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Mitochondrial complex IV deficiency, nuclear type 22(MC4DN22)

MedGen UID:
1786100
Concept ID:
C5543491
Disease or Syndrome
Synonyms: MC4DN22; MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 22
 
Gene (location): COX16 (14q24.2)
 
Monarch Initiative: MONDO:0859160
OMIM®: 619355

Definition

Mitochondrial complex IV deficiency nuclear type 22 (MC4DN22) is an autosomal recessive metabolic disorder characterized by neonatal hypertrophic cardiomyopathy, encephalopathy, and severe lactic acidosis with fatal outcome (Wintjes et al., 2021). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110. [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.
Dicarboxylic aciduria
MedGen UID:
343550
Concept ID:
C1856432
Finding
An increased concentration of dicarboxylic acid in the urine.
Ethylmalonic aciduria
MedGen UID:
355967
Concept ID:
C1865353
Finding
The concentration of ethylmalonic acid in the urine, normalized for urine concentration, is above the upper limit of normal.
Increased urine alpha-ketoglutarate concentration
MedGen UID:
868516
Concept ID:
C4022915
Finding
A greater than normal concentration of 2-oxoglutaric acid in the urine.
3-hydroxydicarboxylic aciduria
MedGen UID:
870283
Concept ID:
C4024725
Finding
The concentration of 2-hydroxydicarboxylic acid in the urine, normalized for urine concentration, is above the upper limit of normal.
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Left ventricular hypertrophy
MedGen UID:
57442
Concept ID:
C0149721
Disease or Syndrome
Enlargement or increased size of the heart left ventricle.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Liver failure
MedGen UID:
88444
Concept ID:
C0085605
Disease or Syndrome
A disorder characterized by the inability of the liver to metabolize chemicals in the body. Causes include cirrhosis and drug-induced hepatotoxicity. Signs and symptoms include jaundice and encephalopathy. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic dehydrogenase, and alkaline phosphatase.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Congenital sensorineural hearing impairment
MedGen UID:
356101
Concept ID:
C1865866
Disease or Syndrome
A type of hearing impairment caused by an abnormal functionality of the cochlear nerve with congenital onset.
Cerebral edema
MedGen UID:
2337
Concept ID:
C0006114
Pathologic Function
Abnormal accumulation of fluid in the brain.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Widened subarachnoid space
MedGen UID:
375826
Concept ID:
C1846151
Finding
An increase in size of the anatomic space between the arachnoid membrane and pia mater.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Elevated brain lactate level by MRS
MedGen UID:
868368
Concept ID:
C4022762
Finding
An increase in the level of lactate in the brain identified by magnetic resonance spectroscopy (MRS).
Brain atrophy
MedGen UID:
1643639
Concept ID:
C4551584
Disease or Syndrome
Partial or complete wasting (loss) of brain tissue that was once present.
Abnormality of the coagulation cascade
MedGen UID:
604
Concept ID:
C0005779
Disease or Syndrome
An abnormality of the coagulation cascade, which is comprised of the contact activation pathway (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway) as well as cofactors and regulators.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Hyperprolinemia
MedGen UID:
75690
Concept ID:
C0268528
Disease or Syndrome
An increased concentration of proline in the blood.
Hyper-beta-alaninemia
MedGen UID:
75702
Concept ID:
C0268630
Disease or Syndrome
An increased concentration of alanine in the blood.
Severe lactic acidosis
MedGen UID:
374223
Concept ID:
C1839436
Finding
A severe form of lactic acidemia.
Hyperglutaminemia
MedGen UID:
326901
Concept ID:
C1839533
Finding
An increased concentration of glutamine in the blood.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Increased serum pyruvate
MedGen UID:
376596
Concept ID:
C1849488
Finding
An increased concentration of pyruvate in the blood.
Elevated circulating dodecanoylcarnitine concentration
MedGen UID:
1788992
Concept ID:
C5539597
Finding
Concentration of dodecanoylcarnitine (C12:0) in the blood circulation above the upper limit of normal.
Elevated circulating tetradecanoylcarnitine concentration
MedGen UID:
1815048
Concept ID:
C5706142
Finding
Elevated circulating tetradecanoyl concentration.
Setting-sun eye phenomenon
MedGen UID:
602082
Concept ID:
C0423128
Sign or Symptom
An ophthalmologic sign in young children resulting from upward-gaze paresis. In this condition, the eyes appear driven downward, the sclera may be seen between the upper eyelid and the iris, and part of the lower pupil may be covered by the lower eyelid.
Decreased activity of mitochondrial complex IV
MedGen UID:
866520
Concept ID:
C4020800
Finding
A reduction in the activity of the mitochondrial respiratory chain complex IV, which is part of the electron transport chain in mitochondria.

Recent clinical studies

Clinical prediction guides

Szklarczyk R, Wanschers BF, Nijtmans LG, Rodenburg RJ, Zschocke J, Dikow N, van den Brand MA, Hendriks-Franssen MG, Gilissen C, Veltman JA, Nooteboom M, Koopman WJ, Willems PH, Smeitink JA, Huynen MA, van den Heuvel LP
Hum Mol Genet 2013 Feb 15;22(4):656-67. Epub 2012 Nov 2 doi: 10.1093/hmg/dds473. PMID: 23125284

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