Lipoic Acid Synthetase Deficiency

👪

Inheritance

1

Autosomal recessive HP:0000007

LIAS deficiency follows autosomal recessive inheritance with biallelic loss-of-function mutations in LIAS.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:22152680 SUPPORT Human Clinical

"We identified the homozygous mutation c.746G>A (p.Arg249His) in LIAS in an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine. "

The index case demonstrates autosomal recessive inheritance with a homozygous missense mutation in LIAS.

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Pathophysiology

4

Defective lipoic acid synthesis via LIAS deficiency

LIAS encodes lipoic acid synthetase, a mitochondrial iron-sulfur cluster enzyme that inserts two sulfur atoms into octanoyl-GCSH to generate lipoyl-GCSH. This is the second step in the lipoylation pathway, after LIPT2-mediated octanoyl transfer and before LIPT1-mediated lipoyl relay to the E2 subunits of alpha-ketoacid dehydrogenases. LIAS deficiency, like LIPT2 deficiency, abolishes lipoylation of all downstream targets including the glycine cleavage system. This disrupts pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, branched-chain ketoacid dehydrogenase, and glycine cleavage, causing combined lactic acidosis and hyperglycinemia.

Neuron link

LIAS link

lipoate biosynthetic process link ↓ DECREASED protein lipoylation link ↓ DECREASED

lipoate synthase activity link ↓ DECREASED

mitochondrion link

Downstream

Combined alpha-ketoacid dehydrogenase deficiency Loss of LIAS-dependent lipoylation impairs pyruvate, alpha-ketoglutarate, and branched-chain ketoacid dehydrogenase complexes.

Glycine cleavage system dysfunction LIAS loss reduces lipoate-dependent glycine cleavage activity, producing the variant nonketotic hyperglycinemia branch of the disease.

Show evidence (2 references)

PMID:22152680 SUPPORT In Vitro

"Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate and decreased pyruvate dehydrogenase complex activity. A pronounced reduction of the prosthetic group lipoamide was found in lipoylated proteins. "

Patient fibroblasts showed reduced PDH activity and decreased lipoylation, confirming that LIAS loss of function impairs the lipoylation pathway.

PMID:32508887 SUPPORT Other

"LIAS was the sulfur insertion enzyme "

Review establishes that LIAS is the enzyme responsible for inserting sulfur atoms into octanoyl-GCSH during lipoic acid assembly.

Combined alpha-ketoacid dehydrogenase deficiency

LIAS deficiency reduces lipoylation of alpha-ketoacid dehydrogenase complexes, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched-chain ketoacid dehydrogenase. Impaired PDHc diverts pyruvate toward lactate, while impaired TCA-cycle entry and flux produce mitochondrial energy failure in high-demand tissues.

Tricarboxylic acid cycle link ↓ DECREASED pyruvate decarboxylation to acetyl-CoA link ↓ DECREASED branched-chain amino acid catabolic process link ↓ DECREASED

Pyruvate dehydrogenase complex link

Downstream

Lactic acidosis Reduced pyruvate dehydrogenase flux causes pyruvate accumulation and lactate production.

Neonatal hypotonia Mitochondrial energy failure and muscle weakness contribute to neonatal hypotonia.

Respiratory insufficiency Impaired TCA-cycle energy metabolism is associated with severe respiratory deficiency in lipoate-assembly disorders.

Failure to thrive Severe respiratory deficiency, extreme muscle weakness, and impaired energy metabolism contribute to poor growth and failure to thrive in severe neonatal LIAS disease.

Show evidence (3 references)

PMID:22152680 SUPPORT In Vitro

"Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate and decreased pyruvate dehydrogenase complex activity."

Demonstrates impaired pyruvate oxidation and PDH complex activity in LIAS-deficient patient cells.

PMID:32508887 SUPPORT Other

"Patients that display absent or low lipoylation of all three enzymes have mutations in either of two genes LIAS or LIPT2"

Review supports impaired lipoylation across lipoate-dependent enzyme complexes in LIAS/LIPT2 disease.

PMID:32508887 SUPPORT Other

"The loss of these two dehydrogenases short-circuits the citric acid cycle, resulting in severe respiratory deficiency and extreme muscle weakness"

Review explains why loss of lipoate-dependent PDH and alpha-KGDH disrupts the TCA cycle and causes energy failure.

Glycine cleavage system dysfunction

LIAS deficiency also reduces lipoylation of the glycine cleavage system H protein, impairing glycine cleavage activity. This produces elevated serum and cerebrospinal-fluid glycine and separates LIAS deficiency from LIPT1 deficiency, where GCSH lipoylation is spared.

glycine catabolic process link ↓ DECREASED

Glycine cleavage complex link

Downstream

Hyperglycinemia Reduced glycine cleavage causes systemic glycine accumulation.

Brain glycine accumulation and encephalopathy Glycine cleavage failure can raise brain glycine and drive neurologic toxicity.

Show evidence (2 references)

PMID:24334290 SUPPORT In Vitro

"deficient glycine cleavage enzyme activity. "

Variant nonketotic hyperglycinemia cases, including LIAS cases, had deficient glycine cleavage activity.

PMID:32508887 SUPPORT Other

"Normal glycine levels demonstrate that the glycine cleavage system is functional whereas abnormally high glycine levels indicate that glycine cleavage is defective."

Review explains why high glycine indicates defective glycine cleavage in lipoic-acid metabolism disorders.

Brain glycine accumulation and encephalopathy

Elevated brain glycine from impaired glycine cleavage contributes to the neurologic branch of LIAS deficiency, including neonatal-onset epilepsy, encephalopathy, and neurodegeneration.

brain development link ⚠ ABNORMAL

brain link

Downstream

Seizures Brain glycine accumulation and encephalopathy are associated with neonatal-onset epilepsy in lipoate-assembly disorders.

Global developmental delay Encephalopathy and neurodegeneration impair early neurodevelopment.

Cerebral atrophy Elevated brain glycine can drive neurodegeneration and encephalopathy; reported LIAS cases include cortical involvement, providing the structural CNS branch for cerebral atrophy.

Show evidence (2 references)

PMID:32508887 SUPPORT Other

"Lack of glycine cleavage activity additionally results in elevated brain glycine levels which can result in a host of neurological disorders, including neurodegeneration, encephalopathy, and neonatal-onset epilepsy"

Review supports the neurologic consequences of brain glycine accumulation in lipoylation disorders.

PMID:24334290 SUPPORT Human Clinical

"Patients with lipoate synthase-deficient variant nonketotic hyperglycinemia varied in severity from mild static encephalopathy to Leigh disease and cortical involvement."

Human LIAS cases show encephalopathy, Leigh disease, and cortical involvement.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Head and Neck 1

Microcephaly Microcephaly (HP:0000252)

Metabolism 2

Lactic acidosis Congenital lactic acidosis (HP:0004902)

Show evidence (2 references)

PMID:22152680 SUPPORT Human Clinical

"an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine "

Lactic acidosis was a cardinal biochemical finding in the index LIAS-deficient patient.

PMID:24334290 PARTIAL Human Clinical

"They had low pyruvate dehydrogenase enzyme activity but most did not have lactic acidosis. "

In the Baker et al. cohort, most LIAS patients had low PDH activity but lactic acidosis was not consistently present, suggesting variable severity.

Hyperglycinemia OBLIGATE Hyperglycinemia (HP:0002154)

Show evidence (2 references)

PMID:22152680 SUPPORT Human Clinical

"elevated glycine concentration in plasma and urine "

The index patient had elevated glycine in both plasma and urine, consistent with impaired glycine cleavage system function.

PMID:24334290 SUPPORT Human Clinical

"All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio "

In the Baker et al. cohort, all variant NKH patients including those with LIAS mutations had elevated glycine.

Musculoskeletal 1

Neonatal hypotonia VERY_FREQUENT Neonatal hypotonia (HP:0001319)

Show evidence (1 reference)

PMID:22152680 SUPPORT Human Clinical

"an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine "

The index patient presented with muscular hypotonia as one of the cardinal features of LIAS deficiency.

Nervous System 3

Seizures OBLIGATE Seizure (HP:0001250)

Show evidence (2 references)

PMID:22152680 SUPPORT Human Clinical

"an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine "

The index LIAS-deficient patient presented with neonatal-onset epilepsy as a prominent clinical feature.

PMID:24334290 SUPPORT Human Clinical

"Patients with lipoate synthase-deficient variant nonketotic hyperglycinemia varied in severity from mild static encephalopathy to Leigh disease and cortical involvement. "

Baker et al. confirm seizures and encephalopathy as features of LIAS deficiency across a wider spectrum of severity.

Global developmental delay OBLIGATE Profound global developmental delay (HP:0012736)

Show evidence (1 reference)

PMID:24334290 SUPPORT Human Clinical

"Patients with lipoate synthase-deficient variant nonketotic hyperglycinemia varied in severity from mild static encephalopathy to Leigh disease and cortical involvement. "

Baker et al. describe a range of severity in LIAS patients from mild encephalopathy to Leigh disease, confirming neurodevelopmental impairment as a consistent feature.

Cerebral atrophy Cerebral atrophy (HP:0002059)

Show evidence (1 reference)

PMID:24334290 PARTIAL Human Clinical

"Patients with lipoate synthase-deficient variant nonketotic hyperglycinemia varied in severity from mild static encephalopathy to Leigh disease and cortical involvement."

Baker et al. describe cortical involvement and progression to Leigh disease in LIAS patients; this supports CNS structural involvement but does not specifically establish cerebral atrophy in the cached abstract.

Respiratory 2

Apnea Apnea (HP:0002104)

Respiratory insufficiency Respiratory insufficiency (HP:0002093)

Show evidence (1 reference)

PMID:32508887 PARTIAL Other

"severe respiratory deficiency and extreme muscle weakness due to citric acid cycle disfunction"

Review supports severe respiratory deficiency in LIAS/LIPT2 lipoylation defects, though this is a general lipoylation-disorder statement rather than a LIAS-only patient series.

Growth 1

Failure to thrive Failure to thrive (HP:0001508)

Show evidence (1 reference)

PMID:32508887 PARTIAL Other

"severe respiratory deficiency and extreme muscle weakness due to citric acid cycle disfunction plus the neurological impairments caused by glycine accumulation in the brain"

The combined respiratory deficiency, muscle weakness, and neurological impairment described in LIAS patients contributes to failure to thrive.

