Gamma-glutamylcysteine synthetase deficiency (glutamate-cysteine ligase, GCL, deficiency) is an ultra-rare autosomal recessive inborn error of the gamma-glutamyl cycle caused by biallelic variants in GCLC, the catalytic subunit of glutamate-cysteine ligase. GCL catalyses the first and rate-limiting step of glutathione biosynthesis, the ATP-dependent ligation of glutamate and cysteine to form gamma-glutamylcysteine; the holoenzyme is a heterodimer of the GCLC catalytic subunit and the GCLM regulatory subunit. Loss of activity depletes cellular glutathione, and because the erythrocyte depends on glutathione as its principal antioxidant, the constant and defining manifestation is chronic non-spherocytic hemolytic anemia, typically presenting in the neonatal period. A minority of reported patients additionally develop progressive neurological disease (spinocerebellar degeneration, ataxia, spasticity, peripheral neuropathy, cognitive impairment, myopathy) and generalized aminoaciduria; no genotype has been shown to predict that neurological arm, and its mechanism is unresolved. The disorder is distinguished from glutathione synthetase deficiency, the other glutathione biosynthetic defect, by the absence of 5-oxoprolinuria: because the enzymatic block is at the first step, gamma-glutamylcysteine is not overproduced and cannot be cyclised to 5-oxoproline.
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name: Gamma-Glutamylcysteine Synthetase Deficiency
category: Mendelian
creation_date: '2026-08-17T00:00:00Z'
synonyms:
- Glutamate-cysteine ligase deficiency
- GCL deficiency
- GCLC deficiency
- Gamma-GCS deficiency
- Hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency
- Anemia, congenital, nonspherocytic hemolytic, 7
description: >
Gamma-glutamylcysteine synthetase deficiency (glutamate-cysteine ligase, GCL,
deficiency) is an ultra-rare autosomal recessive inborn error of the
gamma-glutamyl cycle caused by biallelic variants in GCLC, the catalytic
subunit of glutamate-cysteine ligase. GCL catalyses the first and
rate-limiting step of glutathione biosynthesis, the ATP-dependent ligation of
glutamate and cysteine to form gamma-glutamylcysteine; the holoenzyme is a
heterodimer of the GCLC catalytic subunit and the GCLM regulatory subunit.
Loss of activity depletes cellular glutathione, and because the erythrocyte
depends on glutathione as its principal antioxidant, the constant and defining
manifestation is chronic non-spherocytic hemolytic anemia, typically presenting
in the neonatal period. A minority of reported patients additionally develop
progressive neurological disease (spinocerebellar degeneration, ataxia,
spasticity, peripheral neuropathy, cognitive impairment, myopathy) and
generalized aminoaciduria; no genotype has been shown to predict that
neurological arm, and its mechanism is unresolved. The disorder is
distinguished from glutathione synthetase deficiency, the other glutathione
biosynthetic defect, by the absence of 5-oxoprolinuria: because the enzymatic
block is at the first step, gamma-glutamylcysteine is not overproduced and
cannot be cyclised to 5-oxoproline.
disease_term:
preferred_term: gamma-glutamylcysteine synthetase deficiency
term:
id: MONDO:0009259
label: gamma-glutamylcysteine synthetase deficiency
parents:
- Inherited Glutathione Metabolism Disease
- Inborn Error of Metabolism
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: BELOW_1_IN_1000000
notes: >
Ultra-rare. A 2024 review of the published literature counted 12 cases from
6 independent families worldwide; a 2025 case report using a different
counting convention gives nine patients from seven families. No
population-based prevalence estimate exists, so the published case count is
the meaningful figure and no numeric rate is asserted.
evidence:
- reference: PMID:39359943
reference_title: "Clinical and Biochemical Analysis of Glutamate-Cysteine Ligase Deficiency Presented with Late-Onset Spinocerebellar Ataxia and Hemolytic Anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GCLC deficiency manifesting with hemolysis has been reported in 12 cases worldwide from 6 independent families, with only 4 cases having additional neurological manifestations."
explanation: Gives the published worldwide case count and the fraction with neurological involvement.
- reference: PMID:40277844
reference_title: "Hemolytic Anemia Due to Gamma-Glutamylcysteine Synthetase Deficiency: A Rare Novel Case in an Arab-Muslim Israeli Child."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Gamma-glutamylcysteine synthetase deficiency is a very rare condition that has so far been detected so far in nine patients from seven families worldwide."
explanation: >-
A later report gives a lower worldwide tally than the 2024 review, nine
patients from seven families against twelve from six. Both are counts of
published cases and either supports the ultra-rare class asserted here;
neither is a population-based estimate, and the notes record the
discrepancy rather than reconciling it.
progression:
- phase: Neonatal-onset hemolytic anemia
notes: >
Presentation is typically in the neonatal period with hemolytic anemia,
reticulocytosis and jaundice, sometimes severe enough to require transfusion.
In the mild non-neurological form the hemolysis abates after the neonatal
period, leaving a chronic compensated or mild anemia.
evidence:
- reference: PMID:28571779
reference_title: "Clinical and molecular characterization of 6 children with glutamate-cysteine ligase deficiency causing hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All the children presented with neonatal hemolytic anemia. Beyond the neonatal period, they did not have jaundice or hemolysis, but continued to have mild anemia."
explanation: Documents neonatal onset followed by a chronic mild anemia in the non-neurological form.
- phase: Divergence into a non-neurological and a neurological course
notes: >
Two clinical courses are recognised. Most patients have hemolytic anemia
alone with normal development. A minority develop progressive neurological
disease, which in the most recently reported case did not become manifest
until the sixth decade, so the neurological arm cannot be excluded by a
normal childhood examination.
evidence:
- reference: PMID:28571779
reference_title: "Clinical and molecular characterization of 6 children with glutamate-cysteine ligase deficiency causing hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GCL deficiency can have a mild non-neurological phenotype or a more severe phenotype with neurological manifestations."
explanation: States the two-course clinical division explicitly.
