Branched-chain organic acid 3-methylglutaconic acid: the biochemical basis
Measuring 3-MGA by gas chromatography/mass spectrometry (GC-MS) and one-dimensional [1H]-NMR spectroscopy
3-MGA-uria type I (MIM 250950)
3-MGA-uria type II (Barth syndrome, MIM 302060)
3-MGA-uria type III (Costeff syndrome, MIM 258501)
3-MGA-uria type IV (MIM 250951)
3-MGA-uria type V (MIM 610198)
Other causes of 3-MGA-uria
Conclusion and approach to the patient with unexplained 3-MGA-uria
Clinical feature in the patient with 3-MGA-uria | Type | Next diagnostic step | Genetic confirmationb
|
---|---|---|---|
Leukoencephalopathy | I | UOA: 3-MGA cis:trans isoforms (2:1), no ↑3-HIVA |
AUH
|
3-MGH activity in leucocytes/fibroblasts | |||
Optic atrophy | I | UOA: 3-MGA cis:trans isoforms (2:1), no ↑3-HIVA |
AUH
|
3-MGH activity in leucocytes/fibroblasts | |||
III | + Iraqi Jewish origin: proceed to genetic testing |
OPA3
| |
Ataxia/spasticity | I | UOA: 3-MGA cis:trans isoforms (2:1), no ↑3-HIVA |
AUH
|
3-MGH activity in leucocytes/fibroblasts | |||
III | + Optic atrophy: proceed to genetic testing |
OPA3
| |
Sensorineural deafness | IV | OXPHOS measurements in muscle/fibroblastsa
|
SUCLA2
|
Encephalopathy (epilepsy, psychosis, depression) | IV | OXPHOS measurements in muscle/fibroblastsa
|
POLG1, SUCLA2
|
Cardiomyopathy (± cataracts) | II | Cardiolipin profile |
TAZ
|
+ Neutropenia: proceed to genetic testing | |||
IV | OXPHOS measurements in muscle/fibroblastsa
|
m.3243A>G
| |
+ Gypsy origin: proceed to genetic testing |
TMEM70
| ||
V | + Canadian-Hutterite origin: proceed to genetic testing |
DNAJC19
| |
Liver failure | IV | OXPHOS measurements in muscle/fibroblastsa
|
POLG1
|
Typical case of Alpers syndrome: proceed to genetic testing | |||
Bone marrow failure, exocrine pancreas insufficiency | IV | Proceed to genetic testing |
mtDNA deletions
|
Gene | Type | Protein | Predicted function in | No. patientsa
|
---|---|---|---|---|
AUH
| I | 3-methylglutaconyl-CoA hydratase | Leucine catabolism | 10 |
TAZ-
| II | Tafazzin, a mitochondrial cardiolipin transacylase | Cardiolipin remodelling | >100 |
OPA3
| III | OPA3A and OPA3B protein | Mitochondrial (mt) fisson, apoptosis | >36 |
TMEM70
| IV | Transmembrane protein 70 | Biosynthesis and assembly of ATP synthase | 53 |
ATP5E
| IV | ATP synthase, epsilon subunit | Biosynthesis and assembly of ATP synthase | 1 |
ATP12
| IV | ATP 12 protein | Biosynthesis and assembly of ATP synthase | 1 |
POLG1
| IV | Polymerase gamma | mtDNA replication | 3 |
m.3243A>G | IV | tRNA leucine | mtDNA translation | 1 |
mtDNA deletions | IV | Not applicable | mtDNA replication and translation | 6 |
mtDNA depletion | IV | Not applicable | mtDNA replication and translation | 5 |
SUCLA2
| IV | Succinate-CoA ligase | Tricarboxylic acid cycle | 3 |
RYR1
| IV | Ryanodine receptor | Calcium channel of sarcoplasmatic reticulum | 1 |
DNAJC19
| V | Translocase of inner mitochondrial membrane 14 | Mitochondrial protein import | 16 |