COXPD12
MCID: CMB026
MIFTS: 28

Combined Oxidative Phosphorylation Deficiency 12 (COXPD12)

Categories: Genetic diseases, Metabolic diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Combined Oxidative Phosphorylation Deficiency 12

MalaCards integrated aliases for Combined Oxidative Phosphorylation Deficiency 12:

Name: Combined Oxidative Phosphorylation Deficiency 12 58 54 26 76 30 13 6 74
Coxpd12 58 54 26 60 76
Ltbl 58 54 26 60 76
Leukoencephalopathy with Thalamus and Brainstem Involvement and High Lactate 58 54 26 76
Leukoencephalopathy-Thalamus and Brainstem Anomalies-High Lactate Syndrome 54 60
Combined Oxidative Phosphorylation Defect Type 12 54 60
Leukoencephalopathy with Thalamus and Brainstem Involvement and High Lactate; Ltbl 58
Combined Oxidative Phosphorylation Deficiency, Type 12 41

Characteristics:

Orphanet epidemiological data:

60
leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome
Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy,Neonatal;

OMIM:

58
Inheritance:
autosomal recessive

Miscellaneous:
onset in first year of life
two main phenotypes, severe and mild
mild cases show clinical, biochemical, and mri improvement after the second year of life


HPO:

33
combined oxidative phosphorylation deficiency 12:
Onset and clinical course infantile onset
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Combined Oxidative Phosphorylation Deficiency 12

NIH Rare Diseases : 54 Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) is a rare disorder that affects the brain. It is part of a group of disorders known as leukodystrophies. Leukodystrophies are diseases that affect the white matter of the brain. The white matter contains nerve fibers (axons), surrounded by a type of sheath or covering called myelin (a fatty, white colored substance) that allows the transmission of impulses or communication among brain cells (neurons).  LTBL is characterized by changes in specific parts of the brain including the cerebellum, thalamus and brainstem. These changes can be seen by brain imaging exams (MRI). High levels of lactate in the blood and in the cerebral spinal fluid are also seen. There are basically two forms of the disease based on severity of symptoms and age of onset:  A mild disease, with onset around 6 months of age, characterized by the loss of acquired skills (psychomotor regression), muscle stiffness (spasticity), irritability and seizures. These symptoms often improve during the toddler years.  A severe disease with symptoms that start in newborns and include brain and liver problems. Symptoms generally do not improve with age.  LTBL is caused by changes (mutations) in the EARS2 gene. Mutations in this gene decrease the amount of a specific mitochondrial enzyme needed for proper mitochondrial function (mitochondria are cell structures that convert the energy from food into a form that cells can use), and therefore, LTBL is also considered a type of mitochondrial disorder. It is inherited in an autosomal recessive pattern. There is still no cure for this disease. Treatment is typically supportive based on presenting symptoms.

MalaCards based summary : Combined Oxidative Phosphorylation Deficiency 12, also known as coxpd12, is related to metabolic acidosis, and has symptoms including seizures and ophthalmoplegia. An important gene associated with Combined Oxidative Phosphorylation Deficiency 12 is EARS2 (Glutamyl-TRNA Synthetase 2, Mitochondrial). Affiliated tissues include thalamus, brain and liver, and related phenotypes are hepatomegaly and cleft palate

Genetics Home Reference : 26 Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) is a disorder that affects the brain. LTBL is one of a group of genetic disorders called leukodystrophies, which feature abnormalities of the nervous system's white matter. White matter consists of nerve fibers covered by a fatty substance, called myelin, that insulates nerve fibers and promotes the rapid transmission of nerve impulses.

