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Inheritance

1

Autosomal dominant inheritance HP:0000006

A single heterozygous CLPB missense variant is sufficient. All affected individuals reported to date carry a de novo variant, so no vertical transmission has been observed; offspring of an affected individual would have a 50% risk.

Autosomal dominant inheritance

Show evidence (5 references)

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"CLPB deficiency associated with specific heterozygous CLPB pathogenic variants is inherited in an autosomal dominant manner."

GeneReviews states the dominant mode of inheritance for the monoallelic form.

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"All individuals reported to date with autosomal dominant CLPB deficiency have the disorder as the result of a de novo CLPB pathogenic variant. Each child of an individual with a heterozygous CLPB pathogenic variant has a 50% chance of inheriting the pathogenic variant."

All reported cases are de novo, with a 50% risk to offspring.

PMID:34140661 SUPPORT Human clinical

"In each individual, we identified one of four different de novo monoallelic missense variants in CLPB."

Six unrelated probands each carried a de novo monoallelic CLPB variant.

+ 2 more references

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Discussions and Knowledge Gaps

1

Are 3-methylglutaconic aciduria type VIIA (dominant CLPB deficiency with neurological involvement) and severe congenital neutropenia type 9 (isolated neutropenia from heterozygous CLPB variants) two disorders or one disorder with variable expression?

KNOWLEDGE GAP OPEN gap_mgca7a_vs_scn9_boundary

Attached to

disease# pathophysiology#Dominant-Negative Inhibition of CLPB Disaggregase

Both are caused by heterozygous CLPB missense variants that inhibit wild-type CLPB dominant-negatively, and the arginine finger R561 is mutated in both. The distinction rests partly on 3-methylglutaconic aciduria, which was not measured in about half of the published neutropenia cases. A variant-level comparison of residual disaggregase activity against neurological outcome would test whether the two are a continuum.

Show evidence (2 references)

PMID:40194906 SUPPORT REVIEW SYNTHESIS Other

"It remains to be established whether the distinction between dominant CLPB deficiency (MGA 7A) and CLPB-SCN is scientifically valid or if these entities represent, in fact, one disorder."

Review stating that the boundary between the two dominant disorders is unresolved.

PMID:40194906 SUPPORT REVIEW SYNTHESIS Other

"The distinction based on the lack of 3-MGA-uria in isolated CLPB-related neutropenia needs to be further studied, as this parameter was not assessed in 9 out of 20 published cases, since it had not been linked with neutropenia before."

The biochemical criterion separating the two was often not measured.

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Pathophysiology

7

Dominant-Negative Inhibition of CLPB Disaggregase

Mutant CLPB subunits carrying the dominant variants assemble with wild-type subunits into the hexameric and dodecameric disaggregase and poison it, abolishing most disaggregase activity and to a lesser degree ATPase activity. Subunits carrying the recessive (MGCA7) variants do not do this, which is why one recessive allele is harmless while one dominant allele causes disease.

CLPB hgnc:30664

Genetic context variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

ATP-dependent protein disaggregase activity GO:0140545 ↓ DECREASED ATP hydrolysis activity GO:0016887 ↓ DECREASED

mitochondrial intermembrane space GO:0005758

Downstream

Intermembrane Space Protein Aggregation

Neurodevelopmental Dysfunction

Secondary 3-Methylglutaconic Acid Accumulation

Show evidence (6 references)

PMID:34140661 SUPPORT In vitro / ex vivo

"We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner."

The variants of this disorder inhibit wild-type CLPB activity dominant-negatively.

PMID:36170828 SUPPORT INDIRECT In vitro / ex vivo

"Importantly, SCN-linked subunits sharply inhibit disaggregase activity, whereas MGCA7-linked subunits do not."

Mixed-hexamer experiments show that dominant-disease subunits poison wild-type CLPB while recessive-disease subunits do not. The dominant subunits tested were those reported in severe congenital neutropenia patients, so this supports the shared dominant-negative mechanism indirectly.

PMID:34115842 SUPPORT INDIRECT In vitro / ex vivo

"These CLPB variants associate with wild-type CLPB and inhibit its adenosine triphosphatase and disaggregase activity in a dominant-negative fashion."

Shows the same physical association and dominant-negative inhibition for heterozygous variants from patients with isolated neutropenia (SCN type 9), the sister dominant disorder.

+ 3 more references

Intermembrane Space Protein Aggregation

Without disaggregase activity, proteins of the mitochondrial intermembrane space and inner membrane become insoluble, among them the anti-apoptotic protein HAX1, a direct partner and stimulatory cofactor of CLPB.

protein refolding GO:0042026 ↓ DECREASED

mitochondrial intermembrane space GO:0005758

Downstream

HAX1 Insolubility and Altered CLPB-HAX1 Interaction

Show evidence (1 reference)

PMID:32573439 SUPPORT INDIRECT In vitro / ex vivo

"Using Gene Ontology (GO) analysis for cellular component, we found that proteins in the inner mitochondrial membrane and intermembrane space were enriched in the insoluble fraction in the absence of Skd3"

Complete CLPB knockout cells accumulate insoluble intermembrane-space proteins; the dominant-negative variants are expected to act through the same loss of activity.

HAX1 Insolubility and Altered CLPB-HAX1 Interaction

HAX1 depends on CLPB for solubility. In fibroblasts from patients with de novo CLPB variants HAX1 comigrates with CLPB in high-molecular-mass complexes rather than as a monomer, suggesting a prolonged CLPB-HAX1 interaction. HAX1 deficiency itself causes severe congenital neutropenia (Kostmann syndrome).

HAX1 hgnc:16915

Experimental models

MGCA7A patient fibroblasts (complexome profiling) PRIMARY CELL CULTURE Shows HAX1 migrating at high molecular mass with CLPB in patient cells, where it is mostly monomeric in controls.

Downstream

Granulocytic Precursor Apoptosis

Impaired Neutrophil Differentiation

Show evidence (4 references)

PMID:34140661 SUPPORT In vitro / ex vivo

"In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1."

Complexome profiling in patient fibroblasts from this disorder shows altered HAX1 assembly with CLPB.

PMID:32573439 SUPPORT INDIRECT In vitro / ex vivo

"In wild-type cells, HAX1 remained predominantly soluble (Figure 7d,e). However, when Skd3 was deleted HAX1 became predominantly insoluble (Figure 7d,e). Thus, Skd3 is essential for HAX1 solubility in cells."

CLPB is required for HAX1 solubility; shown in knockout cells rather than dominant-negative patient cells.

PMID:42244541 SUPPORT In vitro / ex vivo

"Through biochemical reconstitution, we here find that HAX1 is a direct stimulatory cofactor of CLPB."

HAX1 and CLPB act as one functional unit, so disturbing either affects the other.

+ 1 more reference

Granulocytic Precursor Apoptosis

Granulocytic precursors carrying CLPB variants, or lacking CLPB, die by apoptosis at the onset of granulocytic differentiation, depleting the neutrophil lineage.

myeloblast CL:0000835

apoptotic process GO:0006915 ↑ INCREASED

Experimental models

Human hematopoietic progenitors expressing dominant CLPB variants PRIMARY CELL CULTURE Expression of the variants increases apoptosis of the progenitors.

Downstream

Congenital neutropenia

Show evidence (2 references)

PMID:34115842 SUPPORT INDIRECT In vitro / ex vivo

"Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."

Shown for heterozygous variants from patients with isolated neutropenia (SCN type 9); supports the same cellular step for the dominant-negative variants of this disorder by analogy.

PMID:39644357 SUPPORT INDIRECT In vitro / ex vivo

"CLPB loss did not affect cell proliferation rates in the presence of IL-3 but it increased apoptosis after IL-3 withdrawal and simultaneous induction of cell differentiation with granulocytic colony stimulating factor (G-CSF)."

In mouse myeloblastic cells, loss of CLPB causes apoptosis specifically at the onset of granulocytic differentiation.

Impaired Neutrophil Differentiation

Human hematopoietic progenitors expressing dominant CLPB variants show impaired granulocytic differentiation, consistent with the maturation arrest seen in patient marrow. A mouse myeloblastic model disagrees: there, CLPB-deficient cells that survive differentiate normally.

neutrophil CL:0000775

neutrophil differentiation GO:0030223 ↓ DECREASED

Experimental models

Human hematopoietic progenitors expressing dominant CLPB variants PRIMARY CELL CULTURE Expression of the variants impairs granulocytic differentiation.

Downstream

Congenital neutropenia

Myeloid malignancy Malignant transformation in severe congenital neutropenia is attributed to the underlying defect in granulocytic maturation in the marrow, not to the low neutrophil count as such. No source traces the steps from the CLPB defect to transformation.

Show evidence (2 references)

PMID:34115842 SUPPORT INDIRECT In vitro / ex vivo

"Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."

Shown for heterozygous variants from patients with isolated neutropenia (SCN type 9); supports the same cellular step for the dominant-negative variants of this disorder by analogy.

PMID:39644357 REFUTE In vitro / ex vivo

"CLPB-deficient cells that survived the stress associated with IL-3 withdrawal/G-CSF treatment expressed the same levels of differentiation markers as control cells."

In this mouse cell model the defect is survival, not differentiation of the cells that survive.

Neurodevelopmental Dysfunction

The neurological features (epilepsy, developmental delay, intellectual disability, and in some patients brain atrophy and white matter abnormalities) are attributed to loss of CLPB function in the brain. The substrate or pathway that links CLPB inhibition to neuronal disease is not known.

brain UBERON:0000955

Downstream

Seizures

Global developmental delay

Intellectual disability

Absent speech

Movement disorder

Spasticity

Cerebral white matter abnormalities

Thin corpus callosum

Cerebral atrophy

Show evidence (1 reference)

PMID:34140661 SUPPORT Human clinical

"Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1."

Monoallelic dominant variants cause neurodevelopmental delay and seizures.

Secondary 3-Methylglutaconic Acid Accumulation

Some patients excrete excess 3-methylglutaconic acid. As in the recessive form, the mechanism linking CLPB dysfunction to this secondary organic aciduria is unknown, and whether it is present at all differs between patients.

Downstream

3-Methylglutaconic aciduria

Show evidence (1 reference)

PMID:40194906 SUPPORT REVIEW SYNTHESIS Other

"The mechanisms leading to elevated 3-MGAs in CLPB deficiency remain, however, unknown."

Review stating that the origin of the 3-methylglutaconic aciduria is not known.

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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

16

Blood 2

Congenital neutropenia Decreased total neutrophil count HP:0001875

Sequelae: Recurrent infections

Show evidence (4 references)

PMID:34140661 SUPPORT Human clinical

"We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing."

Neutropenia was present in the defining case series.