🧬

Genetic Associations

1

LIAS loss-of-function variants (Causative)

Show evidence (3 references)

PMID:22152680 SUPPORT Human Clinical

"We identified the homozygous mutation c.746G>A (p.Arg249His) in LIAS in an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine. "

First report of a causal LIAS mutation: homozygous c.746G>A (p.Arg249His) in the index patient.

PMID:24334290 SUPPORT Human Clinical

"Mutations were identified in the genes for lipoate synthase (LIAS), BolA type 3 (BOLA3), and a novel gene glutaredoxin 5 (GLRX5). "

Baker et al. identified additional LIAS mutations in a larger cohort of variant NKH patients, confirming LIAS as a causal gene.

PMID:24334290 SUPPORT In Vitro

"transfection with native genes corrected the biochemical deficiency proving pathogenicity. "

Functional validation by gene complementation confirmed that the identified LIAS mutations were pathogenic.

💊

Treatments

2

Supportive care

Action: supportive care MAXO:0000950

Management is primarily supportive with anticonvulsant therapy and nutritional support. Lipoic acid supplementation is ineffective as the defect lies in the de novo synthesis pathway and exogenous lipoic acid cannot be incorporated into the mitochondrial lipoylation pathway.

Show evidence (2 references)

PMID:24334290 SUPPORT In Vitro

"Treatments of cells with lipoate and with mitochondrially-targeted lipoate were unsuccessful at correcting the deficiency. "

Baker et al. demonstrated that lipoic acid supplementation, even with mitochondrially-targeted forms, failed to correct the biochemical deficiency in patient cells, supporting the need for purely supportive care.

PMID:32508887 SUPPORT Other

"lipoic acid supplementation of the diets of human LIAS, LIPT1, and LIPT2 patients or of their fibroblast cultures failed to alleviate the physiological and biochemical effects of the mutant genes "

Review confirms that lipoic acid supplementation is ineffective in LIAS patients, as exogenous lipoate cannot enter the mitochondrial de novo synthesis pathway.

Engineered bacterial lipoate ligase (experimental)

Action: Pharmacotherapy NCIT:C15986

An engineered mitochondrially-targeted bacterial lipoate protein ligase A (lplA) has been shown to restore lipoylation in LIAS-deficient cell models. This approach bypasses the defective de novo synthesis pathway by allowing cells to utilize exogenous lipoic acid through the bacterial salvage enzyme. This has only been demonstrated in cell models and is not yet available as a clinical therapy.

Show evidence (1 reference)

PMID:39547509 SUPPORT In Vitro

"This synthetic approach offers a potential therapeutic strategy for treating lipoylation disorders."

Bick et al. demonstrated that engineered bacterial lplA could restore lipoylation in LIAS knockout cell models, providing proof of concept for a therapeutic bypass of the defective de novo synthesis pathway.

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Biochemical Markers

4

Lipoylated mitochondrial proteins (DECREASED)

Context: LIAS deficiency reduces the lipoamide prosthetic group on mitochondrial proteins that require lipoate for activity.

Pathograph Readouts

Readout Of Defective lipoic acid synthesis via LIAS deficiency Negative Diagnostic

Reduced lipoamide on mitochondrial proteins reports the proximal LIAS-dependent protein-lipoylation defect.

Show evidence (1 reference)

PMID:22152680 SUPPORT In Vitro

"A pronounced reduction of the prosthetic group lipoamide was found in lipoylated proteins."

Patient fibroblast data directly show reduced lipoamide on lipoylated proteins downstream of LIAS deficiency.

Show evidence (2 references)

PMID:22152680 SUPPORT In Vitro

"A pronounced reduction of the prosthetic group lipoamide was found in lipoylated proteins."

Direct patient-cell evidence for reduced protein lipoylation.

PMID:24334290 SUPPORT In Vitro

"Patients were deficient in lipoylation of mitochondrial proteins."

Variant nonketotic hyperglycinemia cohort supports deficient mitochondrial protein lipoylation.

Pyruvate dehydrogenase activity (DECREASED)

Context: Impaired lipoylation reduces pyruvate dehydrogenase complex activity and limits oxidative pyruvate metabolism.

Pathograph Readouts

Readout Of Combined alpha-ketoacid dehydrogenase deficiency Negative Diagnostic

Reduced pyruvate dehydrogenase activity reports impaired lipoate-dependent alpha-ketoacid dehydrogenase function.

Show evidence (1 reference)

PMID:22152680 SUPPORT In Vitro

"Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate and decreased pyruvate dehydrogenase complex activity."

Direct patient-cell enzymology shows reduced PDH complex activity.

Show evidence (2 references)

PMID:22152680 SUPPORT In Vitro

"Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate and decreased pyruvate dehydrogenase complex activity."

Directly supports reduced PDH activity in the index LIAS patient.

PMID:24334290 SUPPORT In Vitro

"They had low pyruvate dehydrogenase enzyme activity but most did not have lactic acidosis."

Supports reduced PDH activity across lipoate synthase-deficient variant NKH patients.

Glycine (INCREASED)

Context: Elevated plasma, urine, and borderline cerebrospinal-fluid glycine reflect impaired glycine cleavage system activity.

Pathograph Readouts

Readout Of Glycine cleavage system dysfunction Positive Diagnostic

Higher glycine reports impaired lipoate-dependent glycine cleavage activity.

Show evidence (1 reference)

PMID:24334290 SUPPORT Human Clinical

"All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio"

Human LIAS/lipoate-synthase deficient cases show elevated glycine in serum and borderline-elevated CSF.

Show evidence (2 references)

PMID:22152680 SUPPORT Human Clinical

"elevated glycine concentration in plasma and urine"

Supports increased glycine as a biochemical hallmark in the index LIAS patient.

PMID:24334290 SUPPORT Human Clinical

"All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio"

Supports elevated glycine in variant NKH patients.

Lactate (INCREASED)

Context: Lactate can rise when PDH dysfunction causes pyruvate accumulation and reduction to lactate, although lactic acidosis is variable in reported LIAS cases.

Pathograph Readouts

Readout Of Combined alpha-ketoacid dehydrogenase deficiency Positive Diagnostic

Higher lactate reports pyruvate diversion caused by impaired lipoate-dependent PDH activity.

Show evidence (1 reference)

PMID:32508887 SUPPORT Other

"the presence of very high levels of lactate (resulting from reduction of the pyruvate that accumulates due to loss pyruvate dehydrogenase activity)"

Review evidence explains why impaired lipoate-dependent PDH activity raises lactate.

Show evidence (2 references)

PMID:22152680 SUPPORT Human Clinical

"lactic acidosis, and elevated glycine concentration in plasma and urine"

The index patient had lactic acidosis.

PMID:24334290 PARTIAL Human Clinical

"They had low pyruvate dehydrogenase enzyme activity but most did not have lactic acidosis."

Supports reduced PDH activity while documenting that lactic acidosis is not universal.

