Pyruvate dehydrogenase E3 deficiency

General Information (adopted from Orphanet):

Synonyms, Signs: DLDD
Lipoamide dehydrogenase deficiency, lactic acidosis due to
Dihydrolipoamide dehydrogenase deficiency
dld deficiency
Maple syrup urine disease, type III
E3 deficiency
E3-deficient maple syrup urine disease
Number of Symptoms 53
OrphanetNr: 2394
OMIM Id: 246900
ICD-10: E74.4
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: 20 cases [Orphanet]
Inheritance: Autosomal recessive
16770810; 15712224 [IBIS]
Age of onset: All ages
23290025; 16770810; 8968745 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Mitochondrial myopathy
 -Rare genetic disease
 -Rare neurologic disease
Pyruvate dehydrogenase deficiency
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare neurologic disease

Comment:

Dihydrolipoamide dehydrogenase (dihydrolipoamide: NAD+ oxidoreductase, DLD, EC 1.8.1.4) is a component of a number of mitochondrial multienzyme complexes: pyruvate dehydrogenase complex, 2-oxoglutarate dehydrogenase (a -ketoglutarate dehydrogenase), and branched chain 2-oxoacid dehydrogenase (branched chain alpha-keto acid dehydrogenase). In these enzyme complexes, it is known as E3, as it catalyzes the third part of each reaction. DLD (DLD = DLDDH, E3, GCSL, LAD, PHE3) is also a component of the glycine cleavage system, in which it is known as L protein. For these reasons, the clinical outcome of DLD deficiency may vary markedly, as several biochemical pathways will be affected and their functions within the mitochondria are diverse (PMID:16770810).

