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Lipoic acid synthetase deficiency(PDHLD; HGCLAS)

MedGen UID:
482517
Concept ID:
C3280887
Disease or Syndrome
Synonyms: HYPERGLYCINEMIA, LACTIC ACIDOSIS, AND SEIZURES; Pyruvate dehydrogenase lipoic acid synthetase deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): LIAS (4p14)
 
Monarch Initiative: MONDO:0013762
OMIM®: 614462
Orphanet: ORPHA401859

Definition

Hyperglycinemia, lactic acidosis, and seizures (HGCLAS) 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). [from OMIM]

Clinical features

From HPO
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Cerebral edema
MedGen UID:
2337
Concept ID:
C0006114
Pathologic Function
Abnormal accumulation of fluid in the brain.
Leukodystrophy
MedGen UID:
6070
Concept ID:
C0023520
Disease or Syndrome
Leukodystrophy refers to deterioration of white matter of the brain resulting from degeneration of myelin sheaths in the CNS. Their basic defect is directly related to the synthesis and maintenance of myelin membranes. Symmetric white matter involvement at MRI is a typical finding in patients with leukodystrophies.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Sleep abnormality
MedGen UID:
52372
Concept ID:
C0037317
Finding
An abnormal pattern in the quality, quantity, or characteristics of sleep.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Joint contracture
MedGen UID:
3228
Concept ID:
C0009918
Anatomical Abnormality
A limitation in the passive range of motion of a joint resulting from loss of elasticity in the periarticular tissues owing to structural changes of non-bony tissues, such as muscles, tendons, ligaments, joint capsules or skin. A contracture prevents movement of the associated body part.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
Reduced tissue glycine cleavage enzyme activity
MedGen UID:
1053784
Concept ID:
CN377977
Finding
Concentration or activity of the glycine cleavage enzyme below the lower limit of normal. This enzyme can be measured in multiple tissues including leukocytes and cultured fibroblasts.
Decreased activity of the pyruvate dehydrogenase complex
MedGen UID:
326605
Concept ID:
C1839888
Finding

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVLipoic acid synthetase deficiency
Follow this link to review classifications for Lipoic acid synthetase deficiency in Orphanet.

Recent clinical studies

Etiology

Paredes F, Sheldon K, Lassègue B, Williams HC, Faidley EA, Benavides GA, Torres G, Sanhueza-Olivares F, Yeligar SM, Griendling KK, Darley-Usmar V, San Martin A
Proc Natl Acad Sci U S A 2018 Feb 20;115(8):1789-1794. Epub 2018 Feb 6 doi: 10.1073/pnas.1720693115. PMID: 29434038Free PMC Article
Mayr JA, Zimmermann FA, Fauth C, Bergheim C, Meierhofer D, Radmayr D, Zschocke J, Koch J, Sperl W
Am J Hum Genet 2011 Dec 9;89(6):792-7. doi: 10.1016/j.ajhg.2011.11.011. PMID: 22152680Free PMC Article
Atamna H
Ageing Res Rev 2004 Jul;3(3):303-18. doi: 10.1016/j.arr.2004.02.002. PMID: 15231238

Diagnosis

Paredes F, Sheldon K, Lassègue B, Williams HC, Faidley EA, Benavides GA, Torres G, Sanhueza-Olivares F, Yeligar SM, Griendling KK, Darley-Usmar V, San Martin A
Proc Natl Acad Sci U S A 2018 Feb 20;115(8):1789-1794. Epub 2018 Feb 6 doi: 10.1073/pnas.1720693115. PMID: 29434038Free PMC Article
Bruun TUJ, DesRoches CL, Wilson D, Chau V, Nakagawa T, Yamasaki M, Hasegawa S, Fukao T, Marshall C, Mercimek-Andrews S
Genet Med 2018 Apr;20(5):486-494. Epub 2017 Aug 17 doi: 10.1038/gim.2017.129. PMID: 28817111
Mayr JA, Zimmermann FA, Fauth C, Bergheim C, Meierhofer D, Radmayr D, Zschocke J, Koch J, Sperl W
Am J Hum Genet 2011 Dec 9;89(6):792-7. doi: 10.1016/j.ajhg.2011.11.011. PMID: 22152680Free PMC Article

Therapy

Zuo L, Motherwell MS
Gene 2013 Dec 10;532(1):18-23. Epub 2013 Aug 15 doi: 10.1016/j.gene.2013.07.085. PMID: 23954870

Prognosis

Eidi M, Garshasbi M
BMC Neurol 2019 Jul 6;19(1):153. doi: 10.1186/s12883-019-1387-2. PMID: 31279336Free PMC Article
Mayr JA, Zimmermann FA, Fauth C, Bergheim C, Meierhofer D, Radmayr D, Zschocke J, Koch J, Sperl W
Am J Hum Genet 2011 Dec 9;89(6):792-7. doi: 10.1016/j.ajhg.2011.11.011. PMID: 22152680Free PMC Article

Clinical prediction guides

Eidi M, Garshasbi M
BMC Neurol 2019 Jul 6;19(1):153. doi: 10.1186/s12883-019-1387-2. PMID: 31279336Free PMC Article
Paredes F, Sheldon K, Lassègue B, Williams HC, Faidley EA, Benavides GA, Torres G, Sanhueza-Olivares F, Yeligar SM, Griendling KK, Darley-Usmar V, San Martin A
Proc Natl Acad Sci U S A 2018 Feb 20;115(8):1789-1794. Epub 2018 Feb 6 doi: 10.1073/pnas.1720693115. PMID: 29434038Free PMC Article
Habarou F, Hamel Y, Haack TB, Feichtinger RG, Lebigot E, Marquardt I, Busiah K, Laroche C, Madrange M, Grisel C, Pontoizeau C, Eisermann M, Boutron A, Chrétien D, Chadefaux-Vekemans B, Barouki R, Bole-Feysot C, Nitschke P, Goudin N, Boddaert N, Nemazanyy I, Delahodde A, Kölker S, Rodenburg RJ, Korenke GC, Meitinger T, Strom TM, Prokisch H, Rotig A, Ottolenghi C, Mayr JA, de Lonlay P
Am J Hum Genet 2017 Aug 3;101(2):283-290. Epub 2017 Jul 27 doi: 10.1016/j.ajhg.2017.07.001. PMID: 28757203Free PMC Article

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