{ }

Source YAML

click to show

name: Lipoic Acid Synthetase Deficiency
creation_date: '2026-02-13T00:59:22Z'
updated_date: "2026-05-19T16:21:31Z"
category: Mendelian
description: >
  Lipoic acid synthetase deficiency (OMIM 614462), also known as hyperglycinemia
  with lactic acidosis and seizures (HGCLAS), is a rare autosomal recessive
  mitochondrial disorder caused by biallelic mutations in LIAS, encoding lipoic
  acid synthetase. LIAS catalyzes the insertion of sulfur atoms into octanoyl-GCSH
  to form lipoyl-GCSH, the second step in the mitochondrial lipoylation pathway.
  Loss of function impairs lipoylation of all lipoic acid-dependent enzyme
  complexes: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase,
  branched-chain ketoacid dehydrogenase, and the glycine cleavage system. The
  biochemical signature is identical to LIPT2 deficiency (NELABA), with lactic
  acidosis, hyperglycinemia, and combined dehydrogenase deficiency. Clinical
  features include neonatal-onset seizures, severe encephalopathy, hypotonia,
  and failure to thrive. Brain MRI shows cerebral atrophy and white matter
  abnormalities.
disease_term:
  preferred_term: lipoic acid synthetase deficiency
  term:
    id: MONDO:0013762
    label: lipoic acid synthetase deficiency
parents:
- Mitochondrial lipoylation defect
- Neonatal encephalopathy
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    LIAS deficiency follows autosomal recessive inheritance with biallelic
    loss-of-function mutations in LIAS.
  evidence:
  - reference: PMID:22152680
    reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      We identified the homozygous mutation c.746G>A (p.Arg249His) in
      LIAS in an individual with neonatal-onset epilepsy, muscular hypotonia, lactic
      acidosis, and elevated glycine concentration in plasma and urine.
    explanation: >
      The index case demonstrates autosomal recessive inheritance with a
      homozygous missense mutation in LIAS.
prevalence:
- population: Global reported patients
  percentage: Unknown
  notes: >-
    No population-based prevalence study was identified. The published evidence
    located in PubMed consists of isolated case reports and occasional exome
    sequencing cohort diagnoses, consistent with an ultra-rare disorder.
  evidence:
  - reference: PMID:22152680
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified the homozygous mutation c.746G>A (p.Arg249His) in LIAS in
      an individual with neonatal-onset epilepsy, muscular hypotonia, lactic
      acidosis, and elevated glycine concentration in plasma and urine.
    explanation: >-
      The original LIAS report is a single-patient description, supporting that
      lipoic acid synthetase deficiency is reported mainly through isolated
      cases rather than prevalence studies.
  - reference: PMID:28817111
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We confirmed a genetic diagnosis in five patients (36%): epileptic
      encephalopathy associated with autosomal dominant de novo variants in
      SCN2A (p.Met1545Val), KCNQ2 (p.Asp212Tyr), and GNAO1 (p.Gly40Arg); lipoic
      acid synthetase deficiency due to compound heterozygous variants in LIAS
      (p.Ala253Pro and p.His236Gln); and encephalopathy associated with an
      X-linked variant in CUL4B (p.Asn211Ser).
    explanation: >-
      This prospective neonatal encephalopathy cohort found LIAS deficiency as a
      rare diagnosis within a highly selected exome-sequenced group, reinforcing
      that prevalence remains unknown and extremely low.
pathophysiology:
- name: Defective lipoic acid synthesis via LIAS deficiency
  description: >
    LIAS encodes lipoic acid synthetase, a mitochondrial iron-sulfur cluster
    enzyme that inserts two sulfur atoms into octanoyl-GCSH to generate
    lipoyl-GCSH. This is the second step in the lipoylation pathway, after
    LIPT2-mediated octanoyl transfer and before LIPT1-mediated lipoyl relay to
    the E2 subunits of alpha-ketoacid dehydrogenases. LIAS deficiency, like
    LIPT2 deficiency, abolishes lipoylation of all downstream targets including
    the glycine cleavage system. This disrupts pyruvate dehydrogenase,
    alpha-ketoglutarate dehydrogenase, branched-chain ketoacid dehydrogenase,
    and glycine cleavage, causing combined lactic acidosis and hyperglycinemia.
  genes:
  - preferred_term: LIAS
    term:
      id: hgnc:16429
      label: LIAS
  gene:
    preferred_term: LIAS
    description: Lipoic acid synthetase, inserts sulfur atoms into octanoyl-GCSH to form lipoyl-GCSH in the mitochondrial lipoylation pathway.
    modifier: DECREASED
    term:
      id: hgnc:16429
      label: LIAS
  molecular_functions:
  - preferred_term: lipoate synthase activity
    modifier: DECREASED
    term:
      id: GO:0016992
      label: lipoate synthase activity
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: lipoate biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0009107
      label: lipoate biosynthetic process
  - preferred_term: protein lipoylation
    modifier: DECREASED
    term:
      id: GO:0009249
      label: protein lipoylation
  chemical_entities:
  - preferred_term: lipoic acid
    modifier: DECREASED
    term:
      id: CHEBI:16494
      label: lipoic acid
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  downstream:
  - target: Combined alpha-ketoacid dehydrogenase deficiency
    description: Loss of LIAS-dependent lipoylation impairs pyruvate, alpha-ketoglutarate, and branched-chain ketoacid dehydrogenase complexes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22152680
      reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate and decreased pyruvate dehydrogenase complex activity."
      explanation: Patient fibroblast data directly connect LIAS deficiency to impaired pyruvate oxidation and PDH complex activity.
    - reference: PMID:32508887
      reference_title: "Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Patients that display absent or low lipoylation of all three enzymes have mutations in either of two genes LIAS or LIPT2"
      explanation: Review supports that LIAS mutations can reduce lipoylation across the lipoate-dependent enzyme set, not just PDH.
  - target: Glycine cleavage system dysfunction
    description: LIAS loss reduces lipoate-dependent glycine cleavage activity, producing the variant nonketotic hyperglycinemia branch of the disease.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24334290
      reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "deficient glycine cleavage enzyme activity."
      explanation: Variant nonketotic hyperglycinemia cases with lipoate synthase deficiency show deficient glycine cleavage activity.
  evidence:
  - reference: PMID:22152680
    reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >
      Investigation
      of the mitochondrial energy metabolism showed reduced oxidation of pyruvate
      and
      decreased pyruvate dehydrogenase complex activity. A pronounced reduction of
      the
      prosthetic group lipoamide was found in lipoylated proteins.
    explanation: >
      Patient fibroblasts showed reduced PDH activity and decreased lipoylation,
      confirming that LIAS loss of function impairs the lipoylation pathway.
  - reference: PMID:32508887
    reference_title: "Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >
      LIAS was the sulfur insertion enzyme
    explanation: >
      Review establishes that LIAS is the enzyme responsible for inserting
      sulfur atoms into octanoyl-GCSH during lipoic acid assembly.
- name: Combined alpha-ketoacid dehydrogenase deficiency
  description: >
    LIAS deficiency reduces lipoylation of alpha-ketoacid dehydrogenase
    complexes, including pyruvate dehydrogenase, alpha-ketoglutarate
    dehydrogenase, and branched-chain ketoacid dehydrogenase. Impaired PDHc
    diverts pyruvate toward lactate, while impaired TCA-cycle entry and flux
    produce mitochondrial energy failure in high-demand tissues.
  biological_processes:
  - preferred_term: Tricarboxylic acid cycle
    modifier: DECREASED
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
  - preferred_term: pyruvate decarboxylation to acetyl-CoA
    modifier: DECREASED
    term:
      id: GO:0006086
      label: pyruvate decarboxylation to acetyl-CoA
  - preferred_term: branched-chain amino acid catabolic process
    modifier: DECREASED
    term:
      id: GO:0009083
      label: branched-chain amino acid catabolic process
  cellular_components:
  - preferred_term: Pyruvate dehydrogenase complex
    term:
      id: GO:0045254
      label: pyruvate dehydrogenase complex
  chemical_entities:
  - preferred_term: pyruvate
    modifier: INCREASED
    term:
      id: CHEBI:15361
      label: pyruvate
  - preferred_term: lactate
    modifier: INCREASED
    term:
      id: CHEBI:24996
      label: lactate
  evidence:
  - reference: PMID:22152680
    reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate and decreased pyruvate dehydrogenase complex activity."
    explanation: Demonstrates impaired pyruvate oxidation and PDH complex activity in LIAS-deficient patient cells.
  - reference: PMID:32508887
    reference_title: "Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients that display absent or low lipoylation of all three enzymes have mutations in either of two genes LIAS or LIPT2"
    explanation: Review supports impaired lipoylation across lipoate-dependent enzyme complexes in LIAS/LIPT2 disease.
  - reference: PMID:32508887
    reference_title: "Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The loss of these two dehydrogenases short-circuits the citric acid cycle, resulting in severe respiratory deficiency and extreme muscle weakness"
    explanation: Review explains why loss of lipoate-dependent PDH and alpha-KGDH disrupts the TCA cycle and causes energy failure.
  downstream:
  - target: Lactic acidosis
    description: Reduced pyruvate dehydrogenase flux causes pyruvate accumulation and lactate production.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32508887
      reference_title: "Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "the presence of very high levels of lactate (resulting from reduction of the pyruvate that accumulates due to loss pyruvate dehydrogenase activity)"
      explanation: Review directly links defective lipoic acid metabolism, loss of PDH activity, pyruvate accumulation, and high lactate.
  - target: Neonatal hypotonia
    description: Mitochondrial energy failure and muscle weakness contribute to neonatal hypotonia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - mitochondrial energy failure
    - muscle weakness
  - target: Respiratory insufficiency
    description: Impaired TCA-cycle energy metabolism is associated with severe respiratory deficiency in lipoate-assembly disorders.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - citric acid cycle dysfunction
    - severe respiratory deficiency
  - target: Failure to thrive
    description: Severe respiratory deficiency, extreme muscle weakness, and impaired energy metabolism contribute to poor growth and failure to thrive in severe neonatal LIAS disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - citric acid cycle dysfunction
    - severe respiratory deficiency
    - extreme muscle weakness
    evidence:
    - reference: PMID:32508887
      reference_title: "Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Hence patients defective in either of these genes have undetectable or severely decreased levels of all lipoylated proteins and undergo the severe respiratory deficiency and extreme muscle weakness due to citric acid cycle disfunction plus the neurological impairments caused by glycine accumulation in the brain"
      explanation: The review directly links LIAS/LIPT2 lipoylation defects to respiratory deficiency, extreme muscle weakness, and neurologic impairment, supporting failure to thrive as a downstream systemic consequence.
- name: Glycine cleavage system dysfunction
  description: >
    LIAS deficiency also reduces lipoylation of the glycine cleavage system H
    protein, impairing glycine cleavage activity. This produces elevated serum
    and cerebrospinal-fluid glycine and separates LIAS deficiency from LIPT1
    deficiency, where GCSH lipoylation is spared.
  biological_processes:
  - preferred_term: glycine catabolic process
    modifier: DECREASED
    term:
      id: GO:0006546
      label: glycine catabolic process
  chemical_entities:
  - preferred_term: glycine
    modifier: INCREASED
    term:
      id: CHEBI:15428
      label: glycine
  cellular_components:
  - preferred_term: Glycine cleavage complex
    term:
      id: GO:0005960
      label: glycine cleavage complex
  evidence:
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >
      deficient glycine cleavage enzyme
      activity.
    explanation: >
      Variant nonketotic hyperglycinemia cases, including LIAS cases, had
      deficient glycine cleavage activity.
  - reference: PMID:32508887
    reference_title: "Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Normal glycine levels demonstrate that the glycine cleavage system is functional whereas abnormally high glycine levels indicate that glycine cleavage is defective."
    explanation: >
      Review explains why high glycine indicates defective glycine cleavage
      in lipoic-acid metabolism disorders.
  downstream:
  - target: Hyperglycinemia
    description: Reduced glycine cleavage causes systemic glycine accumulation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24334290
      reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio"
      explanation: Directly supports glycine cleavage dysfunction leading to hyperglycinemia.
  - target: Brain glycine accumulation and encephalopathy
    description: Glycine cleavage failure can raise brain glycine and drive neurologic toxicity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - elevated brain glycine
    evidence:
    - reference: PMID:32508887
      reference_title: "Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Lack of glycine cleavage activity additionally results in elevated brain glycine levels which can result in a host of neurological disorders, including neurodegeneration, encephalopathy, and neonatal-onset epilepsy"
      explanation: Review connects loss of glycine cleavage to brain glycine accumulation and neurologic disease.
- name: Brain glycine accumulation and encephalopathy
  description: >
    Elevated brain glycine from impaired glycine cleavage contributes to the
    neurologic branch of LIAS deficiency, including neonatal-onset epilepsy,
    encephalopathy, and neurodegeneration.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  biological_processes:
  - preferred_term: brain development
    modifier: ABNORMAL
    term:
      id: GO:0007420
      label: brain development
  evidence:
  - reference: PMID:32508887
    reference_title: "Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Lack of glycine cleavage activity additionally results in elevated brain glycine levels which can result in a host of neurological disorders, including neurodegeneration, encephalopathy, and neonatal-onset epilepsy"
    explanation: Review supports the neurologic consequences of brain glycine accumulation in lipoylation disorders.
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with lipoate synthase-deficient variant nonketotic hyperglycinemia varied in severity from mild static encephalopathy to Leigh disease and cortical involvement."
    explanation: Human LIAS cases show encephalopathy, Leigh disease, and cortical involvement.
  downstream:
  - target: Seizures
    description: Brain glycine accumulation and encephalopathy are associated with neonatal-onset epilepsy in lipoate-assembly disorders.
    causal_link_type: DIRECT
  - target: Global developmental delay
    description: Encephalopathy and neurodegeneration impair early neurodevelopment.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - encephalopathy
    - neurodegeneration
  - target: Cerebral atrophy
    description: Elevated brain glycine can drive neurodegeneration and encephalopathy; reported LIAS cases include cortical involvement, providing the structural CNS branch for cerebral atrophy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - elevated brain glycine
