MCID: DHY010
MIFTS: 34

Dihydrolipoamide Dehydrogenase Deficiency

Categories: Genetic diseases, Rare diseases, Nephrological diseases, Neuronal diseases, Metabolic diseases, Fetal diseases

Aliases & Classifications for Dihydrolipoamide Dehydrogenase Deficiency

MalaCards integrated aliases for Dihydrolipoamide Dehydrogenase Deficiency:

Name: Dihydrolipoamide Dehydrogenase Deficiency 53 23 49 24 55 71 36 13
Dld Deficiency 53 23 49 24 55 71
E3 Deficiency 53 23 49 24 71
Maple Syrup Urine Disease, Type Iii 53 49 24
Lactic Acidosis Due to Lipoamide Dehydrogenase Deficiency 24 71
E3-Deficient Maple Syrup Urine Disease 49 55
Pyruvate Dehydrogenase E3 Deficiency 49 55
Lipoamide Dehydrogenase Deficiency 23 24
Dldd 53 71
Lactic Acidosis, Congenital Infantile, Due to Lad Deficiency 69
Lipoamide Dehydrogenase Deficiency, Lactic Acidosis Due to 53
Nadh Cytochrome B5 Reductase Deficiency 69
Dihydrolipoyl Dehydrogenase Deficiency 24
Lactic Acidosis Due to Lad Deficiency 24
Maple Syrup Urine Disease Type Iii 71
Maple Syrup Urine Disease, Type 3 28
Msud Type Iii 71

Characteristics:

Orphanet epidemiological data:

55
pyruvate dehydrogenase e3 deficiency
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Childhood; Age of death: adolescent,late childhood;

OMIM:

53
Inheritance:
autosomal recessive

Miscellaneous:
highly variable severity
onset usually in the neonatal period although later onset has been reported
some patients may have normal psychomotor development
high mortality in infancy and early childhood (in some patients)


HPO:

31
dihydrolipoamide dehydrogenase deficiency:
Onset and clinical course variable expressivity
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Dihydrolipoamide Dehydrogenase Deficiency

NIH Rare Diseases : 49 Dihydrolipoamide dehydrogenase (DLD) deficiency is a very rare condition that can vary in age of onset, symptoms and severity. The condition may be characterized by early-onset lactic acidosis and delayed development (most commonly); later-onset neurological dysfunction; or adult-onset isolated liver disease. Signs and symptoms may include lactic acidosis shortly after birth; hypotonia and lethargy in infancy; feeding difficulties; seizures; and various other health issues. Liver problems can range from hepatomegaly to life-threatening liver failure. Symptoms often occur in episodes that may be triggered by illness or other stresses on the body. Many affected infants do not survive the first few years of life; those who survive through early childhood often have growth delay and intellectual disability. Some with onset later in childhood may have neurological dysfunction with normal cognitive development. DLD deficiency is caused by mutations in the DLD gene and is inherited in an autosomal recessive manner. Last updated: 8/26/2015

MalaCards based summary : Dihydrolipoamide Dehydrogenase Deficiency, also known as dld deficiency, is related to maple syrup urine disease and pyruvate dehydrogenase e3-binding protein deficiency, and has symptoms including ataxia, seizures and vomiting. An important gene associated with Dihydrolipoamide Dehydrogenase Deficiency is DLD (Dihydrolipoamide Dehydrogenase), and among its related pathways/superpathways are Glycolysis / Gluconeogenesis and Citrate cycle (TCA cycle). Affiliated tissues include liver.

OMIM : 53 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 a common component of all 3 mitochondrial multienzyme complexes. Clinically, affected individuals have lactic acidosis and neurologic deterioration due to sensitivity of the central nervous system to defects in oxidative metabolism. E3 deficiency is often associated with increased urinary excretion of alpha-keto acids, such as pyruvate (summary by Hong et al., 1996). E3 deficiency can also be associated with increased concentrations of branched-chain amino acids, as observed in maple syrup urine disease (MSUD; 248600), and is sometimes referred to as 'MSUD type III,' although patients with E3 deficiency have additional biochemical defects (Chuang and Shih, 2001; Robinson, 2001). (246900)

UniProtKB/Swiss-Prot : 71 Dihydrolipoamide dehydrogenase deficiency: 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). Clinically, affected individuals have lactic acidosis and neurologic deterioration due to sensitivity of the central nervous system to defects in oxidative metabolism.