- reference: PMID:39359943
reference_title: "Clinical and Biochemical Analysis of Glutamate-Cysteine Ligase Deficiency Presented with Late-Onset Spinocerebellar Ataxia and Hemolytic Anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report a 55-year-old female patient with progressive late-onset ataxia, lower limb spasticity, and chronic hemolytic anemia found to have a GCLC pathogenic variant and low glutathione level."
explanation: Documents late-onset (sixth-decade) emergence of the neurological arm.
pathophysiology:
- name: Destabilized GCLC-GCLM holoenzyme
biological_scale: MOLECULAR
description: >
Glutamate-cysteine ligase is a heterodimer of a catalytic subunit (GCLC) and
a regulatory/modifier subunit (GCLM), the latter enhancing catalytic
efficiency on heterodimer formation. Recombinant characterization of the
clinical GCLC missense alleles shows that they do not all fail the same way:
Arg127Cys, His370Leu and Pro414Leu have intrinsically compromised catalysis
that is largely rescued by adding GCLM, whereas Pro158Leu has near-wild-type
kinetic constants and is instead inferred to be destabilized in vivo through
failure to form or persist as the heterodimer. This node captures that
variant-specific, holoenzyme-level lesion upstream of the measured enzyme
deficiency.
genes:
- preferred_term: GCLC
term:
id: hgnc:4311
label: GCLC
- preferred_term: GCLM
term:
id: hgnc:4312
label: GCLM
molecular_functions:
- preferred_term: glutamate-cysteine ligase activity
term:
id: GO:0004357
label: glutamate-cysteine ligase activity
modifier: DECREASED
genetic_context:
description: >
Biallelic hypomorphic missense variants in GCLC; reported patients are
homozygous, frequently in consanguineous kindreds. Complete loss of GCLC
has not been observed in patients.
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
zygosity: HOMOZYGOUS
variant_origin: GERMLINE
evidence:
- reference: PMID:21657237
reference_title: "Enzymatic defects underlying hereditary glutamate cysteine ligase deficiency are mitigated by association of the catalytic and regulatory subunits."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Kinetic characterizations of the recombinant GCLC mutants indicated that the Arg127Cys, His370Leu, and Pro414Leu mutants have compromised enzymatic activity that can largely be rescued by the addition of GCLM. Interestingly, the Pro158Leu mutant has kinetic constants comparable to those of wild-type GCLC, suggesting that heterodimer formation is needed for stability in vivo."
explanation: >-
Establishes two distinct molecular failure modes among the clinical GCLC
alleles - impaired catalysis versus impaired heterodimer-dependent
stability - and the modifier role of GCLM.
- reference: PMID:28571779
reference_title: "Clinical and molecular characterization of 6 children with glutamate-cysteine ligase deficiency causing hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GCL is composed of a catalytic subunit encoded by the GCLC gene and a regulatory subunit encoded by the GCLM gene."
explanation: Establishes the two-subunit composition of the affected holoenzyme.
downstream:
- target: Reduced glutamate-cysteine ligase activity
causal_link_type: DIRECT
description: >
Loss of catalytic competence or of heterodimer-dependent stability reduces
measurable glutamate-cysteine ligase activity.
evidence:
- reference: PMID:21657237
reference_title: "Enzymatic defects underlying hereditary glutamate cysteine ligase deficiency are mitigated by association of the catalytic and regulatory subunits."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The four mutant transfectants each had significantly lower levels of glutathione relative to that of the wild type, with the Pro414Leu mutant being most compromised."
explanation: Transfection of each clinical allele into GCLC-null cells reduces glutathione output, the functional consequence of the enzyme lesion.
- name: Reduced glutamate-cysteine ligase activity
biological_scale: MOLECULAR
description: >
Glutamate-cysteine ligase catalyses the first and rate-limiting step of
glutathione biosynthesis, the ATP-dependent ligation of glutamate and
cysteine to gamma-glutamylcysteine. Erythrocyte enzyme activity in affected
homozygotes has been measured at under 2% of normal, with heterozygous
relatives at roughly half-normal activity. Because the block is at the first
step, both gamma-glutamylcysteine and glutathione fall - the biochemical
signature that separates this disorder from glutathione synthetase
deficiency, in which gamma-glutamylcysteine instead accumulates.
genes:
- preferred_term: GCLC
term:
id: hgnc:4311
label: GCLC
molecular_functions:
- preferred_term: glutamate-cysteine ligase activity
term:
id: GO:0004357
label: glutamate-cysteine ligase activity
modifier: DECREASED
biological_processes:
- preferred_term: glutathione biosynthetic process
term:
id: GO:0006750
label: glutathione biosynthetic process
modifier: DECREASED
chemical_entities:
- preferred_term: L-gamma-glutamyl-L-cysteine
term:
id: CHEBI:17515
label: L-gamma-glutamyl-L-cysteine
modifier: DECREASED
evidence:
- reference: PMID:12663448
reference_title: "A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Gamma-glutamylcysteine synthetase (gamma-GCS) catalyzes the first and rate-limiting step in glutathione (GSH) biosynthesis: the adenosine triphosphate (ATP)-dependent ligation of glutamate and cysteine."
explanation: Defines the catalysed reaction and its rate-limiting position in glutathione biosynthesis.
- reference: PMID:10733484
reference_title: "A missense mutation in the heavy subunit of gamma-glutamylcysteine synthetase gene causes hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The enzyme defect was confirmed and GCS activity was found to be less than 2% of normal in the erythrocytes of both patients."
explanation: Quantifies the residual erythrocyte enzyme activity in affected patients.