    - neurodegeneration
    - cortical involvement
    evidence:
    - reference: PMID:32508887
      reference_title: "Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Lack of glycine cleavage activity additionally results in elevated brain glycine levels which can result in a host of neurological disorders, including neurodegeneration, encephalopathy, and neonatal-onset epilepsy"
      explanation: The review links glycine cleavage failure to elevated brain glycine, neurodegeneration, and encephalopathy.
    - reference: PMID:24334290
      reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with lipoate synthase-deficient variant nonketotic hyperglycinemia varied in severity from mild static encephalopathy to Leigh disease and cortical involvement."
      explanation: Human LIAS cases include cortical involvement, supporting the structural brain-injury branch but not proving cerebral atrophy by itself.
phenotypes:
- name: Seizures
  description: >
    Neonatal-onset epilepsy is a cardinal feature of LIAS deficiency.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:22152680
    reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      an individual with neonatal-onset epilepsy, muscular hypotonia, lactic
      acidosis, and elevated glycine concentration in plasma and urine
    explanation: >
      The index LIAS-deficient patient presented with neonatal-onset epilepsy
      as a prominent clinical feature.
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Patients with lipoate
      synthase-deficient variant nonketotic hyperglycinemia varied in severity from
      mild static encephalopathy to Leigh disease and cortical involvement.
    explanation: >
      Baker et al. confirm seizures and encephalopathy as features of LIAS
      deficiency across a wider spectrum of severity.
- name: Neonatal hypotonia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Neonatal hypotonia
    term:
      id: HP:0001319
      label: Neonatal hypotonia
  evidence:
  - reference: PMID:22152680
    reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      an individual with neonatal-onset epilepsy, muscular hypotonia, lactic
      acidosis, and elevated glycine concentration in plasma and urine
    explanation: >
      The index patient presented with muscular hypotonia as one of the
      cardinal features of LIAS deficiency.
- name: Lactic acidosis
  description: >
    Lactic acidosis results from impaired pyruvate dehydrogenase complex
    activity due to deficient lipoylation. While a cardinal biochemical
    feature, its severity varies across patients.
  phenotype_term:
    preferred_term: Congenital lactic acidosis
    term:
      id: HP:0004902
      label: Congenital lactic acidosis
  evidence:
  - reference: PMID:22152680
    reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      an individual with neonatal-onset epilepsy, muscular hypotonia, lactic
      acidosis, and elevated glycine concentration in plasma and urine
    explanation: >
      Lactic acidosis was a cardinal biochemical finding in the index
      LIAS-deficient patient.
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      They had low pyruvate dehydrogenase enzyme activity but most did not
      have lactic acidosis.
    explanation: >
      In the Baker et al. cohort, most LIAS patients had low PDH activity
      but lactic acidosis was not consistently present, suggesting
      variable severity.
- name: Hyperglycinemia
  description: >
    Elevated glycine in plasma and urine due to impaired glycine cleavage
    system lipoylation. A distinguishing feature shared with LIPT2 deficiency
    but absent in LIPT1 deficiency.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Hyperglycinemia
    term:
      id: HP:0002154
      label: Hyperglycinemia
  evidence:
  - reference: PMID:22152680
    reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      elevated glycine concentration in plasma and urine
    explanation: >
      The index patient had elevated glycine in both plasma and urine,
      consistent with impaired glycine cleavage system function.
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      All
      patients had high serum and borderline elevated cerebrospinal fluid glycine
      and
      cerebrospinal fluid:plasma glycine ratio
    explanation: >
      In the Baker et al. cohort, all variant NKH patients including those
      with LIAS mutations had elevated glycine.
- name: Global developmental delay
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Profound global developmental delay
    term:
      id: HP:0012736
      label: Profound global developmental delay
  evidence:
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Patients with lipoate
      synthase-deficient variant nonketotic hyperglycinemia varied in severity from
      mild static encephalopathy to Leigh disease and cortical involvement.
    explanation: >
      Baker et al. describe a range of severity in LIAS patients from
      mild encephalopathy to Leigh disease, confirming neurodevelopmental
      impairment as a consistent feature.
- name: Failure to thrive
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:32508887
    reference_title: "Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      severe respiratory deficiency and extreme muscle weakness due to citric
      acid cycle disfunction plus the neurological impairments caused by
      glycine accumulation in the brain
    explanation: >-
      The combined respiratory deficiency, muscle weakness, and neurological
      impairment described in LIAS patients contributes to failure to thrive.
- name: Cerebral atrophy
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with lipoate
      synthase-deficient variant nonketotic hyperglycinemia varied in severity from
      mild static encephalopathy to Leigh disease and cortical involvement.
    explanation: >-
      Baker et al. describe cortical involvement and progression to Leigh
      disease in LIAS patients; this supports CNS structural involvement but
      does not specifically establish cerebral atrophy in the cached abstract.
- name: Microcephaly
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
- name: Apnea
  phenotype_term:
    preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
- name: Respiratory insufficiency
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:32508887
    reference_title: "Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "severe respiratory deficiency and extreme muscle weakness due to citric acid cycle disfunction"
    explanation: Review supports severe respiratory deficiency in LIAS/LIPT2 lipoylation defects, though this is a general lipoylation-disorder statement rather than a LIAS-only patient series.
biochemical:
- name: Lipoylated mitochondrial proteins
  presence: DECREASED
  context: >
    LIAS deficiency reduces the lipoamide prosthetic group on mitochondrial
    proteins that require lipoate for activity.
  biomarker_term:
    preferred_term: lipoic acid
    term:
      id: CHEBI:16494
      label: lipoic acid
  readouts:
  - target: Defective lipoic acid synthesis via LIAS deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced lipoamide on mitochondrial proteins reports the proximal LIAS-dependent protein-lipoylation defect.
    evidence:
    - reference: PMID:22152680
      reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "A pronounced reduction of the prosthetic group lipoamide was found in lipoylated proteins."
      explanation: Patient fibroblast data directly show reduced lipoamide on lipoylated proteins downstream of LIAS deficiency.
  evidence:
  - reference: PMID:22152680
    reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A pronounced reduction of the prosthetic group lipoamide was found in lipoylated proteins."
    explanation: Direct patient-cell evidence for reduced protein lipoylation.
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patients were deficient in lipoylation of mitochondrial proteins."
    explanation: Variant nonketotic hyperglycinemia cohort supports deficient mitochondrial protein lipoylation.
- name: Pyruvate dehydrogenase activity
  presence: DECREASED
  context: >
    Impaired lipoylation reduces pyruvate dehydrogenase complex activity and
    limits oxidative pyruvate metabolism.
  readouts:
  - target: Combined alpha-ketoacid dehydrogenase deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced pyruvate dehydrogenase activity reports impaired lipoate-dependent alpha-ketoacid dehydrogenase function.
    evidence:
    - reference: PMID:22152680
      reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate and decreased pyruvate dehydrogenase complex activity."
      explanation: Direct patient-cell enzymology shows reduced PDH complex activity.
  evidence:
  - reference: PMID:22152680
    reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate and decreased pyruvate dehydrogenase complex activity."
    explanation: Directly supports reduced PDH activity in the index LIAS patient.
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "They had low pyruvate dehydrogenase enzyme activity but most did not have lactic acidosis."
    explanation: Supports reduced PDH activity across lipoate synthase-deficient variant NKH patients.
- name: Glycine
  presence: INCREASED
  context: >
    Elevated plasma, urine, and borderline cerebrospinal-fluid glycine reflect
    impaired glycine cleavage system activity.
  biomarker_term:
    preferred_term: glycine
    term:
      id: CHEBI:15428
      label: glycine
  readouts:
  - target: Glycine cleavage system dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Higher glycine reports impaired lipoate-dependent glycine cleavage activity.
    evidence:
    - reference: PMID:24334290
      reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio"
      explanation: Human LIAS/lipoate-synthase deficient cases show elevated glycine in serum and borderline-elevated CSF.
  evidence:
  - reference: PMID:22152680
    reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated glycine concentration in plasma and urine"
    explanation: Supports increased glycine as a biochemical hallmark in the index LIAS patient.
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio"
    explanation: Supports elevated glycine in variant NKH patients.
- name: Lactate
  presence: INCREASED
  context: >
    Lactate can rise when PDH dysfunction causes pyruvate accumulation and
    reduction to lactate, although lactic acidosis is variable in reported LIAS
    cases.
  biomarker_term:
    preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
  readouts:
  - target: Combined alpha-ketoacid dehydrogenase deficiency
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Higher lactate reports pyruvate diversion caused by impaired lipoate-dependent PDH activity.
    evidence:
    - reference: PMID:32508887
      reference_title: "Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "the presence of very high levels of lactate (resulting from reduction of the pyruvate that accumulates due to loss pyruvate dehydrogenase activity)"
      explanation: Review evidence explains why impaired lipoate-dependent PDH activity raises lactate.
  evidence:
  - reference: PMID:22152680
    reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lactic acidosis, and elevated glycine concentration in plasma and urine"
    explanation: The index patient had lactic acidosis.
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "They had low pyruvate dehydrogenase enzyme activity but most did not have lactic acidosis."
    explanation: Supports reduced PDH activity while documenting that lactic acidosis is not universal.
genetic:
- name: LIAS loss-of-function variants
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: LIAS
    term:
      id: hgnc:16429
      label: LIAS
  variant_origin: GERMLINE
  notes: >
    Biallelic loss-of-function mutations in LIAS cause lipoic acid synthetase
    deficiency. Multiple families have been reported with various missense and
    splice-site mutations.
  evidence:
  - reference: PMID:22152680
    reference_title: "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      We identified the homozygous mutation c.746G>A (p.Arg249His) in
      LIAS in an individual with neonatal-onset epilepsy, muscular hypotonia, lactic
      acidosis, and elevated glycine concentration in plasma and urine.
    explanation: >
      First report of a causal LIAS mutation: homozygous c.746G>A
      (p.Arg249His) in the index patient.
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Mutations were
      identified in the genes for lipoate synthase (LIAS), BolA type 3 (BOLA3), and
      a
      novel gene glutaredoxin 5 (GLRX5).
    explanation: >
      Baker et al. identified additional LIAS mutations in a larger cohort
      of variant NKH patients, confirming LIAS as a causal gene.
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >
      transfection with native genes corrected the
      biochemical deficiency proving pathogenicity.
    explanation: >
      Functional validation by gene complementation confirmed that the
      identified LIAS mutations were pathogenic.
treatments:
- name: Supportive care
  description: >
    Management is primarily supportive with anticonvulsant therapy and
    nutritional support. Lipoic acid supplementation is ineffective as the
    defect lies in the de novo synthesis pathway and exogenous lipoic acid
    cannot be incorporated into the mitochondrial lipoylation pathway.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:24334290
    reference_title: "Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >
      Treatments of cells with lipoate
      and with mitochondrially-targeted lipoate were unsuccessful at correcting the
      deficiency.
    explanation: >
      Baker et al. demonstrated that lipoic acid supplementation, even
      with mitochondrially-targeted forms, failed to correct the biochemical
      deficiency in patient cells, supporting the need for purely supportive care.
  - reference: PMID:32508887
    reference_title: "Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >
      lipoic acid supplementation of the diets of human LIAS, LIPT1, and LIPT2 patients
      or of their fibroblast cultures failed to alleviate the physiological and biochemical
      effects of the mutant genes
    explanation: >
      Review confirms that lipoic acid supplementation is ineffective in
      LIAS patients, as exogenous lipoate cannot enter the mitochondrial
      de novo synthesis pathway.
- name: Engineered bacterial lipoate ligase (experimental)
  description: >
    An engineered mitochondrially-targeted bacterial lipoate protein ligase A
    (lplA) has been shown to restore lipoylation in LIAS-deficient cell models.
    This approach bypasses the defective de novo synthesis pathway by allowing
    cells to utilize exogenous lipoic acid through the bacterial salvage enzyme.
    This has only been demonstrated in cell models and is not yet available as
    a clinical therapy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:39547509
    reference_title: "Engineered bacterial lipoate protein ligase A (lplA) restores lipoylation in cell models of lipoylation deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This synthetic approach offers a potential therapeutic strategy for
      treating lipoylation disorders.
    explanation: >-
      Bick et al. demonstrated that engineered bacterial lplA could restore
      lipoylation in LIAS knockout cell models, providing proof of concept
      for a therapeutic bypass of the defective de novo synthesis pathway.
datasets:
references:
- reference: DOI:10.1016/j.ajhg.2011.11.011
  title: Lipoic Acid Synthetase Deficiency Causes Neonatal-Onset Epilepsy, Defective Mitochondrial Energy Metabolism, and Glycine Elevation
  findings: []
- reference: DOI:10.1038/s41589-022-01159-4
  title: Functional spectrum and specificity of mitochondrial ferredoxins FDX1 and FDX2
  findings: []
- reference: DOI:10.1098/rsob.220274
  title: Mitochondrial biology and dysfunction in secondary mitochondrial disease
  findings: []
- reference: DOI:10.3390/antiox13081023
  title: A Multi-Target Pharmacological Correction of a Lipoyltransferase LIPT1 Gene Mutation in Patient-Derived Cellular Models
  findings: []

📚

References & Deep Research

References

4

DOI:10.1016/j.ajhg.2011.11.011

Lipoic Acid Synthetase Deficiency Causes Neonatal-Onset Epilepsy, Defective Mitochondrial Energy Metabolism, and Glycine Elevation

No top-level findings curated for this source.

DOI:10.1038/s41589-022-01159-4

Functional spectrum and specificity of mitochondrial ferredoxins FDX1 and FDX2

No top-level findings curated for this source.

DOI:10.1098/rsob.220274

Mitochondrial biology and dysfunction in secondary mitochondrial disease

No top-level findings curated for this source.

DOI:10.3390/antiox13081023

A Multi-Target Pharmacological Correction of a Lipoyltransferase LIPT1 Gene Mutation in Patient-Derived Cellular Models

No top-level findings curated for this source.

Deep Research

2

Disorder ▸

Disorder

Name: Lipoic Acid Synthetase Deficiency
Category: Mendelian
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 25

Key Pathophysiology Nodes

Defective lipoic acid synthesis via LIAS deficiency
Combined alpha-ketoacid dehydrogenase and glycine cleavage deficiency
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1016/j.ajhg.2011.11.011
DOI:10.1038/s41589-022-01159-4
DOI:10.1098/rsob.220274
DOI:10.3390/antiox13081023

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Disease Pathophysiology Research Report

Edison Scientific Literature 19 citations 2026-02-10T23:16:15.123517

Disease Pathophysiology Research Report

Target Disease - Disease Name: Lipoic Acid Synthetase (LIAS) Deficiency - MONDO ID: not definitively established in retrieved evidence - Category: Mendelian

Pathophysiology overview LIAS deficiency is a mitochondrial disorder of protein lipoylation. LIAS (HGNC:6612) catalyzes the insertion of sulfur atoms into an octanoyl moiety (derived from mitochondrial fatty-acid synthesis, mtFAS) to produce protein-bound lipoate required by the E2 subunits of 2‑oxoacid dehydrogenase complexes—pyruvate dehydrogenase (PDH), 2‑oxoglutarate dehydrogenase (OGDH/α-KGDH), branched-chain α‑ketoacid dehydrogenase (BCKDH)—and by the H protein (GCSH) of the glycine cleavage system (GCS). Loss of LIAS activity causes loss of lipoylation on these targets, resulting in impaired pyruvate oxidation (lactic acidosis), reduced TCA cycle flux (bioenergetic failure), and glycine accumulation (hyperglycinemia), typically presenting as neonatal‑onset encephalopathy with seizures. URL: https://doi.org/10.1016/j.ajhg.2011.11.011 (Dec 2011) (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 1-2, mayr2011lipoicacidsynthetase pages 2-3, mayr2011lipoicacidsynthetase pages 5-6). A 2022 synthesis of secondary mitochondrial diseases reiterates that LIAS loss and defects in lipoyl-transferases (LIPT1/LIPT2) converge on impaired lipoylation of PDH/OGDH/BCKDH and GCS with characteristic neurological phenotypes. URL: https://doi.org/10.1098/rsob.220274 (Dec 2022) (baker2022mitochondrialbiologyand pages 10-11).

Recent developments (2023–2024) - Ferredoxins and Fe–S dependency: Human mitochondrial ferredoxins FDX1 and FDX2 have distinct and overlapping specificities supporting mitochondrial iron–sulfur (Fe–S) chemistry; LIAS is an Fe–S protein whose activity depends on intact Fe–S biogenesis and ferredoxin electron transfer. The 2023 study by Schulz et al. provides functional/structural characterization of FDX1/FDX2 and experimental tools (antibodies to LIAS and lipoate; genetic constructs) used to interrogate lipoylation pathways, reinforcing that perturbation of ferredoxin/Fe–S systems can secondarily compromise protein lipoylation. URL: https://doi.org/10.1038/s41589-022-01159-4 (Oct 2023) (schulz2023functionalspectrumand pages 12-17, schulz2023functionalspectrumand pages 17-19). - Experimental therapeutics in related lipoylation disorders: In patient-derived LIPT1 mutant cells, a multi-agent “cocktail” (pantothenate, nicotinamide, vitamin E, thiamine, biotin, α‑lipoic acid) restored mitochondrial protein lipoylation, rescued PDH/OGDH activities, improved bioenergetics, and reduced iron accumulation and lipid peroxidation, with evidence for SIRT3 involvement. Though centered on LIPT1, these findings illustrate tractable cellular endpoints and candidate pathways (NAD+/sirtuins, antioxidant defense) relevant across mitochondrial lipoylation deficiencies, including LIAS. URL: https://doi.org/10.3390/antiox13081023 (Aug 2024) (gomezfernandez2024amultitargetpharmacological pages 1-2, gomezfernandez2024amultitargetpharmacological pages 29-30, gomezfernandez2024amultitargetpharmacological pages 26-29).

1) Core Pathophysiology - Primary mechanism: Failure of mitochondrial protein lipoylation due to deficient LIAS sulfur insertion into octanoyl substrates, leading to loss of lipoyl moieties on PDH E2 (DLAT/PDHX), OGDH E2 (DLST), BCKDH E2 (DBT), and GCSH. URL: https://doi.org/10.1016/j.ajhg.2011.11.011 (Dec 2011) (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 2-3, mayr2011lipoicacidsynthetase pages 5-6); URL: https://doi.org/10.1098/rsob.220274 (Dec 2022) (baker2022mitochondrialbiologyand pages 10-11). - Dysregulated pathways: Pyruvate oxidation (PDH) and TCA cycle flux (OGDH) are markedly reduced; glycine degradation via the GCS is impaired, leading to hyperglycinemia. URL: https://doi.org/10.1016/j.ajhg.2011.11.011 (Dec 2011) (mayr2011lipoicacidsynthetase pages 1-2, mayr2011lipoicacidsynthetase pages 2-3, mayr2011lipoicacidsynthetase pages 5-6); URL: https://doi.org/10.1098/rsob.220274 (Dec 2022) (baker2022mitochondrialbiologyand pages 10-11). - Cellular processes affected: Mitochondrial energy production declines, with secondary redox imbalance and oxidative stress; in experimental lipoylation deficiency models, intracellular iron accumulates and lipid peroxidation increases—plausible mechanisms in LIAS deficiency given shared endpoints of lost PDH/OGDH lipoylation. URL: https://doi.org/10.3390/antiox13081023 (Aug 2024) (gomezfernandez2024amultitargetpharmacological pages 26-29). - Fe–S/ferredoxin linkage: LIAS harbors Fe–S cofactors; Fe–S biogenesis defects (e.g., NFU1/BOLA3) or impaired ferredoxin function (FDX1/FDX2) can secondarily reduce LIAS activity and mitochondrial lipoylation. URL: https://doi.org/10.1016/j.ajhg.2011.11.011 (Dec 2011) (mayr2011lipoicacidsynthetase pages 2-3); URL: https://doi.org/10.1038/s41589-022-01159-4 (Oct 2023) (schulz2023functionalspectrumand pages 12-17, schulz2023functionalspectrumand pages 17-19).

