Editing SDHD (section)

==Clinical significance==
Mutations in the ''SDHD'' [[gene]] can cause familial [[paraganglioma]].<ref name = "entrez" /> [[Germline mutation]]s in ''SDHD'' were first linked to hereditary paraganglioma in 2000.<ref name="Baysal">{{cite journal | vauthors = Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard CW, Cornelisse CJ, Devilee P, Devlin B | title = Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma | journal = Science | volume = 287 | issue = 5454 | pages = 848–51 | date = February 2000 | pmid = 10657297 | doi = 10.1126/science.287.5454.848 | bibcode = 2000Sci...287..848B }}</ref>  Since then, it has been shown that mutations in ''SDHB'' and to a lesser degree ''SDHC'' can cause paranglioma as well as familial [[pheochromocytoma]]. Notably, the tumor spectrum is different for the different mutations. ''SDHB'' mutations often lead to metastatic disease that is extra-adrenal, while ''SDHD'' mutation related tumors are more typically benign, originating in the head and neck.<ref name = GHR-HPP>{{cite web|title=Hereditary paraganglioma-pheochromocytoma|url=http://ghr.nlm.nih.gov/condition/hereditary-paraganglioma-pheochromocytoma|website=Genetics Home Reference|publisher=U.S. National Library of Medicine|access-date=26 March 2015}}</ref>

The exact mechanism for tumorigenesis is not determined, but it is suspected that malfunction of the SDH complex can cause a [[Hypoxia (medical)|hypoxic]] response in the cell that leads to tumor formation. Mutations in the [[SDHB]], [[SDHC (gene)|SDHC]], SDHD, and [[SDHAF2]] genes lead to the loss or reduction of SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. As a result, the hypoxia pathways are triggered in normal oxygen conditions, which lead to abnormal cell growth and tumor formation.<ref name = GHR-HPP /> People living at higher altitudes (for example, the Andes mountains) are known to have an increased rate of benign paraganglioma, with the rate of disease increasing with the altitude of the population.

At least five variants in the SDHD gene have been identified in people with [[Cowden syndrome]] or a similar disorder called Cowden-like syndrome. These conditions are characterized by multiple tumor-like growths called [[hamartomas]] and an increased risk of developing certain cancers. When Cowden syndrome and Cowden-like syndrome are caused by SDHD gene mutations, the conditions are associated with a particularly high risk of developing [[breast cancer|breast]] and [[thyroid cancer|thyroid]] cancers. The SDHD gene variants associated with Cowden syndrome and Cowden-like syndrome change single amino acids in the SDHD protein, which likely alters the function of the SDH enzyme. Studies suggest that the defective enzyme could allow cells to grow and divide unchecked, leading to the formation of hamartomas and cancerous tumors. However, researchers are uncertain whether the identified SDHD gene variants are directly associated with Cowden syndrome and Cowden-like syndrome. Some of the variants described above have rarely been found in people without the features of these conditions.<ref name = GHR-SDHD>{{cite web|title=SDHD|url=http://ghr.nlm.nih.gov/gene/SDHD|website=Genetics Home Reference|publisher=U.S. National Library of Medicine|access-date=26 March 2015}}</ref>

Mutations in the ''SDHD'' gene have been found in a small number of people with [[Carney–Stratakis syndrome]], a hereditary form of a cancer of the gastrointestinal tract called [[gastrointestinal stromal tumor]] (GIST). Those with Carney-Stratakis syndrome present with a noncancerous tumor associated with the nervous system called a [[paraganglioma]] or [[pheochromocytoma]] (a type of paraganglioma). An inherited SDHD gene mutation predisposes an individual to cancer formation. An additional mutation that deletes the normal copy of the gene is needed to cause Carney-Stratakis syndrome. This second mutation, called a [[somatic mutation]], is acquired during a person's lifetime and is present only in tumor cells.<ref name="GHR-SDHD"/>

Mitochondrial complex II deficiency (MT-C2D), a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, has also been associated with mutations in the ''SDHD'' gene. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, cardiomyopathy. Some patients manifest [[Leigh syndrome]] or [[Kearns–Sayre syndrome]].<ref>{{cite web |title=SDHD Gene |url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=SDHD |website=www.genecards.org |publisher=GeneCards Human Gene Database |access-date=30 July 2018}}</ref><ref>{{cite journal | vauthors = Jackson CB, Nuoffer JM, Hahn D, Prokisch H, Haberberger B, Gautschi M, Häberli A, Gallati S, Schaller A | title = Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency | journal = Journal of Medical Genetics | volume = 51 | issue = 3 | pages = 170–5 | date = March 2014 | pmid = 24367056 | doi = 10.1136/jmedgenet-2013-101932 | s2cid = 25057245 }}</ref><ref>{{cite journal | vauthors = Alston CL, Ceccatelli Berti C, Blakely EL, Oláhová M, He L, McMahon CJ, Olpin SE, Hargreaves IP, Nolli C, McFarland R, Goffrini P, O'Sullivan MJ, Taylor RW | title = A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency | journal = Human Genetics | volume = 134 | issue = 8 | pages = 869–79 | date = August 2015 | pmid = 26008905 | pmc = 4495259 | doi = 10.1007/s00439-015-1568-z }}</ref>