- reference: PMID:10515893
reference_title: "The molecular basis of a case of gamma-glutamylcysteine synthetase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A patient with hemolytic anemia and low red blood cell glutathione levels was found to have a deficiency of gamma-glutamylcysteine synthetase activity."
explanation: >-
The first molecular characterization of the disorder, tying measured
enzyme deficiency to hemolytic anemia with low red-cell glutathione.
downstream:
- target: Cellular glutathione depletion
causal_link_type: DIRECT
description: >
Blockade of the rate-limiting biosynthetic step lowers cellular
glutathione, most conspicuously in the erythrocyte.
evidence:
- reference: PMID:10733484
reference_title: "A missense mutation in the heavy subunit of gamma-glutamylcysteine synthetase gene causes hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hereditary deficiency of GCS has been reported in 6 patients with hemolytic anemia and low erythrocyte levels of glutathione and gamma-glutamylcysteine."
explanation: Directly links the enzyme deficiency to low erythrocyte glutathione and gamma-glutamylcysteine.
- name: Cellular glutathione depletion
biological_scale: CELLULAR
conforms_to: "hemolytic_anemia_erythrocyte_destruction#Reduced Erythrocyte Integrity"
description: >
Glutathione is the erythrocyte's principal sulfhydryl antioxidant and a
general cellular redox buffer and enzyme cofactor. Affected patients have
markedly reduced erythrocyte glutathione, which removes the red cell's main
defence against oxidative injury. Glutathione was effectively absent in a
severely affected GCL-deficient proband. A three-patient Japanese series
reported values of 4.4%, 13.1% and 6.9% of normal, but only two of those
three patients had GCL deficiency (the third had glutathione synthetase
deficiency) and the report does not say which value belongs to which enzyme
defect, so that range is indicative of glutathione-synthesis defects
generally rather than GCL-specific. This is the
disease-specific substitution for the module's generic intrinsic erythrocyte
lesion.
cell_types:
- preferred_term: erythrocyte
term:
id: CL:0000232
label: erythrocyte
biological_processes:
- preferred_term: glutathione metabolic process
term:
id: GO:0006749
label: glutathione metabolic process
modifier: DECREASED
- preferred_term: cell redox homeostasis
term:
id: GO:0045454
label: cell redox homeostasis
modifier: DECREASED
chemical_entities:
- preferred_term: glutathione
term:
id: CHEBI:16856
label: glutathione
modifier: DECREASED
evidence:
- reference: PMID:8634459
reference_title: "Three cases of hereditary nonspherocytic hemolytic anemia associated with red blood cell glutathione deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "marked deficiency of red blood cell (RBC) reduced glutathoine (GSH) (4.4%, 13.1%, and 6.9% of normal, respectively)"
explanation: >-
Quantifies erythrocyte glutathione depletion in a three-patient series of
red-cell glutathione-synthesis defects. Two of the three were GCL
deficient and one had glutathione synthetase deficiency, and the paper
does not assign the three values to individual enzymes, so this supports
marked depletion in this disorder without establishing a GCL-specific
range.
- reference: PMID:21657237
reference_title: "Enzymatic defects underlying hereditary glutamate cysteine ligase deficiency are mitigated by association of the catalytic and regulatory subunits."
supports: SUPPORT
evidence_source: OTHER
snippet: "Glutamate cysteine ligase (GCL) deficiency is a rare autosomal recessive trait that compromises production of glutathione, a critical redox buffer and enzymatic cofactor."
explanation: >-
States the role of glutathione as redox buffer and cofactor whose
production is compromised. Marked OTHER because this framing sentence
summarizes the disorder rather than reporting this paper's own experiment.
downstream:
- target: Oxidative erythrocyte injury
causal_link_type: DIRECT
description: >
Loss of the erythrocyte's principal antioxidant leaves haemoglobin and the
red-cell membrane exposed to oxidative damage.
evidence:
- reference: PMID:21657237
reference_title: "Enzymatic defects underlying hereditary glutamate cysteine ligase deficiency are mitigated by association of the catalytic and regulatory subunits."
supports: SUPPORT
evidence_source: OTHER
snippet: "Patients have markedly reduced levels of erythrocyte glutathione, leading to hemolytic anemia and, in some cases, impaired neurological function."
explanation: States the causal step from erythrocyte glutathione depletion to hemolysis.
- target: Progressive neurological dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >
In a minority of patients, systemic glutathione depletion is associated
with progressive neuromuscular and spinocerebellar disease. The
intermediate steps, and why only some patients are affected, are unknown;
no GCLC genotype has been shown to predict it.
evidence:
- reference: PMID:17397529
reference_title: "Inborn errors in the metabolism of glutathione."
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: "Gamma-glutamylcysteine synthetase deficiency is also associated with hemolytic\nanemia, and some patients with this disorder show defects of neuromuscular\nfunction and generalized aminoaciduria."
explanation: >-
Review records that some patients show neuromuscular dysfunction. It
asserts co-occurrence with the deficiency rather than the causal step
from glutathione depletion, so this edge follows by an inference the
node description already flags as having unknown intermediates.
- name: Oxidative erythrocyte injury
biological_scale: CELLULAR
conforms_to: "hemolytic_anemia_erythrocyte_destruction#Oxidative and Membrane Injury"
description: >
Without glutathione the erythrocyte cannot reduce peroxides or maintain
protein and membrane sulfhydryls, so reactive oxygen species progressively
damage haemoglobin and the red-cell membrane. This is the disease-specific
amplification step in a red cell that is otherwise structurally and
enzymatically normal - the peripheral smear, Coombs test, G6PD assay and
spherocytosis screen are all normal in these patients, which is why the
diagnosis is easily missed.
cell_types:
- preferred_term: erythrocyte
term:
id: CL:0000232
label: erythrocyte
biological_processes:
- preferred_term: response to oxidative stress
term:
id: GO:0006979
label: response to oxidative stress
modifier: INCREASED
evidence:
- reference: PMID:40277844
reference_title: "Hemolytic Anemia Due to Gamma-Glutamylcysteine Synthetase Deficiency: A Rare Novel Case in an Arab-Muslim Israeli Child."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Investigation for common causes of hemolytic anemia was negative (peripheral blood smear was normal, and he had a negative Coombs test, normal G6PD, and normal flow cytometry spherocytosis)."
explanation: >-
Documents that the standard hemolysis workup is normal, supporting an
oxidative-antioxidant lesion rather than a membrane, immune or glycolytic
defect.
