Mitochondrial complex II deficiency

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Image 1: Mitochondrial complex II SuccDeh.svg
Image 1: Mitochondrial complex II

Mitochondrial complex II deficiency, also called CII deficiency, is a rare mitochondrial disease caused by deficiency of mitochondrial complex II, also known as Succinate dehydrogenase (SDH). SDH plays a key role in metabolism; the catalytic end, made up of SDHA and SDHB oxidizes succinate to fumarate in the tricarboxylic acid (TCA) cycle. The electrons from this reaction then reduce FAD to FADH2, which ultimately reduces ubiquinone to ubiquinol in the mitochondrial electron transport chain. As of 2020, about 61 cases have been reported with genetic studies [1] , but there are also documented cases of CII deficiencies as determined by biochemical and histological analysis without genetic studies. [2]

Contents

Signs and symptoms

Mitochondrial complex II deficiency affects the body's mitochondria [3] and can have a variety of presentations. In some cases, the brain, peripheral nervous system, heart, liver, kidneys, and muscles are affected, while in other cases, only a subset of these organs are affected. [4] The condition can present differently among different individuals, even those in the same family, but symptoms can largely be separated into two categories. Those with biallelic loss of function who don't have any functional SDH have an average age of onset of 8.6 ± 7.9 months, while those with monoallelic loss of function have an average age of onset of 21.5 ± 20.3 years. [1] In the biallelic form, there is typically a Leigh syndrome phenotype with symptoms including seizures, white matter lesions, nystagmus, developmental delay, microcephaly, leukodystrophy, hypertonia, multiorgan failure, spasticity, tetraparesis, and more. In the monallelic form, often caused by heterozygous mutations of SDHA, symptoms include exercise intolerance, rhabdomyolosis, muscle pain, dyspnea, hypertension, dilated cardiomyopathy, hypertrophic cardiomyopathy, and optic atrophy. [1]

Causes

CII deficiency is a genetic disorder caused by Nuclear DNA (as opposed to mitochondrial DNA) and has both autosomal recessive and dominant inheritance patterns. Most pathogenic mutations for CII deficiency occur on SDHA or SDHAF1, but other pathogenic mutations for CII are known for SDHB and SDHD. SDHA is the only SDHx gene reported to date in which a dominant pathogenic variant has been identified, although most affected individuals harbour either homozygous or compound heterozygous pathogenic variants. [1]

For unknown reasons, several cases of CII deficiency have been linked to Umeå, Sweden. [5]

Diagnosis

The most effective way to diagnose CII deficiency is by measuring the activity of complex II in muscle biopsy, however, there is no clear correlation between residual complex II activity and severity or clinical outcome. [4] Other diagnostic tests include brain MRIs, which can detect symptoms characteristic of leigh syndrome, electromyography (EMG), which can detect myopathies, and blood tests for biochemical signals of mitochondrial dysfunction.

Prognosis

The prognosis can vary wildly for CII deficiency: In those who present earlier, the prognosis is worse, and especially for the biallelic form, few reach the age of 4. [1] Those presenting with Leigh syndrome or greater neurological involvement have worse outcomes. In severe cases where multiple organ systems are affected, death can occur in early life due to multisystem failure. [2]

There is no cure for CII deficiency, though some reported patients showed clinical improvement following riboflavin therapy, a vitamin essential for mitochondrial function. [6] Vitamins, such as the other B vitamins and Coenzyme Q-10, have been used with little success, and treatments primarily focus on symptoms, such as sodium bicarbonate for managing acidosis and opthamological procedures for correcting eyesight.

Epidemiology

CII deficiency is extremely rare, with less than 100 documented cases worldwide. [1] [7] Most cases recorded in literature are due to the biallelic form, and these are most common for those whose parents are consanguineous. There are potentially more cases of the monallelic form, but possibly due to their less severe nature or less unique presentation, they may not be reported as frequently. As human mitochondrial diseases and the effects of herbicides and fungicides on the mitochondria are a current area of research, our understanding of CII deficiency may progress significantly. [1]


Related Research Articles

<span class="mw-page-title-main">Leigh syndrome</span> Metabolic disease

Leigh syndrome is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951. Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found, but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase, and therefore treatment in some patients would be to take thiamine triphosphate daily. While the majority of patients typically exhibit symptoms between the ages of 3 and 12 months, instances of adult onset have also been documented.

<span class="mw-page-title-main">Succinate dehydrogenase</span> Enzyme

Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates in both the citric acid cycle and the electron transport chain. Histochemical analysis showing high succinate dehydrogenase in muscle demonstrates high mitochondrial content and high oxidative potential.