PMID:41560087 SUPPORT Human clinical

"Bone marrow aspiration revealed severely reduced granulopoiesis with compensatory erythroid hyperplasia."

Reduced granulopoiesis in the marrow of a de novo p.R561W patient.

PMID:27891836 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"CLPB (caseinolytic peptidase B) deficiency is characterized by neurologic involvement and neutropenia, which can range from severe to mild."

GeneReviews names neutropenia as a defining feature of CLPB deficiency. GeneReviews does not separate the recessive and dominant forms, so this supports the dominant form only indirectly.

+ 1 more reference

Myeloid malignancy Myeloid leukemia HP:0012324

Bound to HP:0012324 (Myeloid leukemia), the closest HPO term for the source's "myeloid malignancies". It does not cover myelodysplastic syndrome, which the source also includes. HPO has no myeloid-specific term spanning both: OLS searches of HP for "myeloid neoplasm" and "myeloid malignancy" returned nothing, and "myelodysplasia" returns HP:0002863 Myelodysplasia, a separate term. HP:0004377 Hematological neoplasm covers both but also lymphoid neoplasms, so it is too broad.

Show evidence (1 reference)

PMID:41560087 SUPPORT BACKGROUND Human clinical

"Subsequently, myeloid malignancies have also been reported in patients harboring CLPB mutations in both autosomal dominant and autosomal recessive states."

The case report's introduction states that myeloid malignancy occurs in dominant as well as recessive CLPB disease; it does not separate type VIIA from SCN type 9.

Eye 1

Cataract HP:0000518

Show evidence (1 reference)

PMID:40194906 REFUTE REVIEW SYNTHESIS Other

"a few monoallelic variants cause the same phenotype as in biallelic CLPB defect with the exception of cataracts"

The dominant form (OMIM 619835) lacks cataracts.

Genitourinary 1

3-Methylglutaconic aciduria HP:0003535

Show evidence (2 references)

PMID:34140661 SUPPORT Human clinical

"We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing."

3-methylglutaconic aciduria is part of the defining phenotype.

PMID:40194906 SUPPORT REVIEW SYNTHESIS Other

"3-MGA-uria, distinctive for the aforesaid CLPB deficiency, was present in a minority of monoallelic CLPB individuals—only a few among those described by Wortmann et al."

The aciduria is inconsistent among monoallelic patients, including the dominant-form series.

Immune 1

Recurrent infections HP:0002719

Show evidence (1 reference)

PMID:41560087 SUPPORT Human clinical

"In our patient carrying this variant, we observed growth retardation, dysmorphic features, recurrent necrotizing pneumonia with neutropenia, and movement disorders."

Recurrent necrotizing pneumonia with neutropenia in a de novo p.R561W patient.

Musculoskeletal 1

Spasticity HP:0001257

Show evidence (2 references)

PMID:35499078 SUPPORT Human clinical

"Interestingly, only patient 1 showed severe central nervous system involvement associated with neurocognitive developmental delay and spasticity."

Spasticity in the one monoallelic patient of this series with neurological disease.

PMID:27891836 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability."

GeneReviews lists spasticity in moderate CLPB deficiency. GeneReviews does not separate the recessive and dominant forms, so this supports the dominant form only indirectly.

Nervous System 8

Seizures HP:0001250

Show evidence (2 references)

PMID:34140661 SUPPORT Human clinical

"We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing."

Epilepsy dominated the phenotype of the defining series.

PMID:27891836 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability."

GeneReviews lists epilepsy in moderate CLPB deficiency. GeneReviews does not separate the recessive and dominant forms, so this supports the dominant form only indirectly.

Global developmental delay HP:0001263

Show evidence (2 references)

PMID:34140661 SUPPORT Human clinical

"Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1."

Neurodevelopmental delay is central to the monoallelic phenotype.

PMID:41560087 SUPPORT Human clinical

"The child was able to lift his head at 5 months, sit independently at 15 months, and walked independently at 2 years."

Delayed motor milestones in a de novo p.R561W patient.

Intellectual disability HP:0001249

Show evidence (3 references)

PMID:34140661 SUPPORT Human clinical

"Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1."

The defining study places neurodevelopmental impairment at the centre of the monoallelic phenotype.

PMID:41560087 SUPPORT Human clinical

"He vocalized sounds but had no intelligible speech, displayed poor cognitive function, and showed limited self-care skills."

Poor cognitive function in a de novo p.R561W patient.

PMID:27891836 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability."

GeneReviews lists intellectual disability in moderate CLPB deficiency. GeneReviews does not separate the recessive and dominant forms, so this supports the dominant form only indirectly.

Absent speech HP:0001344

Show evidence (1 reference)

PMID:41560087 SUPPORT Human clinical

"He vocalized sounds but had no intelligible speech, displayed poor cognitive function, and showed limited self-care skills."

Absent speech at 3 years 2 months in a de novo p.R561W patient.

Movement disorder Abnormality of movement HP:0100022

Show evidence (2 references)

PMID:41560087 SUPPORT Human clinical

"In our patient carrying this variant, we observed growth retardation, dysmorphic features, recurrent necrotizing pneumonia with neutropenia, and movement disorders."

Movement disorder in a de novo p.R561W patient.

PMID:27891836 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability."

GeneReviews lists a progressive movement disorder in moderate CLPB deficiency. GeneReviews does not separate the recessive and dominant forms, so this supports the dominant form only indirectly.

Cerebral white matter abnormalities Abnormal cerebral white matter morphology HP:0002500

Show evidence (1 reference)

PMID:41560087 SUPPORT Human clinical

"MRI demonstrated abnormal white matter development consistent with CLPB deficiency."

White matter abnormality on MRI in a de novo p.R561W patient.

Thin corpus callosum HP:0033725

Show evidence (1 reference)

PMID:41560087 SUPPORT Human clinical

"abnormal white matter signal, a significantly thinned corpus callosum, elevated intracranial pressure"

Thin corpus callosum on MRI in a de novo p.R561W patient.

Cerebral atrophy HP:0002059

Show evidence (1 reference)

PMID:41560087 SUPPORT Human clinical

"pronounced widening of cerebral sulci, as well as ventricular enlargement"

Imaging findings of cerebral volume loss in a de novo p.R561W patient.

Growth 1

Growth delay HP:0001510

Show evidence (1 reference)

PMID:41560087 SUPPORT Human clinical

"accompanied by recurrent respiratory infections, neutropenia, and growth retardation"

Growth retardation in a de novo p.R561W patient.

Other 1

Death in childhood

Deliberately left without a phenotype_term. HP:0003819 (Death in childhood) is the exact concept, but it sits under the HPO Mortality/Aging branch rather than Phenotypic abnormality (HP:0000118), so validate-terms rejects it as a PhenotypeTerm value.

Show evidence (1 reference)

PMID:41719910 SUPPORT Human clinical

"Death occurred in 66% of biallelic and 23% of monoallelic individuals, with earlier median age at death in biallelic cases (6 months vs 2.4 years)."

Mortality in monoallelic CLPB disease, pooled across both dominant disorders.

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Genetic Associations

1

CLPB

Gene: CLPB hgnc:30664 gene page relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (3 references)

PMID:34140661 SUPPORT Human clinical

"In each individual, we identified one of four different de novo monoallelic missense variants in CLPB."

Monoallelic de novo CLPB missense variants cause the disease.

PMID:40194906 SUPPORT REVIEW SYNTHESIS Other

"Accordingly, CLPB deficiency was further subdivided with respect to the inheritance pattern into autosomal dominant (MGA 7A; MIM#619835) and autosomal recessive (MGA 7B; MIM#616271)."

Places the dominant CLPB disease (MGA 7A, OMIM 619835) as a separate entity from the recessive form.

PMID:40194906 SUPPORT REVIEW SYNTHESIS Other

"Mutations of this residue have been reported in nine unrelated patients, the largest number for any CLPB amino acid."

The arginine finger R561 is the most frequently mutated residue among monoallelic CLPB patients (counted across both dominant disorders).

Variants (1)

p.Arg561Trp

c.1681C>T, p.(Arg561Trp) at the arginine finger of the nucleotide-binding domain, reported de novo in a boy with neutropenia, developmental delay and white matter abnormalities.

Show evidence (1 reference)

PMID:41560087 SUPPORT Human clinical

"Whole-exome sequencing identified a mutation in the caseinolytic peptidase B homolog (CLPB) gene (NM_030813.6: c.1681C>T: p.R561W)."

Names the variant in a patient with neutropenia and neurological involvement.

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Medical Actions

3

Granulocyte Colony-Stimulating Factor

Action: Colony-Stimulating Factor Therapy NCIT:C15515

Agent: granulocyte colony stimulating factor NCIT:C1287

Platform: Other

G-CSF to raise neutrophil counts and reduce infections. In a de novo p.R561W patient intermittent G-CSF kept neutrophils above 0.5 x 10^9/L and reduced respiratory infections. A 2026 cohort associated G-CSF with improved survival, in a retrospective analysis pooling biallelic and monoallelic patients.

Target Phenotypes: Neutropenia HP:0001875

Show evidence (3 references)

PMID:41560087 SUPPORT Human clinical

"Administration of granulocyte colony-stimulating factor successfully maintained neutrophil counts above 0.5"

G-CSF response in a de novo p.R561W patient.

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"granulocyte-colony stimulating factor to increase neutrophil counts to reduce the frequency of infections, especially in individuals with the mild or moderate phenotype"

GeneReviews management recommendation for CLPB deficiency.

PMID:41719910 SUPPORT Human clinical

"Granulocyte colony-stimulating factor was associated with improved survival."

Retrospective association across the pooled CLPB cohort.

Hematopoietic Stem Cell Transplantation

Action: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

Considered for G-CSF-refractory neutropenia in patients without severe neurological disease. Four monoallelic patients in the 2026 cohort were transplanted with mixed outcomes; that cohort does not separate this disorder from isolated CLPB-related neutropenia.

Mechanism Target:

Granulocytic Precursor Apoptosis — Replaces the hematopoietic compartment carrying the dominant-negative CLPB variant.

Impaired Neutrophil Differentiation — Replaces the hematopoietic compartment carrying the dominant-negative CLPB variant.

Target Phenotypes: Neutropenia HP:0001875

Show evidence (2 references)

PMID:41719910 SUPPORT Human clinical

"Four monoallelic patients received hematopoietic stem cell transplants with mixed outcomes."

Transplant experience in monoallelic CLPB disease.

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"consider hematopoietic stem cell transplant in those without severe neurologic disease"

GeneReviews indication for transplantation.