- reference: PMID:18024385
reference_title: "Chronic non-spherocytic hemolytic anemia associated with severe neurological disease due to gamma-glutamylcysteine synthetase deficiency in a patient of Moroccan origin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The activity of glycolytic enzymes were found to be normal in the propositus"
explanation: Excludes a glycolytic-enzyme cause, isolating the antioxidant defect as the operative red-cell lesion.
downstream:
- target: Premature erythrocyte destruction
causal_link_type: DIRECT
description: >
Oxidatively injured erythrocytes are cleared prematurely from the
circulation.
evidence:
- reference: PMID:12663448
reference_title: "A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hereditary deficiency of gamma-GCS has been reported in a small number of patients and is associated with low erythrocyte levels of gamma-GCS and GSH leading to hemolytic anemia."
explanation: States the causal chain from low erythrocyte enzyme and glutathione to hemolytic anemia.
- name: Premature erythrocyte destruction
biological_scale: TISSUE
conforms_to: "hemolytic_anemia_erythrocyte_destruction#Premature Erythrocyte Destruction"
description: >
Oxidatively damaged red cells are destroyed before their normal lifespan,
producing chronic non-spherocytic hemolytic anemia with reticulocytosis and
jaundice, and hepatosplenomegaly in some patients. Severity is variable, from
a compensated hemolysis discovered in a 68-year-old proband to
transfusion-dependent neonatal anemia.
cell_types:
- preferred_term: erythrocyte
term:
id: CL:0000232
label: erythrocyte
biological_processes:
- preferred_term: erythrocyte clearance
term:
id: GO:0034102
label: erythrocyte clearance
modifier: INCREASED
evidence:
- reference: PMID:9679548
reference_title: "Patients with genetic defects in the gamma-glutamyl cycle."
supports: SUPPORT
evidence_source: OTHER
snippet: "In gamma-GC synthetase deficiency hemolytic anemia is the most prominent symptom, with or without hepatosplenomegaly."
explanation: Review identifies hemolytic anemia, with or without hepatosplenomegaly, as the dominant manifestation.
- reference: PMID:10733484
reference_title: "A missense mutation in the heavy subunit of gamma-glutamylcysteine synthetase gene causes hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The proband was a 68-year-old woman with a history of transient jaundice and compensated hemolytic anemia."
explanation: Documents the mild, compensated end of the hemolytic spectrum.
downstream:
- target: Chronic non-spherocytic hemolytic anemia
causal_link_type: DIRECT
description: Sustained premature red-cell destruction produces the chronic anemia.
evidence:
- reference: PMID:8634459
reference_title: "Three cases of hereditary nonspherocytic hemolytic anemia associated with red blood cell glutathione deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Three unrelated Japanese patients with chronic nonspherocytic hemolytic anemia"
explanation: Identifies the resulting clinical entity as chronic non-spherocytic hemolytic anemia.
- name: Chronic non-spherocytic hemolytic anemia
biological_scale: ORGANISM
conforms_to: "hemolytic_anemia_erythrocyte_destruction#Hemolytic Anemia"
description: >
The defining and universal clinical consequence. It presents neonatally with
anemia, reticulocytosis and jaundice, may require transfusion in the newborn
period, and settles into a chronic mild anemia in patients without
neurological involvement.
evidence:
- reference: PMID:28571779
reference_title: "Clinical and molecular characterization of 6 children with glutamate-cysteine ligase deficiency causing hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GCL deficiency can be an underdiagnosed cause of hemolytic anemia, thus awareness may aid in early diagnosis, appropriate genetic counseling, and management."
explanation: Frames hemolytic anemia as the presenting and diagnostically decisive manifestation.
- name: Progressive neurological dysfunction
biological_scale: ORGANISM
description: >
A minority of reported patients - 4 of the 12 in the published literature -
develop progressive neurological disease. The reported constellation spans
spinocerebellar degeneration with cerebellar atrophy, ataxia, lower-limb
spasticity, motor-sensory peripheral neuropathy, cognitive impairment and
myopathy, and may not appear until adulthood. Some of these patients also
have generalized aminoaciduria, consistent with the gamma-glutamyl cycle's
role in amino-acid transport. No GCLC genotype has been shown to predict the
neurological arm, and the mechanism connecting glutathione depletion to
neurodegeneration in this disorder is unresolved (see the knowledge-gap
discussion). The node is therefore modelled as a consequence with unknown
intermediates rather than being wired into a specific neurodegeneration
module.
evidence:
- reference: PMID:28571779
reference_title: "Clinical and molecular characterization of 6 children with glutamate-cysteine ligase deficiency causing hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All presented with hemolytic anemia and 4 had additional neurological manifestations including cognitive impairment, neuropathy, ataxia, and myopathy."
explanation: Enumerates the neurological manifestations and their restriction to a subset of patients.
- reference: PMID:39359943
reference_title: "Clinical and Biochemical Analysis of Glutamate-Cysteine Ligase Deficiency Presented with Late-Onset Spinocerebellar Ataxia and Hemolytic Anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "To date, no specific GCLC gene mutation has been attributed to the reported neurological constellation of symptoms."
explanation: Establishes the absence of a genotype-phenotype correlation for the neurological arm.