OMIM : 58 COXPD12 is an autosomal recessive mitochondrial neurologic disorder characterized by onset in infancy of hypotonia and delayed psychomotor development, or early developmental regression, associated with T2-weighted hyperintensities in the deep cerebral white matter, brainstem, and cerebellar white matter. Serum lactate is increased due to a defect in mitochondrial respiration. There are 2 main phenotypic groups: those with a milder disease course and some recovery of skills after age 2 years, and those with a severe disease course resulting in marked disability (summary by Steenweg et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060). (614924)

UniProtKB/Swiss-Prot : 76 Combined oxidative phosphorylation deficiency 12: An autosomal recessive, mitochondrial, neurologic disorder characterized by onset in infancy of hypotonia and delayed psychomotor development, or early developmental regression, associated with T2- weighted hyperintensities in the deep cerebral white matter, brainstem, and cerebellar white matter. Serum lactate is increased due to a defect in mitochondrial respiration. There are 2 main phenotypic groups: those with a milder disease course and some recovery of skills after age 2 years, and those with a severe disease course resulting in marked disability.

Related Diseases for Combined Oxidative Phosphorylation Deficiency 12

Diseases related to Combined Oxidative Phosphorylation Deficiency 12 via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 metabolic acidosis 10.2

Symptoms & Phenotypes for Combined Oxidative Phosphorylation Deficiency 12

Human phenotypes related to Combined Oxidative Phosphorylation Deficiency 12:

33 (show all 25)
# Description HPO Frequency HPO Source Accession
1 hepatomegaly 33 occasional (7.5%) HP:0002240
2 cleft palate 33 occasional (7.5%) HP:0000175
3 cholestasis 33 occasional (7.5%) HP:0001396
4 macrovesicular hepatic steatosis 33 occasional (7.5%) HP:0001403
5 ptosis 33 HP:0000508
6 seizures 33 HP:0001250
7 failure to thrive 33 HP:0001508
8 developmental regression 33 HP:0002376
9 global developmental delay 33 HP:0001263
10 visual impairment 33 HP:0000505
11 neonatal hypotonia 33 HP:0001319
12 absent speech 33 HP:0001344
13 dystonia 33 HP:0001332
14 increased serum lactate 33 HP:0002151
15 lactic acidosis 33 HP:0003128
16 ragged-red muscle fibers 33 HP:0003200
17 ophthalmoplegia 33 HP:0000602
18 bradykinesia 33 HP:0002067
19 hypoplasia of the corpus callosum 33 HP:0002079
20 spastic tetraparesis 33 HP:0001285
21 dysplastic corpus callosum 33 HP:0006989
22 decreased activity of mitochondrial complex i 33 HP:0011923
23 leukoencephalopathy 33 HP:0002352
24 decreased activity of mitochondrial complex iii 33 HP:0011924
25 decreased activity of mitochondrial complex iv 33 HP:0008347

Symptoms via clinical synopsis from OMIM:

58
Head And Neck Eyes:
ptosis
visual impairment
ophthalmoplegia

Growth Other:
failure to thrive

Metabolic Features:
lactic acidosis

Abdomen Liver:
cholestasis (1 patient)
hepatomegaly (1 patient)
macrovesicular steatosis (1 patient)
fibrosis, mild (1 patient)

Cardiovascular Heart:
interventricular septal hypertrophy (1 patient)

Neurologic Central Nervous System:
seizures
dysplastic corpus callosum
thinning of the corpus callosum
delayed psychomotor development (in severe cases)
psychomotor regression (in milder cases)
more
Laboratory Abnormalities:
increased serum lactate
abnormal liver enzymes, intermittent (1 patient)
increased alpha-fetoprotein (1 patient)

Muscle Soft Tissue:
hypotonia, neonatal
ragged-red fibers
muscle biopsy shows cytochrome c oxidase-negative fibers
decreased activities of mitochondrial complexes i, iii, and iv
impaired mitochondrial respiration

Head And Neck Mouth:
cleft palate (1 patient)

Clinical features from OMIM:

614924

UMLS symptoms related to Combined Oxidative Phosphorylation Deficiency 12:


seizures, ophthalmoplegia

Drugs & Therapeutics for Combined Oxidative Phosphorylation Deficiency 12

Search Clinical Trials , NIH Clinical Center for Combined Oxidative Phosphorylation Deficiency 12