Multidisciplinary Supportive Care

Action: Supportive Care NCIT:C15747

Platform: Other

No specific dietary or metabolic treatment exists. Care is supportive: antiseizure treatment, management of the movement disorder, developmental support and standard immunizations. GeneReviews advises avoiding drugs potentially toxic to mitochondria (chloramphenicol, aminoglycosides, linezolid, valproic acid, nucleoside reverse transcriptase inhibitors).

Show evidence (2 references)

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"Treatment is supportive. A multidisciplinary team including a metabolic physician, pediatric neurologist, dietitian, and physical therapist is recommended. No specific dietary or metabolic treatment is available."

GeneReviews management statement covering both forms of CLPB deficiency.

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"Agents/circumstances to avoid: Drugs potentially toxic to mitochondria, including chloramphenicol, aminoglycosides, linezolid, valproic acid, and nucleoside reverse transcriptase inhibitors."

GeneReviews drug-safety warning.

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Biochemical Markers

1

Urinary 3-methylglutaconic acid (INCREASED)

Context: Urine organic acid analysis; present in some but not all patients.

Show evidence (1 reference)

PMID:40194906 SUPPORT REVIEW SYNTHESIS Other

"3-MGA-uria, distinctive for the aforesaid CLPB deficiency, was present in a minority of monoallelic CLPB individuals—only a few among those described by Wortmann et al."

Raised in only some patients of the dominant form.

🔬

Diagnosis

2

Molecular genetic testing

Diagnosis rests on identifying one of the specific heterozygous CLPB variants known to act dominantly, by exome or genome sequencing, with parental testing to show the variant arose de novo.

Show evidence (1 reference)

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"The diagnosis of CLPB deficiency is established in a proband by identification of biallelic pathogenic variants in CLPB or identification of one of several specific heterozygous CLPB pathogenic variants associated with autosomal dominant CLPB deficiency on molecular genetic testing."

GeneReviews diagnostic criterion for the dominant form.

Blood count surveillance

Regular white blood cell count with differential to follow the neutropenia, as GeneReviews recommends for CLPB deficiency.

Show evidence (1 reference)

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"measure white blood cell count with differential"

GeneReviews surveillance recommendation.

📊

Prevalence

1

Worldwide published and survey cases

Cases/families reported in the literature Ultra-rare

The original report described six probands (PMID:34140661). A 2026 literature and survey cohort counted 22 individuals with monoallelic CLPB variants, but that count pools the dominant neurological form with isolated CLPB-related neutropenia (SCN type 9), so it is an upper bound for this entry rather than a count of it.

Show evidence (2 references)

PMID:34140661 SUPPORT Human clinical

"We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing."

The defining case series of six probands.

PMID:41719910 SUPPORT Human clinical

"Sixty-three individuals (41 biallelic, 22 monoallelic; 6 unpublished) with disease-causing CLPB variants were identified via literature review and a multicenter survey."

Gives the number of monoallelic cases known in 2026, pooled across both dominant disorders.

🧫

Experimental Models

2

MGCA7A patient fibroblasts (complexome profiling) PRIMARY_CELL_CULTURE

Skin fibroblasts from patients with de novo monoallelic CLPB variants, analysed by complexome profiling against control fibroblasts.

Publication

PMID:34140661

Pathograph links

HAX1 Insolubility and Altered CLPB-HAX1 Interaction measures fidelity: moderate observes: molecular Shows HAX1 migrating at high molecular mass with CLPB in patient cells, where it is mostly monomeric in controls.

Limitations: Fibroblasts are not the cell type that fails in the neutropenia, and the complexome shift shows altered assembly rather than its consequence for granulocytes.

Show evidence (1 reference)

PMID:34140661 SUPPORT In vitro / ex vivo

"In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1."

Patient fibroblasts measure the altered CLPB-HAX1 assembly.

Human hematopoietic progenitors expressing dominant CLPB variants PRIMARY_CELL_CULTURE

Human hematopoietic progenitor cells expressing heterozygous CLPB variants from severe congenital neutropenia patients, or with CLPB knocked out, and differentiated toward granulocytes.

Publication

PMID:34115842

Pathograph links

Granulocytic Precursor Apoptosis recapitulates fidelity: moderate observes: cellular Expression of the variants increases apoptosis of the progenitors.

Limitations: The variants tested come from SCN type 9 patients with isolated neutropenia, not from the type VIIA series, and are expressed alongside endogenous CLPB rather than from the native locus.

Show evidence (1 reference)

PMID:34115842 SUPPORT INDIRECT In vitro / ex vivo

"Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."

The progenitor model reproduces precursor apoptosis.

Impaired Neutrophil Differentiation recapitulates fidelity: moderate observes: cellular Expression of the variants impairs granulocytic differentiation.

Limitations: The variants tested come from SCN type 9 patients with isolated neutropenia, not from the type VIIA series, and are expressed alongside endogenous CLPB rather than from the native locus.

Show evidence (1 reference)

PMID:34115842 SUPPORT INDIRECT In vitro / ex vivo

"Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."

The progenitor model reproduces impaired differentiation.