<span class="mw-page-title-main">SDHD</span> Protein-coding gene in the species Homo sapiens

Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial (CybS), also known as succinate dehydrogenase complex subunit D (SDHD), is a protein that in humans is encoded by the SDHD gene. Names previously used for SDHD were PGL and PGL1. Succinate dehydrogenase is an important enzyme in both the citric acid cycle and the electron transport chain. Hereditary PGL-PCC syndrome is caused by a parental imprint of the SDHD gene. Screening can begin by 6 years of age.

<span class="mw-page-title-main">Succinate dehydrogenase complex subunit C</span> Protein found in humans

Succinate dehydrogenase complex subunit C, also known as succinate dehydrogenase cytochrome b560 subunit, mitochondrial, is a protein that in humans is encoded by the SDHC gene. 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 pheochromocytomas and paragangliomas. Alternatively spliced transcript variants have been described.

<span class="mw-page-title-main">Mitochondrial myopathy</span> Medical condition

Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. Adenosine triphosphate (ATP), the chemical used to provide energy for the cell, cannot be produced sufficiently by oxidative phosphorylation when the mitochondrion is either damaged or missing necessary enzymes or transport proteins. With ATP production deficient in mitochondria, there is an over-reliance on anaerobic glycolysis which leads to lactic acidosis either at rest or exercise-induced.

Pantothenate kinase-associated neurodegeneration (PKAN), formerly called Hallervorden–Spatz syndrome, is a genetic degenerative disease of the brain that can lead to parkinsonism, dystonia, dementia, and ultimately death. Neurodegeneration in PKAN is accompanied by an excess of iron that progressively builds up in the brain.

<span class="mw-page-title-main">MELAS syndrome</span> Medical condition

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MIDD, MERRF syndrome, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984. A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent. The most common MELAS mutation is mitochondrial mutation, mtDNA, referred to as m.3243A>G.

<span class="mw-page-title-main">SDHB</span> Protein-coding gene in the species Homo sapiens

Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial (SDHB) also known as iron-sulfur subunit of complex II (Ip) is a protein that in humans is encoded by the SDHB gene.

<span class="mw-page-title-main">MERRF syndrome</span> Medical condition

MERRF syndrome is a mitochondrial disease. It is extremely rare, and has varying degrees of expressivity owing to heteroplasmy. MERRF syndrome affects different parts of the body, particularly the muscles and nervous system. The signs and symptoms of this disorder appear at an early age, generally childhood or adolescence. The causes of MERRF syndrome are difficult to determine, but because it is a mitochondrial disorder, it can be caused by the mutation of nuclear DNA or mitochondrial DNA. The classification of this disease varies from patient to patient, since many individuals do not fall into one specific disease category. The primary features displayed on a person with MERRF include myoclonus, seizures, cerebellar ataxia, myopathy, and ragged red fibers (RRF) on muscle biopsy, leading to the disease's name. Secondary features include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, or multiple lipomata. Mitochondrial disorders, including MERRFS, may present at any age.

<span class="mw-page-title-main">SDHA</span> Protein-coding gene in humans

Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHA gene. 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. SDHA contains the FAD binding site where succinate is deprotonated and converted to fumarate. 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.

<span class="mw-page-title-main">MT-ATP6</span> Mitochondrial protein-coding gene whose product is involved in ATP synthesis

MT-ATP6 is a mitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 6' that encodes the ATP synthase Fo subunit 6. This subunit belongs to the Fo complex of the large, transmembrane F-type ATP synthase. This enzyme, which is also known as complex V, is responsible for the final step of oxidative phosphorylation in the electron transport chain. Specifically, one segment of ATP synthase allows positively charged ions, called protons, to flow across a specialized membrane inside mitochondria. Another segment of the enzyme uses the energy created by this proton flow to convert a molecule called adenosine diphosphate (ADP) to ATP. Mutations in the MT-ATP6 gene have been found in approximately 10 to 20 percent of people with Leigh syndrome.

Mitochondrially encoded tRNA glutamic acid also known as MT-TE is a transfer RNA which in humans is encoded by the mitochondrial MT-TE gene. MT-TE is a small 69 nucleotide RNA that transfers the amino acid glutamic acid to a growing polypeptide chain at the ribosome site of protein synthesis during translation.

Mitochondrially encoded tRNA phenylalanine also known as MT-TF is a transfer RNA which in humans is encoded by the mitochondrial MT-TF gene.

