HGCLAS
MCID: HYP719
MIFTS: 30

Hyperglycinemia, Lactic Acidosis, and Seizures (HGCLAS)

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

Aliases & Classifications for Hyperglycinemia, Lactic Acidosis, and Seizures

MalaCards integrated aliases for Hyperglycinemia, Lactic Acidosis, and Seizures:

Name: Hyperglycinemia, Lactic Acidosis, and Seizures 57 72 36
Pyruvate Dehydrogenase Lipoic Acid Synthetase Deficiency 57 72 29 13 6 39 70
Hgclas 57 72
Pdhld 57 72
Pyruvate Dehydrogenase Lipoic Acid Synthetase Deficiency; Pdhld 57
Lipoic Acid Synthetase Deficiency 58

Characteristics:

Orphanet epidemiological data:

58
lipoic acid synthetase deficiency
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Neonatal; Age of death: early childhood;

OMIM®:

57 (Updated 05-Apr-2021)
Inheritance:
autosomal recessive

Miscellaneous:
severe disorder
onset in first days of life
metabolic decompensation, episodic
four patients from 3 families have been reported (last curated march 2016)


HPO:

31
hyperglycinemia, lactic acidosis, and seizures:
Inheritance autosomal recessive inheritance


Classifications:

Orphanet: 58  
Rare neurological diseases
Inborn errors of metabolism


Summaries for Hyperglycinemia, Lactic Acidosis, and Seizures

OMIM® : 57 Hyperglycinemia, lactic acidosis, and seizures is a severe autosomal recessive disorder characterized by onset of hypotonia and seizures associated with increased serum glycine and lactate in the first days of life. Affected individuals develop an encephalopathy or severely delayed psychomotor development, which may result in death in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including HGCLAS, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014). (614462) (Updated 05-Apr-2021)

MalaCards based summary : Hyperglycinemia, Lactic Acidosis, and Seizures, also known as pyruvate dehydrogenase lipoic acid synthetase deficiency, is related to lipoic acid synthetase deficiency and dihydrolipoamide dehydrogenase deficiency, and has symptoms including seizures, myoclonus and apnea. An important gene associated with Hyperglycinemia, Lactic Acidosis, and Seizures is LIAS (Lipoic Acid Synthetase), and among its related pathways/superpathways is Lipoic acid metabolism. Related phenotypes are leukodystrophy and cerebral atrophy

KEGG : 36 Hyperglycinemia, lactic acidosis, and seizures (HGCLAS) is characterized by neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine. Mutations in the lipoate synthase gene (LIAS) have been identified in patients with HGCLAS. LIAS is essential in the maturation of lipoic acid which acts as cofactor for mitochondrial enzymes.

UniProtKB/Swiss-Prot : 72 Hyperglycinemia, lactic acidosis, and seizures: An enzymatic defect resulting in an autosomal recessive disorder of mitochondrial metabolism. It is characterized by early-onset lactic acidosis, severe encephalomyopathy, and a pyruvate oxidation defect. Affected individuals have neonatal-onset epilepsy, poor growth, psychomotor retardation, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine.

Related Diseases for Hyperglycinemia, Lactic Acidosis, and Seizures

Diseases related to Hyperglycinemia, Lactic Acidosis, and Seizures via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 lipoic acid synthetase deficiency 11.7
2 dihydrolipoamide dehydrogenase deficiency 10.1
3 epilepsy 10.1
4 lactic acidosis 10.1
5 hypotonia 10.1

Graphical network of the top 20 diseases related to Hyperglycinemia, Lactic Acidosis, and Seizures:



Diseases related to Hyperglycinemia, Lactic Acidosis, and Seizures

Symptoms & Phenotypes for Hyperglycinemia, Lactic Acidosis, and Seizures

Human phenotypes related to Hyperglycinemia, Lactic Acidosis, and Seizures:

31 (show all 20)
# Description HPO Frequency HPO Source Accession
1 leukodystrophy 31 occasional (7.5%) HP:0002415
2 cerebral atrophy 31 occasional (7.5%) HP:0002059
3 sleep disturbance 31 HP:0002360
4 respiratory insufficiency 31 HP:0002093
5 microcephaly 31 HP:0000252
6 flexion contracture 31 HP:0001371
7 spastic tetraplegia 31 HP:0002510
8 myoclonus 31 HP:0001336
9 growth delay 31 HP:0001510
10 hypertrophic cardiomyopathy 31 HP:0001639
11 motor delay 31 HP:0001270
12 increased serum lactate 31 HP:0002151
13 apnea 31 HP:0002104
14 severe global developmental delay 31 HP:0011344
15 profound global developmental delay 31 HP:0012736
16 encephalopathy 31 HP:0001298
17 lactic acidosis 31 HP:0003128
18 feeding difficulties 31 HP:0011968
19 generalized hypotonia 31 HP:0001290
20 seizure 31 HP:0001250

