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Severe X-linked mitochondrial encephalomyopathy(COXPD6)

MedGen UID:
463103
Concept ID:
C3151753
Disease or Syndrome
Synonyms: Combined oxidative phosphorylation deficiency 6; ENCEPHALOMYOPATHY, MITOCHONDRIAL, X-LINKED
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
 
Gene (location): AIFM1 (Xq26.1)
 
Monarch Initiative: MONDO:0010437
OMIM®: 300816
Orphanet: ORPHA238329

Definition

Combined oxidative phosphorylation deficiency-6 (COXPD6) is an X-linked recessive severe encephalomyopathic disorder with onset in utero or in infancy. Affected patients have hypotonia and severely impaired psychomotor development associated with variably decreased enzymatic activity of mitochondrial respiratory complexes in skeletal muscle or fibroblasts. More variable features may include sensorimotor neuropathy, seizures, severe muscle weakness, abnormal signals in the basal ganglia, hypertrophic cardiomyopathy, deafness, swallowing difficulties, and respiratory insufficiency. Death in childhood may occur (summary by Berger et al., 2011). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060). [from OMIM]

Clinical features

From HPO
Tetraplegia
MedGen UID:
19617
Concept ID:
C0034372
Disease or Syndrome
Paralysis of all four limbs, and trunk of the body below the level of an associated injury to the spinal cord. The etiology of quadriplegia is similar to that of paraplegia except that the lesion is in the cervical spinal cord rather than in the thoracic or lumbar segments of the spinal cord.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Hypokinesia
MedGen UID:
39223
Concept ID:
C0086439
Finding
Abnormally diminished motor activity. In contrast to paralysis, hypokinesia is not characterized by a lack of motor strength, but rather by a poverty of movement. The typical habitual movements (e.g., folding the arms, crossing the legs) are reduced in frequency.
Polyneuropathy
MedGen UID:
57502
Concept ID:
C0152025
Disease or Syndrome
A generalized disorder of peripheral nerves.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Generalized-onset seizure
MedGen UID:
115963
Concept ID:
C0234533
Disease or Syndrome
A generalized-onset seizure is a type of seizure originating at some point within, and rapidly engaging, bilaterally distributed networks. The networks may include cortical and subcortical structures but not necessarily the entire cortex.
Motor polyneuropathy
MedGen UID:
82885
Concept ID:
C0271683
Disease or Syndrome
Inflammation or degeneration of the peripheral motor nerves.
Involuntary movements
MedGen UID:
140884
Concept ID:
C0427086
Sign or Symptom
Involuntary contractions of muscle leading to involuntary movements of extremities, neck, trunk, or face.
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.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Increased CSF lactate
MedGen UID:
257904
Concept ID:
C1167918
Finding
Increased concentration of lactate in the cerebrospinal fluid.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Abnormal basal ganglia morphology
MedGen UID:
1619147
Concept ID:
C4520981
Anatomical Abnormality
Abnormality of the basal ganglia.
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.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Ragged-red muscle fibers
MedGen UID:
477048
Concept ID:
C3275417
Finding
An abnormal appearance of muscle fibers observed on muscle biopsy. Ragged red fibers can be visualized with Gomori trichrome staining as irregular and intensely red subsarcolemmal zones, whereas the normal myofibrils are green. The margins of affect fibers appear red and ragged. The ragged-red is due to the accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber, leading to the appearance of a red rim and speckled sarcoplasm.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
Increased circulating lactate concentration
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).
Increased serum pyruvate
MedGen UID:
376596
Concept ID:
C1849488
Finding
An increased concentration of pyruvate in the blood.
Tongue fasciculations
MedGen UID:
65987
Concept ID:
C0239548
Finding
Fasciculations or fibrillation affecting the tongue muscle.
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Severe X-linked mitochondrial encephalomyopathy in Orphanet.