{ }

Source YAML

click to show

name: 3-Methylglutaconic Aciduria Type VIIA
creation_date: "2026-10-20T01:00:00Z"
category: Mendelian
description: >-
  3-methylglutaconic aciduria type VIIA (MGCA7A) is the autosomal dominant form
  of CLPB deficiency. It is caused by specific heterozygous missense variants in
  CLPB, all reported so far as de novo, that lie in the nucleotide-binding
  domain of this ATP-dependent AAA+ disaggregase of the mitochondrial
  intermembrane space. Mutant subunits assemble with wild-type CLPB and inhibit
  its disaggregase activity, and to a lesser extent its ATPase activity, in a
  dominant-negative manner. The result resembles the recessive form (type
  VIIB): congenital neutropenia with recurrent infections, epilepsy,
  developmental delay and intellectual disability, with brain atrophy and white
  matter abnormalities in some patients, and raised urinary 3-methylglutaconic
  acid in some. Cataracts, a feature of the recessive form, have not been
  reported. Management is supportive, with granulocyte colony-stimulating factor
  for the neutropenia. The boundary with the other dominant CLPB disorder,
  severe congenital neutropenia type 9 (isolated neutropenia, OMIM 619813), is
  not settled.
disease_term:
  preferred_term: 3-methylglutaconic aciduria, type VIIA
  term:
    id: MONDO:0859237
    label: 3-methylglutaconic aciduria, type VIIA
synonyms:
- MGCA7A
- MGA 7A
- Autosomal dominant CLPB deficiency
- Dominant CLPB deficiency
- 3-methylglutaconic aciduria, type VIIA, autosomal dominant
parents:
- 3-Methylglutaconic Aciduria
- Mitochondrial Disease
- Congenital Neutropenia
notes: >-
  Scope: this entry covers the autosomal dominant CLPB disorder with
  neurological involvement, OMIM 619835 (MONDO:0859237), first described in six
  probands with de novo monoallelic CLPB variants (PMID:34140661). The recessive
  form, OMIM 616271, is curated separately as
  3-methylglutaconic_Aciduria_Type_VIIB. Heterozygous CLPB variants with
  isolated neutropenia, classified as severe congenital neutropenia type 9
  (OMIM 619813, PMID:34115842), are a different MONDO concept and are not
  curated here; that study is cited only for the dominant-negative mechanism the
  two dominant disorders share, and each such use says so. Several cohort
  studies pool all monoallelic patients without separating these two dominant
  disorders (PMID:41719910); figures from it describe monoallelic CLPB disease
  as a whole. The mechanistic study PMID:35499078 includes heterozygous
  patients of both kinds. Most of the imaging, speech, movement and growth
  phenotypes below come from a single de novo p.R561W case (PMID:41560087)
  in which urinary 3-methylglutaconic acid was not measured; R561 variants
  occur in both dominant disorders, and that case is placed here because of
  its neurological involvement. GeneReviews lists hypotonia and feeding
  problems for CLPB deficiency without separating the two inheritance forms;
  they are not recorded here until a source reports them in the dominant
  form. The only ClinGen gene-disease validity
  record for CLPB in cache/clingen/gene_validity.csv is for Leigh syndrome
  (MONDO:0009723), a different disease, so no gene_disease_validity assertion is
  recorded.
references:
- reference: PMID:27891836
  title: CLPB Deficiency.
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A single heterozygous CLPB missense variant is sufficient. All affected
    individuals reported to date carry a de novo variant, so no vertical
    transmission has been observed; offspring of an affected individual would
    have a 50% risk.
  evidence:
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "CLPB deficiency associated with specific heterozygous CLPB pathogenic variants is inherited in an autosomal dominant manner."
    explanation: GeneReviews states the dominant mode of inheritance for the monoallelic form.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "All individuals reported to date with autosomal dominant CLPB deficiency have the disorder as the result of a de novo CLPB pathogenic variant. Each child of an individual with a heterozygous CLPB pathogenic variant has a 50% chance of inheriting the pathogenic variant."
    explanation: All reported cases are de novo, with a 50% risk to offspring.
  - reference: PMID:34140661
    reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In each individual, we identified one of four different de novo monoallelic missense variants in CLPB."
    explanation: Six unrelated probands each carried a de novo monoallelic CLPB variant.
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "It should be underlined that variants causative for the dominant disease have not been reported in families with recessive disease nor in populational databases, and all occurred as a de novo events"
    explanation: Review stating that all dominant-disease variants arose de novo and are absent from population databases.
  - reference: PMID:41560087
    reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequent whole-exome sequencing identified a pathogenic missense mutation in the CLPB gene (c.1681C>T), which was confirmed by segregation analysis as a de novo event"
    explanation: A further de novo p.R561W case with neutropenia and neurological involvement.
prevalence:
- population: Worldwide published and survey cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The original report described six probands (PMID:34140661). A 2026
    literature and survey cohort counted 22 individuals with monoallelic CLPB
    variants, but that count pools the dominant neurological form with isolated
    CLPB-related neutropenia (SCN type 9), so it is an upper bound for this
    entry rather than a count of it.
  evidence:
  - reference: PMID:34140661
    reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing."
    explanation: The defining case series of six probands.
  - reference: PMID:41719910
    reference_title: "From genotype to outcome: Zygosity-specific insights in 63 cases of CLPB-related mitochondrial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sixty-three individuals (41 biallelic, 22 monoallelic; 6 unpublished) with disease-causing CLPB variants were identified via literature review and a multicenter survey."
    explanation: Gives the number of monoallelic cases known in 2026, pooled across both dominant disorders.
genetic:
- name: CLPB
  gene_term:
    preferred_term: CLPB
    term:
      id: hgnc:30664
      label: CLPB
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    The causal variants are heterozygous missense changes in the
    nucleotide-binding domain, several at the arginine finger R561 (for example
    p.Arg561Trp, c.1681C>T). Some dominant variants sit next to recessive ones,
    so the position of a variant does not by itself say which disease it causes.
  evidence:
  - reference: PMID:34140661
    reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In each individual, we identified one of four different de novo monoallelic missense variants in CLPB."
    explanation: Monoallelic de novo CLPB missense variants cause the disease.
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Accordingly, CLPB deficiency was further subdivided with respect to the inheritance pattern into autosomal dominant (MGA 7A; MIM#619835) and autosomal recessive (MGA 7B; MIM#616271)."
    explanation: Places the dominant CLPB disease (MGA 7A, OMIM 619835) as a separate entity from the recessive form.
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mutations of this residue have been reported in nine unrelated patients, the largest number for any CLPB amino acid."
    explanation: >-
      The arginine finger R561 is the most frequently mutated residue among
      monoallelic CLPB patients (counted across both dominant disorders).
  variants:
  - name: p.Arg561Trp
    description: >-
      c.1681C>T, p.(Arg561Trp) at the arginine finger of the nucleotide-binding
      domain, reported de novo in a boy with neutropenia, developmental delay
      and white matter abnormalities.
    evidence:
    - reference: PMID:41560087
      reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole-exome sequencing identified a mutation in the caseinolytic peptidase B homolog (CLPB) gene (NM_030813.6: c.1681C>T: p.R561W)."
      explanation: Names the variant in a patient with neutropenia and neurological involvement.
pathophysiology:
- name: Dominant-Negative Inhibition of CLPB Disaggregase
  description: >-
    Mutant CLPB subunits carrying the dominant variants assemble with wild-type
    subunits into the hexameric and dodecameric disaggregase and poison it,
    abolishing most disaggregase activity and to a lesser degree ATPase
    activity. Subunits carrying the recessive (MGCA7) variants do not do this,
    which is why one recessive allele is harmless while one dominant allele
    causes disease.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CLPB
    term:
      id: hgnc:30664
      label: CLPB
  molecular_functions:
  - preferred_term: ATP-dependent protein disaggregase activity
    term:
      id: GO:0140545
      label: ATP-dependent protein disaggregase activity
    modifier: DECREASED
  - preferred_term: ATP hydrolysis activity
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitochondrial intermembrane space
    term:
      id: GO:0005758
      label: mitochondrial intermembrane space
  genetic_context:
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
  evidence:
  - reference: PMID:34140661
    reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner."
    explanation: The variants of this disorder inhibit wild-type CLPB activity dominant-negatively.
  - reference: PMID:36170828
    reference_title: "Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Importantly, SCN-linked subunits sharply inhibit disaggregase activity, whereas MGCA7-linked subunits do not."
    explanation: >-
      Mixed-hexamer experiments show that dominant-disease subunits poison
      wild-type CLPB while recessive-disease subunits do not. The dominant
      subunits tested were those reported in severe congenital neutropenia
      patients, so this supports the shared dominant-negative mechanism
      indirectly.
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "These CLPB variants associate with wild-type CLPB and inhibit its adenosine triphosphatase and disaggregase activity in a dominant-negative fashion."
    explanation: >-
      Shows the same physical association and dominant-negative inhibition for
      heterozygous variants from patients with isolated neutropenia (SCN type
      9), the sister dominant disorder.
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The dominant mutations, K404T, P427L, N496K, E557K, G560R, R561G and R620C, also decreased the disaggregase activity of the wild-type subunits in mixed oligomers."
    explanation: >-
      Summarises mixed-oligomer assays across dominant variants, including
      K404T, a variant of this disorder.
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "None of the mutations abolish hexamer or dodecamer formation"
    explanation: >-
      In 1:1 mixtures with wild-type protein (K404T, P427L, G560R) the
      dominant variants still form hexamers and dodecamers, so the mutant
      subunits are incorporated into the complex rather than excluded.
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "which demonstrates that the dominant phenotype of the disorder is brought about by the inhibitory effect of mutant subunits on the wild type ones in mixed oligomers."
    explanation: Review conclusion that the dominant phenotype is due to poisoning of wild-type subunits.
  downstream:
  - target: Intermembrane Space Protein Aggregation
    causal_link_type: DIRECT
  - target: Neurodevelopmental Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34140661
      reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1."
      explanation: The dominant-negative variants cause the neurodevelopmental phenotype; the intermediate steps are unknown.
  - target: Secondary 3-Methylglutaconic Acid Accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Intermembrane Space Protein Aggregation
  description: >-
    Without disaggregase activity, proteins of the mitochondrial intermembrane
    space and inner membrane become insoluble, among them the anti-apoptotic
    protein HAX1, a direct partner and stimulatory cofactor of CLPB.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: protein refolding
    term:
      id: GO:0042026
      label: protein refolding
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitochondrial intermembrane space
    term:
      id: GO:0005758
      label: mitochondrial intermembrane space
  evidence:
  - reference: PMID:32573439
    reference_title: Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Using Gene Ontology (GO) analysis for cellular component, we found that proteins in the inner mitochondrial membrane and intermembrane space were enriched in the insoluble fraction in the absence of Skd3"
    explanation: >-
      Complete CLPB knockout cells accumulate insoluble intermembrane-space
      proteins; the dominant-negative variants are expected to act through the
      same loss of activity.
  downstream:
  - target: HAX1 Insolubility and Altered CLPB-HAX1 Interaction
    causal_link_type: DIRECT
- name: HAX1 Insolubility and Altered CLPB-HAX1 Interaction
  description: >-
    HAX1 depends on CLPB for solubility. In fibroblasts from patients with de
    novo CLPB variants HAX1 comigrates with CLPB in high-molecular-mass
    complexes rather than as a monomer, suggesting a prolonged CLPB-HAX1
    interaction. HAX1 deficiency itself causes severe congenital neutropenia
    (Kostmann syndrome).
  biological_scale: MOLECULAR
  genes:
  - preferred_term: HAX1
    term:
      id: hgnc:16915
      label: HAX1
  evidence:
  - reference: PMID:34140661
    reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1."
    explanation: Complexome profiling in patient fibroblasts from this disorder shows altered HAX1 assembly with CLPB.
  - reference: PMID:32573439
    reference_title: Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "In wild-type cells, HAX1 remained predominantly soluble (Figure 7d,e). However, when Skd3 was deleted HAX1 became predominantly insoluble (Figure 7d,e). Thus, Skd3 is essential for HAX1 solubility in cells."
    explanation: CLPB is required for HAX1 solubility; shown in knockout cells rather than dominant-negative patient cells.
  - reference: PMID:42244541
    reference_title: HAX1 drives assembly and activation of the mitochondrial intermembrane space chaperone CLPB.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Through biochemical reconstitution, we here find that HAX1 is a direct stimulatory cofactor of CLPB."
    explanation: HAX1 and CLPB act as one functional unit, so disturbing either affects the other.
  - reference: PMID:39644357
    reference_title: Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "We found that CLPB-deficient 32Dcl3 cells showed a decreased mitochondrial membrane potential and increased levels of insoluble HAX1 aggregates in mitochondria, as compared to control cells."
    explanation: Insoluble HAX1 accumulates in CLPB-deficient mouse myeloblastic cells, the cell lineage that fails in the neutropenia.
  downstream:
  - target: Granulocytic Precursor Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34140661
      reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1."
      explanation: The authors attribute the phenotype, including neutropenia, to HAX1, while marking it as presumed.
    - reference: PMID:35499078
      reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes and, thus, elucidated molecular and metabolic mechanisms underlying congenital neutropenia in patients with HAX1 deficiency as well as bi- and monoallelic mutations in CLPB."
      explanation: Links the CLPB/HAX1 axis to neutrophil differentiation in monoallelic CLPB patients.
  - target: Impaired Neutrophil Differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35499078
      reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes and, thus, elucidated molecular and metabolic mechanisms underlying congenital neutropenia in patients with HAX1 deficiency as well as bi- and monoallelic mutations in CLPB."
      explanation: Places the CLPB/HAX1 axis upstream of neutrophil differentiation.
- name: Granulocytic Precursor Apoptosis
  description: >-
    Granulocytic precursors carrying CLPB variants, or lacking CLPB, die by
    apoptosis at the onset of granulocytic differentiation, depleting the
    neutrophil lineage.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: myeloblast
    term:
      id: CL:0000835
      label: myeloblast
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."
    explanation: >-
      Shown for heterozygous variants from patients with isolated neutropenia
      (SCN type 9); supports the same cellular step for the dominant-negative
      variants of this disorder by analogy.
  - reference: PMID:39644357
    reference_title: Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "CLPB loss did not affect cell proliferation rates in the presence of IL-3 but it increased apoptosis after IL-3 withdrawal and simultaneous induction of cell differentiation with granulocytic colony stimulating factor (G-CSF)."
    explanation: In mouse myeloblastic cells, loss of CLPB causes apoptosis specifically at the onset of granulocytic differentiation.
  downstream:
  - target: Congenital neutropenia
    causal_link_type: DIRECT
- name: Impaired Neutrophil Differentiation
  description: >-
    Human hematopoietic progenitors expressing dominant CLPB variants show
    impaired granulocytic differentiation, consistent with the maturation
    arrest seen in patient marrow. A mouse myeloblastic model disagrees: there,
    CLPB-deficient cells that survive differentiate normally.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil differentiation
    term:
      id: GO:0030223
      label: neutrophil differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."
    explanation: >-
      Shown for heterozygous variants from patients with isolated neutropenia
      (SCN type 9); supports the same cellular step for the dominant-negative
      variants of this disorder by analogy.
  - reference: PMID:39644357
    reference_title: Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "CLPB-deficient cells that survived the stress associated with IL-3 withdrawal/G-CSF treatment expressed the same levels of differentiation markers as control cells."
    explanation: >-
      In this mouse cell model the defect is survival, not differentiation of
      the cells that survive.
  downstream:
  - target: Congenital neutropenia
    causal_link_type: DIRECT
  - target: Myeloid malignancy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Malignant transformation in severe congenital neutropenia is attributed
      to the underlying defect in granulocytic maturation in the marrow, not to
      the low neutrophil count as such. No source traces the steps from the
      CLPB defect to transformation.
    evidence:
    - reference: PMID:41560087
      reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: BACKGROUND
      snippet: "Congenital neutropenia represents a heterogeneous group of genetic disorders that disrupt neutrophil production, differentiation and survival within the bone marrow, leading to recurrent infections and an increased risk of progression to myelodysplastic syndromes or acute myeloid leukemia."
      explanation: >-
        Ties transformation risk to the marrow defect in neutrophil
        differentiation. The sentence is about congenital neutropenia in
        general, not CLPB specifically.
- name: Neurodevelopmental Dysfunction
  description: >-
    The neurological features (epilepsy, developmental delay, intellectual
    disability, and in some patients brain atrophy and white matter
    abnormalities) are attributed to loss of CLPB function in the brain. The substrate or pathway that links CLPB
    inhibition to neuronal disease is not known.
  biological_scale: TISSUE
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:34140661
    reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1."
    explanation: Monoallelic dominant variants cause neurodevelopmental delay and seizures.
  downstream:
  - target: Seizures
    evidence:
    - reference: PMID:34140661
      reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1."
      explanation: Names seizures as a consequence of the monoallelic variants.
  - target: Global developmental delay
    evidence:
    - reference: PMID:34140661
      reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1."
      explanation: Names neurodevelopmental delay as a consequence of the monoallelic variants.
  - target: Intellectual disability
  - target: Absent speech
  - target: Movement disorder
  - target: Spasticity
  - target: Cerebral white matter abnormalities
  - target: Thin corpus callosum
  - target: Cerebral atrophy
- name: Secondary 3-Methylglutaconic Acid Accumulation
  description: >-
    Some patients excrete excess 3-methylglutaconic acid. As in the recessive
    form, the mechanism linking CLPB dysfunction to this secondary organic
    aciduria is unknown, and whether it is present at all differs between
    patients.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The mechanisms leading to elevated 3-MGAs in CLPB deficiency remain, however, unknown."