- reference: PMID:18024385
reference_title: "Chronic non-spherocytic hemolytic anemia associated with severe neurological disease due to gamma-glutamylcysteine synthetase deficiency in a patient of Moroccan origin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He presented with chronic haemolytic anaemia, delayed psychomotor development and progressive motor sensitive neuropathy of lower extremities."
explanation: Case documenting the combined hemolytic and progressive neuropathic presentation.
phenotypes:
- category: Hematologic
name: Hemolytic anemia
frequency: VERY_FREQUENT
description: >
Chronic non-spherocytic hemolytic anemia is present in every reported
patient and is usually the presenting feature in the neonatal period.
phenotype_term:
preferred_term: Hemolytic anemia
term:
id: HP:0001878
label: Hemolytic anemia
evidence:
- reference: PMID:28571779
reference_title: "Clinical and molecular characterization of 6 children with glutamate-cysteine ligase deficiency causing hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All presented with hemolytic anemia and 4 had additional neurological manifestations including cognitive impairment, neuropathy, ataxia, and myopathy."
explanation: All reported patients in the reviewed series had hemolytic anemia.
- category: Hematologic
name: Reticulocytosis
frequency: FREQUENT
description: Compensatory reticulocytosis accompanies the neonatal hemolysis.
phenotype_term:
preferred_term: Reticulocytosis
term:
id: HP:0001923
label: Reticulocytosis
evidence:
- reference: PMID:40277844
reference_title: "Hemolytic Anemia Due to Gamma-Glutamylcysteine Synthetase Deficiency: A Rare Novel Case in an Arab-Muslim Israeli Child."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "presented at the age of 2 days with severe anemia, reticulocytosis, and leukocytosis"
explanation: Neonatal presentation with reticulocytosis.
- category: Hematologic
name: Prolonged neonatal jaundice
frequency: FREQUENT
description: >
Neonatal jaundice from hemolysis is a common presenting sign; a reported
proband's grandson came to attention through a history of neonatal jaundice.
phenotype_term:
preferred_term: Prolonged neonatal jaundice
term:
id: HP:0006579
label: Prolonged neonatal jaundice
evidence:
- reference: PMID:10733484
reference_title: "A missense mutation in the heavy subunit of gamma-glutamylcysteine synthetase gene causes hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "he was 11 years old and had a history of neonatal jaundice"
explanation: Records neonatal jaundice in a genetically confirmed patient.
- category: Hepatic
name: Hepatosplenomegaly
frequency: OCCASIONAL
description: Hepatosplenomegaly accompanies the hemolysis in some patients.
phenotype_term:
preferred_term: Hepatosplenomegaly
term:
id: HP:0001433
label: Hepatosplenomegaly
evidence:
- reference: PMID:9679548
reference_title: "Patients with genetic defects in the gamma-glutamyl cycle."
supports: SUPPORT
evidence_source: OTHER
snippet: "In gamma-GC synthetase deficiency hemolytic anemia is the most prominent symptom, with or without hepatosplenomegaly."
explanation: Review notes hepatosplenomegaly as a variable accompaniment.
- category: Neurologic
name: Progressive cerebellar ataxia
frequency: OCCASIONAL
description: >
Spinocerebellar degeneration with progressive ataxia occurs in the
neurological subset and may present as late as the sixth decade.
phenotype_term:
preferred_term: Progressive cerebellar ataxia
term:
id: HP:0002073
label: Progressive cerebellar ataxia
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:39359943
reference_title: "Clinical and Biochemical Analysis of Glutamate-Cysteine Ligase Deficiency Presented with Late-Onset Spinocerebellar Ataxia and Hemolytic Anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report a 55-year-old female patient with progressive late-onset ataxia, lower limb spasticity, and chronic hemolytic anemia found to have a GCLC pathogenic variant and low glutathione level."
explanation: Documents progressive late-onset ataxia in a genetically confirmed patient.
- category: Neurologic
name: Cerebellar atrophy
frequency: OCCASIONAL
description: Global cerebellar atrophy was demonstrated on MRI in the reported late-onset ataxic patient.
phenotype_term:
preferred_term: Cerebellar atrophy
term:
id: HP:0001272
label: Cerebellar atrophy
evidence:
- reference: PMID:39359943
reference_title: "Clinical and Biochemical Analysis of Glutamate-Cysteine Ligase Deficiency Presented with Late-Onset Spinocerebellar Ataxia and Hemolytic Anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Magnetic resonance imaging of the head and cervical spine showed global cerebellar atrophy with widened folia"
explanation: Imaging confirmation of cerebellar atrophy.
- category: Neurologic
name: Spasticity
frequency: OCCASIONAL
description: Lower-limb spasticity was part of the late-onset spinocerebellar presentation.
phenotype_term:
preferred_term: Spasticity
term:
id: HP:0001257
label: Spasticity
evidence:
- reference: PMID:39359943
reference_title: "Clinical and Biochemical Analysis of Glutamate-Cysteine Ligase Deficiency Presented with Late-Onset Spinocerebellar Ataxia and Hemolytic Anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "progressive late-onset ataxia, lower limb spasticity, and chronic hemolytic anemia"
explanation: Records lower-limb spasticity in the neurological subset.
- category: Neurologic
name: Peripheral neuropathy
frequency: OCCASIONAL
description: >
Progressive motor-sensory neuropathy of the lower extremities is reported in
the neurological subset.
phenotype_term:
preferred_term: Peripheral neuropathy
term:
id: HP:0009830
label: Peripheral neuropathy
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:18024385
reference_title: "Chronic non-spherocytic hemolytic anemia associated with severe neurological disease due to gamma-glutamylcysteine synthetase deficiency in a patient of Moroccan origin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "progressive motor sensitive neuropathy of lower extremities"
explanation: Documents progressive motor-sensory peripheral neuropathy.
- category: Neurologic
name: Cognitive impairment
frequency: OCCASIONAL
description: Cognitive impairment is among the neurological manifestations of the affected subset.
phenotype_term:
preferred_term: Cognitive impairment
term:
id: HP:0100543
label: Cognitive impairment
evidence:
- reference: PMID:28571779
reference_title: "Clinical and molecular characterization of 6 children with glutamate-cysteine ligase deficiency causing hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "4 had additional neurological manifestations including cognitive impairment, neuropathy, ataxia, and myopathy"
explanation: Lists cognitive impairment among the neurological features.
