶƟĐĂů ƉĂƌĂŐĂŶŐůŝŽŵĂƐ͕ďƵƚĚŝīĞƌĞŶƚĐůŝŶŝĐĂůƌŝƐŬƐ;ƉŚĞŶŽƚLJƉĞƐͿ͘ďĞƩĞƌƵŶĚĞƌƐƚĂŶĚŝŶŐ ŽĨƚŚĞŐĞŶŽƚLJƉĞͲƉŚĞŶŽƚLJƉĞƌĞůĂƟŽŶƐŚŝƉƐŝŶĐƌĞĂƐĞƐƚŚĞĂĐĐƵƌĂĐLJŽĨĐůŝŶŝĐĂůƉƌĞĚŝĐ- ƟŽŶ͕ĨĂĐŝůŝƚĂƚĞƐƚŚĞĚĞƐŝŐŶŽĨŽƉƟŵĂůƐƵƌǀĞŝůůĂŶĐĞƉƌŽŐƌĂŵƐĨŽƌĂƐLJŵƉƚŽŵĂƟĐĐĂƌ-ƌŝĞƌƐ͕ĂŶĚŵĂLJŚĞůƉŝŶƚĂŝůŽƌͲŵĂĚĞĐůŝŶŝĐĂůĚĞĐŝƐŝŽŶƐ͘dŚĞĐƵƌƌĞŶƚƚŚĞƐŝƐĚĞƐĐƌŝďĞƐ ƚŚĞĐůŝŶŝĐĂůĐŚĂƌĂĐƚĞƌŝƐƟĐƐŽĨSDHBͲůŝŶŬĞĚĚŝƐĞĂƐĞŝŶƚǁŽSDHBͲůŝŶŬĞĚĨĂŵŝůŝĞƐĂŶĚ ŝŶĂƵƚĐŚŶĂƟŽŶǁŝĚĞĐŽŚŽƌƚŽĨSDHB variant carriers. LJƐƚƵĚLJŝŶŐĂĨŽƵƌͲŐĞŶĞƌĂƟŽŶĨĂŵŝůLJ͕ĂŶŽǀĞůSDHBŐĞŶĞǀĂƌŝĂŶƚĐŽƵůĚďĞĂƐƐŽĐŝ-ĂƚĞĚǁŝƚŚƚŚĞĨŽƌŵĂƟŽŶŽĨŚĞĂĚĂŶĚŶĞĐŬƉĂƌĂŐĂŶŐůŝŽŵĂ͕ĂĚĞůĞƟŽŶŽĨĞdžŽŶϭͲϯ in the SDHB gene. /ŶĂƐĞĐŽŶĚĞdžƚĞŶĚĞĚĨĂŵŝůLJĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂŬŶŽǁŶƵƚĐŚĨŽƵŶĚĞƌĞdžŽŶϯĚĞ- ůĞƟŽŶŝŶƚŚĞSDHBŐĞŶĞ͕ǁĞǁĞƌĞĂďůĞƚŽĐĂůĐƵůĂƚĞƚŚĞƉĞŶĞƚƌĂŶĐĞĨŽƌƚŚŝƐƐƉĞ-ĐŝĮĐŐĞŶĞǀĂƌŝĂŶƚ͘ƚƚŚĞĂŐĞƐŽĨƌĞƐƉĞĐƟǀĞůLJϰϬ͕ϱϬ͕ϲϬĂŶĚϳϬƚŚĞƉĞŶĞƚƌĂŶĐĞ ǁĂƐϰй͕ϵй͕ϭϱйĂŶĚϮϭй͕ŵƵĐŚůŽǁĞƌƚŚĂŶƉƌĞǀŝŽƵƐĞƐƟŵĂƚĞƐĨŽƌSDHBͲůŝŶŬĞĚ ƉĞŶĞƚƌĂŶĐĞ͘dŚŝƐƌĞĚƵĐƟŽŶŝŶƚŚĞĞƐƟŵĂƚĞĚSDHBͲůŝŶŬĞĚƉĞŶĞƚƌĂŶĐĞǁĂƐĨĂĐŝůŝ-ƚĂƚĞĚďLJƚŚĞŝŶĐůƵƐŝŽŶŽĨĂƌĞůĂƟǀĞůLJůĂƌŐĞŶƵŵďĞƌŽĨƵŶĂīĞĐƚĞĚǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐ͘ dŚĞƐƚƵĚLJŽĨĂŶĂƟŽŶǁŝĚĞƵƚĐŚĐŽŚŽƌƚŽĨSDHBǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐƌĞǀĞĂůĞĚƚŚĂƚƚŚĞLJ have ĂŶŝŶƚĞƌŵĞĚŝĂƚĞƌŝƐŬĨŽƌƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨŚĞĂĚĂŶĚŶĞĐŬƉĂƌĂŐĂŶŐůŝŽŵĂƐ Summary and c onclusion 165

;Ϯϳ͘ϴйͿ͕ĂůŽǁƌŝƐŬĨŽƌƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂƐ;Ϯ͘ϭйͿ͕ĂŶŝŶƚĞƌ-ŵĞĚŝĂƚĞƌŝƐŬĨŽƌƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨƐLJŵƉĂƚŚĞƟĐƉĂƌĂŐĂŶŐůŝŽŵĂƐ;ϭϯ͘ϰйͿĂŶĚĂ ƌĞůĂƟǀĞůLJůŽǁƌŝƐŬŽĨ ĚĞǀĞůŽƉŝŶŐŵĞƚĂƐƚĂƟĐĚŝƐĞĂƐĞ͘LJƵƐŝŶŐĂŶŽǀĞůŵĂdžŝŵƵŵ ůŝŬĞůŝŚŽŽĚ ŵĞƚŚŽĚ ĨŽƌ ƉĞŶĞƚƌĂŶĐĞ ĐĂůĐƵůĂƟŽŶƐ͕ ƚŚĞ ŽǀĞƌĂůů ƉĞŶĞƚƌĂŶĐĞ ŽĨ SDHB ǀĂƌŝĂŶƚƐ ŝƐ ĞƐƟŵĂƚĞĚ ƚŽ ďĞ Ϯϭй Ăƚ ĂŐĞ ϱϬ ĂŶĚ ϰϮй Ăƚ ĂŐĞ ϳϬ͕ ĐŽŶĮƌŵŝŶŐ ƚŚĂƚ SDHBͲůŝŶŬĞĚƉĞŶĞƚƌĂŶĐĞŝƐůŽǁĞƌƚŚĂŶƉƌĞǀŝŽƵƐůLJƌĞƉŽƌƚĞĚ͘^ŝŵŝůĂƌĚŝƐĞĂƐĞƌŝƐŬƐ ǁĞƌĞĨŽƵŶĚĨŽƌĚŝīĞƌĞŶƚSDHBǀĂƌŝĂŶƚƐĂƐǁĞůůĂƐĨŽƌŵĂůĞĂŶĚĨĞŵĂůĞSDHB vari-ant carriers. ŽŵƉĂƌĞĚƚŽĂŵĂƚĐŚĞĚĐŽŚŽƌƚŽĨƚŚĞŐĞŶĞƌĂůƉŽƉƵůĂƟŽŶ͕ŵŽƌƚĂůŝƚLJŝƐŝŶĐƌĞĂƐĞĚ in SDHB ǀĂƌŝĂŶƚ ĐĂƌƌŝĞƌƐ ďƵƚ ŶŽƚ ŝŶ SDHD variant carriers. There is