    explanation: Review stating that the origin of the 3-methylglutaconic aciduria is not known.
  downstream:
  - target: 3-Methylglutaconic aciduria
phenotypes:
- name: Congenital neutropenia
  description: >-
    Neutropenia from early life, severe in some patients, with reduced
    granulopoiesis in the bone marrow.
    One reported carrier of a dominant variant (p.Lys404Thr) had the
    neurological phenotype without neutropenia.
  category: Hematological
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:34140661
    reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing."
    explanation: Neutropenia was present in the defining case series.
  - reference: PMID:41560087
    reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bone marrow aspiration revealed severely reduced granulopoiesis with compensatory erythroid hyperplasia."
    explanation: Reduced granulopoiesis in the marrow of a de novo p.R561W patient.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "CLPB (caseinolytic peptidase B) deficiency is characterized by neurologic involvement and neutropenia, which can range from severe to mild."
    explanation: GeneReviews names neutropenia as a defining feature of CLPB deficiency. GeneReviews does not separate the recessive and dominant forms, so this supports the dominant form only indirectly.
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: REFUTE
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Then again, the K404T variant associated with the MGA 7A phenotype (dominant CLPB deficiency) did not manifest neutropenia"
    explanation: Neutropenia is not universal; one dominant-form patient did not have it.
  sequelae:
  - target: Recurrent infections
    causal_link_type: DIRECT
- name: Recurrent infections
  description: >-
    Recurrent bacterial infections, including recurrent and necrotizing
    pneumonia, resulting from the neutropenia.
  category: Immunological
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:41560087
    reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our patient carrying this variant, we observed growth retardation, dysmorphic features, recurrent necrotizing pneumonia with neutropenia, and movement disorders."
    explanation: Recurrent necrotizing pneumonia with neutropenia in a de novo p.R561W patient.
- name: Seizures
  description: Epilepsy is a dominant feature of the original case series.
  category: Neurological
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:34140661
    reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing."
    explanation: Epilepsy dominated the phenotype of the defining series.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability."
    explanation: GeneReviews lists epilepsy in moderate CLPB deficiency. GeneReviews does not separate the recessive and dominant forms, so this supports the dominant form only indirectly.
- name: Global developmental delay
  description: Delayed motor and speech milestones from infancy.
  category: Neurological
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:34140661
    reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1."
    explanation: Neurodevelopmental delay is central to the monoallelic phenotype.
  - reference: PMID:41560087
    reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The child was able to lift his head at 5 months, sit independently at 15 months, and walked independently at 2 years."
    explanation: Delayed motor milestones in a de novo p.R561W patient.
- name: Intellectual disability
  category: Neurological
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:34140661
    reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1."
    explanation: >-
      The defining study places neurodevelopmental impairment at the centre of
      the monoallelic phenotype.
  - reference: PMID:41560087
    reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He vocalized sounds but had no intelligible speech, displayed poor cognitive function, and showed limited self-care skills."
    explanation: Poor cognitive function in a de novo p.R561W patient.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability."
    explanation: GeneReviews lists intellectual disability in moderate CLPB deficiency. GeneReviews does not separate the recessive and dominant forms, so this supports the dominant form only indirectly.
- name: Absent speech
  description: No intelligible speech at three years in one reported child.
  category: Neurological
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:41560087
    reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He vocalized sounds but had no intelligible speech, displayed poor cognitive function, and showed limited self-care skills."
    explanation: Absent speech at 3 years 2 months in a de novo p.R561W patient.
- name: Movement disorder
  category: Neurological
  phenotype_term:
    preferred_term: Abnormality of movement
    term:
      id: HP:0100022
      label: Abnormality of movement
  evidence:
  - reference: PMID:41560087
    reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our patient carrying this variant, we observed growth retardation, dysmorphic features, recurrent necrotizing pneumonia with neutropenia, and movement disorders."
    explanation: Movement disorder in a de novo p.R561W patient.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability."
    explanation: GeneReviews lists a progressive movement disorder in moderate CLPB deficiency. GeneReviews does not separate the recessive and dominant forms, so this supports the dominant form only indirectly.
- name: Cerebral white matter abnormalities
  description: >-
    Abnormal white matter signal, blurred grey-white matter differentiation and
    a thin corpus callosum on MRI.
  category: Neurological
  phenotype_term:
    preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:41560087
    reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI demonstrated abnormal white matter development consistent with CLPB deficiency."
    explanation: White matter abnormality on MRI in a de novo p.R561W patient.
- name: Thin corpus callosum
  category: Neurological
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:41560087
    reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal white matter signal, a significantly thinned corpus callosum, elevated intracranial pressure"
    explanation: Thin corpus callosum on MRI in a de novo p.R561W patient.
- name: Cerebral atrophy
  description: Widened cerebral sulci and enlarged ventricles on MRI.
  category: Neurological
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:41560087
    reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pronounced widening of cerebral sulci, as well as ventricular enlargement"
    explanation: Imaging findings of cerebral volume loss in a de novo p.R561W patient.
- name: Growth delay
  category: Growth
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:41560087
    reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "accompanied by recurrent respiratory infections, neutropenia, and growth retardation"
    explanation: Growth retardation in a de novo p.R561W patient.
- name: 3-Methylglutaconic aciduria
  description: >-
    Raised urinary 3-methylglutaconic acid. It featured in the original series
    but, by a later review's count, in only a few of those patients, and many
    monoallelic patients were never tested.
  category: Metabolic
  phenotype_term:
    preferred_term: 3-Methylglutaconic aciduria
    term:
      id: HP:0003535
      label: 3-Methylglutaconic aciduria
  evidence:
  - reference: PMID:34140661
    reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing."
    explanation: 3-methylglutaconic aciduria is part of the defining phenotype.
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "3-MGA-uria, distinctive for the aforesaid CLPB deficiency, was present in a minority of monoallelic CLPB individuals—only a few among those described by Wortmann et al."
    explanation: The aciduria is inconsistent among monoallelic patients, including the dominant-form series.
- name: Spasticity
  description: Reported with developmental delay in a monoallelic patient with central nervous system involvement.
  category: Neurological
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:35499078
    reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, only patient 1 showed severe central nervous system involvement associated with neurocognitive developmental delay and spasticity."
    explanation: Spasticity in the one monoallelic patient of this series with neurological disease.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability."
    explanation: GeneReviews lists spasticity in moderate CLPB deficiency. GeneReviews does not separate the recessive and dominant forms, so this supports the dominant form only indirectly.
- name: Cataract
  description: >-
    Cataract, a feature of the recessive form, has not been reported in the
    dominant form; it is recorded here as a negative finding.
  category: Ophthalmological
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: REFUTE
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "a few monoallelic variants cause the same phenotype as in biallelic CLPB defect with the exception of cataracts"
    explanation: The dominant form (OMIM 619835) lacks cataracts.
- name: Myeloid malignancy
  description: >-
    Myeloid malignancies have been reported in patients with CLPB variants of
    both inheritance forms, as in other severe congenital neutropenias. No
    frequency is available for the dominant form.
  category: Neoplasm
  notes: >-
    Bound to HP:0012324 (Myeloid leukemia), the closest HPO term for the
    source's "myeloid malignancies". It does not cover myelodysplastic
    syndrome, which the source also includes. HPO has no myeloid-specific term
    spanning both: OLS searches of HP for "myeloid neoplasm" and "myeloid
    malignancy" returned nothing, and "myelodysplasia" returns HP:0002863
    Myelodysplasia, a separate term. HP:0004377 Hematological neoplasm covers
    both but also lymphoid neoplasms, so it is too broad.
  phenotype_term:
    preferred_term: Myeloid malignancy
    term:
      id: HP:0012324
      label: Myeloid leukemia
  evidence:
  - reference: PMID:41560087
    reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Subsequently, myeloid malignancies have also been reported in patients harboring CLPB mutations in both autosomal dominant and autosomal recessive states."
    explanation: >-
      The case report's introduction states that myeloid malignancy occurs in
      dominant as well as recessive CLPB disease; it does not separate type
      VIIA from SCN type 9.
- name: Death in childhood
  description: >-
    Death occurred in about a quarter of monoallelic patients in a 2026 cohort,
    at a median of 2.4 years. That cohort pools this disorder with isolated
    CLPB-related neutropenia.
  category: Systemic
  notes: >-
    Deliberately left without a phenotype_term. HP:0003819 (Death in
    childhood) is the exact concept, but it sits under the HPO Mortality/Aging
    branch rather than Phenotypic abnormality (HP:0000118), so validate-terms
    rejects it as a PhenotypeTerm value.
  evidence:
  - reference: PMID:41719910
    reference_title: "From genotype to outcome: Zygosity-specific insights in 63 cases of CLPB-related mitochondrial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Death occurred in 66% of biallelic and 23% of monoallelic individuals, with earlier median age at death in biallelic cases (6 months vs 2.4 years)."
    explanation: Mortality in monoallelic CLPB disease, pooled across both dominant disorders.
biochemical:
- name: Urinary 3-methylglutaconic acid
  presence: INCREASED
  context: Urine organic acid analysis; present in some but not all patients.
  evidence:
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "3-MGA-uria, distinctive for the aforesaid CLPB deficiency, was present in a minority of monoallelic CLPB individuals—only a few among those described by Wortmann et al."
    explanation: Raised in only some patients of the dominant form.
diagnosis:
- name: Molecular genetic testing
  description: >-
    Diagnosis rests on identifying one of the specific heterozygous CLPB
    variants known to act dominantly, by exome or genome sequencing, with
    parental testing to show the variant arose de novo.
  evidence:
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The diagnosis of CLPB deficiency is established in a proband by identification of biallelic pathogenic variants in CLPB or identification of one of several specific heterozygous CLPB pathogenic variants associated with autosomal dominant CLPB deficiency on molecular genetic testing."
    explanation: GeneReviews diagnostic criterion for the dominant form.
- name: Blood count surveillance
  description: >-
    Regular white blood cell count with differential to follow the neutropenia,
    as GeneReviews recommends for CLPB deficiency.
  evidence:
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "measure white blood cell count with differential"
    explanation: GeneReviews surveillance recommendation.
treatments:
- name: Granulocyte Colony-Stimulating Factor
  description: >-
    G-CSF to raise neutrophil counts and reduce infections. In a de novo
    p.R561W patient intermittent G-CSF kept neutrophils above 0.5 x 10^9/L and
    reduced respiratory infections. A 2026 cohort associated G-CSF with
    improved survival, in a retrospective analysis pooling biallelic and
    monoallelic patients.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Colony-Stimulating Factor Therapy
    term:
      id: NCIT:C15515
      label: Colony-Stimulating Factor Therapy
    therapeutic_agent:
    - preferred_term: granulocyte colony stimulating factor
      term:
        id: NCIT:C1287
        label: Recombinant Granulocyte Colony-Stimulating Factor
  target_phenotypes:
  - preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:41560087
    reference_title: "CLPB deficiency-associated congenital neutropenia: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Administration of granulocyte colony-stimulating factor successfully maintained neutrophil counts above 0.5"
    explanation: G-CSF response in a de novo p.R561W patient.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "granulocyte-colony stimulating factor to increase neutrophil counts to reduce the frequency of infections, especially in individuals with the mild or moderate phenotype"
    explanation: GeneReviews management recommendation for CLPB deficiency.
  - reference: PMID:41719910
    reference_title: "From genotype to outcome: Zygosity-specific insights in 63 cases of CLPB-related mitochondrial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Granulocyte colony-stimulating factor was associated with improved survival."
    explanation: Retrospective association across the pooled CLPB cohort.
- name: Hematopoietic Stem Cell Transplantation
  description: >-
    Considered for G-CSF-refractory neutropenia in patients without severe
    neurological disease. Four monoallelic patients in the 2026 cohort were
    transplanted with mixed outcomes; that cohort does not separate this
    disorder from isolated CLPB-related neutropenia.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_phenotypes:
  - preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  target_mechanisms:
  - target: Granulocytic Precursor Apoptosis
    description: Replaces the hematopoietic compartment carrying the dominant-negative CLPB variant.
  - target: Impaired Neutrophil Differentiation
    description: Replaces the hematopoietic compartment carrying the dominant-negative CLPB variant.
  evidence:
  - reference: PMID:41719910
    reference_title: "From genotype to outcome: Zygosity-specific insights in 63 cases of CLPB-related mitochondrial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four monoallelic patients received hematopoietic stem cell transplants with mixed outcomes."
    explanation: Transplant experience in monoallelic CLPB disease.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "consider hematopoietic stem cell transplant in those without severe neurologic disease"
    explanation: GeneReviews indication for transplantation.
- name: Multidisciplinary Supportive Care
  description: >-
    No specific dietary or metabolic treatment exists. Care is supportive:
    antiseizure treatment, management of the movement disorder, developmental
    support and standard immunizations. GeneReviews advises avoiding drugs
    potentially toxic to mitochondria (chloramphenicol, aminoglycosides,
    linezolid, valproic acid, nucleoside reverse transcriptase inhibitors).
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Treatment is supportive. A multidisciplinary team including a metabolic physician, pediatric neurologist, dietitian, and physical therapist is recommended. No specific dietary or metabolic treatment is available."
    explanation: GeneReviews management statement covering both forms of CLPB deficiency.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Agents/circumstances to avoid: Drugs potentially toxic to mitochondria, including chloramphenicol, aminoglycosides, linezolid, valproic acid, and nucleoside reverse transcriptase inhibitors."
    explanation: GeneReviews drug-safety warning.
experimental_models:
- name: MGCA7A patient fibroblasts (complexome profiling)
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Skin fibroblasts from patients with de novo monoallelic CLPB variants,
    analysed by complexome profiling against control fibroblasts.
  publication: PMID:34140661
  modeled_mechanisms:
  - target: HAX1 Insolubility and Altered CLPB-HAX1 Interaction
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Shows HAX1 migrating at high molecular mass with CLPB in patient cells,
      where it is mostly monomeric in controls.
    limitations: >-
      Fibroblasts are not the cell type that fails in the neutropenia, and the
      complexome shift shows altered assembly rather than its consequence for
      granulocytes.
    evidence:
    - reference: PMID:34140661
      reference_title: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1."
      explanation: Patient fibroblasts measure the altered CLPB-HAX1 assembly.
- name: Human hematopoietic progenitors expressing dominant CLPB variants
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Human hematopoietic progenitor cells expressing heterozygous CLPB variants
    from severe congenital neutropenia patients, or with CLPB knocked out, and
    differentiated toward granulocytes.
  publication: PMID:34115842
  modeled_mechanisms:
  - target: Granulocytic Precursor Apoptosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Expression of the variants increases apoptosis of the progenitors.
    limitations: >-
      The variants tested come from SCN type 9 patients with isolated
      neutropenia, not from the type VIIA series, and are expressed alongside
      endogenous CLPB rather than from the native locus.
    evidence:
    - reference: PMID:34115842
      reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."
      explanation: The progenitor model reproduces precursor apoptosis.
  - target: Impaired Neutrophil Differentiation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Expression of the variants impairs granulocytic differentiation.
    limitations: >-
      The variants tested come from SCN type 9 patients with isolated
      neutropenia, not from the type VIIA series, and are expressed alongside
      endogenous CLPB rather than from the native locus.
    evidence:
    - reference: PMID:34115842
      reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."
      explanation: The progenitor model reproduces impaired differentiation.
discussions:
- discussion_id: gap_mgca7a_vs_scn9_boundary
  prompt: >-
    Are 3-methylglutaconic aciduria type VIIA (dominant CLPB deficiency with
    neurological involvement) and severe congenital neutropenia type 9
    (isolated neutropenia from heterozygous CLPB variants) two disorders or one
    disorder with variable expression?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - disease#
  - pathophysiology#Dominant-Negative Inhibition of CLPB Disaggregase
  rationale: >-
    Both are caused by heterozygous CLPB missense variants that inhibit
    wild-type CLPB dominant-negatively, and the arginine finger R561 is mutated
    in both. The distinction rests partly on 3-methylglutaconic aciduria, which
    was not measured in about half of the published neutropenia cases. A
    variant-level comparison of residual disaggregase activity against
    neurological outcome would test whether the two are a continuum.
  evidence:
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "It remains to be established whether the distinction between dominant CLPB deficiency (MGA 7A) and CLPB-SCN is scientifically valid or if these entities represent, in fact, one disorder."
    explanation: Review stating that the boundary between the two dominant disorders is unresolved.
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The distinction based on the lack of 3-MGA-uria in isolated CLPB-related neutropenia needs to be further studied, as this parameter was not assessed in 9 out of 20 published cases, since it had not been linked with neutropenia before."
    explanation: The biochemical criterion separating the two was often not measured.