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Neurologic Central Nervous System:
seizures
spastic tetraplegia
myoclonus
sleep disturbances
cerebral atrophy (in some patients)
more
Head And Neck Head:
microcephaly

Metabolic Features:
lactic acidosis

Growth Other:
poor feeding
poor growth

Cardiovascular Heart:
hypertrophic cardiomyopathy (in some patients)

Respiratory:
respiratory insufficiency
apnea

Laboratory Abnormalities:
increased serum lactate
decreased activity of the pyruvate dehydrogenase (pdh) complex
increased urinary and serum glycine
increased urinary glutaric acid
decreased activity of the glycine cleavage enzyme system

Muscle Soft Tissue:
hypotonia
enlarged mitochondria
biopsy shows defects in pyruvate oxidation
decreased lipoic acid

Skeletal:
contractures

Clinical features from OMIM®:

614462 (Updated 05-Apr-2021)

UMLS symptoms related to Hyperglycinemia, Lactic Acidosis, and Seizures:


seizures; myoclonus; apnea; sleep disturbances

Drugs & Therapeutics for Hyperglycinemia, Lactic Acidosis, and Seizures

Search Clinical Trials , NIH Clinical Center for Hyperglycinemia, Lactic Acidosis, and Seizures

Genetic Tests for Hyperglycinemia, Lactic Acidosis, and Seizures

Genetic tests related to Hyperglycinemia, Lactic Acidosis, and Seizures:

# Genetic test Affiliating Genes
1 Pyruvate Dehydrogenase Lipoic Acid Synthetase Deficiency 29 LIAS

Anatomical Context for Hyperglycinemia, Lactic Acidosis, and Seizures

Publications for Hyperglycinemia, Lactic Acidosis, and Seizures

Articles related to Hyperglycinemia, Lactic Acidosis, and Seizures:

# Title Authors PMID Year
1
Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation. 61 6 57
22152680 2011
2
Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. 57 6
24334290 2014
3
Mitochondrial Protein Lipoylation and the 2-Oxoglutarate Dehydrogenase Complex Controls HIF1α Stability in Aerobic Conditions. 6
27923773 2016
4
Prospective cohort study for identification of underlying genetic causes in neonatal encephalopathy using whole-exome sequencing. 61
28817111 2018

Variations for Hyperglycinemia, Lactic Acidosis, and Seizures

ClinVar genetic disease variations for Hyperglycinemia, Lactic Acidosis, and Seizures:

6 (show top 50) (show all 130)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 LIAS NM_006859.4(LIAS):c.664_665delinsTA (p.Ala222Ter) Indel Pathogenic 936919 GRCh37: 4:39469193-39469194
GRCh38: 4:39467573-39467574
2 LIAS NM_006859.4(LIAS):c.440dup (p.Thr148fs) Duplication Pathogenic 937476 GRCh37: 4:39466710-39466711
GRCh38: 4:39465090-39465091
3 LIAS NM_006859.4(LIAS):c.645T>A (p.Asp215Glu) SNV Pathogenic 224602 rs869312808 GRCh37: 4:39469174-39469174
GRCh38: 4:39467554-39467554
4 LIAS NM_006859.4(LIAS):c.475_477delinsAAA (p.Glu159Lys) Indel Pathogenic 224601 rs869320760 GRCh37: 4:39466747-39466749
GRCh38: 4:39465127-39465129
5 LIAS NM_006859.4(LIAS):c.64dup (p.Cys22fs) Duplication Pathogenic 540088 rs960319940 GRCh37: 4:39462423-39462424
GRCh38: 4:39460803-39460804
6 LIAS NM_006859.4(LIAS):c.363del (p.Glu122fs) Deletion Pathogenic 540089 rs1553934199 GRCh37: 4:39465195-39465195
GRCh38: 4:39463575-39463575
7 LIAS NM_006859.4(LIAS):c.266dup (p.Asn89fs) Duplication Pathogenic 951412 GRCh37: 4:39463858-39463859
GRCh38: 4:39462238-39462239
8 LIAS NM_006859.4(LIAS):c.277del (p.Lys92_Leu93insTer) Deletion Pathogenic 523916 rs1553934069 GRCh37: 4:39463874-39463874
GRCh38: 4:39462254-39462254
9 LIAS NM_006859.4(LIAS):c.212del (p.Gly71fs) Deletion Pathogenic 940068 GRCh37: 4:39462575-39462575
GRCh38: 4:39460955-39460955
10 LIAS NM_006859.4(LIAS):c.643del (p.Asp215fs) Deletion Likely pathogenic 930324 GRCh37: 4:39469172-39469172
GRCh38: 4:39467552-39467552
11 LIAS NM_006859.4(LIAS):c.587C>A (p.Thr196Asn) SNV Likely pathogenic 978713 GRCh37: 4:39466941-39466941
GRCh38: 4:39465321-39465321
12 LIAS NM_006859.4(LIAS):c.1063G>C (p.Ala355Pro) SNV Likely pathogenic 978714 GRCh37: 4:39474828-39474828
GRCh38: 4:39473208-39473208
13 LIAS NM_006859.4(LIAS):c.737+1G>A SNV Likely pathogenic 572236 rs546751789 GRCh37: 4:39469267-39469267
GRCh38: 4:39467647-39467647
14 LIAS NM_006859.4(LIAS):c.393+4G>A SNV Conflicting interpretations of pathogenicity 384227 rs368453789 GRCh37: 4:39465229-39465229
GRCh38: 4:39463609-39463609
15 LIAS NM_006859.4(LIAS):c.877A>G (p.Met293Val) SNV Uncertain significance 594895 rs943564525 GRCh37: 4:39471778-39471778
GRCh38: 4:39470158-39470158
16 LIAS NM_006859.4(LIAS):c.152G>A (p.Gly51Asp) SNV Uncertain significance 1030163 GRCh37: 4:39462516-39462516
GRCh38: 4:39460896-39460896
17 LIAS NM_006859.4(LIAS):c.76A>G (p.Arg26Gly) SNV Uncertain significance 1030164 GRCh37: 4:39462440-39462440
GRCh38: 4:39460820-39460820
18 LIAS NM_006859.4(LIAS):c.943C>T (p.Arg315Cys) SNV Uncertain significance 1036174 GRCh37: 4:39472915-39472915
GRCh38: 4:39471295-39471295
19 LIAS NM_006859.4(LIAS):c.242A>G (p.Lys81Arg) SNV Uncertain significance 1037491 GRCh37: 4:39463839-39463839
GRCh38: 4:39462219-39462219
20 LIAS NM_006859.4(LIAS):c.788A>G (p.Lys263Arg) SNV Uncertain significance 1039917 GRCh37: 4:39471689-39471689
GRCh38: 4:39470069-39470069
21 LIAS NC_000004.11:g.(?_39460738)_(39478735_?)dup Duplication Uncertain significance 1040780 GRCh37: 4:39460738-39478735
GRCh38:
22 LIAS NM_006859.4(LIAS):c.313G>A (p.Val105Ile) SNV Uncertain significance 1042630 GRCh37: 4:39465145-39465145
GRCh38: 4:39463525-39463525
23 LIAS NM_006859.4(LIAS):c.391A>G (p.Met131Val) SNV Uncertain significance 1045017 GRCh37: 4:39465223-39465223
GRCh38: 4:39463603-39463603
24 LIAS NM_006859.4(LIAS):c.988T>C (p.Tyr330His) SNV Uncertain significance 1046322 GRCh37: 4:39474753-39474753
GRCh38: 4:39473133-39473133
25 LIAS NM_006859.4(LIAS):c.56G>C (p.Arg19Thr) SNV Uncertain significance 945963 GRCh37: 4:39462420-39462420
GRCh38: 4:39460800-39460800
26 LIAS NM_006859.4(LIAS):c.746G>A (p.Arg249His) SNV Uncertain significance 30629 rs144133667 GRCh37: 4:39471647-39471647
GRCh38: 4:39470027-39470027
27 LIAS NM_006859.4(LIAS):c.348G>C (p.Glu116Asp) SNV Uncertain significance 958190 GRCh37: 4:39465180-39465180
GRCh38: 4:39463560-39463560
28 LIAS NM_006859.4(LIAS):c.833T>C (p.Ile278Thr) SNV Uncertain significance 999890 GRCh37: 4:39471734-39471734
GRCh38: 4:39470114-39470114