Recent clinical studies

Diagnosis

Moss T, May M, Flanagan-Steet H, Caylor R, Jiang YH, McDonald M, Friez M, McConkie-Rosell A, Steet R
Cold Spring Harb Mol Case Stud 2021 Jun;7(3) Epub 2021 Jun 11 doi: 10.1101/mcs.a006081. PMID: 34117073Free PMC Article
Heimer G, Eyal E, Zhu X, Ruzzo EK, Marek-Yagel D, Sagiv D, Anikster Y, Reznik-Wolf H, Pras E, Oz Levi D, Lancet D, Ben-Zeev B, Nissenkorn A
Eur J Paediatr Neurol 2018 Jan;22(1):93-101. Epub 2017 Sep 15 doi: 10.1016/j.ejpn.2017.09.004. PMID: 28967629
Rinaldi C, Grunseich C, Sevrioukova IF, Schindler A, Horkayne-Szakaly I, Lamperti C, Landouré G, Kennerson ML, Burnett BG, Bönnemann C, Biesecker LG, Ghezzi D, Zeviani M, Fischbeck KH
Am J Hum Genet 2012 Dec 7;91(6):1095-102. doi: 10.1016/j.ajhg.2012.10.008. PMID: 23217327Free PMC Article
Ghezzi D, Sevrioukova I, Invernizzi F, Lamperti C, Mora M, D'Adamo P, Novara F, Zuffardi O, Uziel G, Zeviani M
Am J Hum Genet 2010 Apr 9;86(4):639-49. Epub 2010 Apr 1 doi: 10.1016/j.ajhg.2010.03.002. PMID: 20362274Free PMC Article
De Kremer RD, Paschini-Capra A, Bacman S, Argaraña C, Civallero G, Kelley RI, Guelbert N, Latini A, Noher de Halac I, Giner-Ayala A, Johnston J, Proujansky R, Gonzalez I, Depetris-Boldini C, Oller-Ramírez A, Angaroni C, Theaux RA, Hliba E, Juaneda E
Am J Med Genet 2001 Mar 1;99(2):83-93. doi: 10.1002/1096-8628(2001)9999:9999<::aid-ajmg1136>3.0.co;2-x. PMID: 11241464

Therapy

Heimer G, Eyal E, Zhu X, Ruzzo EK, Marek-Yagel D, Sagiv D, Anikster Y, Reznik-Wolf H, Pras E, Oz Levi D, Lancet D, Ben-Zeev B, Nissenkorn A
Eur J Paediatr Neurol 2018 Jan;22(1):93-101. Epub 2017 Sep 15 doi: 10.1016/j.ejpn.2017.09.004. PMID: 28967629
Ghezzi D, Sevrioukova I, Invernizzi F, Lamperti C, Mora M, D'Adamo P, Novara F, Zuffardi O, Uziel G, Zeviani M
Am J Hum Genet 2010 Apr 9;86(4):639-49. Epub 2010 Apr 1 doi: 10.1016/j.ajhg.2010.03.002. PMID: 20362274Free PMC Article

Prognosis

Rinaldi C, Grunseich C, Sevrioukova IF, Schindler A, Horkayne-Szakaly I, Lamperti C, Landouré G, Kennerson ML, Burnett BG, Bönnemann C, Biesecker LG, Ghezzi D, Zeviani M, Fischbeck KH
Am J Hum Genet 2012 Dec 7;91(6):1095-102. doi: 10.1016/j.ajhg.2012.10.008. PMID: 23217327Free PMC Article

Clinical prediction guides

Indrieri A, Franco B
Genes (Basel) 2021 Feb 11;12(2) doi: 10.3390/genes12020263. PMID: 33670341Free PMC Article
Riley LG, Heeney MM, Rudinger-Thirion J, Frugier M, Campagna DR, Zhou R, Hale GA, Hilliard LM, Kaplan JA, Kwiatkowski JL, Sieff CA, Steensma DP, Rennings AJ, Simons A, Schaap N, Roodenburg RJ, Kleefstra T, Arenillas L, Fita-Torró J, Ahmed R, Abboud M, Bechara E, Farah R, Tamminga RYJ, Bottomley SS, Sanchez M, Huls G, Swinkels DW, Christodoulou J, Fleming MD
Haematologica 2018 Dec;103(12):2008-2015. Epub 2018 Jul 19 doi: 10.3324/haematol.2017.182659. PMID: 30026338Free PMC Article
Heimer G, Eyal E, Zhu X, Ruzzo EK, Marek-Yagel D, Sagiv D, Anikster Y, Reznik-Wolf H, Pras E, Oz Levi D, Lancet D, Ben-Zeev B, Nissenkorn A
Eur J Paediatr Neurol 2018 Jan;22(1):93-101. Epub 2017 Sep 15 doi: 10.1016/j.ejpn.2017.09.004. PMID: 28967629
Rinaldi C, Grunseich C, Sevrioukova IF, Schindler A, Horkayne-Szakaly I, Lamperti C, Landouré G, Kennerson ML, Burnett BG, Bönnemann C, Biesecker LG, Ghezzi D, Zeviani M, Fischbeck KH
Am J Hum Genet 2012 Dec 7;91(6):1095-102. doi: 10.1016/j.ajhg.2012.10.008. PMID: 23217327Free PMC Article
De Kremer RD, Paschini-Capra A, Bacman S, Argaraña C, Civallero G, Kelley RI, Guelbert N, Latini A, Noher de Halac I, Giner-Ayala A, Johnston J, Proujansky R, Gonzalez I, Depetris-Boldini C, Oller-Ramírez A, Angaroni C, Theaux RA, Hliba E, Juaneda E
Am J Med Genet 2001 Mar 1;99(2):83-93. doi: 10.1002/1096-8628(2001)9999:9999<::aid-ajmg1136>3.0.co;2-x. PMID: 11241464

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