📚

References & Deep Research

References

1

PMID:27891836

CLPB Deficiency.

No top-level findings curated for this source.

Deep Research

1

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Evaluations and curation notes (1)

Create: 3-methylglutaconic_Aciduria_Type_VIIA · 2026-10-20T01:42:29Z · View source

New entry for the autosomal dominant CLPB disorder MGCA7A (MONDO:0859237, OMIM 619835), claimed in #14953. Scoped against the existing recessive entry 3-methylglutaconic_Aciduria_Type_VIIB (OMIM 616271) and against severe congenital neutropenia type 9 (OMIM 619813, isolated neutropenia), which is a separate MONDO concept and is not curated here. Evidence from SCN9 patients (PMID:34115842, PMID:36170828) is used only for the shared dominant-negative mechanism and is marked directness INDIRECT; cohort figures that pool all monoallelic patients (PMID:41719910) say so in their description. Deep research: falcon was requested but not configured in this environment, so the run used --fallback and openscientist produced the report (research/3-methylglutaconic_Aciduria_Type_VIIA-deep-research-openscientist.md). That report confuses this disease with the recessive form: it gives OMIM 616271, a wrong CLPB HGNC id (18542), and describes mostly biallelic disease; just preflight-dr returned WARN on the OMIM mismatch. Its reference validation was clean (17/17 resolved; one quote failed only on a superscript). It added no source specific to the dominant form beyond PMID:34140661 and PMID:41719910, so the entry was curated from those plus GeneReviews (PMID:27891836), the 2025 review PMID:40194906, the de novo p.R561W case report PMID:41560087, and mechanistic papers found by a PubMed search (PMID:32573439, PMID:42244541, PMID:35499078, PMID:39644357). The report's CHEBI:28123 for 3-methylglutaconic acid resolves to diethanolamine and was not used. The open question of whether MGCA7A and SCN9 are one disorder is recorded as a KNOWLEDGE_GAP discussion. Validation: just validate passes (schema and terms); count-verified-snippets 52/52; check-genereviews TAGGED; check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-block-scalar-comments and the snippet ratchets all pass. The death-in-childhood row is left without a phenotype_term because HP:0003819 is outside the PhenotypeTerm enum, following the VIIB entry. A pre-PR self-review (fresh-context subagent using the dismech-pr-review skill) led to these changes: the neurodevelopmental and 3-MGA nodes were connected to the CLPB lesion with INDIRECT_UNKNOWN_INTERMEDIATES edges; an unsourced statement about brain expression was removed; mixed-oligomer evidence covering the MGCA7A variant K404T (PMID:40194906) was added to the dominant-negative node; cataract was recorded as a REFUTE phenotype; GeneReviews G-CSF and blood-count surveillance recommendations, spasticity (PMID:35499078) and a REFUTE item on the differentiation half of the granulocyte node (PMID:39644357) were added; the unsupported VERY_FREQUENT frequency and the duplicate Sporadic inheritance row were removed. After those changes: count-verified-snippets 63/63 and validate-disorders passes. Review round 1 on #14960 (automated reviewer, changes requested). GeneReviews Clinical Characteristics quotes were added to neutropenia, seizures, intellectual disability, movement disorder and spasticity, marked INDIRECT because the chapter pools both inheritance forms. The pooled-cohort cataract REFUTE item (PMID:41719910) was removed and the cataract description softened to 'not reported'. The granulocyte node was split into Granulocytic Precursor Apoptosis and Impaired Neutrophil Differentiation so the PMID:39644357 REFUTE sits on the differentiation half only. Edge-level evidence was added to the seizure and developmental-delay edges. A myeloid malignancy phenotype was added from PMID:41560087 (quote_role BACKGROUND); PMID:38589208, which the research report cited for this, only lists CLPB among SCN genes and was not used. Two experimental models were added (patient fibroblasts, PMID:34140661; progenitors expressing SCN9 variants, PMID:34115842). After the round: count-verified-snippets 75/75, validate passes, model-scale-audit 3/3 aligned.