29 LIAS NM_006859.4(LIAS):c.930G>A (p.Met310Ile) SNV Uncertain significance 206041 rs796052700 GRCh37: 4:39472902-39472902
GRCh38: 4:39471282-39471282
30 LIAS NM_006859.4(LIAS):c.883G>A (p.Ala295Thr) SNV Uncertain significance 1003576 GRCh37: 4:39471784-39471784
GRCh38: 4:39470164-39470164
31 LIAS NM_006859.4(LIAS):c.1037G>A (p.Gly346Asp) SNV Uncertain significance 1005537 GRCh37: 4:39474802-39474802
GRCh38: 4:39473182-39473182
32 LIAS NM_006859.4(LIAS):c.89C>T (p.Ser30Phe) SNV Uncertain significance 206043 rs796052701 GRCh37: 4:39462453-39462453
GRCh38: 4:39460833-39460833
33 LIAS NM_006859.4(LIAS):c.101A>G (p.Lys34Arg) SNV Uncertain significance 1007275 GRCh37: 4:39462465-39462465
GRCh38: 4:39460845-39460845
34 LIAS NM_006859.4(LIAS):c.917T>C (p.Leu306Ser) SNV Uncertain significance 1008690 GRCh37: 4:39472889-39472889
GRCh38: 4:39471269-39471269
35 LIAS NM_006859.4(LIAS):c.163G>A (p.Asp55Asn) SNV Uncertain significance 1010805 GRCh37: 4:39462527-39462527
GRCh38: 4:39460907-39460907
36 LIAS NM_006859.4(LIAS):c.399G>A (p.Met133Ile) SNV Uncertain significance 1010844 GRCh37: 4:39466671-39466671
GRCh38: 4:39465051-39465051
37 LIAS NM_006859.4(LIAS):c.120G>T (p.Gln40His) SNV Uncertain significance 472877 rs1041843537 GRCh37: 4:39462484-39462484
GRCh38: 4:39460864-39460864
38 LIAS NM_006859.4(LIAS):c.637A>G (p.Thr213Ala) SNV Uncertain significance 206048 rs374709255 GRCh37: 4:39469166-39469166
GRCh38: 4:39467546-39467546
39 LOC112939935 , LIAS NM_006859.4(LIAS):c.11G>T (p.Arg4Leu) SNV Uncertain significance 859391 GRCh37: 4:39460748-39460748
GRCh38: 4:39459128-39459128
40 LOC112939935 , LIAS NM_006859.4(LIAS):c.14G>C (p.Cys5Ser) SNV Uncertain significance 933263 GRCh37: 4:39460751-39460751
GRCh38: 4:39459131-39459131
41 LIAS NM_006859.4(LIAS):c.542A>T (p.Asp181Val) SNV Uncertain significance 206047 rs796052704 GRCh37: 4:39466814-39466814
GRCh38: 4:39465194-39465194
42 LIAS NM_006859.4(LIAS):c.779G>A (p.Arg260His) SNV Uncertain significance 938088 GRCh37: 4:39471680-39471680
GRCh38: 4:39470060-39470060
43 LIAS NM_006859.4(LIAS):c.894G>C (p.Glu298Asp) SNV Uncertain significance 944162 GRCh37: 4:39472866-39472866
GRCh38: 4:39471246-39471246
44 LIAS NM_006859.4(LIAS):c.266A>T (p.Asn89Ile) SNV Uncertain significance 944532 GRCh37: 4:39463863-39463863
GRCh38: 4:39462243-39462243
45 LIAS NM_006859.4(LIAS):c.616A>G (p.Lys206Glu) SNV Uncertain significance 959459 GRCh37: 4:39469145-39469145
GRCh38: 4:39467525-39467525
46 LIAS NM_006859.4(LIAS):c.1057T>C (p.Tyr353His) SNV Uncertain significance 1019063 GRCh37: 4:39474822-39474822
GRCh38: 4:39473202-39473202
47 LIAS NM_006859.4(LIAS):c.947A>G (p.His316Arg) SNV Uncertain significance 1019462 GRCh37: 4:39472919-39472919
GRCh38: 4:39471299-39471299
48 LIAS NM_006859.4(LIAS):c.50T>C (p.Phe17Ser) SNV Uncertain significance 1021868 GRCh37: 4:39462414-39462414
GRCh38: 4:39460794-39460794
49 LIAS NM_006859.4(LIAS):c.1065A>T (p.Ala355=) SNV Uncertain significance 1024027 GRCh37: 4:39474830-39474830
GRCh38: 4:39473210-39473210
50 LOC112939935 , LIAS NM_006859.4(LIAS):c.15C>G (p.Cys5Trp) SNV Uncertain significance 1024031 GRCh37: 4:39460752-39460752
GRCh38: 4:39459132-39459132

UniProtKB/Swiss-Prot genetic disease variations for Hyperglycinemia, Lactic Acidosis, and Seizures:

72
# Symbol AA change Variation ID SNP ID
1 LIAS p.Arg249His VAR_067839 rs144133667

Expression for Hyperglycinemia, Lactic Acidosis, and Seizures

Search GEO for disease gene expression data for Hyperglycinemia, Lactic Acidosis, and Seizures.

Pathways for Hyperglycinemia, Lactic Acidosis, and Seizures

Pathways related to Hyperglycinemia, Lactic Acidosis, and Seizures according to KEGG:

36
# Name Kegg Source Accession
1 Lipoic acid metabolism hsa00785

GO Terms for Hyperglycinemia, Lactic Acidosis, and Seizures

Sources for Hyperglycinemia, Lactic Acidosis, and Seizures

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 05-Apr-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
Content
Loading form....