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Mitochondrial complex 2 deficiency, nuclear type 3(MC2DN3)

MedGen UID:
1751884
Concept ID:
C5436934
Disease or Syndrome
Synonym: MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 3
 
Gene (location): SDHD (11q23.1)
 
Monarch Initiative: MONDO:0030937
OMIM®: 619167

Definition

Mitochondrial complex II deficiency nuclear type 3 (MC2DN3) is an autosomal recessive multisystemic metabolic disorder with a highly variable phenotype. Some patients may have an encephalomyopathic picture with episodic developmental regression, loss of motor skills, hypotonia, ataxia, dystonia, and seizures or myoclonus. Other patients present in infancy with hypertrophic cardiomyopathy, which may be fatal. Laboratory studies show increased serum lactate and mitochondrial complex II deficiency in muscle and fibroblasts (summary by Jackson et al., 2014 and Alston et al., 2015). For a discussion of genetic heterogeneity of MC2DN, see MC2DN1 (252011). [from OMIM]

Clinical features

From HPO
Ketonuria
MedGen UID:
56402
Concept ID:
C0162275
Finding
High levels of ketone bodies (acetoacetic acid, beta-hydroxybutyric acid, and acetone) in the urine. Ketone bodies are insignificant in the blood and urine of normal individuals in the postprandial or overnight-fasted state.
Lacticaciduria
MedGen UID:
871116
Concept ID:
C4025585
Finding
An increased concentration of lactic acid in the urine.
Primary dilated cardiomyopathy
MedGen UID:
2880
Concept ID:
C0007193
Disease or Syndrome
Familial dilated cardiomyopathy is a genetic form of heart disease. It occurs when heart (cardiac) muscle becomes thin and weakened in at least one chamber of the heart, causing the open area of the chamber to become enlarged (dilated). As a result, the heart is unable to pump blood as efficiently as usual. To compensate, the heart attempts to increase the amount of blood being pumped through the heart, leading to further thinning and weakening of the cardiac muscle. Over time, this condition results in heart failure.\n\nIt usually takes many years for symptoms of familial dilated cardiomyopathy to cause health problems. They typically begin in mid-adulthood, but can occur at any time from infancy to late adulthood. Signs and symptoms of familial dilated cardiomyopathy can include an irregular heartbeat (arrhythmia), shortness of breath (dyspnea), extreme tiredness (fatigue), fainting episodes (syncope), and swelling of the legs and feet. In some cases, the first sign of the disorder is sudden cardiac death. The severity of the condition varies among affected individuals, even in members of the same family.
Patent foramen ovale
MedGen UID:
8891
Concept ID:
C0016522
Congenital Abnormality
Failure of the foramen ovale to seal postnatally, leaving a potential conduit between the left and right cardiac atria.
Mitral regurgitation
MedGen UID:
7670
Concept ID:
C0026266
Disease or Syndrome
An abnormality of the mitral valve characterized by insufficiency or incompetence of the mitral valve resulting in retrograde leaking of blood through the mitral valve upon ventricular contraction.
Tricuspid regurgitation
MedGen UID:
11911
Concept ID:
C0040961
Disease or Syndrome
Failure of the tricuspid valve to close sufficiently upon contraction of the right ventricle, causing blood to regurgitate (flow backward) into the right atrium.
Left ventricular hypertrophy
MedGen UID:
57442
Concept ID:
C0149721
Disease or Syndrome
Enlargement or increased size of the heart left ventricle.
Left ventricular systolic dysfunction
MedGen UID:
226908
Concept ID:
C1277187
Disease or Syndrome
Abnormality of left ventricular contraction, often defined operationally as an ejection fraction of less than 40 percent.
Left ventricular noncompaction
MedGen UID:
450531
Concept ID:
C1960469
Disease or Syndrome
Left ventricular noncompaction is a heart (cardiac) muscle disorder that occurs when the lower left chamber of the heart (left ventricle), which helps the heart pump blood, does not develop correctly. Instead of the muscle being smooth and firm, the cardiac muscle in the left ventricle is thick and appears spongy. The abnormal cardiac muscle is weak and has an impaired ability to pump blood because it either cannot completely contract or it cannot completely relax. For the heart to pump blood normally, cardiac muscle must contract and relax fully.\n\nSome individuals with left ventricular noncompaction experience no symptoms at all; others have heart problems that can include sudden cardiac death. Additional signs and symptoms include abnormal blood clots, irregular heart rhythm (arrhythmia), a sensation of fluttering or pounding in the chest (palpitations), extreme fatigue during exercise (exercise intolerance), shortness of breath (dyspnea), fainting (syncope), swelling of the legs (lymphedema), and trouble laying down flat. Some affected individuals have features of other heart defects. Left ventricular noncompaction can be diagnosed at any age, from birth to late adulthood. Approximately two-thirds of individuals with left ventricular noncompaction develop heart failure.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Reduced brain N-acetyl aspartate level by MRS
MedGen UID:
868367
Concept ID:
C4022761
Finding
A decrease in the level of N-acetyl aspartate in the brain identified by magnetic resonance spectroscopy (MRS).
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Secondary microcephaly
MedGen UID:
608952
Concept ID:
C0431352
Finding
Head circumference which falls below 2 standard deviations below the mean for age and gender because of insufficient head growth after birth.
Aspiration pneumonia
MedGen UID:
10814
Concept ID:
C0032290
Disease or Syndrome
Pneumonia due to the aspiration (breathing in) of food, liquid, or gastric contents into the upper respiratory tract.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Pendular nystagmus
MedGen UID:
78770
Concept ID:
C0271388
Disease or Syndrome
Rhythmic, involuntary sinusoidal oscillations of one or both eyes. The waveform of pendular nystagmus may occur in any direction.
Optic disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
A pale yellow discoloration of the optic disk (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.
Decreased activity of mitochondrial complex II
MedGen UID:
892305
Concept ID:
C4024705
Finding
A reduction in the activity of the mitochondrial respiratory chain complex II, which is part of the electron transport chain in mitochondria.

