Diseases Associated with SDH Mutations
SDHA
Neoplastic Syndromes, Hereditary
Paraganglioma
Pheochromocytoma
Gastrointestinal Stromal Tumors (GIST)
Renal cell carcinoma
Pituitary tumor
Neuroblastomas (rare)
Carcinoids (rare)
Carney’s Triad - at least 2 of these 5 lesions: GIST, pulmonary chondroma, paraganglionic system (extra-adrenal PGL), adrenal cortex (adenoma), esophagus leiomyoma
Carney-Stratakis Syndrome: GIST and paraganglioma
Leigh Disease (to have that, you need 2 SDHA gene mutations)
Cardiomyopathy, Dilated
Muscular Diseases
Mitochondrial Complex II Deficiency
SDHB
Neoplastic Syndromes, Hereditary
Paraganglioma
Pheochromocytoma
Gastrointestinal Stromal Tumors (GIST)**
Renal Cell Carcinoma
Pituitary tumors
Neuroblastomas (rare)
Carcinoids (rare)
Carney’s Triad - at least 2 of these 5 lesions: GIST, pulmonary chondroma, paraganglionic system (extra-adrenal PGL), adrenal cortex (adenoma), esophagus leiomyoma
Carney-Stratakis Dyad: GIST and Paraganglioma
Cowden-Like Syndrome - Harmartomas, Breast Cancer, Thyroid, Endometrium, Colorectal, Melanoma
Thyroid
pNET (pancreatic)*
SDHC
Neoplastic Syndromes, Hereditary
Paraganglioma (PGL)
Pheochromocytoma
Gastrointestinal Stromal Tumors (GIST)
Pituitary tumors
Renal Cell Carcinoma
Neuroblastomas (rare)
Carcinoids (rare)
Carney’s Triad - at least 2 of these 5 lesions: GIST, pulmonary chondroma, paraganglionic system (extra-adrenal PGL), adrenal cortex (adenoma), esophagus leiomyoma
Carney-Stratakis Syndrome: GIST and paraganglioma
Adrenal adenoma (can screen negative for adrenocortical hormone production)
Adrenocortical carcinoma
SDHD
Neoplastic Syndromes, Hereditary
Paraganglioma (PGL)
Pheochromocytoma (Pheo)
Gastrointestinal Stromal Tumors (GIST)
Pituitary tumors
Renal Cell Carcinoma
Neuroblastomas (rare)
Carcinoids, Intestinal Carcinoid Tumors, Merkel Cell Carcinoma
Carney’s Triad: at least 2 of these 5 lesions: GIST, pulmonary chondroma, paraganglionic system (extra-adrenal PGL), adrenal cortex (adenoma), esophagus leiomyoma
Carney-Stratakis Syndrome: GIST and paraganglioma
Combined Oxidative Phosphorylation Deficiency 8
Cowden-Like Syndrome - Harmartomas, Breast Cancer, Thyroid, Endometrium, Colorectal, Melanoma
Hamartoma Syndrome, Multiple
Carotid Body Tumor
Mitochondrial Complex II Deficiency
SDHAF1
Vascular Dementia
Mitochondrial Complex II Deficiency
SDHAF2
Hepatolenticular Degeneration
Paraganglioma
Pheochromocytoma
Neoplastic Syndrome, Hereditary
Tumor Predisposition Syndrome
Source: http://rgd.mcw.edu/rgdweb/report/gene/main.html?id=1318463
*Pancreatic NET
https://www.ncbi.nlm.nih.gov/pubmed/26259135?fbclid=IwAR3d4g4ZDqfNAJPir84gt2mnc5mgSQrHfK-G054C9QnMFSS4R4lJ9jhv19Y
*GIST - neuroendocrine tumor?