- category: Musculoskeletal
name: Myopathy
frequency: OCCASIONAL
description: Myopathy is reported among the neuromuscular manifestations.
phenotype_term:
preferred_term: Myopathy
term:
id: HP:0003198
label: Myopathy
evidence:
- reference: PMID:28571779
reference_title: "Clinical and molecular characterization of 6 children with glutamate-cysteine ligase deficiency causing hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "4 had additional neurological manifestations including cognitive impairment, neuropathy, ataxia, and myopathy"
explanation: Lists myopathy among the neurological features.
- category: Renal
name: Aminoaciduria
frequency: OCCASIONAL
description: >
Generalized aminoaciduria has been reported in patients who also developed
neurological symptoms, consistent with the gamma-glutamyl cycle's role in
membrane amino-acid transport.
phenotype_term:
preferred_term: Generalized aminoaciduria
term:
id: HP:0002909
label: Generalized aminoaciduria
evidence:
- reference: PMID:10733484
reference_title: "A missense mutation in the heavy subunit of gamma-glutamylcysteine synthetase gene causes hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "2 patients also had generalized aminoaciduria and developed neurologic symptoms"
explanation: Reports generalized aminoaciduria co-occurring with neurological involvement.
biochemical:
- name: Reduced erythrocyte glutathione
presence: DECREASED
context: >
Markedly reduced erythrocyte reduced glutathione is the biochemical hallmark
and the finding that first directs the workup towards a glutathione-synthesis
defect. Reported values range from a few percent of normal to effectively
absent.
biomarker_term:
preferred_term: glutathione
term:
id: CHEBI:16856
label: glutathione
readouts:
- target: Cellular glutathione depletion
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
interpretation: Erythrocyte glutathione concentration directly reports the depleted cellular glutathione pool.
evidence:
- reference: PMID:18024385
reference_title: "Chronic non-spherocytic hemolytic anemia associated with severe neurological disease due to gamma-glutamylcysteine synthetase deficiency in a patient of Moroccan origin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a complete lack of GSH was found in the propositus"
explanation: Demonstrates profound erythrocyte glutathione depletion in a severely affected patient.
- reference: PMID:8634459
reference_title: "Three cases of hereditary nonspherocytic hemolytic anemia associated with red blood cell glutathione deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "marked deficiency of red blood cell (RBC) reduced glutathoine (GSH) (4.4%, 13.1%, and 6.9% of normal, respectively)"
explanation: >-
Quantifies the degree of erythrocyte glutathione deficiency across a
three-patient series of glutathione-synthesis defects. Only two of the
three were GCL deficient and the values are not assigned per enzyme, so
the figures are not a GCL-specific range.
- name: Reduced erythrocyte glutamate-cysteine ligase activity
presence: DECREASED
context: >
Direct enzyme assay in erythrocytes is the confirmatory functional test;
affected homozygotes have under 2% of normal activity and heterozygous
carriers roughly half-normal activity, so the assay also identifies carriers.
readouts:
- target: Reduced glutamate-cysteine ligase activity
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
interpretation: Measured erythrocyte enzyme activity is the direct functional readout of the GCLC lesion.
evidence:
- reference: PMID:10733484
reference_title: "A missense mutation in the heavy subunit of gamma-glutamylcysteine synthetase gene causes hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GCS activity was found to be less than 2% of normal in the erythrocytes of both patients"
explanation: Establishes the residual enzyme activity in affected individuals.
- reference: PMID:10733484
reference_title: "A missense mutation in the heavy subunit of gamma-glutamylcysteine synthetase gene causes hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Several family members with half-normal GCS activity in their erythrocytes were heterozygous for the mutation."
explanation: Supports gene-dosage-proportional enzyme activity and carrier detection by assay.
- name: Reduced erythrocyte gamma-glutamylcysteine
presence: DECREASED
context: >
Because the block is at the first biosynthetic step, the immediate product
gamma-glutamylcysteine is low - the opposite of glutathione synthetase
deficiency, where it accumulates and is cyclised to 5-oxoproline. This
contrast is the key discriminating biochemistry between the two disorders,
and explains why 5-oxoprolinuria is absent here.
biomarker_term:
preferred_term: L-gamma-glutamyl-L-cysteine
term:
id: CHEBI:17515
label: L-gamma-glutamyl-L-cysteine
readouts:
- target: Reduced glutamate-cysteine ligase activity
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
interpretation: Low gamma-glutamylcysteine localizes the enzymatic block to the first step of glutathione synthesis.
evidence:
- reference: PMID:10733484
reference_title: "A missense mutation in the heavy subunit of gamma-glutamylcysteine synthetase gene causes hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "low erythrocyte levels of glutathione and gamma-glutamylcysteine"
explanation: Both the product and the intermediate are low, locating the block at the first step.
- reference: PMID:9679548
reference_title: "Patients with genetic defects in the gamma-glutamyl cycle."
supports: SUPPORT
evidence_source: OTHER
snippet: "In generalized GSH synthetase deficiency 5-oxoproline is overproduced due to lack of feedback inhibition of gamma-GC synthetase."
explanation: >-
Explains why 5-oxoproline overproduction requires an intact
gamma-glutamylcysteine synthetase, and so cannot occur when that enzyme is
itself deficient.
treatments:
- name: Antioxidant supplementation and avoidance of oxidative triggers
description: >
There is no disease-modifying therapy. Management of the glutathione
synthesis defects aims to avoid hemolytic crises and increase defence
against reactive oxygen species, using high-dose vitamins E and C and
avoidance of the drugs that precipitate hemolysis in G6PD deficiency. The
evidence base is small case series and expert review, not trials.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
therapeutic_agent:
- preferred_term: vitamin E
term:
id: CHEBI:33234
label: vitamin E
- preferred_term: L-ascorbic acid
term:
id: CHEBI:29073
label: L-ascorbic acid
therapeutic_modality: SMALL_MOLECULE
target_phenotypes:
- preferred_term: Hemolytic anemia
term:
id: HP:0001878
label: Hemolytic anemia
target_mechanisms:
- target: Oxidative erythrocyte injury
treatment_effect: INHIBITS
description: >
Antioxidant supplementation and trigger avoidance are directed at the
oxidative-injury step, the only point in the chain reachable without
restoring enzyme activity.