an interest-ŝŶŐ ƉĂƌĂĚŽdž ďĞŚŝŶĚ ƚŚŝƐ ŽďƐĞƌǀĂƟŽŶ͕ ŝůůƵƐƚƌĂƟŶŐ ƚŚĞ ĚŝīĞƌĞŶĐĞƐ ŝŶ ĐůŝŶŝĐĂů ƌŝƐŬƐ ďĞƚǁĞĞŶĐĂƌƌŝĞƌƐŽĨƉĂƚŚŽŐĞŶŝĐSDHB and SDHDǀĂƌŝĂŶƚƐ͘tŚĞƌĞĂƐSDHDͲůŝŶŬĞĚ ĐĂƌƌŝĞƌƐǁŝůůĚĞǀĞůŽƉŽŶĞŽƌŵŽƌĞ;ŚĞĂĚĂŶĚŶĞĐŬͿƉĂƌĂŐĂŶŐůŝŽŵĂƐŝŶŵŽƐƚĐĂƐĞƐ ;ϴϴͲϭϬϬйͿ͕ŵŽƌƚĂůŝƚLJĨŽƌƚŚĞŐƌŽƵƉĂƐĂǁŚŽůĞŝƐŶŽƚŝŶĐƌĞĂƐĞĚ͘ŽŶǀĞƌƐĞůLJ͕ŽŶůLJĂ ŵŝŶŽƌŝƚLJŽĨSDHBͲůŝŶŬĞĚĐĂƌƌŝĞƌƐǁŝůůĚĞǀĞůŽƉĂƉĂƌĂŐĂŶŐůŝŽŵĂĂŶĚͬŽƌƉŚĞŽĐŚƌŽ-ŵŽĐLJƚŽŵĂ;ϰϯйͿ͕ďƵƚƚŚŝƐĚŽĞƐƌĞƐƵůƚŝŶĂŚŝŐŚĞƌŵŽƌƚĂůŝƚLJƌĂƚĞʹĂŶĞīĞĐƚƚŚĂƚ ƐĞĞŵƐƚŽďĞĂƩƌŝďƵƚĂďůĞƚŽƚŚĞĐůŝŶŝĐĂůůLJĂīĞĐƚĞĚSDHBͲůŝŶŬĞĚĐĂƌƌŝĞƌƐ͘

/ŶƐƵŵŵĂƌLJ͕ƚŚŝƐƚŚĞƐŝƐŝŶĐƌĞĂƐĞƐŽƵƌƵŶĚĞƌƐƚĂŶĚŝŶŐŽĨSDHB gene variants and ƚŚĞĂƐƐŽĐŝĂƚĞĚĐůŝŶŝĐĂůƉŝĐƚƵƌĞŝŶdŚĞEĞƚŚĞƌůĂŶĚƐ͕ĂŶĚƌĞǀĞĂůƐŶĞǁŝŶƐŝŐŚƚƐĞƐƉĞ-ĐŝĂůůLJŝŶƚŚĞƉĞŶĞƚƌĂŶĐĞĂŶĚŵŽƌƚĂůŝƚLJŽĨSDHBͲůŝŶŬĞĚĚŝƐĞĂƐĞ͘

9.3

FUTURE PERSPECTIVES

/ƚ ŝƐ ŝŶƚƌŝŐƵŝŶŐ ƚŚĂƚ ƚŚĞ ĐĂƵƐĂƟǀĞ ŐĞŶĞ ĚĞƚĞƌŵŝŶĞƐ ǀĂƌŝĂƟŽŶ ŝŶ ƚŚĞ ƉŚĞŶŽ-ƚLJƉĞ ĂŶĚ ƉƌŽŐŶŽƐŝƐ ĨŽƌ ƉĂƌĂŐĂŶŐůŝŽŵĂ ĂŶĚ ƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂ ƉĂƟĞŶƚƐ͕ ĞǀĞŶ ƚŚŽƵŐŚ ƉĂƚŚŽŐĞŶŝĐ ǀĂƌŝĂŶƚƐ ŝŶ ĚŝīĞƌĞŶƚ SDH ŐĞŶĞƐ ĐĂƵƐĞ ƉĂƌĂŐĂŶŐůŝŽŵĂ ƐLJŶ-ĚƌŽŵĞ ƚŚƌŽƵŐŚ ĚĞĨĞĐƚƐ ŝŶ ƚŚĞ ƐĂŵĞ ƉƌŽƚĞŝŶ ĐŽŵƉůĞdž ;SDHͿ͘ tŚĂƚ ŝƐ ŵŽƌĞ͕ ƚŚĞƌĞ ŵĂLJ ďĞ ĞǀŝĚĞŶĐĞ ƚŚĂƚ ƚŚŝƐ ƉŚĞŶŽƚLJƉŝĐ ĚŝǀĞƌŐĞŶĐĞ ŝƐ ŶŽƚ ũƵƐƚ ĚĞƉĞŶĚĞŶƚ ŽŶ ƚŚĞ ŐĞŶĞ ďƵƚ ĂůƐŽ ŽŶ ǀĂƌŝĂŶƚ ĐůĂƐƐ ;ŝ͘Ğ͘ ŵŝƐƐĞŶƐĞͬŶŽŶƐĞŶƐĞͿ͘ dŚĞ ĨƵƌƚŚĞƌ ĚŝƐƐĞĐƟŽŶ ĂŶĚ ƌĞĮŶĞŵĞŶƚ ŽĨ ǀĂƌŝĂŶƚͲƐƉĞĐŝĮĐ ƉŚĞŶŽƚLJƉĞƐ ǁŝůů ƉŽƐƐŝďůLJ ƐŚĞĚ ŵŽƌĞ ůŝŐŚƚ ŽŶ ƚŚĞ ǁĂLJƐ ŝŶ ǁŚŝĐŚ ƚŚĞ ĚŝƐƌƵƉƟŽŶ ŽĨ ƚŚĞ ŐĞŶĞ ĐĂƵƐĞƐ Ă ƉĂƌĂŐĂŶ-ŐůŝŽŵĂ͕ ĂŶĚ ůŝŬĞůLJ ĨƵƌƚŚĞƌ ŽƵƌ ƵŶĚĞƌƐƚĂŶĚŝŶŐ ŽĨ ŐĞŶŽƚLJƉĞͲƉŚĞŶŽƚLJƉĞ ĐŽƌƌĞůĂ-ƟŽŶƐ͕ůĞĂĚŝŶŐƚŽŵŽƌĞƉĞƌƐŽŶĂůŝnjĞĚƌŝƐŬĂƐƐĞƐƐŵĞŶƚ͕ĐŽƵŶƐĞůŝŶŐ͕ĂŶĚƚŚĞƌĂƉŝĞƐ͘  ďĞƩĞƌ ƵŶĚĞƌƐƚĂŶĚŝŶŐ ŽĨ ƚŚĞ ƚƵŵŽƌ ďŝŽůŽŐLJ ŵŝŐŚƚ ĂůƐŽ ŝŶĐƌĞĂƐĞ ƚŚĞ ĂǀĂŝůĂďůĞ ƚƌĞĂƚŵĞŶƚŽƉƟŽŶƐĨŽƌƉĂƌĂŐĂŶŐůŝŽŵĂƐĂŶĚƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂƐ͕ĞƐƉĞĐŝĂůůLJĨŽƌ ŵĂůŝŐŶĂŶƚĂŶĚŵƵůƟƉůĞƉĂƌĂŐĂŶŐůŝŽŵĂƐ͘ƐŽĨLJĞƚ͕ƚŚĞƌĞĂƌĞŶŽĐƵƌĂƟǀĞŽƉƟŽŶƐ ĨŽƌ ŵĞƚĂƐƚĂƐŝnjĞĚ ĚŝƐĞĂƐĞ͘ ZĞƐĞĂƌĐŚ ŝƐ ŶĞĞĚĞĚ ƚŽ ĞǀĂůƵĂƚĞ ƚŚĞƌĂƉŝĞƐ ǁŝƚŚ ŶŽǀĞů 166 Chapt er 9

ŵĞĐŚĂŶŝƐŵƐŽĨĂĐƟŽŶ͘dŚĞƵƐĞŽĨƚLJƌŽƐŝŶĞŬŝŶĂƐĞŝŶŚŝďŝƚŽƌƐ͕ƌĂĚŝŽŶƵĐůŝĚĞĂŐĞŶƚƐ͕ ĂŶĚƚĂƌŐĞƚĞĚŝŵŵƵŶŽƚŚĞƌĂƉLJŵĂLJŝŵƉƌŽǀĞƚŚĞŽƵƚĐŽŵĞƐŽĨƉĂƟĞŶƚƐǁŝƚŚŵĂůŝŐ-ŶĂŶƚŽƌŵƵůƟƉůĞƉĂƌĂŐĂŶŐůŝŽŵĂƐĂŶĚƉŚĞŽĐŚƌŽŵŽĐLJƚŽŵĂƐŝŶƚŚĞĨƵƚƵƌĞ͘