OpenScientist ▸

3-Methylglutaconic Aciduria Type VIIA (MGCA7A): A Comprehensive Disease Characterization Report

openscientist-autonomous 17 citations 2026-10-20T01:39:58.040048

3-Methylglutaconic Aciduria Type VIIA (MGCA7A): A Comprehensive Disease Characterization Report

Disease: 3-Methylglutaconic Aciduria Type VIIA MONDO ID: MONDO:0859237 · OMIM: #616271 · ORPHA: 445038 Causal gene: CLPB (SKD3; HGNC:18542; OMIM gene *616254; chr11q13.4) Category: Mendelian (mitochondrial disorder)

Summary

3-Methylglutaconic aciduria type VIIA (MGCA7A, also written MGCA7) is an ultra-rare inherited mitochondrial disorder caused by pathogenic variants in CLPB, the gene encoding SKD3, an ATP-dependent AAA+ protein disaggregase/refoldase that resides in the mitochondrial intermembrane space (IMS). Two independent 2015 exome/homozygosity-mapping studies established the gene–disease relationship, and the disorder now sits at the intersection of inborn errors of metabolism, congenital neutropenia, and neurodevelopmental disease. It is inherited chiefly as an autosomal recessive trait (biallelic CLPB variants), with a distinct dominant de novo monoallelic subset acting through a dominant-negative mechanism (PMID: 25597510, PMID: 25597511, PMID: 34140661).

The clinical hallmark is a graded multisystem tetrad: congenital neutropenia (with risk of progression to bone-marrow failure, myelodysplastic syndrome, and acute leukemia), neurodevelopmental impairment ranging from nonprogressive intellectual disability to prenatal encephalopathy with progressive cerebral/cerebellar atrophy, movement disorder and epilepsy, bilateral cataracts, and 3-methylglutaconic aciduria detectable on urine organic-acid screening. Postpubertal female survivors frequently develop premature ovarian insufficiency (POI). Disease severity spans a continuum from neonatal death to survival into adulthood, and this severity tracks with the degree of residual CLPB (refoldase) activity retained by the mutant protein.

Mechanistically, loss of CLPB disaggregase activity destabilizes IMS client proteins—most notably the anti-apoptotic protein HAX1 (itself mutated in Kostmann severe congenital neutropenia)—linking the enzymatic lesion to neutropenia and apoptosis. There is no curative therapy; management is supportive (G-CSF for neutropenia, cataract surgery, antiepileptics, infection prophylaxis, and hematologic surveillance), and prevention is entirely genetic (counseling, carrier/cascade testing with a Greenlandic Inuit founder emphasis, and prenatal/preimplantation genetic testing). This report synthesizes 12 confirmed findings across 17 reviewed papers into a complete disease-knowledge-base entry organized by the requested domains.

Section 1 — Disease Information

MGCA7A is a Mendelian mitochondrial disorder defined at the molecular level by loss of function of the CLPB-encoded disaggregase. Key identifiers: MONDO:0859237 · OMIM phenotype #616271 · OMIM gene *616254 (CLPB) · Orphanet ORPHA:445038 · gene HGNC:18542 · UniProt Q9H078. It is classified among the inborn errors of metabolism with 3-methylglutaconic aciduria as a discriminative feature (PMID: 23296368).

Synonyms / alternative names: 3-methylglutaconic aciduria type VII; MGCA7; MGCA7A; CLPB deficiency; "MEGCANN" (Methylglutaconic aciduria, cataracts, neurologic involvement, neutropenia); CLPB-related mitochondrial disorder with cataract, neutropenia, epilepsy and methylglutaconic aciduria.

The evidence base is aggregated disease-level (OMIM/Orphanet curation, cohort studies, mechanistic biochemistry) supplemented by individual patient reports/case series; there is no large EHR-derived dataset for this ultra-rare condition.

Section 2 — Etiology

Disease causal factor: purely genetic. MGCA7A is a monogenic disorder of CLPB. There is no environmental, infectious, or multifactorial cause. Two mutational mechanisms operate:

Biallelic (autosomal recessive) loss-of-function — the classical form.
Monoallelic de novo dominant-negative missense variants — a distinct subset.

Genetic risk factors: the only risk factor is possession of pathogenic CLPB alleles. Consanguinity and founder effects (Greenlandic/Inuit) raise biallelic risk in defined populations. No modifier loci have been formally mapped, though variant class strongly modifies severity (see Section 4/11).

Environmental risk / protective factors: none identified; diet, toxins, lifestyle, age, and sex are not causal. POI affects only females (a sex-specific manifestation, not a risk factor for the disease itself).

Gene–environment interactions: none documented. The oxidation-sensitive Y272C mutation introduces an aberrant disulfide bond (PMID: 37041140), raising a theoretical (unproven) redox-environment interaction, but no clinical GxE effect is established.

Section 3 — Phenotypes

Across cohorts the phenotype comprises congenital neutropenia (which can progress to leukemia), a neurological spectrum from nonprogressive intellectual disability to prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and elevated urinary 3-methylglutaconic acid. The pivotal review states the disorder spans "a neurological phenotype ranging from nonprogressive intellectual disability to prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, 3-methylglutaconic aciduria, and neutropenia" (PMID: 34140661).

Pronicka et al. (31 patients) stratified severity into mild (n=4), moderate (n=13), severe (n=14); the severe subtype featured "the neonatal absence of voluntary movements in combination with ventilator dependency and hyperexcitability," making MGCA7A an important differential diagnosis of hyperekplexia (PMID: 28687938). Postpubertal female survivors commonly develop premature ovarian insufficiency: "POI is a common feature of postpubertal female individuals with CLPB deficiency" (PMID: 36074910).

Phenotype	Type	HPO term	Onset	Severity/progression	Frequency
Neutropenia	Lab abnormality	HP:0001875	Congenital	Variable; leukemia risk	Very frequent
Intellectual disability	Clinical sign	HP:0001249	Congenital/early	Nonprogressive→severe	Frequent
Cerebral atrophy	Imaging	HP:0002059	Prenatal–early	Progressive	Frequent
Cerebellar atrophy	Imaging	HP:0001272	Prenatal–early	Progressive	Frequent
Cataract	Physical	HP:0000518	Congenital/early	Stable (surgical)	Frequent
3-Methylglutaconic aciduria	Lab abnormality	HP:0003535	Congenital	Persistent	Obligate marker
Movement disorder	Clinical sign	HP:0100022	Early	Variable	Frequent
Seizures/epilepsy	Clinical sign	HP:0001250	Early	Variable	Frequent
Neonatal hyperexcitability	Clinical sign	HP:0032322	Neonatal	Severe subtype	Severe form
Premature ovarian insufficiency	Clinical sign	HP:0008209	Postpubertal	Progressive	Common (female survivors)
Respiratory insufficiency	Clinical sign	HP:0002093	Neonatal	Severe form	Severe subtype

Quality of life impact: severe neonatal disease causes ventilator dependency, absent voluntary movement, and early death (median 35 days in the severe group), with profound QoL loss; milder disease permits survival into adulthood (median age 17.5 years in the mild group) but with intellectual disability, visual impairment from cataracts, and (in females) infertility from POI (PMID: 28687938, PMID: 36074910). No formal EQ-5D/SF-36 data exist.

Section 4 — Genetic / Molecular Information

Causal gene: CLPB (caseinolytic peptidase B homolog; chr11q13.4; HGNC:18542; OMIM *616254), encoding the mitochondrial AAA+ ATPase/disaggregase SKD3 (UniProt Q9H078). Wortmann et al. identified "mutations in CLPB define a syndrome" in 14 individuals from 9 families (PMID: 25597510). Saunders et al. independently reported "biallelic variants in the caseinolytic peptidase B homolog (CLPB). The causative variants included one missense variant, c.803C>T (p.Thr268Met), and two nonsense variants, c.961A>T (p.Lys321*) and c.1249C>T (p.Arg417*)" (PMID: 25597511).

Variant types & classification: missense, nonsense, frameshift, and splicing variants are all reported (pathogenic/likely pathogenic per ACMG). Stop/stop (nonsense-mediated decay) and ankyrin/N-domain-disrupting alleles confer the greatest burden. The dominant subset comprises de novo monoallelic missense variants: "we identified one of four different de novo monoallelic missense variants in CLPB. We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner" (PMID: 34140661).

Functional consequences: biallelic variants cause loss of function (markedly decreased CLPB protein in patient fibroblasts/liver); de novo monoallelic variants act by dominant-negative interference with the oligomeric disaggregase. Allele frequency: all causal alleles are rare/absent in gnomAD, consistent with an ultra-rare disorder; the Greenlandic founder allele is enriched locally.

Structural insights: the N-domain mutation Y272C "forms an intramolecular disulfide bond with Cys267 and severely impairs SKD3" (PMID: 37041140). SKD3 assembles into nucleotide-stabilized dodecamers (two hexameric rings) (PMID: 35247700).

Modifier genes / epigenetics / chromosomal abnormalities: no formal modifier loci, methylation signatures, or large structural/chromosomal changes have been described; disease is point-mutation/small-variant driven.

Section 5 — Environmental Information

Not applicable. MGCA7A is a monogenic disorder with no environmental, lifestyle, or infectious contribution. No toxins, radiation, occupational exposures, dietary factors, or pathogens are implicated in causation or triggering. (The 3-methylglutaconic acid elevation is an endogenous metabolic consequence, not an environmental exposure.)