Recent clinical studies

Etiology

Hipps D, Dobson PF, Warren C, McDonald D, Fuller A, Filby A, Bulmer D, Laude A, Russell O, Deehan DJ, Turnbull DM, Lawless C
Bone 2022 May;158:116371. Epub 2022 Feb 19 doi: 10.1016/j.bone.2022.116371. PMID: 35192969
Feichtinger RG, Oláhová M, Kishita Y, Garone C, Kremer LS, Yagi M, Uchiumi T, Jourdain AA, Thompson K, D'Souza AR, Kopajtich R, Alston CL, Koch J, Sperl W, Mastantuono E, Strom TM, Wortmann SB, Meitinger T, Pierre G, Chinnery PF, Chrzanowska-Lightowlers ZM, Lightowlers RN, DiMauro S, Calvo SE, Mootha VK, Moggio M, Sciacco M, Comi GP, Ronchi D, Murayama K, Ohtake A, Rebelo-Guiomar P, Kohda M, Kang D, Mayr JA, Taylor RW, Okazaki Y, Minczuk M, Prokisch H
Am J Hum Genet 2017 Oct 5;101(4):525-538. Epub 2017 Sep 21 doi: 10.1016/j.ajhg.2017.08.015. PMID: 28942965Free PMC Article
Salminen A, Kaarniranta K, Kauppinen A, Ojala J, Haapasalo A, Soininen H, Hiltunen M
Prog Neurobiol 2013 Jul-Aug;106-107:33-54. Epub 2013 Jul 1 doi: 10.1016/j.pneurobio.2013.06.002. PMID: 23827971
Ritov VB, Menshikova EV, Azuma K, Wood R, Toledo FG, Goodpaster BH, Ruderman NB, Kelley DE
Am J Physiol Endocrinol Metab 2010 Jan;298(1):E49-58. Epub 2009 Nov 3 doi: 10.1152/ajpendo.00317.2009. PMID: 19887598Free PMC Article
Silva JP, Köhler M, Graff C, Oldfors A, Magnuson MA, Berggren PO, Larsson NG
Nat Genet 2000 Nov;26(3):336-40. doi: 10.1038/81649. PMID: 11062475

Diagnosis

Paez HG, Ferrandi PJ, Pitzer CR, Mohamed JS, Alway SE
FASEB J 2023 Aug;37(8):e23050. doi: 10.1096/fj.202202029R. PMID: 37389860
Hipps D, Dobson PF, Warren C, McDonald D, Fuller A, Filby A, Bulmer D, Laude A, Russell O, Deehan DJ, Turnbull DM, Lawless C
Bone 2022 May;158:116371. Epub 2022 Feb 19 doi: 10.1016/j.bone.2022.116371. PMID: 35192969
Kumar A, Corey C, Scott I, Shiva S, D'Cunha J
PLoS One 2016;11(8):e0160783. Epub 2016 Aug 8 doi: 10.1371/journal.pone.0160783. PMID: 27501149Free PMC Article
Szarek E, Ball ER, Imperiale A, Tsokos M, Faucz FR, Giubellino A, Moussallieh FM, Namer IJ, Abu-Asab MS, Pacak K, Taïeb D, Carney JA, Stratakis CA
Endocr Relat Cancer 2015 Jun;22(3):345-52. Epub 2015 Mar 25 doi: 10.1530/ERC-15-0069. PMID: 25808178Free PMC Article
Wollheim CB
Diabetologia 2000 Mar;43(3):265-77. doi: 10.1007/s001250050044. PMID: 10768087

Therapy

Carraway MS, Suliman HB, Jones WS, Chen CW, Babiker A, Piantadosi CA
Circ Res 2010 Jun 11;106(11):1722-30. Epub 2010 Apr 15 doi: 10.1161/CIRCRESAHA.109.214353. PMID: 20395592Free PMC Article

Prognosis

Hallmann K, Kudin AP, Zsurka G, Kornblum C, Reimann J, Stüve B, Waltz S, Hattingen E, Thiele H, Nürnberg P, Rüb C, Voos W, Kopatz J, Neumann H, Kunz WS
Brain 2016 Feb;139(Pt 2):338-45. Epub 2015 Dec 17 doi: 10.1093/brain/awv357. PMID: 26685157

Clinical prediction guides

Hipps D, Dobson PF, Warren C, McDonald D, Fuller A, Filby A, Bulmer D, Laude A, Russell O, Deehan DJ, Turnbull DM, Lawless C
Bone 2022 May;158:116371. Epub 2022 Feb 19 doi: 10.1016/j.bone.2022.116371. PMID: 35192969
Fam HK, Choi K, Fougner L, Lim CJ, Boerkoel CF
Sci Rep 2018 Mar 9;8(1):4304. doi: 10.1038/s41598-018-22547-8. PMID: 29523818Free PMC Article
Lee WJ, Ahn HM, Na Y, Wadhwa R, Hong J, Yun CO
Sci Rep 2017 Oct 11;7(1):12957. doi: 10.1038/s41598-017-13485-y. PMID: 29021584Free PMC Article
Silva JP, Köhler M, Graff C, Oldfors A, Magnuson MA, Berggren PO, Larsson NG
Nat Genet 2000 Nov;26(3):336-40. doi: 10.1038/81649. PMID: 11062475

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