evidence:
- reference: PMID:17397529
reference_title: "Inborn errors in the metabolism of glutathione."
supports: SUPPORT
evidence_source: OTHER
snippet: "The aims of the\ntreatment of glutathione synthesis defects are to avoid hemolytic crises and to\nincrease the defense against reactive oxygen species."
explanation: States the therapeutic target as reducing oxidative stress and hemolytic crises.
evidence:
- reference: PMID:9679548
reference_title: "Patients with genetic defects in the gamma-glutamyl cycle."
supports: SUPPORT
evidence_source: OTHER
snippet: "Treatment includes acidosis correction, high doses of vitamin E and C and avoidance of drugs precipitating hemolytic crises in G6PD deficiency."
explanation: >-
Review states the management of gamma-glutamyl-cycle defects; acidosis
correction applies to the 5-oxoprolinuric disorders rather than to this
one, so only the antioxidant and trigger-avoidance components are curated
here.
- name: Red blood cell transfusion for severe neonatal anemia
description: >
Transfusion is required when neonatal hemolysis produces severe anemia. In
the most recent reported case, haemoglobin fell to 7.2 g/dL in the first days
of life and several transfusions were needed.
treatment_term:
preferred_term: packed red blood cell transfusion
term:
id: NCIT:C15409
label: Packed Red Blood Cell Transfusion
therapeutic_modality: OTHER
target_phenotypes:
- preferred_term: Hemolytic anemia
term:
id: HP:0001878
label: Hemolytic anemia
evidence:
- reference: PMID:40277844
reference_title: "Hemolytic Anemia Due to Gamma-Glutamylcysteine Synthetase Deficiency: A Rare Novel Case in an Arab-Muslim Israeli Child."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The anemia worsened during the following days (hemoglobin (Hb): 7.2 g/dL) and he needed several blood transfusions."
explanation: Documents transfusion requirement for severe neonatal hemolytic anemia.
- name: High-dose alpha-lipoic acid and glutathione supplementation with physical therapy
description: >
A single reported patient with late-onset spinocerebellar degeneration was
given a trial of high-dose alpha-lipoic acid, glutathione supplementation and
physical therapy. This is an n-of-1 experience in one adult with the
neurological form; no outcome data establish efficacy, and it is recorded
here as reported management rather than as a recommended therapy.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
therapeutic_agent:
- preferred_term: lipoic acid
term:
id: CHEBI:16494
label: lipoic acid
- preferred_term: glutathione
term:
id: CHEBI:16856
label: glutathione
therapeutic_modality: SMALL_MOLECULE
target_phenotypes:
- preferred_term: Progressive cerebellar ataxia
term:
id: HP:0002073
label: Progressive cerebellar ataxia
evidence:
- reference: PMID:39359943
reference_title: "Clinical and Biochemical Analysis of Glutamate-Cysteine Ligase Deficiency Presented with Late-Onset Spinocerebellar Ataxia and Hemolytic Anemia."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Management encompassed a multidisciplinary approach with a trial of high-dose alpha-lipoic acid, glutathione supplement, and physical therapy."
explanation: >-
Directly reports the management given in this single case, which is what
this entry claims. No treatment effect is reported, so it substantiates
the intervention as reported management and not its efficacy.
inheritance:
- name: Autosomal recessive
description: >
Affected individuals are homozygous or compound heterozygous for GCLC
variants; several reported families are consanguineous. Heterozygous
relatives have roughly half-normal erythrocyte enzyme activity and are
clinically unaffected.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:40277844
reference_title: "Hemolytic Anemia Due to Gamma-Glutamylcysteine Synthetase Deficiency: A Rare Novel Case in an Arab-Muslim Israeli Child."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The inheritance of this disorder is autosomal recessive."
explanation: States the mode of inheritance.
- reference: PMID:39359943
reference_title: "Clinical and Biochemical Analysis of Glutamate-Cysteine Ligase Deficiency Presented with Late-Onset Spinocerebellar Ataxia and Hemolytic Anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GCLC gene mutation is an autosomal recessive biallelic mutation."
explanation: Confirms biallelic autosomal recessive inheritance.
genetic:
- name: GCLC variants
gene_term:
preferred_term: GCLC
term:
id: hgnc:4311
label: GCLC
variant_origin: GERMLINE
inheritance:
- name: Autosomal recessive
evidence:
- reference: PMID:39359943
reference_title: "Clinical and Biochemical Analysis of Glutamate-Cysteine Ligase Deficiency Presented with Late-Onset Spinocerebellar Ataxia and Hemolytic Anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GCLC gene mutation is an autosomal recessive biallelic mutation."
explanation: Establishes autosomal recessive biallelic inheritance.
variants:
- name: Biallelic GCLC missense variants
description: >
All disease alleles reported to date are missense and hypomorphic
(partial loss of function). The published set is c.379C>T (p.Arg127Cys),
c.473C>T (p.Pro158Leu), c.514T>A (p.Ser172Thr), c.1109A>T (p.His370Leu),
c.1241C>T (p.Pro414Leu) and c.1772G>A (p.Ser591Asn). Complete loss of GCLC
is not observed in patients.
evidence:
- reference: PMID:39359943
reference_title: "Clinical and Biochemical Analysis of Glutamate-Cysteine Ligase Deficiency Presented with Late-Onset Spinocerebellar Ataxia and Hemolytic Anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Previously reported mutations encompassing c.379C > T (p.R127C), c.1109A > T (p.H370L), c.473C > T (p.P158L), c.1241C > T (p.P414L), c.1772G > A (p.S591N), c.514T > A (p.S172T)."
explanation: Enumerates the reported pathogenic GCLC alleles.
