Fatal mitochondrial disease due to combined oxidative phosphorylation deficiency 3

General Information (adopted from Orphanet):

Synonyms, Signs: COXPD3
Encephalomyopathy, respiratory failure, and Lactic Acidosis
Concentric Cardiomyopathy, Hypotonia, and Lactic Acidosis
Number of Symptoms 60
OrphanetNr: 168566
OMIM Id: 610505
ICD-10: E88.8
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: 2 cases
Inheritance:
Age of onset: Neonatal
Infancy
Childhood
Adolescent
17033963; 25037205 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Mitochondrial disorder due to a defect in mitochondrial protein synthesis
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare neurologic disease

Comment:

TSFM is a gene coding for the mitochondrial translation elongation factor EFTs. EFTs functions as a guanine nucleotide exchange factor for EFTu, another translation elongation factor that brings aminoacylated transfer RNAs to the ribosomal A site as a ternary complex with guanosine triphosphate. An Arg333Trp substitution in a subdomain of EFTs that interacts with EFTu showed that the steady-state levels of EFTs and EFTu in patient fibroblasts were reduced by 75% and 60%, respectively, and the amounts of assembled complexes I, IV, and V were reduced by 35%–91% compared with the amounts in controls. These phenotypes and the translation defect were rescued by retroviral expression of either EFTs or EFTu. The fact that the same mutation is associated with distinct clinical phenotypes suggests the presence of genetic modifiers of the mitochondrial translation apparatus (PMID:17033963). Sequence data from 35,000 Finnish population controls indicated that the heterozygous carrier frequency of c.856C.T [p.Q286X], in the TSFM gene encoding mitochondrial EFTs was exceptionally high in Finland, 1:80, but no homozygotes were found in the population, in our mitochondrial disease patient collection, or in an intrauterine fetal death material, suggesting early developmental lethality of the homozygotes (PMID:25037205).