Genetics Home Reference : 24 Dihydrolipoamide dehydrogenase deficiency is a severe condition that can affect several body systems. Signs and symptoms of this condition usually appear shortly after birth, and they can vary widely among affected individuals.

GeneReviews: NBK220444

Related Diseases for Dihydrolipoamide Dehydrogenase Deficiency

Diseases related to Dihydrolipoamide Dehydrogenase Deficiency via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 maple syrup urine disease 11.2
2 pyruvate dehydrogenase e3-binding protein deficiency 11.0
3 mitochondrial myopathy 9.9
4 infantile liver failure syndrome 1 9.9
5 acute liver failure 9.9
6 myopathy 9.9
7 blood group, i system 9.6

Graphical network of the top 20 diseases related to Dihydrolipoamide Dehydrogenase Deficiency:



Diseases related to Dihydrolipoamide Dehydrogenase Deficiency

Symptoms & Phenotypes for Dihydrolipoamide Dehydrogenase Deficiency

Symptoms via clinical synopsis from OMIM:

53
Neurologic Central Nervous System:
ataxia
seizures
lethargy
dystonia
hypotonia
more
Cardiovascular Heart:
hypertrophic cardiomyopathy

Metabolic Features:
lactic acidosis
metabolic acidosis
episodic decompensation

Abdomen Liver:
hepatomegaly (in some patients)
liver dysfunction (in some patients)

Head And Neck Head:
microcephaly

Laboratory Abnormalities:
hypoglycemia
elevated pyruvate (in most patients)
elevated branched-chain amino acids (in most patients)
elevated alpha-ketoglutarate (in most patients)
decreased activities of the pyruvate dehydrogenase complex, the alpha-ketoglutarate dehydrogenase complex, and the branched-chain alpha-keto acid dehydrogenase complex
more
Abdomen Gastroin testinal:
poor feeding
vomiting, recurrent, severe


Clinical features from OMIM:

246900

Human phenotypes related to Dihydrolipoamide Dehydrogenase Deficiency:

55 31 (show all 34)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 ataxia 55 31 occasional (7.5%) Occasional (29-5%) HP:0001251
2 seizures 55 31 frequent (33%) Frequent (79-30%) HP:0001250
3 vomiting 55 31 hallmark (90%) Very frequent (99-80%) HP:0002013
4 lethargy 55 31 frequent (33%) Frequent (79-30%) HP:0001254
5 spasticity 55 31 frequent (33%) Frequent (79-30%) HP:0001257
6 failure to thrive 55 31 occasional (7.5%) Occasional (29-5%) HP:0001508
7 behavioral abnormality 55 31 occasional (7.5%) Occasional (29-5%) HP:0000708
8 hepatomegaly 55 31 occasional (7.5%) Frequent (79-30%) HP:0002240
9 microcephaly 55 31 occasional (7.5%) Occasional (29-5%) HP:0000252
10 hypoglycemia 55 31 frequent (33%) Frequent (79-30%) HP:0001943
11 hypercoagulability 55 31 frequent (33%) Frequent (79-30%) HP:0100724
12 feeding difficulties 55 31 frequent (33%) Frequent (79-30%) HP:0011968
13 elevated hepatic transaminases 55 31 occasional (7.5%) Frequent (79-30%) HP:0002910
14 neurodevelopmental delay 55 31 hallmark (90%) Very frequent (99-80%) HP:0012758
15 cardiomyopathy 55 31 occasional (7.5%) Occasional (29-5%) HP:0001638
16 reduced visual acuity 55 31 occasional (7.5%) Occasional (29-5%) HP:0007663
17 increased serum lactate 55 31 hallmark (90%) Very frequent (99-80%) HP:0002151
18 lactic acidosis 55 31 hallmark (90%) Very frequent (99-80%) HP:0003128
19 muscle cramps 55 31 occasional (7.5%) Occasional (29-5%) HP:0003394
20 hepatic failure 55 31 occasional (7.5%) Occasional (29-5%) HP:0001399
21 hyperammonemia 55 31 occasional (7.5%) Occasional (29-5%) HP:0001987
22 generalized hypotonia 55 31 hallmark (90%) Very frequent (99-80%) HP:0001290
23 elevated plasma branched chain amino acids 55 31 frequent (33%) Frequent (79-30%) HP:0008344
24 abnormal cardiac ventricular function 55 31 occasional (7.5%) Occasional (29-5%) HP:0030872
25 decreased plasma carnitine 55 31 occasional (7.5%) Occasional (29-5%) HP:0003234
26 hepatic encephalopathy 55 31 frequent (33%) Frequent (79-30%) HP:0002480
27 increased urine alpha-ketoglutarate concentration 55 31 frequent (33%) Frequent (79-30%) HP:0012402
28 hyperisoleucinemia 55 31 occasional (7.5%) Occasional (29-5%) HP:0010913
29 dystonia 31 HP:0001332
30 global developmental delay 31 hallmark (90%) HP:0001263
31 hypertrophic cardiomyopathy 31 HP:0001639
32 decreased liver function 31 occasional (7.5%) HP:0001410
33 metabolic acidosis 31 HP:0001942
34 encephalopathy 31 HP:0001298