https://www.ncbi.nlm.nih.gov/pubmed/30306789
SDHA
This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is
localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been
identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]
SDHAF2
This gene encodes a mitochondrial protein needed for the flavination of a succinate dehydrogenase complex subunit required for activity of the complex. Mutations in this gene are associated with
paraganglioma.[provided by RefSeq, Jul 2010
SDHB
Complex II of the respiratory chain, which is specifically involved in the oxidation of succinate, carries electrons from FADH to CoQ. The complex is composed of four nuclear-encoded subunits and is
localized in the mitochondrial inner membrane. The iron-sulfur subunit is highly conserved and contains three cysteine-rich clusters which may comprise the iron-sulfur centers of the enzyme. Sporadic
and familial mutations in this gene result in paragangliomas and pheochromocytoma, and support a link between mitochondrial dysfunction and tumorigenesis. [provided by RefSeq, Jul
2008]
DEPMAP.ORG/SDHB linked to SOD2
SDHC
This gene encodes one of four nuclear-encoded subunits that comprise succinate dehydrogenase, also known as mitochondrial complex II, a key enzyme complex of the tricarboxylic acid cycle and aerobic
respiratory chains of mitochondria. The encoded protein is one of two integral membrane proteins that anchor other subunits of the complex, which form the catalytic core, to the inner mitochondrial
membrane. There are several related pseudogenes for this gene on different chromosomes. Mutations in this gene have been associated with paragangliomas. Alternatively spliced transcript variants have
been described. [provided by RefSeq, May 2013]
SDHD
This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013] Side note: I've met a mother with SDHD who passed the mutaton to her daughter who developed SDHD deficient Gist tumors. Thus thought to only come from the father there are exceptions.
http://rgd.mcw.edu/rgdweb/search/genes.html?term=SDHB&chr=ALL&start=&stop=&map=360&speciesType=1&obj=gene
Pheochromocytoma: Gasping for Air
Mutations in genes encoding metabolic enzymes, such as SDHx subunits, IDH1, FH, or MDH2
(all were identified in PHEOs/PGLs as well as in a variety of other tumors, including:
acute myelogenous leukemia,
gliomas,
chondrosarcomas,
kidney cancer,
disrupt the tricarboxylic acid (TCA) cycle and increase dependence on oxidative mitochondrial metabolism.
https://link.springer.com/article/10.1007%2Fs12672-015-0231-4
Succinate Dehydrogenase (SDH)-Deficient Pancreatic Neuroendocrine Tumor Expands the SDH-Related Tumor Spectrum
This study strengthens the etiological association of SDH genes with pituitary neoplasia, renal tumorigenesis, and gastric gastrointestinal stromal tumors. Furthermore, our results indicate that pancreatic neuroendocrine tumor also falls within the SDH-related tumor spectrum.
The phenotype of SDHB germline mutation carriers: a nationwide study.
August 2017, The Netherlands
Succinate dehydrogenase B subunit (SDHB) gene germline mutations predispose to pheochromocytomas, sympathetic paragangliomas, head and neck paragangliomas and non-paraganglionic tumors (e.g. renal cell carcinoma, gastrointestinal stromal tumor and pituitary neoplasia). The aim of this study was to determine phenotypical characteristics of a large Dutch cohort of SDHB germline mutation carriers and assess differences in clinical phenotypes related to specific SDHB mutations.
RESULTS:
We included 194 SDHB mutation carriers consisting 65 (33.5%) index patients and 129 (66.5%) relatives.
Fifty-four mutation carriers (27.8%) had one or multiple head and neck paragangliomas,
4 (2.1%) had a pheochromocytoma and 26 (13.4%) had one or more sympathetic paragangliomas.
Fifteen patients (7.7%) developed metastatic paraganglioma and 17 (8.8%) developed non-paraganglionic tumors.
There were 111 (57.2%) unaffected mutation carriers.
1% GIST, 1% Renal cell carcioma and 1% Pituitary tumors
https://www.ncbi.nlm.nih.gov/pubmed/28490599
SDHx mutations can be inherited from the mother or father (except for SDHD which is passed down from the father only, 99% of the time). Children have a 50:50 chance of being born with a DNA mutation. Not everyone with a mutation develops disease. We'd love a researcher to discover why.
2016 Chart of the Wildtype and SDH Deficient Gist patients that have been seen at the Pediatric Gist Clinic at National Institute of Health in Bethesda, Maryland. I am SDHB Deficient Germline Gist and I'd be one in the "B" group with orange in circle labeled "4". Note that all SDHx patients have negative IHC staining for SDHB.
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