Symptom Information: Sort by abundance 

1
 (HPO:0011968) Feeding difficulties 17033963 IBIS 240 / 7739
2
 (HPO:0008872) Feeding difficulties in infancy 17033963 IBIS 153 / 7739
3
 (HPO:0002033) Poor suck 17033963 IBIS 37 / 7739
4
 (HPO:0002093) Respiratory insufficiency 17033963 IBIS 410 / 7739
5
 (HPO:0002094) Dyspnea 17033963 IBIS 132 / 7739
6
 (HPO:0002151) Increased serum lactate 17033963 IBIS 92 / 7739
7
 (HPO:0003128) Lactic acidosis Very frequent [IBIS] 17033963 IBIS 116 / 7739
8
 (HPO:0001942) Metabolic acidosis 17033963 IBIS 81 / 7739
9
 (HPO:0001655) Patent foramen ovale 17033963 IBIS 31 / 7739
10
 (HPO:0001639) Hypertrophic cardiomyopathy 17033963 IBIS 137 / 7739
11
 (HPO:0005157) Concentric hypertrophic cardiomyopathy Very frequent [IBIS] 17033963 IBIS 5 / 7739
12
 (HPO:0002119) Ventriculomegaly 17033963 IBIS 253 / 7739
13
 (HPO:0001643) Patent ductus arteriosus 17033963 IBIS 228 / 7739
14
 (HPO:0011648) Patent ductus arteriosus after birth at term 17033963 IBIS 18 / 7739
15
 (HPO:0011923) Decreased activity of mitochondrial complex I 17033963 IBIS 35 / 7739
16
 (HPO:0011924) Decreased activity of mitochondrial complex III 17033963 IBIS 22 / 7739
17
 (HPO:0008347) Decreased activity of mitochondrial complex IV 17033963 IBIS 31 / 7739
18
 (HPO:0003236) Elevated serum creatine phosphokinase 17033963 IBIS 214 / 7739
19
 (HPO:0002902) Hyponatremia 17033963 IBIS 37 / 7739
20
 (HPO:0001987) Hyperammonemia 17033963 IBIS 50 / 7739
21
 (HPO:0003554) Type 2 muscle fiber atrophy 25037205 IBIS 14 / 7739
22
 (HPO:0003198) Myopathy 17033963 IBIS 151 / 7739
23
 (HPO:0003458) EMG: myopathic abnormalities 25037205 IBIS 38 / 7739
24
 (HPO:0003201) Rhabdomyolysis 17033963 IBIS 27 / 7739
25
 (HPO:0011804) Abnormality of muscle physiology 25037205 IBIS 1 / 7739
26
 (HPO:0001252) Muscular hypotonia Very frequent [IBIS] 17033963 IBIS 990 / 7739
27
 (HPO:0008947) Infantile muscular hypotonia Very frequent [IBIS] 17033963 IBIS 482 / 7739
28
 (HPO:0001319) Neonatal hypotonia 17033963 IBIS 101 / 7739
29
 (HPO:0001324) Muscle weakness 25037205 IBIS 859 / 7739
30
 (HPO:0001298) Encephalopathy 17033963 IBIS 72 / 7739
31
 (HPO:0006789) Mitochondrial encephalopathy 17033963 IBIS 5 / 7739
32
 (HPO:0003447) Axonal loss 25037205 IBIS 11 / 7739
33
 (HPO:0007141) Sensorimotor neuropathy 25037205 IBIS 27 / 7739
34
 (HPO:0000741) Apathy 17033963 IBIS 42 / 7739
35
 (HPO:0001268) Mental deterioration 25037205 IBIS 88 / 7739
36
 (HPO:0012378) Fatigue 25037205 IBIS 50 / 7739
37
 (HPO:0100660) Dyskinesia 25037205 IBIS 19 / 7739
38
 (HPO:0002353) EEG abnormality 17033963 IBIS 188 / 7739
39
 (HPO:0001250) Seizures 17033963 IBIS 1245 / 7739
40
 (HPO:0001558) Decreased fetal movement 17033963 IBIS 74 / 7739
41
 (HPO:0001511) Intrauterine growth retardation 25037205 IBIS 358 / 7739
42
 (HPO:0001399) Hepatic failure 21741925 IBIS 80 / 7739
43
 (HPO:0005957) Breathing dysregulation 17033963 IBIS 6 / 7739
44
 (HPO:0001946) Ketosis 17033963 IBIS 17 / 7739
45
 (HPO:0003688) Decreased activity of cytochrome C oxidase in muscle tissue 17033963 IBIS 20 / 7739
46
 (HPO:0003737) Mitochondrial myopathy 17033963 IBIS 18 / 7739
47
 (HPO:0001522) Death in infancy 17033963 IBIS 275 / 7739
48
 (HPO:0002878) Respiratory failure Very frequent [IBIS] 17033963 IBIS 57 / 7739
49
 (MedDRA:10057977) Lactate pyruvate ratio increased 17033963 IBIS 3 / 7739
50
 (MedDRA:10067221) Mechanical ventilation 17033963 IBIS 1 / 7739
51
 (MedDRA:10058799) Mitochondrial encephalomyopathy Very frequent [IBIS] 17033963 IBIS 5 / 7739
52
 (OMIM) Abnormal signals in the thalami seen on MRI 17033963 IBIS 1 / 7739
53
 (OMIM) COX-deficient fibers 25037205 IBIS 3 / 7739
54
 (OMIM) Decreased activity of mitochondrial respiratory complexes I, III, and IV 17033963 IBIS 1 / 7739
55
 (OMIM) Early death 17033963 IBIS 13 / 7739
56
 (OMIM) Increased serum ammonia 17033963 IBIS 5 / 7739
57
 (OMIM) Increased serum ketones 17033963 IBIS 1 / 7739
58
 (OMIM) Irregular breathing 17033963 IBIS 2 / 7739
59
 (OMIM) Nerve hypertrophy 25037205 IBIS 2 / 7739
60
 (OMIM) Reduced brain gyri 17033963 IBIS 1 / 7739

Associated genes:

TSFM;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Clinical Description OMIM Smeitink et al. (2006) reported 2 unrelated patients with COXPD3. The first proband was the child of consanguineous Turkish parents. Muscular hypotonia, sucking weakness, and severe lactic acidosis were the initial clinical signs and symptoms, followed by rhabdomyolysis ...
Molecular genetics OMIM In 2 unrelated patients with COXPD3, Smeitink et al. (2006) identified a homozygous mutation in the TSFM gene (R333W; 604723.0001). The fact that the same mutation was associated with distinct clinical phenotypes suggested that genetic modifiers of the ...