Mitochondrially encoded tRNA isoleucine also known as MT-TI is a transfer RNA which in humans is encoded by the mitochondrial MT-TI gene.

Mitochondrially encoded tRNA lysine also known as MT-TK is a transfer RNA which in humans is encoded by the mitochondrial MT-TK gene.

<span class="mw-page-title-main">Mitochondrial DNA depletion syndrome</span> Medical condition

Mitochondrial DNA depletion syndrome, or Alper's disease, is any of a group of autosomal recessive disorders that cause a significant drop in mitochondrial DNA in affected tissues. Symptoms can be any combination of myopathic, hepatopathic, or encephalomyopathic. These syndromes affect tissue in the muscle, liver, or both the muscle and brain, respectively. The condition is typically fatal in infancy and early childhood, though some have survived to their teenage years with the myopathic variant and some have survived into adulthood with the SUCLA2 encephalomyopathic variant. There is currently no curative treatment for any form of MDDS, though some preliminary treatments have shown a reduction in symptoms.

<span class="mw-page-title-main">SDHAF2</span> Protein-coding gene in humans

Succinate dehydrogenase complex assembly factor 2, formerly known as SDH5 and also known as SDH assembly factor 2 or SDHAF2 is a protein that in humans is encoded by the SDHAF2 gene. 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 pheochromocytoma and paraganglioma.

<span class="mw-page-title-main">MIPEP</span> Protein-coding gene in the species Homo sapiens

Mitochondrial intermediate peptidase is an enzyme that in humans is encoded by the MIPEP gene. This protein is a critical component of human mitochondrial protein import machinery involved in the maturing process of nuclear coded mitochondrial proteins that with a mitochondrial translocation peptide, especially those OXPHOS-related proteins.

<span class="mw-page-title-main">Sengers syndrome</span> Medical condition

Sengers syndrome is a rare autosomal recessive mitochondrial disease characterised by congenital cataract, hypertrophic cardiomyopathy, muscle weakness and lactic acidosis after exercise. Biallelic pathogenic mutations in the AGK gene, which encodes the acylglycerol kinase enzyme, cause Sengers syndrome. In addition, heart disease and muscle disease are prevalent, meaning that life expectancy is short for many patients.

<span class="mw-page-title-main">SDHAF1</span> Protein-coding gene in the species Homo sapiens

Succinate dehydrogenase complex assembly factor 1 (SDHAF1), also known as LYR motif-containing protein 8 (LYRM8), is a protein that, in humans, is encoded by the SDHAF1, or LYRM8, gene. SDHAF1 is a chaperone protein involved in the assembly of the succinate dehydrogenase (SDH) complex. Mutations in this gene are associated with SDH-defective infantile leukoencephalopathy and mitochondrial complex II deficiency.

References

  1. 1 2 3 4 5 6 7 Fullerton M, McFarland R, Taylor RW, Alston CL. The genetic basis of isolated mitochondrial complex II deficiency. Mol Genet Metab. 2020 Sep-Oct;131(1-2):53-65. doi: 10.1016/j.ymgme.2020.09.009. Epub 2020 Oct 3. PMID 33162331; PMCID: PMC7758838.
  2. 1 2 Sciacovelli, Marco; Schmidt, Christina; Maher, Eamonn R.; Frezza, Christian (2020). "Metabolic Drivers in Hereditary Cancer Syndromes". Annual Review of Cancer Biology. 4: 77–97. doi: 10.1146/annurev-cancerbio-030419-033612 .
  3. ↑ "Mitochondrial complex II deficiency". Genetic and Rare Diseases Information Center. Retrieved 25 June 2020.
  4. 1 2 "MITOCHONDRIAL COMPLEX II DEFICIENCY". OMIM. Retrieved 25 June 2020.
  5. ↑ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC495765/pdf/jnnpsyc00257-0001.pdf
  6. ↑ Ürey BC, Ceylan AC, Çavdarlı B, Çıtak Kurt AN, Köylü OK, Yürek B, Kasapkara ÇS. Two Patients Diagnosed as Succinate Dehydrogenase Deficiency: Case Report. Mol Syndromol. 2023 Apr;14(2):171-174. doi: 10.1159/000527538. Epub 2023 Jan 13. PMID 37064335; PMCID: PMC10090973.
  7. ↑ Jain-Ghai S, Cameron JM, Al Maawali A, Blaser S, MacKay N, Robinson B, Raiman J. 2013. Complex II deficiency—A case report and review of the literature. Am J Med Genet Part A 161A:285–294.
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