UMLS symptoms related to Dihydrolipoamide Dehydrogenase Deficiency:


dyspnea on exertion, seizures, lethargy, headache, cyanosis, ataxia

Drugs & Therapeutics for Dihydrolipoamide Dehydrogenase Deficiency

Search Clinical Trials , NIH Clinical Center for Dihydrolipoamide Dehydrogenase Deficiency

Genetic Tests for Dihydrolipoamide Dehydrogenase Deficiency

Genetic tests related to Dihydrolipoamide Dehydrogenase Deficiency:

# Genetic test Affiliating Genes
1 Maple Syrup Urine Disease, Type 3 28 DLD

Anatomical Context for Dihydrolipoamide Dehydrogenase Deficiency

MalaCards organs/tissues related to Dihydrolipoamide Dehydrogenase Deficiency:

38
Liver

Publications for Dihydrolipoamide Dehydrogenase Deficiency

Articles related to Dihydrolipoamide Dehydrogenase Deficiency:

# Title Authors Year
1
Riboflavin responsive mitochondrial myopathy is a new phenotype of dihydrolipoamide dehydrogenase deficiency. The chaperon-like effect of vitamin B2. ( 25251739 )
2014
2
Newborn screening for dihydrolipoamide dehydrogenase deficiency: Citrulline as a useful analyte. ( 27896107 )
2014
3
Dihydrolipoamide dehydrogenase deficiency: a still overlooked cause of recurrent acute liver failure and Reye-like syndrome. ( 23478190 )
2013
4
Elevated plasma citrulline: look for dihydrolipoamide dehydrogenase deficiency. ( 23995961 )
2013
5
Novel mutations in dihydrolipoamide dehydrogenase deficiency in two cousins with borderline-normal PDH complex activity. ( 16770810 )
2006
6
Novel mutations in a boy with dihydrolipoamide dehydrogenase deficiency. ( 11687750 )
2001
7
Identification of two mutations in a compound heterozygous child with dihydrolipoamide dehydrogenase deficiency. ( 8968745 )
1996
8
Identification of two missense mutations in a dihydrolipoamide dehydrogenase-deficient patient. ( 8506365 )
1993
9
Dihydrolipoamide Dehydrogenase Deficiency ( 25032271 )
1993

Variations for Dihydrolipoamide Dehydrogenase Deficiency

UniProtKB/Swiss-Prot genetic disease variations for Dihydrolipoamide Dehydrogenase Deficiency:

71
# Symbol AA change Variation ID SNP ID
1 DLD p.Lys72Glu VAR_006907 rs121964987
2 DLD p.Pro488Leu VAR_006908 rs121964988
3 DLD p.Gly229Cys VAR_015820 rs121964990
4 DLD p.Arg495Gly VAR_015821 rs121964989
5 DLD p.Ile47Thr VAR_076985 rs397514651
6 DLD p.Met361Val VAR_076987 rs121964993
7 DLD p.Glu375Lys VAR_076988 rs121964992
8 DLD p.Ile393Thr VAR_076989 rs121964991
9 DLD p.Asp479Val VAR_076990 rs397514649
10 DLD p.Arg482Gly VAR_076991 rs397514650

ClinVar genetic disease variations for Dihydrolipoamide Dehydrogenase Deficiency:

6 (show all 19)
# Gene Variation Type Significance SNP ID Assembly Location
1 DLD NM_000108.4(DLD): c.214A> G (p.Lys72Glu) single nucleotide variant Pathogenic rs121964987 GRCh37 Chromosome 7, 107542785: 107542785
2 DLD NM_000108.4(DLD): c.1463C> T (p.Pro488Leu) single nucleotide variant Pathogenic rs121964988 GRCh37 Chromosome 7, 107559543: 107559543
3 DLD NM_000108.4(DLD): c.685G> T (p.Gly229Cys) single nucleotide variant Pathogenic rs121964990 GRCh37 Chromosome 7, 107555951: 107555951
4 DLD DLD, 1-BP INS, 105A insertion Pathogenic
5 DLD NM_000108.4(DLD): c.1483A> G (p.Arg495Gly) single nucleotide variant Pathogenic rs121964989 GRCh37 Chromosome 7, 107559657: 107559657
6 DLD NM_000108.4(DLD): c.1178T> C (p.Ile393Thr) single nucleotide variant Pathogenic rs121964991 GRCh37 Chromosome 7, 107557849: 107557849
7 DLD DLD, IVS9DS, G-A, +1 single nucleotide variant Pathogenic
8 DLD NM_000108.4(DLD): c.1123G> A (p.Glu375Lys) single nucleotide variant Pathogenic/Likely pathogenic rs121964992 GRCh37 Chromosome 7, 107557794: 107557794
9 DLD NM_000108.4(DLD): c.1081A> G (p.Met361Val) single nucleotide variant Pathogenic rs121964993 GRCh37 Chromosome 7, 107557752: 107557752
10 DLD NM_000108.4(DLD): c.1436A> T (p.Asp479Val) single nucleotide variant Pathogenic rs397514649 GRCh37 Chromosome 7, 107559516: 107559516
11 DLD NM_000108.4(DLD): c.1444A> G (p.Arg482Gly) single nucleotide variant Pathogenic rs397514650 GRCh37 Chromosome 7, 107559524: 107559524
12 DLD NM_000108.4(DLD): c.140T> C (p.Ile47Thr) single nucleotide variant Pathogenic rs397514651 GRCh37 Chromosome 7, 107542204: 107542204
13 DLD NM_000108.4(DLD): c.39+1G> A single nucleotide variant Likely pathogenic rs111257462 GRCh38 Chromosome 7, 107891290: 107891290
14 DLD NM_000108.4(DLD): c.82delT (p.Ser28Leufs) deletion Likely pathogenic rs1057517380 GRCh38 Chromosome 7, 107893242: 107893242
15 DLD NM_000108.4(DLD): c.104dupA (p.Tyr35Terfs) duplication Likely pathogenic rs1057516213 GRCh37 Chromosome 7, 107533709: 107533709
16 DLD NM_000108.4(DLD): c.112C> T (p.Gln38Ter) single nucleotide variant Likely pathogenic rs1057516698 GRCh37 Chromosome 7, 107533717: 107533717
17 DLD NM_000108.4(DLD): c.223dupA (p.Thr75Asnfs) duplication Likely pathogenic rs1057517214 GRCh38 Chromosome 7, 107902349: 107902349
18 DLD NM_000108.4(DLD): c.633dupA (p.Val212Serfs) duplication Likely pathogenic rs1057517016 GRCh37 Chromosome 7, 107546762: 107546762
19 DLD NM_000108.4(DLD): c.1520_1523delTCAA (p.Ile507Thrfs) deletion Likely pathogenic rs1057517354 GRCh37 Chromosome 7, 107559694: 107559697

Expression for Dihydrolipoamide Dehydrogenase Deficiency

Search GEO for disease gene expression data for Dihydrolipoamide Dehydrogenase Deficiency.

Pathways for Dihydrolipoamide Dehydrogenase Deficiency

Pathways related to Dihydrolipoamide Dehydrogenase Deficiency according to KEGG:

36
# Name Kegg Source Accession
1 Glycolysis / Gluconeogenesis hsa00010
2 Citrate cycle (TCA cycle) hsa00020
3 Pyruvate metabolism hsa00620

GO Terms for Dihydrolipoamide Dehydrogenase Deficiency

Sources for Dihydrolipoamide Dehydrogenase Deficiency

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
16 ExPASy
18 FMA
27 GO
28 GTR
29 HGMD
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 MedGen
41 MeSH
42 MESH via Orphanet
43 MGI
45 NCI
46 NCIt
47 NDF-RT
50 NINDS
51 Novoseek
53 OMIM
54 OMIM via Orphanet
58 PubMed
60 QIAGEN
65 SNOMED-CT via HPO
66 SNOMED-CT via Orphanet
67 TGDB
68 Tocris
69 UMLS
70 UMLS via Orphanet
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