2) Key Molecular Players - Genes/Proteins (HGNC): LIAS (lipoic acid synthetase); LIPT1/LIPT2 (lipoyl transfer enzymes); GCSH (glycine cleavage H-protein); DLAT/PDHX (PDH E2/E3-binding); DLST (OGDH E2); DBT (BCKDH E2); DLD (shared E3); NFU1/BOLA3 (Fe–S assembly); FDX1/FDX2 (mitochondrial ferredoxins). Mechanistic and disease roles as summarized in the ontology artifact below (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 2-3, mayr2011lipoicacidsynthetase pages 5-6, baker2022mitochondrialbiologyand pages 10-11, schulz2023functionalspectrumand pages 12-17, schulz2023functionalspectrumand pages 17-19, gomezfernandez2024amultitargetpharmacological pages 26-29). - Chemical entities (CHEBI) implicated: lipoic acid (α‑lipoate), octanoyl‑ACP, thiamine pyrophosphate, NAD+, FAD; experimental cocktail agents that support redox/cofactor metabolism. URL: https://doi.org/10.3390/antiox13081023 (Aug 2024) (gomezfernandez2024amultitargetpharmacological pages 1-2, gomezfernandez2024amultitargetpharmacological pages 26-29); URL: https://doi.org/10.1016/j.ajhg.2011.11.011 (Dec 2011) (mayr2011lipoicacidsynthetase pages 3-5). - Cell types: Neurons and astrocytes (high sensitivity to mitochondrial energy failure and glycine dysmetabolism), cardiomyocytes and skeletal muscle (high oxidative demand). Evidence from clinical neuro/cardio involvement and biopsy ultrastructure. URL: https://doi.org/10.1016/j.ajhg.2011.11.011 (Dec 2011) (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6), and overview in 2022 review (baker2022mitochondrialbiologyand pages 10-11). - Anatomical locations: Brain (seizures, encephalopathy), heart (cardiomyopathy in some cases), skeletal muscle (mitochondrial changes), liver (systemic lactate/glycine handling). URL: https://doi.org/10.1016/j.ajhg.2011.11.011 (Dec 2011) (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6); URL: https://doi.org/10.1098/rsob.220274 (Dec 2022) (baker2022mitochondrialbiologyand pages 10-11).

Category	Entity / Term	Standard ID	Role / Relevance (1-2 lines)	Key Evidence
Gene / Protein	LIAS	HGNC:6612	Mitochondrial lipoic acid synthetase; catalyzes sulfur insertion into octanoyl moiety to form protein-bound lipoate.	(mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6, baker2022mitochondrialbiologyand pages 10-11)
Gene / Protein	LIPT1	HGNC:19085	Lipoyltransferase that transfers lipoyl group to E2 subunits; mutations cause lipoylation disorders.	(gomezfernandez2024amultitargetpharmacological pages 1-2, gomezfernandez2024amultitargetpharmacological pages 26-29, baker2022mitochondrialbiologyand pages 10-11)
Gene / Protein	LIPT2	HGNC:30832	Upstream lipoyl-transfer / octanoyl transfer step in mitochondrial lipoylation pathway.	(gomezfernandez2024amultitargetpharmacological pages 1-2, baker2022mitochondrialbiologyand pages 10-11)
Gene / Protein	GCSH	HGNC:4190	H-protein of glycine cleavage system; requires lipoylation for activity.	(mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11)
Gene / Protein	PDHX / DLAT	HGNC:8818 / HGNC:2704	E2/E3 subunits of pyruvate dehydrogenase complex; lipoylation essential for PDH activity.	(mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6, gomezfernandez2024amultitargetpharmacological pages 26-29)
Gene / Protein	DLST	HGNC:2875	E2 subunit component of 2-oxoglutarate (α-KGDH) dehydrogenase complex; lipoylation required.	(mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11)
Gene / Protein	DBT	HGNC:2701	E2 subunit of branched-chain α-ketoacid dehydrogenase (BCKDH); lipoylation implicated in branched-chain metabolism.	(mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11)
Gene / Protein	DLD	HGNC:2703	E3 (dihydrolipoamide dehydrogenase) shared flavoprotein in dehydrogenase complexes; interacts functionally with lipoylated E2s.	(mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11)
Gene / Protein	NFU1	HGNC:24573	Fe–S cluster assembly factor; mutations can secondarily impair LIAS/ protein lipoylation.	(mayr2011lipoicacidsynthetase pages 2-3, baker2022mitochondrialbiologyand pages 10-11)
Gene / Protein	BOLA3	HGNC:24676	Fe–S cluster biogenesis factor linked to secondary lipoylation defects when mutated.	(mayr2011lipoicacidsynthetase pages 2-3, baker2022mitochondrialbiologyand pages 10-11)
Gene / Protein	FDX1	HGNC:3645	Mitochondrial ferredoxin implicated in electron transfer/Fe–S chemistry that supports LIAS function.	(schulz2023functionalspectrumand pages 12-17, schulz2023functionalspectrumand pages 17-19)
Gene / Protein	FDX2	HGNC:33839	Mitochondrial ferredoxin with distinct specificity; contributes to Fe–S cluster assembly and lipoylation indirectly.	(schulz2023functionalspectrumand pages 12-17, schulz2023functionalspectrumand pages 17-19)
Biological Process	Protein lipoylation	GO:0031405	Covalent attachment of lipoic acid to E2 subunits and GCSH; central biochemical defect in LIAS deficiency.	(mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11)
Biological Process	Lipoic acid biosynthetic process	GO:0009108	Mitochondrial de novo synthesis of lipoate from octanoyl-ACP via LIAS and related enzymes.	(mayr2011lipoicacidsynthetase pages 3-5, gomezfernandez2024amultitargetpharmacological pages 26-29)
Biological Process	Pyruvate dehydrogenase complex activity	GO:0004738	PDH activity dependent on lipoylation; loss causes impaired pyruvate oxidation and lactic acidosis.	(mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6)
Biological Process	Glycine catabolic process (GCS)	GO:0006546	Glycine cleavage requires lipoylated GCSH; LIAS defects produce hyperglycinemia.	(mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11)
Biological Process	Tricarboxylic acid cycle	GO:0006099	TCA flux reduced due to loss of PDH/OGDH activity from lipoylation defects, causing bioenergetic failure.	(mayr2011lipoicacidsynthetase pages 3-5, gomezfernandez2024amultitargetpharmacological pages 26-29)
Biological Process	Iron–sulfur cluster assembly	GO:0016226	Fe–S biogenesis supplies cofactors required for LIAS activity; defects (e.g., NFU1/BOLA3) impair lipoylation.	(mayr2011lipoicacidsynthetase pages 2-3, schulz2023functionalspectrumand pages 12-17)
Biological Process	Mitochondrial electron transport	GO:0006120	Secondary impairment due to reduced dehydrogenase inputs and altered redox balance in lipoylation disorders.	(baker2022mitochondrialbiologyand pages 10-11, gomezfernandez2024amultitargetpharmacological pages 26-29)
Biological Process	Response to oxidative stress	GO:0006979	Lipoylation defects associate with increased oxidative stress, lipid peroxidation and ROS in cellular models.	(gomezfernandez2024amultitargetpharmacological pages 26-29)
Cellular Component	Mitochondrial matrix	GO:0005759	Primary subcellular locale where LIAS and lipoylation occur.	(mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11)
Cellular Component	Mitochondrial inner membrane	GO:0005743	Houses respiratory chain affected secondarily by impaired substrate supply from dehydrogenases.	(baker2022mitochondrialbiologyand pages 10-11, gomezfernandez2024amultitargetpharmacological pages 26-29)
Cellular Component	2-oxoglutarate dehydrogenase complex	GO:0045252	Lipoylation-dependent enzyme complex (OGDH) required for TCA cycle; activity reduced in LIAS deficiency.	(mayr2011lipoicacidsynthetase pages 3-5, gomezfernandez2024amultitargetpharmacological pages 26-29)
Cellular Component	Pyruvate dehydrogenase complex	GO:0005940	Lipoylated PDH complex localized to mitochondrial matrix; central to pyruvate→acetyl-CoA conversion.	(mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6)
Phenotype	Lactic acidosis	HP:0003128	Marked hyperlactatemia is a cardinal biochemical finding from impaired PDH activity in LIAS deficiency.	(mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6)
Phenotype	Neonatal-onset seizures	HP:0001270	Early-infant encephalopathy with seizures commonly reported in LIAS-deficient patients.	(mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6)
Phenotype	Hyperglycinemia	HP:0002154	Elevated glycine results from dysfunction of the lipoylation-dependent glycine cleavage system.	(mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11)
Phenotype	Hypotonia	HP:0001252	Neuromuscular weakness observed clinically in affected infants.	(mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6)
Phenotype	Encephalopathy	HP:0001298	Progressive neonatal/infantile encephalopathy with structural brain changes and developmental arrest.	(mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6)
Phenotype	Cardiomyopathy	HP:0001638	Cardiac involvement reported in LIAS deficiency, likely via impaired α-KGDH/TCA flux.	(mayr2011lipoicacidsynthetase pages 5-6, baker2022mitochondrialbiologyand pages 10-11)
Phenotype	Microcephaly	HP:0000252	Developmental brain growth impairment described in case reports.	(mayr2011lipoicacidsynthetase pages 3-5)
Cell Type	Neuron	CL:0000540	CNS neurons are highly sensitive to mitochondrial energy failure; primary cells affected clinically.	(mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11)
Cell Type	Cardiomyocyte	CL:0000746	Cardiac myocytes can be affected due to high TCA/oxidative metabolism requirements.	(mayr2011lipoicacidsynthetase pages 5-6, baker2022mitochondrialbiologyand pages 10-11)
Cell Type	Astrocyte	CL:0000127	Glial metabolic support and glycine handling may be perturbed in lipoylation disorders.	(mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11)
Cell Type	Skeletal muscle cell	CL:0000187	Muscle shows mitochondrial abnormalities and reduced lipoylation in biopsies.	(mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6)
Cell Type	Hepatocyte	CL:0000182	Liver contributes to systemic lactate/glycine handling and shows metabolic dysfunction.	(mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11)
Anatomical Location	Brain	UBERON:0000955	Primary organ manifesting seizures, encephalopathy and structural injury.	(mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6)
Anatomical Location	Heart	UBERON:0000948	Reported site of cardiomyopathy in some patients with LIAS defects.	(mayr2011lipoicacidsynthetase pages 5-6)
Anatomical Location	Liver	UBERON:0002107	Involved in systemic metabolic derangements (lactate, glycine); shows mitochondrial dysfunction.	(mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11)
Anatomical Location	Skeletal muscle	UBERON:0001134	Muscle biopsies reveal decreased lipoylation and mitochondrial ultrastructural changes.	(mayr2011lipoicacidsynthetase pages 3-5)
Chemical	Lipoic acid (α-LA)	CHEBI:16495	Prosthetic cofactor synthesized in mitochondria and covalently attached to E2/GCSH; exogenous LA not incorporated into proteins in humans.	(mayr2011lipoicacidsynthetase pages 3-5, gomezfernandez2024amultitargetpharmacological pages 26-29)
Chemical	Octanoyl-ACP	CHEBI:28644	Mitochondrial fatty-acid synthesis intermediate that donates octanoyl substrate for LIAS-mediated sulfur insertion.	(mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11)
Chemical	Thiamine pyrophosphate (TPP)	CHEBI:9534	Cofactor of PDH complex that interacts functionally with lipoylation-dependent E2 activity.	(gomezfernandez2024amultitargetpharmacological pages 26-29, baker2022mitochondrialbiologyand pages 10-11)
Chemical	NAD+	CHEBI:57540	Redox cofactor linked to mitochondrial metabolism and reported as part of therapeutic cocktails restoring bioenergetics.	(gomezfernandez2024amultitargetpharmacological pages 1-2, gomezfernandez2024amultitargetpharmacological pages 26-29)
Chemical	FAD	CHEBI:16238	Flavin cofactor (e.g., DLD) participating in dehydrogenase complexes affected by lipoylation loss.	(mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11)