Pathogenic SDHBǀĂƌŝĂŶƚƐƐĞĞŵƚŽĐŽŶĨĞƌŚŝŐŚĞƌƌŝƐŬƐƚŽƉĂƟĞŶƚƐĂƐŽƉƉŽƐĞĚƚŽ͕ for instance, SDHDǀĂƌŝĂŶƚĐĂƌƌŝĞƌƐ͘dŚŝƐŝƐƌĞŇĞĐƚĞĚďLJƚŚĞŚŝŐŚĞƌŵŽƌƚĂůŝƚLJƌĂƟŽ for carriers of pathogenic SDHBǀĂƌŝĂŶƚƐƌĞƉŽƌƚĞĚŝŶƚŚŝƐƚŚĞƐŝƐ͘ĂƐĞĚŽŶƚŚŝƐĮŶĚ- ŝŶŐ͕ĂŵŽƌĞĂŐŐƌĞƐƐŝǀĞƚƌĞĂƚŵĞŶƚƐƚƌĂƚĞŐLJŵĂLJďĞǁĂƌƌĂŶƚĞĚŝŶSDHBͲůŝŶŬĞĚƉĂƌĂ- ŐĂŶŐůŝŽŵĂƉĂƟĞŶƚƐ͘,ŽǁĞǀĞƌ͕ƚŚĞĞīĞĐƚŽĨĞĂƌůLJĂŶĚͬŽƌŵŽƌĞĂŐŐƌĞƐƐŝǀĞŝŶƚĞƌǀĞŶ-ƟŽŶŽŶŵĂůŝŐŶĂŶƚƚƌĂŶƐĨŽƌŵĂƟŽŶŽƌŵŽƌƚĂůŝƚLJƌĂƚĞƐŝŶSDHBͲůŝŶŬĞĚƉĂƟĞŶƚƐŝƐƐƟůů ƵŶŬŶŽǁŶ͕ĂŶĚĐƵƌƌĞŶƚƚƌĞĂƚŵĞŶƚŽƉƟŽŶƐƐƵĐŚĂƐƐƵƌŐĞƌLJĂŶĚƌĂĚŝŽƚŚĞƌĂƉLJĐŽŵĞ ǁŝƚŚŝŶŚĞƌĞŶƚƌŝƐŬƐƚŽƚŚĞƉĂƟĞŶƚ͘&ƵƌƚŚĞƌŵŽƌĞ͕ƚŚĞĐůŝŶŝĐĂůĐŽƵƌƐĞŽĨƚŚĞĚŝƐĞĂƐĞ ǀĂƌŝĞƐǁŝĚĞůLJǁŝƚŚŝŶƚŚĞŐƌŽƵƉSDHBͲůŝŶŬĞĚƉĂƟĞŶƚƐ͕ĂŶƚŚƵƐŶŽƚĂůůǁŝůůďĞŶĞĮƚ ĞƋƵĂůůLJĨƌŽŵƐƵĐŚĂƐŚŝŌŝŶŵĂŶĂŐĞŵĞŶƚƐƚƌĂƚĞŐLJ͘&ƵƚƵƌĞƐƚƵĚŝĞƐǁŝůůŚŽƉĞĨƵůůLJ ŚĞůƉƚŽĚŝƐƟŶŐƵŝƐŚƚŚŽƐĞƉĂƟĞŶƚƐƚŚĂƚǁŽƵůĚďĞŶĞĮƚĨƌŽŵƐƉĞĐŝĮĐŝŶƚĞƌǀĞŶƟŽŶƐ ĨƌŽŵ ƚŚŽƐĞ ǁŚŽ ĚŽŶ͛ƚ͕ ƚŚĞƌĞďLJ ŝŵƉƌŽǀŝŶŐ ƚŚĞ ŽƵƚĐŽŵĞ ĨŽƌ ƉĂƌĂŐĂŶŐůŝŽŵĂ ƉĂ-ƟĞŶƚƐǁŝƚŚŽƵƚĞdžƉŽƐŝŶŐƚŚĞŵƵŶŶĞĐĞƐƐĂƌŝůLJƚŽƚŚĞƌĂƉLJͲƌĞůĂƚĞĚƌŝƐŬƐ͘ /ŶƚŚĞƉĂƐƚ͕ƉĂƌĂŐĂŶŐůŝŽŵĂƌĞƐĞĂƌĐŚŚĂƐďĞĞŶĂǁŽŶĚĞƌĨƵůĞdžĂŵƉůĞŽĨŚŽǁƚŚĞ ƐƚƵĚLJŽĨĂƌĂƌĞĐŽŶĚŝƟŽŶĐĂŶĞůƵĐŝĚĂƚĞďĂƐŝĐƉƌŝŶĐŝƉůĞƐŝŶďŝŽůŽŐŝĐĂůĂŶĚƉĂƚŚŽ-ŐĞŶŝĐƉƌŽĐĞƐƐĞƐĂŶĚĨĂĐŝůŝƚĂƚĞĚŝƐĐŽǀĞƌŝĞƐƚŚĂƚĂƌĞĂƉƉůŝĐĂďůĞŝŶĂŵƵĐŚďƌŽĂĚĞƌ ĐŽŶƚĞdžƚ͘/ƚŚĂƐƉůĂLJĞĚĂƌŽůĞŝŶƚŚĞƌĞĐŽŐŶŝƟŽŶĂŶĚƵŶĚĞƌƐƚĂŶĚŝŶŐŽĨƚŚĞƌŽůĞŽĨ ƚŚĞŵĞƚĂďŽůŝƐŵŝŶƚƵŵŽƌŝŐĞŶĞƐŝƐ͕ƐŚĞĚůŝŐŚƚŽŶƚŚĞŵĞĐŚĂŶŝƐŵƐďĞŚŝŶĚƉĞĐƵůŝĂƌ ŵŽĚĞƐŽĨŝŶŚĞƌŝƚĂŶĐĞ͕ĂŶĚŚĂƐƐŚŽǁŶƚŚĞŐĞŶĞƟĐŚĞƚĞƌŽŐĞŶĞŝƚLJƚŚĂƚŵĂLJƵŶĚĞƌůŝĞ ĂƐƉĞĐŝĮĐĚŝƐĞĂƐĞ͘/ŶƚŚŝƐƚŚĞƐŝƐƚŽŽ͕ĂŶŽǀĞůŵĞƚŚŽĚĨŽƌƉĞŶĞƚƌĂŶĐĞĐĂůĐƵůĂƟŽŶƐ ǁĂƐ ĚĞǀĞůŽƉĞĚ ƚŽ ŵĞĞƚ ƚŚĞ ĐŚĂůůĞŶŐĞƐ ƐĞƚ ďLJ SDHBͲůŝŶŬĞĚ ƉĂƌĂŐĂŶŐůŝŽŵĂ ƐLJŶ-ĚƌŽŵĞ͕ĂŶĚĂƐĂƌĞƐƵůƚĂŵŽƌĞƌŽďƵƐƚŵĞƚŚŽĚŽůŽŐLJĨŽƌƉĞŶĞƚƌĂŶĐĞĐĂůĐƵůĂƟŽŶƐ ŝƐŶŽǁĂǀĂŝůĂďůĞƚŚĂƚŝƐƵƐĞĨƵůŶŽƚũƵƐƚĨŽƌƉĂƌĂŐĂŶŐůŝŽŵĂďƵƚĨŽƌƉĞŶĞƚƌĂŶĐĞĞƐƟ-ŵĂƟŽŶƐŝŶŐĞŶĞƌĂů͕ĞƐƉĞĐŝĂůůLJŝŶƌĂƌĞĂŶĚůŽǁͲƉĞŶĞƚƌĂŶƚŚĞƌĞĚŝƚĂƌLJĚŝƐĞĂƐĞ͕ǁŚĞŶ ĚĂƚĂŽŶƉĞĚŝŐƌĞĞƐŝnjĞĂŶĚƐƚƌƵĐƚƵƌĞĂƌĞŵŝƐƐŝŶŐ͘,ŽƉĞĨƵůůLJĨƵƚƵƌĞƉĂƌĂŐĂŶŐůŝŽŵĂ ƌĞƐĞĂƌĐŚǁŝůůŶŽƚŽŶůLJƉƌŽǀŝĚĞŶĞǁŝŶƐŝŐŚƚƐŝŶƉĂƌĂŐĂŶŐůŝŽŵĂƉĂƚŚŽŐĞŶĞƐŝƐ͕ĐůŝŶ-ŝĐĂůĐŚĂƌĂĐƚĞƌŝƐƟĐƐĂŶĚƚƌĞĂƚŵĞŶƚ͕ďƵƚĂůƐŽĐŽŶƟŶƵĞƚŽĐŽŶƚƌŝďƵƚĞƚŽƚŚĞǁŝĚĞƌ ĮĞůĚŽĨŵĞĚŝĐŝŶĞ͘ Summary and c onclusion 167