Severe X-linked mitochondrial encephalomyopathy

General Information (adopted from Orphanet):

Synonyms, Signs: COXPD6
Mitochondrial encephalomyopathy due to combined oxidative phosphorylation deficiency 6
Encephalomyopathy, mitochondrial, X-LINKED
Mitochondrial encephalomyopathy due to COXPD6
Number of Symptoms 37
OrphanetNr: 238329
OMIM Id: 300816
ICD-10:
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: No data available.
Inheritance: X-linked
20362274 [IBIS]
Age of onset: Infancy
20362274 [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
Neurometabolic disease
 -Rare genetic disease
 -Rare neurologic disease

Comment:

A disease-segregating mutation in the X-linked AIFM1 (= COXPD6) gene, encoding the Apoptosis-Inducing Factor (AIF) mitochondrion-associated 1 precursor, deleted arginine201 (R201del). Under normal conditions, mature AIF is a FAD-dependent NADH oxidase of unknown function and is targeted to the mitochondrial intermembrane space (= AIF(mit)). Upon apoptogenic stimuli, a soluble form (= AIF(sol)) is released by proteolytic cleavage and migrates to the nucleus, where it induces "parthanatos," i.e., caspase-independent fragmentation of chromosomal DNA. In vitro, the AIF(R201 del) mutation decreases stability of both AIF(mit) and AIF(sol) and increases the AIF(sol) DNA binding affinity, a prerequisite for nuclear apoptosis. In AIF(R201 del) fibroblasts, staurosporine-induced parthanatos was markedly increased, whereas re-expression of AIF(wt) induced recovery of RC activities. It is concluded that AIF(R201 del) is an unstable mutant variant associated with increased parthanatos-linked cell death. Data suggest a role for AIF in RC integrity and mtDNA maintenance, at least in some tissues (PMID:20362274).

Symptom Information: Sort by abundance 

1
 (HPO:0002098) Respiratory distress 20362274 IBIS 75 / 7739
2
 (HPO:0002747) Respiratory insufficiency due to muscle weakness 20362274 IBIS 48 / 7739
3
 (HPO:0002090) Pneumonia 20362274 IBIS 59 / 7739
4
 (HPO:0002151) Increased serum lactate 20362274 IBIS 92 / 7739
5
 (HPO:0003542) Increased serum pyruvate 20362274 IBIS 18 / 7739
6
 (HPO:0011924) Decreased activity of mitochondrial complex III 20362274 IBIS 22 / 7739
7
 (HPO:0008347) Decreased activity of mitochondrial complex IV 20362274 IBIS 31 / 7739
8
 (HPO:0003200) Ragged-red muscle fibers 20362274 IBIS 37 / 7739
9
 (HPO:0003202) Skeletal muscle atrophy 20362274 IBIS 281 / 7739
10
 (HPO:0003198) Myopathy 20362274 IBIS 151 / 7739
11
 (HPO:0001252) Muscular hypotonia 20362274 IBIS 990 / 7739
12
 (HPO:0008947) Infantile muscular hypotonia 20362274 IBIS 482 / 7739
13
 (HPO:0004305) Involuntary movements 20362274 IBIS 50 / 7739
14
 (HPO:0002380) Fasciculations 20362274 IBIS 42 / 7739
15
 (HPO:0001308) Tongue fasciculations 20362274 IBIS 18 / 7739
16
 (HPO:0001324) Muscle weakness 20362274 IBIS 859 / 7739
17
 (HPO:0003324) Generalized muscle weakness 20362274 IBIS 48 / 7739
18
 (HPO:0002490) Increased CSF lactate 20362274 IBIS 28 / 7739
19
 (HPO:0001298) Encephalopathy 20362274 IBIS 72 / 7739
20
 (HPO:0003390) Sensory axonal neuropathy 20362274 IBIS 26 / 7739
21
 (HPO:0009830) Peripheral neuropathy 20362274 IBIS 206 / 7739
22
 (HPO:0002445) Tetraplegia 20362274 IBIS 26 / 7739
23
 (HPO:0002376) Developmental regression 20362274 IBIS 74 / 7739
24
 (HPO:0002375) Hypokinesia 20362274 IBIS 25 / 7739
25
 (HPO:0001284) Areflexia 20362274 IBIS 198 / 7739
26
 (HPO:0001265) Hyporeflexia 20362274 IBIS 208 / 7739
27
 (HPO:0001250) Seizures 20362274 IBIS 1245 / 7739
28
 (HPO:0002197) Generalized seizures 20362274 IBIS 30 / 7739
29
 (HPO:0009025) Increased connective tissue 20362274 IBIS 11 / 7739
30
 (HPO:0009141) Depletion of mitochondrial DNA in muscle tissue 20362274 IBIS 5 / 7739
31
 (MedDRA:10006469) Bronchopneumonia 20362274 IBIS 2 / 7739
32
 (MedDRA:10058799) Mitochondrial encephalomyopathy Very frequent [IBIS] 20362274 IBIS 5 / 7739
33
 (OMIM) Hyporeflexia or areflexia 20362274 IBIS 2 / 7739
34
 (OMIM) Increased lactate in serum and CSF 20362274 IBIS 1 / 7739
35
 (OMIM) Increased pyruvate in serum and CSF 20362274 IBIS 1 / 7739
36
 (OMIM) Mitochondrial DNA depletion (20 to 35% of normal) seen on skeletal muscle biopsy 20362274 IBIS 1 / 7739
37
 (OMIM) Sensory and motor axonal polyneuropathy 20362274 IBIS 1 / 7739

Associated genes:

AIFM1;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Clinical Description OMIM Ghezzi et al. (2010) reported 2 Italian male infants, born of monozygotic twin sisters and unrelated fathers, who had an early-onset neurodegenerative disorder associated with dysfunction of the mitochondrial respiratory chain. Both boys had normal development in the ...
Molecular genetics OMIM In 2 Italian first-cousin male patients with an X-linked encephalomyopathy due to combined oxidative phosphorylation deficiency, Ghezzi et al. (2010) identified a hemizygous deletion in the AIFM1 gene (300169.0001). In vitro studies showed that the AIFM1 mutation resulted ...