Table: Compact ontology-annotated table summarizing genes, processes, components, phenotypes, cell types, anatomical sites, and chemicals relevant to LIAS (lipoic acid synthetase) deficiency, with key evidence citations for each entry.

3) Biological Processes for GO annotation - Protein lipoylation (GO:0031405): primary process lost in LIAS deficiency (mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11). - Lipoic acid biosynthetic process (GO:0009108): depends on mtFAS intermediate octanoyl‑ACP and LIAS sulfur insertion (mayr2011lipoicacidsynthetase pages 3-5, gomezfernandez2024amultitargetpharmacological pages 26-29). - Pyruvate dehydrogenase complex activity (GO:0004738) and tricarboxylic acid cycle (GO:0006099): diminished due to loss of PDH/OGDH lipoylation (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6, gomezfernandez2024amultitargetpharmacological pages 26-29). - Glycine catabolic process (GO:0006546): impaired due to non‑lipoylated GCSH, leading to hyperglycinemia (mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11). - Iron–sulfur cluster assembly (GO:0016226): required for LIAS function; defects in NFU1/BOLA3, or loss of FDX1/FDX2 support, secondarily impair lipoylation (mayr2011lipoicacidsynthetase pages 2-3, schulz2023functionalspectrumand pages 12-17, schulz2023functionalspectrumand pages 17-19). - Response to oxidative stress (GO:0006979): increased ROS and lipid peroxidation demonstrated in lipoylation-deficient patient cells (LIPT1 models), suggesting shared downstream consequences (gomezfernandez2024amultitargetpharmacological pages 26-29).

4) Cellular Components - Mitochondrial matrix (GO:0005759): locale of LIAS and PDH/OGDH/BCKDH/GCSH lipoylation (mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11). - Pyruvate dehydrogenase complex (GO:0005940) and 2‑oxoglutarate dehydrogenase complex (GO:0045252): lipoylation-dependent enzyme assemblies diminished in LIAS deficiency (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6, gomezfernandez2024amultitargetpharmacological pages 26-29). - Mitochondrial inner membrane (GO:0005743): respiratory chain impacted secondarily by impaired substrate flux and redox balance (baker2022mitochondrialbiologyand pages 10-11, gomezfernandez2024amultitargetpharmacological pages 26-29).

5) Disease Progression - Initiating lesion: Biallelic LIAS pathogenic variants cause failure of sulfur insertion into octanoyl intermediates (loss of protein lipoylation) (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 2-3). - Biochemical cascade: Loss of PDH/OGDH lipoylation leads to decreased PDH activity (pyruvate→acetyl‑CoA), TCA cycle stalling, increased lactate; loss of GCSH lipoylation causes hyperglycinemia (mayr2011lipoicacidsynthetase pages 1-2, mayr2011lipoicacidsynthetase pages 2-3, mayr2011lipoicacidsynthetase pages 5-6, baker2022mitochondrialbiologyand pages 10-11). - Cellular dysfunction: Mitochondrial bioenergetic failure; in related lipoylation defects, iron accumulation, oxidative stress, lipid peroxidation, and inability to sustain oxidative growth (galactose) are observed—likely convergent features with LIAS deficiency (gomezfernandez2024amultitargetpharmacological pages 26-29). - Clinical manifestation: Neonatal‑onset encephalopathy with seizures, hypotonia, acidosis; some cases with cardiomyopathy; rapid progression to severe neurodevelopmental impairment or early death (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6).

6) Phenotypic Manifestations and Mechanistic Links - Lactic acidosis (HP:0003128): from impaired PDH activity; PDH activity can be profoundly decreased (e.g., 0.4 vs 6.1–19.8 nmol/min/mg in controls), with plasma lactate up to 57.7 mmol/L in a reported case. URL: https://doi.org/10.1016/j.ajhg.2011.11.011 (Dec 2011) (mayr2011lipoicacidsynthetase pages 1-2, mayr2011lipoicacidsynthetase pages 2-3). - Hyperglycinemia (HP:0002154): due to non‑functional GCS; plasma glycine reported at 906 µmol/L in the index case. URL: https://doi.org/10.1016/j.ajhg.2011.11.011 (Dec 2011) (mayr2011lipoicacidsynthetase pages 1-2, mayr2011lipoicacidsynthetase pages 2-3). - Neonatal-onset seizures and encephalopathy (HP:0001270; HP:0001298): reflect neuronal susceptibility to mitochondrial failure and glycine excitotoxicity (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6). - Hypotonia (HP:0001252) and microcephaly (HP:0000252): consistent with severe early neurodevelopmental impact (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 5-6). - Cardiomyopathy (HP:0001638): reported in LIAS deficiency, plausibly via impaired α‑KGDH/TCA flux in the heart (mayr2011lipoicacidsynthetase pages 5-6).

Expert opinions and analysis (with quotes) - Mayr et al. (2011) established human LIAS deficiency and concluded: “Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation.” URL: https://doi.org/10.1016/j.ajhg.2011.11.011 (Dec 2011) (mayr2011lipoicacidsynthetase pages 3-5). - Mechanistic dependency on mitochondrial synthesis is emphasized: eukaryotic cells “depend on de novo mitochondrial synthesis” of lipoic acid; exogenous lipoate does not substitute for protein lipoylation in humans. URL: https://doi.org/10.1016/j.ajhg.2011.11.011 (Dec 2011) (mayr2011lipoicacidsynthetase pages 1-2). - Ferredoxin/Fe–S linkage: 2023 data refine the “functional spectrum and specificity of mitochondrial ferredoxins FDX1 and FDX2,” underscoring their roles in mitochondrial electron transfer/Fe–S chemistry that support Fe–S proteins such as LIAS. URL: https://doi.org/10.1038/s41589-022-01159-4 (Oct 2023) (schulz2023functionalspectrumand pages 12-17, schulz2023functionalspectrumand pages 17-19). - Translational angle from lipoylation-defect models: a “multi-target pharmacological” approach restored lipoylation and bioenergetics and relieved iron/oxidative stress in LIPT1‑mutant cells, illustrating potentially generalizable therapeutic axes (NAD+/sirtuin activation; antioxidant support). URL: https://doi.org/10.3390/antiox13081023 (Aug 2024) (gomezfernandez2024amultitargetpharmacological pages 1-2, gomezfernandez2024amultitargetpharmacological pages 26-29).

Current applications and implementations - Diagnostics: Immunoblot of lipoylated proteins (loss of lipoate signal on PDH/OGDH E2 and GCSH) in fibroblasts/muscle; PDH complex activity assays and pyruvate oxidation testing; targeted/GS-based detection of LIAS variants; functional complementation in model organisms to confirm pathogenicity. URL: https://doi.org/10.1016/j.ajhg.2011.11.011 (Dec 2011) (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 2-3, mayr2011lipoicacidsynthetase pages 5-6). - Mechanism-aware monitoring: Biochemical profiling of lactate, pyruvate, and glycine; consideration of cardiac evaluation given reported cardiomyopathy (mayr2011lipoicacidsynthetase pages 5-6). - Preclinical therapeutic concepts: Redox/cofactor support, NAD+ boosting and sirtuin activation, antioxidant therapy, guided by cellular endpoints (lipoylation status, PDH/OGDH activities, mitochondrial membrane potential, iron handling, lipid peroxidation) from LIPT1 cellular models (gomezfernandez2024amultitargetpharmacological pages 1-2, gomezfernandez2024amultitargetpharmacological pages 26-29).

Relevant statistics and data points from recent/landmark studies - PDH complex activity: as low as 0.4 nmol/min/mg (ref. range 6.1–19.8) in LIAS-deficient tissue (mayr2011lipoicacidsynthetase pages 2-3). - Plasma lactate: up to 57.7 mmol/L during crisis in the index LIAS case (mayr2011lipoicacidsynthetase pages 1-2). - Plasma glycine: 906 µmol/L in the LIAS index case (mayr2011lipoicacidsynthetase pages 1-2). - Cellular rescue metrics (LIPT1 model): restoration of mitochondrial protein lipoylation, recovery of PDH/OGDH activities, improved survival in galactose medium, reduction of iron overload and lipid peroxidation after 7‑day cocktail; SIRT3 dependency demonstrated pharmacologically (gomezfernandez2024amultitargetpharmacological pages 26-29).

