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Mitochondrial complex 4 deficiency, nuclear type 12(MC4DN12)

MedGen UID:
1745691
Concept ID:
C5436695
Disease or Syndrome
Synonym: MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 12
 
Gene (location): PET100 (19p13.2)
 
Monarch Initiative: MONDO:0033646
OMIM®: 619055

Definition

Mitochondrial complex IV deficiency nuclear type 12 (MC4DN12) is an autosomal recessive metabolic disorder characterized by the onset of neurologic dysfunction in early infancy. Affected individuals demonstrate hypotonia with poor head control, profoundly delayed global development with inability to fix and follow, poor overall growth, abnormal spasms or myoclonus, and seizures. Most patients die in the first years of life; those that survive have spastic quadriplegia, feeding difficulties necessitating tube feeding, and profoundly impaired intellectual development with poor or absent communication. More variable features include cortical blindness, nystagmus, scoliosis, and hearing impairment. Brain imaging shows abnormalities consistent with Leigh syndrome (see 256000), as well as cystic cavitation. Laboratory studies show lactic acidosis, increased serum creatine kinase, and decreased levels and activity of mitochondrial respiratory complex IV (summary by Lim et al., 2014). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110. [from OMIM]

Clinical features

From HPO
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Intraventricular hemorrhage
MedGen UID:
116096
Concept ID:
C0240059
Pathologic Function
Bleeding into the ventricles of the brain.
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.
Small for gestational age
MedGen UID:
65920
Concept ID:
C0235991
Finding
Smaller than normal size according to sex and gestational age related norms, defined as a weight below the 10th percentile for the gestational age.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
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.
Clonus
MedGen UID:
40341
Concept ID:
C0009024
Sign or Symptom
A series of rhythmic and involuntary muscle contractions (at a frequency of about 5 to 7 Hz) that occur in response to an abruptly applied and sustained stretch.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Sign or Symptom
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.
Status epilepticus
MedGen UID:
11586
Concept ID:
C0038220
Disease or Syndrome
Status epilepticus is a type of prolonged seizure resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures (after time point t1). It is a condition that can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
Increased CSF lactate
MedGen UID:
257904
Concept ID:
C1167918
Finding
Increased concentration of lactate in the cerebrospinal fluid.
Bulbar palsy
MedGen UID:
898626
Concept ID:
C4082299
Disease or Syndrome
Bulbar weakness (or bulbar palsy) refers to bilateral impairment of function of the lower cranial nerves IX, X, XI and XII, which occurs due to lower motor neuron lesion either at nuclear or fascicular level in the medulla or from bilateral lesions of the lower cranial nerves outside the brain-stem. Bulbar weakness is often associated with difficulty in chewing, weakness of the facial muscles, dysarthria, palatal weakness and regurgitation of fluids, dysphagia, and dysphonia.
Prolonged prothrombin time
MedGen UID:
208879
Concept ID:
C0853225
Finding
Increased time to coagulation in the prothrombin time test, which is a measure of the extrinsic pathway of coagulation. The results of the prothrombin time test are often expressed in terms of the International normalized ratio (INR), which is calculated as a ratio of the patient's prothrombin time (PT) to a control PT standardized for the potency of the thromboplastin reagent developed by the World Health Organization (WHO) using the formula
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Poor head control
MedGen UID:
322809
Concept ID:
C1836038
Finding
Difficulty to maintain correct position of the head while standing or sitting.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
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.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Neonatal hypoglycemia
MedGen UID:
57646
Concept ID:
C0158986
Finding
Blood glucose concentration below the lower limit of established reference ranges in a newborn.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Hypoalbuminemia
MedGen UID:
68694
Concept ID:
C0239981
Finding
Reduction in the concentration of albumin 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.
Increased serum lactate
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
Horizontal nystagmus
MedGen UID:
124399
Concept ID:
C0271385
Disease or Syndrome
Nystagmus consisting of horizontal to-and-fro eye movements.
Vertical nystagmus
MedGen UID:
75749
Concept ID:
C0271386
Disease or Syndrome
Vertical nystagmus may present with either up-beating or down-beating eye movements or both. When present in the straight-ahead position of gaze it is referred to as upbeat nystagmus or downbeat nystagmus.
Cerebral visual impairment
MedGen UID:
890568
Concept ID:
C4048268
Pathologic Function
A form of loss of vision caused by damage to the visual cortex rather than a defect in the eye.
Visual fixation instability
MedGen UID:
1372887
Concept ID:
C4476760
Finding
A deficit in the ability to fixate eye movements in order to stabilize images on the retina
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

Diagnosis

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

Clinical prediction guides

Ale-Agha N, Jakobs P, Goy C, Zurek M, Rosen J, Dyballa-Rukes N, Metzger S, Greulich J, von Ameln F, Eckermann O, Unfried K, Brack F, Grandoch M, Thielmann M, Kamler M, Gedik N, Kleinbongard P, Heinen A, Heusch G, Gödecke A, Altschmied J, Haendeler J
Circulation 2021 Dec 7;144(23):1876-1890. Epub 2021 Oct 21 doi: 10.1161/CIRCULATIONAHA.120.051923. PMID: 34672678

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