Symptom Information: Sort by abundance 

1
 (HPO:0011968) Feeding difficulties 10448086 IBIS 240 / 7739
2
 (HPO:0002013) Vomiting 16770810 IBIS 191 / 7739
3
 (HPO:0000648) Optic atrophy 23290025 IBIS 238 / 7739
4
 (HPO:0000613) Photophobia 23290025 IBIS 158 / 7739
5
 (HPO:0000505) Visual impairment 16770810 IBIS 297 / 7739
6
 (HPO:0000508) Ptosis 23290025 IBIS 459 / 7739
7
 (HPO:0004360) Abnormality of acid-base homeostasis 16770810 IBIS 5 / 7739
8
 (HPO:0002151) Increased serum lactate 8968745 IBIS 92 / 7739
9
 (HPO:0001993) Ketoacidosis 23290025 IBIS 17 / 7739
10
 (HPO:0003128) Lactic acidosis 16770810 IBIS 116 / 7739
11
 (HPO:0001942) Metabolic acidosis 16770810 IBIS 81 / 7739
12
 (HPO:0001943) Hypoglycemia Occasional [Orphanet] 16770810 IBIS 131 / 7739
13
 (HPO:0003542) Increased serum pyruvate 8968745 IBIS 18 / 7739
14
 (HPO:0004337) Abnormality of amino acid metabolism Very frequent [Orphanet] 16770810 IBIS 45 / 7739
15
 (HPO:0008344) Elevated plasma branched chain amino acids 8968745 IBIS 5 / 7739
16
 (HPO:0001639) Hypertrophic cardiomyopathy 16770810 IBIS 137 / 7739
17
 (HPO:0002913) Myoglobinuria 23290025 IBIS 22 / 7739
18
 (HPO:0001635) Congestive heart failure 16770810 IBIS 232 / 7739
19
 (HPO:0002928) Decreased activity of the pyruvate dehydrogenase complex 8968745 IBIS 10 / 7739
20
 (HPO:0100806) Sepsis 16770810 IBIS 48 / 7739
21
 (HPO:0001992) Organic aciduria Very frequent [Orphanet] 16770810 IBIS 28 / 7739
22
 (HPO:0001252) Muscular hypotonia Frequent [Orphanet] 16770810 IBIS 990 / 7739
23
 (HPO:0008947) Infantile muscular hypotonia 16770810 IBIS 482 / 7739
24
 (HPO:0001324) Muscle weakness 16770810 IBIS 859 / 7739
25
 (HPO:0001298) Encephalopathy 16770810 IBIS 72 / 7739
26
 (HPO:0001251) Ataxia 16770810 IBIS 413 / 7739
27
 (HPO:0002066) Gait ataxia 23290025 IBIS 327 / 7739
28
 (HPO:0002509) Limb hypertonia 23290025 IBIS 13 / 7739
29
 (HPO:0001257) Spasticity 23290025 IBIS 251 / 7739
30
 (HPO:0002510) Spastic tetraplegia 23290025 IBIS 54 / 7739
31
 (HPO:0001332) Dystonia 23290025 IBIS 197 / 7739
32
 (HPO:0007018) Attention deficit hyperactivity disorder 16770810 IBIS 56 / 7739
33
 (HPO:0001328) Specific learning disability 23290025 IBIS 114 / 7739
34
 (HPO:0002344) Progressive neurologic deterioration 16770810 IBIS 27 / 7739
35
 (HPO:0001263) Global developmental delay hallmark [HPO:skoehler] 23290025 IBIS 853 / 7739
36
 (HPO:0012378) Fatigue 16770810 IBIS 50 / 7739
37
 (HPO:0100022) Abnormality of movement Frequent [Orphanet] 16770810 IBIS 129 / 7739
38
 (HPO:0001288) Gait disturbance Frequent [Orphanet] 23290025 IBIS 318 / 7739
39
 (HPO:0001250) Seizures 16770810 IBIS 1245 / 7739
40
 (HPO:0000252) Microcephaly Frequent [Orphanet] 16770810 IBIS 832 / 7739
41
 (HPO:0001410) Decreased liver function rare [HPO:skoehler] 16770810 IBIS 59 / 7739
42
 (HPO:0001399) Hepatic failure Occasional [Orphanet] 16770810 IBIS 80 / 7739
43
 (HPO:0002910) Elevated hepatic transaminases rare [HPO:skoehler] 16770810 IBIS 158 / 7739
44
 (HPO:0002240) Hepatomegaly Frequent [Orphanet] rare [HPO:skoehler] 16770810 IBIS 467 / 7739
45
 (HPO:0001744) Splenomegaly 23290025 IBIS 337 / 7739
46
 (HPO:0012402) Increased urine alpha-ketoglutarate concentration 16770810 IBIS 3 / 7739
47
 (HPO:0002919) Ketonuria 16770810 IBIS 18 / 7739
48
 (HPO:0002791) Hypoventilation 16770810 IBIS 10 / 7739
49
 (HPO:0002500) Abnormality of the cerebral white matter 23290025 IBIS 73 / 7739
50
 (HPO:0002120) Cerebral cortical atrophy 16770810 IBIS 187 / 7739
51
 (IBIS) Leigh-like lesions on brain magnetic resonance imaging (MRI) 23290025 IBIS 3 / 7739
52
 (MedDRA:10061296) Motor dysfunction 16770810 IBIS 4 / 7739
53
 (OMIM) Leigh syndrome 16770810 IBIS 7 / 7739

Associated genes:

DLD;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (OMIM) DLD deficiency is an autosomal recessive metabolic disorder characterized biochemically by a combined deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), pyruvate dehydrogenase complex (PDC), and alpha-ketoglutarate dehydrogenase complex (KGDC). This is the result of E3 being ...
Clinical Description OMIM Robinson et al. (1977) reported a male child, born of Caucasian first-cousin parents, who died at age 7 months with progressive neurologic deterioration and persistent metabolic acidosis. He was well until age 8 weeks, when he abruptly became ...
Molecular genetics OMIM In a patient with dihydrolipoyl dehydrogenase deficiency reported by Sakaguchi et al. (1986), Liu et al. (1993) demonstrated compound heterozygosity for 2 missense mutations in the DLD gene (238331.0001 and 238331.0002).

In a female infant with ...
Population genetics OMIM Among 13 affected patients from 7 Ashkenazi Jewish families with LAD deficiency, Shaag et al. (1999) identified a founder mutation (G229C; 238331.0006) in the DLD gene in 12 of 14 mutated alleles. The other 2 alleles had a ...