Genetic Tests for Combined Oxidative Phosphorylation Deficiency 12

Genetic tests related to Combined Oxidative Phosphorylation Deficiency 12:

# Genetic test Affiliating Genes
1 Combined Oxidative Phosphorylation Deficiency 12 30 EARS2

Anatomical Context for Combined Oxidative Phosphorylation Deficiency 12

MalaCards organs/tissues related to Combined Oxidative Phosphorylation Deficiency 12:

42
Thalamus, Brain, Liver, Cerebellum

Publications for Combined Oxidative Phosphorylation Deficiency 12

Articles related to Combined Oxidative Phosphorylation Deficiency 12:

# Title Authors Year
1
Severe Metabolic Acidosis and Hepatopathy due to Leukoencephalopathy with Thalamus and Brainstem Involvement and High Lactate. ( 27875839 )
2017
2
Multisystem fatal infantile disease caused by a novel homozygous EARS2 mutation. ( 23008233 )
2013
3
Leukoencephalopathy with thalamus and brainstem involvement and high lactate 'LTBL' caused by EARS2 mutations. ( 22492562 )
2012

Variations for Combined Oxidative Phosphorylation Deficiency 12

UniProtKB/Swiss-Prot genetic disease variations for Combined Oxidative Phosphorylation Deficiency 12:

76 (show all 14)
# Symbol AA change Variation ID SNP ID
1 EARS2 p.Arg55His VAR_069235 rs770862902
2 EARS2 p.Lys65Glu VAR_069236 rs397514595
3 EARS2 p.Glu96Lys VAR_069237 rs397514593
4 EARS2 p.Arg107His VAR_069238 rs102133056
5 EARS2 p.Arg108Trp VAR_069239 rs376103091
6 EARS2 p.Gly110Ser VAR_069240 rs201842633
7 EARS2 p.Cys167Tyr VAR_069241 rs397514594
8 EARS2 p.Arg168Gly VAR_069242 rs397514591
9 EARS2 p.Gly204Ser VAR_069243 rs397514592
10 EARS2 p.Gly224Ser VAR_069244 rs141129877
11 EARS2 p.Gly317Cys VAR_069245 rs746838793
12 EARS2 p.Arg516Gln VAR_069247 rs201727231
13 EARS2 p.Arg107Cys VAR_076183 rs135568545
14 EARS2 p.Arg489Gln VAR_076184 rs757965573

ClinVar genetic disease variations for Combined Oxidative Phosphorylation Deficiency 12:

6 (show all 22)
# Gene Variation Type Significance SNP ID Assembly Location
1 EARS2 NM_001083614.1(EARS2): c.322C> T (p.Arg108Trp) single nucleotide variant Conflicting interpretations of pathogenicity rs376103091 GRCh37 Chromosome 16, 23555998: 23555998
2 EARS2 NM_001083614.1(EARS2): c.322C> T (p.Arg108Trp) single nucleotide variant Conflicting interpretations of pathogenicity rs376103091 GRCh38 Chromosome 16, 23544677: 23544677
3 EARS2 NM_001083614.1(EARS2): c.502A> G (p.Arg168Gly) single nucleotide variant Pathogenic rs397514591 GRCh37 Chromosome 16, 23546665: 23546665
4 EARS2 NM_001083614.1(EARS2): c.502A> G (p.Arg168Gly) single nucleotide variant Pathogenic rs397514591 GRCh38 Chromosome 16, 23535344: 23535344
5 EARS2 NM_001083614.1(EARS2): c.328G> A (p.Gly110Ser) single nucleotide variant Pathogenic rs201842633 GRCh37 Chromosome 16, 23555992: 23555992
6 EARS2 NM_001083614.1(EARS2): c.328G> A (p.Gly110Ser) single nucleotide variant Pathogenic rs201842633 GRCh38 Chromosome 16, 23544671: 23544671
7 EARS2 NM_001083614.1(EARS2): c.610G> A (p.Gly204Ser) single nucleotide variant Pathogenic rs397514592 GRCh37 Chromosome 16, 23546557: 23546557
8 EARS2 NM_001083614.1(EARS2): c.610G> A (p.Gly204Ser) single nucleotide variant Pathogenic rs397514592 GRCh38 Chromosome 16, 23535236: 23535236
9 EARS2 NM_001083614.1(EARS2): c.286G> A (p.Glu96Lys) single nucleotide variant Pathogenic rs397514593 GRCh37 Chromosome 16, 23563479: 23563479
10 EARS2 NM_001083614.1(EARS2): c.286G> A (p.Glu96Lys) single nucleotide variant Pathogenic rs397514593 GRCh38 Chromosome 16, 23552158: 23552158
11 EARS2 NM_001083614.1(EARS2): c.500G> A (p.Cys167Tyr) single nucleotide variant Pathogenic rs397514594 GRCh37 Chromosome 16, 23546667: 23546667
12 EARS2 NM_001083614.1(EARS2): c.500G> A (p.Cys167Tyr) single nucleotide variant Pathogenic rs397514594 GRCh38 Chromosome 16, 23535346: 23535346
13 EARS2 NM_001083614.1(EARS2): c.193A> G (p.Lys65Glu) single nucleotide variant Pathogenic rs397514595 GRCh37 Chromosome 16, 23563572: 23563572
14 EARS2 NM_001083614.1(EARS2): c.193A> G (p.Lys65Glu) single nucleotide variant Pathogenic rs397514595 GRCh38 Chromosome 16, 23552251: 23552251
15 EARS2 NM_001083614.1(EARS2): c.1547G> A (p.Arg516Gln) single nucleotide variant Pathogenic/Likely pathogenic rs201727231 GRCh37 Chromosome 16, 23535717: 23535717
16 EARS2 NM_001083614.1(EARS2): c.1547G> A (p.Arg516Gln) single nucleotide variant Pathogenic/Likely pathogenic rs201727231 GRCh38 Chromosome 16, 23524396: 23524396
17 EARS2 NM_001083614.1(EARS2): c.334G> C (p.Ala112Pro) single nucleotide variant not provided rs749048646 GRCh37 Chromosome 16, 23555986: 23555986
18 EARS2 NM_001083614.1(EARS2): c.334G> C (p.Ala112Pro) single nucleotide variant not provided rs749048646 GRCh38 Chromosome 16, 23544665: 23544665
19 EARS2 NM_001083614.1(EARS2): c.320G> A (p.Arg107His) single nucleotide variant Pathogenic/Likely pathogenic rs1021330566 GRCh37 Chromosome 16, 23556000: 23556000
20 EARS2 NM_001083614.1(EARS2): c.320G> A (p.Arg107His) single nucleotide variant Pathogenic/Likely pathogenic rs1021330566 GRCh38 Chromosome 16, 23544679: 23544679
21 EARS2 NM_001083614.1(EARS2): c.790C> G (p.Leu264Val) single nucleotide variant Uncertain significance rs1555503379 GRCh37 Chromosome 16, 23546377: 23546377
22 EARS2 NM_001083614.1(EARS2): c.790C> G (p.Leu264Val) single nucleotide variant Uncertain significance rs1555503379 GRCh38 Chromosome 16, 23535056: 23535056

Expression for Combined Oxidative Phosphorylation Deficiency 12

Search GEO for disease gene expression data for Combined Oxidative Phosphorylation Deficiency 12.

Pathways for Combined Oxidative Phosphorylation Deficiency 12

GO Terms for Combined Oxidative Phosphorylation Deficiency 12

Sources for Combined Oxidative Phosphorylation Deficiency 12

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