Key concepts and definitions - LIAS: mitochondrial lipoic acid synthetase; an Fe–S enzyme that performs sulfur insertion on octanoyl-ACP–derived intermediates to generate protein-bound lipoate (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 2-3). - Protein lipoylation: covalent attachment of lipoate to specific lysines on E2 subunits of PDH/OGDH/BCKDH and on GCSH; essential for 2‑oxoacid oxidation and glycine catabolism (mayr2011lipoicacidsynthetase pages 3-5, baker2022mitochondrialbiologyand pages 10-11). - Ferredoxins (FDX1/FDX2): mitochondrial [2Fe–2S] proteins mediating electron transfer required for Fe–S biogenesis and monooxygenase reactions; functional specificity characterized in 2023; necessary to sustain Fe–S protein function including LIAS (schulz2023functionalspectrumand pages 12-17, schulz2023functionalspectrumand pages 17-19). - Secondary lipoylation defects: defects in upstream lipoylation steps (LIPT1/LIPT2), mtFAS, or Fe–S assembly factors (NFU1/BOLA3) phenocopy LIAS loss by depriving PDH/OGDH/BCKDH and GCS of lipoyl cofactors (baker2022mitochondrialbiologyand pages 10-11) (mayr2011lipoicacidsynthetase pages 2-3).

Direct evidence items (with URLs and dates) - Mayr et al. 2011. American Journal of Human Genetics: Human LIAS deficiency defining paper; mechanistic and phenotypic profile. URL: https://doi.org/10.1016/j.ajhg.2011.11.011 (Dec 2011) (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 1-2, mayr2011lipoicacidsynthetase pages 2-3, mayr2011lipoicacidsynthetase pages 5-6). - Baker et al. 2022. Open Biology: Review of secondary mitochondrial diseases; lipoylation machinery overview (LIAS/LIPT1/LIPT2, PDH/OGDH/BCKDH, GCS). URL: https://doi.org/10.1098/rsob.220274 (Dec 2022) (baker2022mitochondrialbiologyand pages 10-11). - Schulz et al. 2023. Nature Chemical Biology: Functional spectrum and specificity of mitochondrial ferredoxins FDX1/FDX2; tools and context for Fe–S support of lipoylation. URL: https://doi.org/10.1038/s41589-022-01159-4 (Oct 2023) (schulz2023functionalspectrumand pages 12-17, schulz2023functionalspectrumand pages 17-19). - Gómez‑Fernández et al. 2024. Antioxidants: LIPT1 cellular models; oxidative stress, iron accumulation, and pharmacologic rescue of lipoylation and bioenergetics via a multi‑agent cocktail, suggesting therapeutic axes for lipoylation disorders. URL: https://doi.org/10.3390/antiox13081023 (Aug 2024) (gomezfernandez2024amultitargetpharmacological pages 1-2, gomezfernandez2024amultitargetpharmacological pages 29-30, gomezfernandez2024amultitargetpharmacological pages 26-29).

Limitations and open questions - Human LIAS-deficiency case numbers are limited; genotype–phenotype correlations and natural history require updated case aggregation. - Translation of multi-target cellular rescue strategies to patients remains to be tested in LIAS deficiency; exogenous α‑lipoic acid is not incorporated into mitochondrial lipoylation in humans, highlighting the need for upstream pathway restoration (gomezfernandez2024amultitargetpharmacological pages 26-29).

Conclusions LIAS deficiency centrally disrupts mitochondrial protein lipoylation, crippling PDH/OGDH/BCKDH and GCS, and producing a characteristic neonatal metabolic encephalopathy with lactic acidosis and hyperglycinemia. Emerging 2023–2024 insights underscore the dependency of LIAS on Fe–S biogenesis and ferredoxin electron transfer, and suggest redox/cofactor-targeted approaches as promising cellular strategies for lipoylation disorders. Continued efforts should prioritize mechanistic biomarkers (lipoylation status, PDH/OGDH activity, iron/ROS metrics) and systematic clinical phenotyping to inform therapeutic development (mayr2011lipoicacidsynthetase pages 3-5, mayr2011lipoicacidsynthetase pages 2-3, mayr2011lipoicacidsynthetase pages 5-6, baker2022mitochondrialbiologyand pages 10-11, schulz2023functionalspectrumand pages 12-17, schulz2023functionalspectrumand pages 17-19, gomezfernandez2024amultitargetpharmacological pages 26-29).

References

(mayr2011lipoicacidsynthetase pages 3-5): Johannes A. Mayr, Franz A. Zimmermann, Christine Fauth, Christa Bergheim, David Meierhofer, Doris Radmayr, Johannes Zschocke, Johannes Koch, and Wolfgang Sperl. Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation. American journal of human genetics, 89 6:792-7, Dec 2011. URL: https://doi.org/10.1016/j.ajhg.2011.11.011, doi:10.1016/j.ajhg.2011.11.011. This article has 170 citations and is from a highest quality peer-reviewed journal.
(mayr2011lipoicacidsynthetase pages 1-2): Johannes A. Mayr, Franz A. Zimmermann, Christine Fauth, Christa Bergheim, David Meierhofer, Doris Radmayr, Johannes Zschocke, Johannes Koch, and Wolfgang Sperl. Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation. American journal of human genetics, 89 6:792-7, Dec 2011. URL: https://doi.org/10.1016/j.ajhg.2011.11.011, doi:10.1016/j.ajhg.2011.11.011. This article has 170 citations and is from a highest quality peer-reviewed journal.
(mayr2011lipoicacidsynthetase pages 2-3): Johannes A. Mayr, Franz A. Zimmermann, Christine Fauth, Christa Bergheim, David Meierhofer, Doris Radmayr, Johannes Zschocke, Johannes Koch, and Wolfgang Sperl. Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation. American journal of human genetics, 89 6:792-7, Dec 2011. URL: https://doi.org/10.1016/j.ajhg.2011.11.011, doi:10.1016/j.ajhg.2011.11.011. This article has 170 citations and is from a highest quality peer-reviewed journal.
(mayr2011lipoicacidsynthetase pages 5-6): Johannes A. Mayr, Franz A. Zimmermann, Christine Fauth, Christa Bergheim, David Meierhofer, Doris Radmayr, Johannes Zschocke, Johannes Koch, and Wolfgang Sperl. Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation. American journal of human genetics, 89 6:792-7, Dec 2011. URL: https://doi.org/10.1016/j.ajhg.2011.11.011, doi:10.1016/j.ajhg.2011.11.011. This article has 170 citations and is from a highest quality peer-reviewed journal.
(baker2022mitochondrialbiologyand pages 10-11): Megan J. Baker, Jordan J. Crameri, David R. Thorburn, Ann E. Frazier, and Diana Stojanovski. Mitochondrial biology and dysfunction in secondary mitochondrial disease. Open Biology, Dec 2022. URL: https://doi.org/10.1098/rsob.220274, doi:10.1098/rsob.220274. This article has 33 citations and is from a peer-reviewed journal.
(schulz2023functionalspectrumand pages 12-17): Vinzent Schulz, Somsuvro Basu, Sven-A. Freibert, Holger Webert, Linda Boss, Ulrich Mühlenhoff, Fabien Pierrel, Lars-O. Essen, Douglas M. Warui, Squire J. Booker, Oliver Stehling, and Roland Lill. Functional spectrum and specificity of mitochondrial ferredoxins fdx1 and fdx2. Nature Chemical Biology, 19:206-217, Oct 2023. URL: https://doi.org/10.1038/s41589-022-01159-4, doi:10.1038/s41589-022-01159-4. This article has 146 citations and is from a highest quality peer-reviewed journal.
(schulz2023functionalspectrumand pages 17-19): Vinzent Schulz, Somsuvro Basu, Sven-A. Freibert, Holger Webert, Linda Boss, Ulrich Mühlenhoff, Fabien Pierrel, Lars-O. Essen, Douglas M. Warui, Squire J. Booker, Oliver Stehling, and Roland Lill. Functional spectrum and specificity of mitochondrial ferredoxins fdx1 and fdx2. Nature Chemical Biology, 19:206-217, Oct 2023. URL: https://doi.org/10.1038/s41589-022-01159-4, doi:10.1038/s41589-022-01159-4. This article has 146 citations and is from a highest quality peer-reviewed journal.
(gomezfernandez2024amultitargetpharmacological pages 1-2): David Gómez-Fernández, Ana Romero-González, Juan M. Suárez-Rivero, Paula Cilleros-Holgado, Mónica Álvarez-Córdoba, Rocío Piñero-Pérez, José Manuel Romero-Domínguez, Diana Reche-López, Alejandra López-Cabrera, Salvador Ibáñez-Mico, Marta Castro de Oliveira, Andrés Rodríguez-Sacristán, Susana González-Granero, José Manuel García-Verdugo, and José A. Sánchez-Alcázar. A multi-target pharmacological correction of a lipoyltransferase lipt1 gene mutation in patient-derived cellular models. Antioxidants, 13:1023, Aug 2024. URL: https://doi.org/10.3390/antiox13081023, doi:10.3390/antiox13081023. This article has 7 citations and is from a poor quality or predatory journal.
(gomezfernandez2024amultitargetpharmacological pages 29-30): David Gómez-Fernández, Ana Romero-González, Juan M. Suárez-Rivero, Paula Cilleros-Holgado, Mónica Álvarez-Córdoba, Rocío Piñero-Pérez, José Manuel Romero-Domínguez, Diana Reche-López, Alejandra López-Cabrera, Salvador Ibáñez-Mico, Marta Castro de Oliveira, Andrés Rodríguez-Sacristán, Susana González-Granero, José Manuel García-Verdugo, and José A. Sánchez-Alcázar. A multi-target pharmacological correction of a lipoyltransferase lipt1 gene mutation in patient-derived cellular models. Antioxidants, 13:1023, Aug 2024. URL: https://doi.org/10.3390/antiox13081023, doi:10.3390/antiox13081023. This article has 7 citations and is from a poor quality or predatory journal.
(gomezfernandez2024amultitargetpharmacological pages 26-29): David Gómez-Fernández, Ana Romero-González, Juan M. Suárez-Rivero, Paula Cilleros-Holgado, Mónica Álvarez-Córdoba, Rocío Piñero-Pérez, José Manuel Romero-Domínguez, Diana Reche-López, Alejandra López-Cabrera, Salvador Ibáñez-Mico, Marta Castro de Oliveira, Andrés Rodríguez-Sacristán, Susana González-Granero, José Manuel García-Verdugo, and José A. Sánchez-Alcázar. A multi-target pharmacological correction of a lipoyltransferase lipt1 gene mutation in patient-derived cellular models. Antioxidants, 13:1023, Aug 2024. URL: https://doi.org/10.3390/antiox13081023, doi:10.3390/antiox13081023. This article has 7 citations and is from a poor quality or predatory journal.

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