- reference: PMID:12663448
reference_title: "A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Transfection studies showed that the mutation is associated with decreased GSH production, and binding studies using purified recombinant protein showed that the mutant protein has markedly decreased enzymatic activity compared to wild type."
explanation: Functional expression confirms a disease missense allele reduces both enzyme activity and glutathione output.
- name: Homozygous family-specific alleles in consanguineous kindreds
description: >
Reported families are frequently consanguineous, and affected sibships are
homozygous for a single family-specific allele - c.1772G>A (p.Ser591Asn)
and c.514T>A (p.Ser172Thr) in two consanguineous families, c.379C>T
(p.Arg127Cys) in an Arab-Muslim Israeli child.
evidence:
- reference: PMID:28571779
reference_title: "Clinical and molecular characterization of 6 children with glutamate-cysteine ligase deficiency causing hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The affected children from the first family had the homozygous mutation c.1772G>A (p.S591N) and the second family had the homozygous mutation c.514T>A (p.S172T) in GCLC."
explanation: Documents family-specific homozygous alleles in consanguineous kindreds.
features: >
Only six pathogenic GCLC alleles have been reported worldwide. Genotype does
not predict whether a patient develops the neurological phenotype: c.514T>A
(p.Ser172Thr) has been reported both in children with normal neurological
examinations and in an adult with late-onset spinocerebellar degeneration.
evidence:
- reference: PMID:39359943
reference_title: "Clinical and Biochemical Analysis of Glutamate-Cysteine Ligase Deficiency Presented with Late-Onset Spinocerebellar Ataxia and Hemolytic Anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "To date, no specific GCLC gene mutation has been attributed to the reported neurological constellation of symptoms."
explanation: States the absence of genotype-phenotype correlation for the neurological arm.
- reference: PMID:28571779
reference_title: "Clinical and molecular characterization of 6 children with glutamate-cysteine ligase deficiency causing hemolytic anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "They all had normal development and neurological examination."
explanation: >-
The children homozygous for c.514T>A had normal neurological examinations,
whereas the same allele was later reported in an adult with spinocerebellar
degeneration - direct support for the absence of genotype-phenotype
correlation.
discussions:
- discussion_id: gclc_neurological_arm_mechanism
prompt: >-
Why do only some patients with glutamate-cysteine ligase deficiency develop
progressive spinocerebellar and neuromuscular disease, and by what mechanism
does glutathione depletion injure the nervous system in this disorder?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Progressive neurological dysfunction
rationale: >-
Only 4 of the 12 published patients have neurological involvement, and no
GCLC genotype predicts it - the same c.514T>A allele appears in children with
normal neurological examinations and in an adult with late-onset
spinocerebellar degeneration. The causal edge from glutathione depletion to
neurodegeneration is therefore curated with unknown intermediates, and this
node is deliberately not wired to cerebellar_purkinje_degeneration or
peripheral_axonal_degeneration: asserting conformance would claim a
mechanistic route the literature does not yet supply. Candidate explanations
include a modifier locus, tissue-specific residual GCL activity, and
cumulative oxidative injury that only becomes clinically apparent after
decades - none of which has been tested.
proposed_experiments:
- experiment_id: exp_gclc_neuro_natural_history
name: Prospective neurological surveillance of a GCLC deficiency cohort
description: >-
Follow every genetically confirmed patient with serial neurological
examination, nerve conduction studies and brain MRI, since the reported
late-onset case shows a normal childhood examination cannot exclude the
neurological arm. Pair with tissue-accessible glutathione measurement to
test whether residual GCL activity outside the erythrocyte, rather than
genotype, stratifies risk.
evidence:
- reference: PMID:39359943
reference_title: "Clinical and Biochemical Analysis of Glutamate-Cysteine Ligase Deficiency Presented with Late-Onset Spinocerebellar Ataxia and Hemolytic Anemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "To date, no specific GCLC gene mutation has been attributed to the reported neurological constellation of symptoms."
explanation: Directly states the unresolved genotype-phenotype question this gap records.
notes: >-
Curated for IEMbase metabolic work-package WP-006 row 2.1.01.01 (issue #5561).
NEC preflight: MONDO:0009259 carries `RO:0004003 HGNC:4311 ! GCLC` and
`xref OMIM:230450`, both matching the seed row, and `RO:0004021 GO:0004357`
matching the curated molecular function.
Two modelling decisions worth flagging. First, the neurological arm is
deliberately left as an INDIRECT_UNKNOWN_INTERMEDIATES edge with a
KNOWLEDGE_GAP discussion rather than being wired to
cerebellar_purkinje_degeneration or peripheral_axonal_degeneration. The
literature reports the association and its restriction to a minority of
patients, but supplies no mechanism and no genotype correlation, so
conformance would assert more than the evidence carries. Second, the
variant-level heterogeneity found in vitro (impaired catalysis for
Arg127Cys/His370Leu/Pro414Leu versus impaired heterodimer-dependent stability
for Pro158Leu) is curated as its own upstream node rather than collapsed into
the enzyme-deficiency node, because it is the target of the only mechanistic
therapeutic proposal in the literature - promoting GCLC-GCLM heterodimer
formation.
Differential note: the closest disorder is glutathione synthetase deficiency
(GSS), the other glutathione biosynthetic defect, which also causes hemolytic
anemia. The two are separated by gamma-glutamylcysteine - low here (the block
is upstream of it) and high in GSS deficiency, where it is cyclised to
5-oxoproline to give 5-oxoprolinuria and metabolic acidosis. Neither
5-oxoprolinuria nor metabolic acidosis is a feature of this disorder, and its
absence is curated as a discriminating point on the "Reduced erythrocyte
gamma-glutamylcysteine" biochemical record rather than as a phenotype.