Combined oxidative phosphorylation defect type 14

General Information (adopted from Orphanet):

Synonyms, Signs: COXPD14
Number of Symptoms 50
OrphanetNr: 319519
OMIM Id: 614946
ICD-10: E88.8
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: No data available.
Inheritance: Monogenic
Autosomal recessive
22833457 [IBIS]
Age of onset: Infancy
22833457 [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:

Compound heterozygous mutations in FARS2 (= COXPD14, FARS1, HSPC320, PheRS, SPG77) encoding the mitochondrial phenylalanyl transfer RNA (tRNA) synthetase (mtPheRS) were found in different patients with mitochondrial encephalopathy. The mutations affected e.g. the highly conserved amino acids p.I329T, p.D391V, and p.Y144C. In vitro characterization indicated reduced affinity of p.D391V mutant protein to phenylalanine, whereas p.Y144C disrupted tRNA binding. The stability of p.I329T and p.D391V mutants in a refolding assay was impaired. The results imply that these FARS2 mutations directly impair aminoacylation function and stability of mtPheRS, leading to a decrease in overall tRNA charging capacity. The clinical features of patients with FARS2 variants resemble each other closely, and the neuropathology is consistent with Alpers syndrome (PMID:22833457).

Symptom Information: Sort by abundance 

1
(HPO:0000496) Abnormality of eye movement 24161539 IBIS 79 / 7739
2
(HPO:0002151) Increased serum lactate 22833457 IBIS 92 / 7739
3
(HPO:0003128) Lactic acidosis 22833457 IBIS 116 / 7739
4
(HPO:0003355) Aminoaciduria rare [HPO:skoehler] 22833457 IBIS 65 / 7739
5
(HPO:0008972) Decreased activity of mitochondrial respiratory chain 22833457 IBIS 34 / 7739
6
(HPO:0011923) Decreased activity of mitochondrial complex I 22833457 IBIS 35 / 7739
7
(HPO:0008347) Decreased activity of mitochondrial complex IV 22833457 IBIS 31 / 7739
8
(HPO:0010836) Abnormality of copper homeostasis 22833457 IBIS 2 / 7739
9
(HPO:0012465) Elevated hepatic iron concentration 22833457 IBIS 8 / 7739
10
(HPO:0001336) Myoclonus 27095821 IBIS 115 / 7739
11
(HPO:0002490) Increased CSF lactate 22833457 IBIS 28 / 7739
12
(HPO:0200134) Epileptic encephalopathy 22833457 IBIS 42 / 7739
13
(HPO:0006789) Mitochondrial encephalopathy 22833457 IBIS 5 / 7739
14
(HPO:0001348) Brisk reflexes 24161539 IBIS 15 / 7739
15
(HPO:0002509) Limb hypertonia 24161539 IBIS 13 / 7739
16
(HPO:0001263) Global developmental delay 22833457 IBIS 853 / 7739
17
(MedDRA:10004153) Basal ganglion degeneration 22833457 IBIS 2 / 7739
18
(HPO:0002353) EEG abnormality 22833457 IBIS 188 / 7739
19
(HPO:0002521) Hypsarrhythmia 24161539 IBIS 43 / 7739
20
(HPO:0001250) Seizures 22833457 IBIS 1245 / 7739
21
(HPO:0012469) Infantile spasms 24161539 IBIS 18 / 7739
22
(HPO:0002123) Generalized myoclonic seizures 22833457 IBIS 62 / 7739
23
(HPO:0000252) Microcephaly 22833457 IBIS 832 / 7739
24
(HPO:0001392) Abnormality of the liver 22833457 IBIS 28 / 7739
25
(HPO:0006568) Increased hepatic glycogen content 22833457 IBIS 34 / 7739
26
(HPO:0000431) Wide nasal bridge 24161539 IBIS 290 / 7739
27
(HPO:0000356) Abnormality of the outer ear 24161539 IBIS 85 / 7739
28
(HPO:0012443) Abnormality of brain morphology 22833457 IBIS 45 / 7739
29
(HPO:0010663) Abnormality of thalamus morphology 22833457 IBIS 6 / 7739
30
(HPO:0006999) Basal ganglia gliosis 22833457 IBIS 4 / 7739
31
(HPO:0001272) Cerebellar atrophy 22833457 IBIS 197 / 7739
32
(HPO:0002059) Cerebral atrophy 22833457 IBIS 171 / 7739
33
(HPO:0002120) Cerebral cortical atrophy 22833457 IBIS 187 / 7739
34
(HPO:0001522) Death in infancy 22833457 IBIS 275 / 7739
35
(HPO:0002171) Gliosis 22833457 IBIS 48 / 7739
36
(MedDRA:10062943) Alpers' disease 22833457 IBIS 1 / 7739
37
(MedDRA:10051990) Cortical laminar necrosis 22833457 IBIS 1 / 7739
38
(MedDRA:10063750) Life expectancy shortened 22833457 IBIS 4 / 7739
39
(MedDRA:10072731) White matter lesion 24161539 IBIS 7 / 7739
40
(OMIM) Anteriorly rotated ears 24161539 IBIS 2 / 7739
41
(OMIM) Brainstem atrophy 22833457 IBIS 5 / 7739
42
(OMIM) Coarse retinal pigmentation (rare) 22833457 IBIS 1 / 7739
43
(OMIM) Decreased pyramidal cells 22833457 IBIS 1 / 7739
44
(OMIM) Deficiency of mitochondrial respiratory enzymes seen on muscle biopsy 22833457 IBIS 1 / 7739
45
(OMIM) Diffuse cerebral atrophy seen on MRI 22833457 IBIS 1 / 7739
46
(OMIM) Enlarged hepatocytes (rare) 22833457 IBIS 1 / 7739
47
(OMIM) Hepatic copper increased 22833457 IBIS 2 / 7739
48
(OMIM) Increased glycogen content (rare) 22833457 IBIS 1 / 7739
49
(OMIM) Laminar necrosis 22833457 IBIS 1 / 7739
50
(OMIM) Reactive gliosis 22833457 IBIS 3 / 7739

Associated genes:

FARS2;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (OMIM) COXPD14 is a severe multisystemic autosomal recessive disorder characterized by neonatal onset of global developmental delay, refractory seizures, and lactic acidosis. Biochemical studies show deficiencies of multiple mitochondrial respiratory enzymes. Neuropathologic studies in 1 patient showed laminar cortical ...
Clinical Description OMIM Shamseldin et al. (2012) reported a consanguineous Saudi Arabian family in which 3 sibs had a severe mitochondrial encephalopathy. The proband was a 1.9-year-old girl with significant global developmental delay, lactic acidosis, and onset of uncontrolled seizures at ...
Molecular genetics OMIM In 3 sibs, born of consanguineous Saudi Arabian parents, with COXPD14, Shamseldin et al. (2012) identified a homozygous mutation in the FARS2 gene (Y144C; 611592.0001). The mutation was identified by exome sequencing and confirmed by Sanger sequencing. ...