Section 6 — Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

1. Biallelic LoF (recessive) OR de novo monoallelic dominant-negative
   CLPB variant
│  leads to
▼
2. Reduced/abolished SKD3 (CLPB) ATP-dependent DISAGGREGASE/REFOLDASE
   activity in the mitochondrial intermembrane space
   (ATPase activity may be preserved; REFOLDASE loss is the key defect)
│  results in
▼
3. Failure to disaggregate/refold IMS client proteins
│
├──► 3a. Reduced solubility & altered assembly of anti-apoptotic
│        HAX1  →  granulocyte apoptosis / maturation arrest
│              →  CONGENITAL NEUTROPENIA  →  infection risk;
│                 MDS / acute leukemia risk
│
├──► 3b. IMS proteostatic stress / mitochondrial membrane
│        pathology  →  accumulation & urinary excretion of
│        3-METHYLGLUTACONIC ACID (nonspecific mito marker)
│
├──► 3c. Neuronal mitochondrial dysfunction  →  prenatal/early
│        encephalopathy  →  PROGRESSIVE CEREBRAL & CEREBELLAR
│        ATROPHY, intellectual disability, movement disorder,
│        epilepsy  (inferred: direct neuronal apoptotic pathway
│        not fully demonstrated)
│
├──► 3d. Lens epithelial mitochondrial dysfunction  →  bilateral
│        CATARACTS  (inferred)
│
└──► 3e. Ovarian (granulosa/oocyte) mitochondrial dysfunction  →
         PREMATURE OVARIAN INSUFFICIENCY in postpubertal females
│
▼
4. SEVERITY is set by RESIDUAL REFOLDASE ACTIVITY:
   stop/stop & NMD/ankyrin-disrupting variants → severe, neonatal death;
   missense with partial function → milder, survival into adulthood.

Detail

Molecular pathway / protein function. SKD3 (human ClpB) couples ATP hydrolysis to protein disaggregation/reactivation in the IMS, regulated by PARL: "A mitochondrial inner-membrane protease, PARL, removes an autoinhibitory peptide from Skd3 to greatly enhance disaggregase activity" (PMID: 32573439). It localizes to the IMS—"CLPB resides in the mitochondrial intermembrane space" (PMID: 32866687)—where it forms ATP-dependent high-molecular-weight complexes/dodecamers (PMID: 35247700).

Biochemical/cellular consequence (the HAX1 bridge). Loss of disaggregase activity destabilizes clients: "Human cells lacking Skd3 exhibit reduced solubility of various mitochondrial proteins, including anti-apoptotic Hax1. Importantly, Skd3 variants linked to 3-methylglutaconic aciduria... display diminished disaggregase activity (but not always reduced ATPase activity), which predicts disease severity" (PMID: 32573439). Because HAX1 is mutated in Kostmann congenital neutropenia, its destabilization provides a direct molecular route to the neutropenia phenotype and to dysregulated apoptosis. Complexome profiling confirms altered assembly: in patients "multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB" (PMID: 34140661).

Upstream vs downstream. The CLPB mutation and loss of refoldase activity are upstream (and encode severity). The HAX1/IMS-client destabilization is the proximal effector (best-demonstrated, explains neutropenia). The brain/lens/ovary manifestations are downstream and mechanistically inferred from shared mitochondrial proteostatic stress in high-energy tissues.

Cell types & processes involved: neutrophils/granulocytes (CL:0000775/CL:0000094), neurons and glia, lens epithelium, ovarian granulosa/oocytes.

Suggested GO terms: GO:0043335 (protein unfolding), GO:0042026 (protein refolding), GO:0016887 (ATP hydrolysis activity), GO:0005758 (mitochondrial intermembrane space), GO:0006915 (apoptotic process). CHEBI: CHEBI:28123 (3-methylglutaconic acid).

Metabolomics / 3-MGA-uria: 3-methylglutaconic aciduria is a nonspecific marker of mitochondrial dysfunction; its exact biochemical origin in CLPB disease is unknown (PMID: 23355087, PMID: 23296368). SKD3/CLPB is also upregulated in acute myeloid leukemia, where it contributes to venetoclax resistance (PMID: 35247700, PMID: 31048321).

Section 7 — Anatomical Structures Affected

Organ level (primary): central nervous system (progressive cerebral and cerebellar atrophy, movement disorder, epilepsy—"Muscular hypo- and hypertonia, movement disorder and progressive brain atrophy are frequently reported" PMID: 28687938); hematopoietic/bone marrow (granulocytic neutropenia with leukemia risk); ocular lens (bilateral cataracts); ovary (POI in female survivors). Secondary involvement: respiratory system and swallowing/feeding apparatus in severe neonates.

Body systems: nervous, hematologic/immune, ocular/visual, reproductive/endocrine.

Tissue/cell level: nervous tissue (neurons, cerebellar Purkinje/granule populations), granulocytic hematopoietic lineage, lens epithelium, ovarian granulosa cells. Cell Ontology: CL:0000775 (neutrophil), CL:0000094 (granulocyte).

Subcellular level: the mitochondrial intermembrane space (GO:0005758) is the primary locus—"indicating that CLPB resides in the mitochondrial intermembrane space" (PMID: 32866687).

UBERON terms: UBERON:0000955 (brain), UBERON:0002037 (cerebellum), UBERON:0002371 (bone marrow), UBERON:0000965 (lens), UBERON:0000992 (ovary). Lateralization: CNS atrophy and cataracts are typically bilateral.

Section 8 — Temporal Development

Onset: congenital, often prenatal in severe cases (reduced fetal movements). Pattern: subacute-to-chronic with a progressive neurological component.

Progression: "The foetal and neonatal presentation mirrored the course of disease with respect to survival (current median age 17.5 years in the mild group, median age of death 35 days in the severe group), severity and age of onset of all findings evaluated" (PMID: 28687938). The neurologic component is progressive (progressive brain atrophy); neutropenia and cataracts are congenital/early. Age of onset predicts rate: "Early-onset disease (<12 months) correlated with more severe progression. Later onset often resulted in milder phenotypes" (PMID: 41719910).

Course / duration: lifelong/chronic in survivors; severe disease is rapidly fatal in the neonatal period. Critical period: the neonatal window (respiratory/feeding support, G-CSF) is decisive for survival. No spontaneous remission; POI emerges postpubertally.

Section 9 — Inheritance and Population

Epidemiology: ultra-rare (ORPHA:445038; prevalence <1/1,000,000). Fewer than ~100 patients are reported worldwide; the largest cohort is 63 individuals (PMID: 41719910). No formal incidence estimate exists.

Inheritance: predominantly autosomal recessive (OMIM #616271; biallelic CLPB), with a distinct autosomal dominant de novo subset (PMID: 34140661).

Penetrance/expressivity: apparently complete penetrance in biallelic/dominant-negative genotypes but highly variable expressivity, graded by residual refoldase activity/variant class.

Founder effect / consanguinity: a Greenlandic (Inuit) founder population is documented—"Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent" (PMID: 25597511). Consanguinity contributes to biallelic cases in some populations. Carrier frequency is elevated in the founder population but not formally quantified globally.

Demographics: both sexes affected; POI is female-specific. No overall sex-ratio skew is established. Genetic anticipation / germline mosaicism: not a repeat-expansion disorder, so no anticipation; germline mosaicism is a theoretical counseling caveat for de novo cases.

Survival by zygosity:

Parameter	Biallelic	Monoallelic (de novo)
N (63-case cohort)	41	22
Mortality	66%	23%
Median age at death	6 months	2.4 years
4-year survival	50%	82%

"Death occurred in 66% of biallelic and 23% of monoallelic individuals, with earlier median age at death in biallelic cases (6 months vs 2.4 years). Biallelic cases had significantly higher DBI scores and poorer survival (4-year survival: 50% vs 82%)" (PMID: 41719910).

Section 10 — Diagnostics

Laboratory / biochemistry: urine GC-MS shows elevated 3-methylglutaconic (and 3-methylglutaric) acid—one neonate's "urine 3-methylpentenedioic acid... increased to 17.53 μmol/L" (PMID: 37906145). CBC demonstrates congenital neutropenia.

Imaging: brain MRI shows progressive cerebral/cerebellar atrophy and may show structural anomalies; ophthalmologic exam detects cataracts.

Genetic testing (definitive): molecular confirmation via NGS—whole-exome/whole-genome sequencing or targeted panels (congenital neutropenia / 3-MGA / mitochondrial disease)—identifying biallelic or de novo monoallelic CLPB variants: "metabolic analysis suggested 3-methylglutaconic aciduria due to elevated 3-methylglutaconic acid and 3-methylglutaric acid. NGS has detected two compound heterozygous CLPB variants" (PMID: 32219827). WES/WGS is first-line; single-gene CLPB testing applies in known founder families. Chromosomal microarray/karyotype/FISH/mtDNA/repeat-expansion testing are not indicated (no structural or mtDNA lesions).

Clinical criteria / differential diagnosis: 3-MGA-uria is the diagnostic key but is nonspecific—"There is... a group of disorders with significantly and consistently increased 3-methylglutaconic acid excretion, where the 3-methylglutaconic aciduria is a hallmark of the phenotype and the key to diagnosis" (PMID: 23296368). Differentials with discriminative 3-MGA-uria include TAZ (Barth syndrome), SERAC1 (MEGDEL), OPA3 (Costeff), DNAJC19 (DCMA), and TMEM70 (PMID: 23355087); among congenital neutropenia syndromes, CLPB disease must be distinguished from HAX1 (Kostmann), ELANE, G6PC3 and others (PMID: 38589208). Severe neonatal CLPB disease is an important differential of hyperekplexia (PMID: 28687938).

Omics diagnostics: RNAseq/quantitative proteomics/complexome profiling confirm causation in difficult cases (PMID: 36074910, PMID: 34140661). Screening: biochemical NBS for 3-MGA is not standard; carrier/cascade testing applies in founder families.

Suggested LOINC/ontology: urine organic acids (GC-MS); HP:0003535 (3-MGA-uria); HP:0001875 (neutropenia).

Section 11 — Outcome / Prognosis

Survival/mortality: strongly genotype-dependent. Biallelic disease carries 66% mortality (median death 6 months; 4-year survival 50%) versus 23% mortality for monoallelic disease (median death 2.4 years; 4-year survival 82%) (PMID: 41719910). The Pronicka cohort spanned "current median age 17.5 years in the mild group, median age of death 35 days in the severe group" (PMID: 28687938).

Morbidity/disability: survivors face intellectual disability, movement disorder, epilepsy, visual impairment (cataracts), recurrent infection (neutropenia), and—in females—infertility from POI. Complications: life-threatening infections; progression to bone-marrow failure, MDS, and acute leukemia (PMID: 38589208); respiratory failure in severe neonates.

Prognostic factors: variant class/structural prediction is the strongest—"Structural predictions—particularly variants causing nonsense-mediated decay or ankyrin domain disruption—were stronger survival predictors than zygosity or age of onset" (PMID: 41719910). Residual disaggregase activity predicts disease severity (PMID: 32573439). Early onset (<12 months) predicts worse course. No formal QoL metrics are published.

Section 12 — Treatment

No disease-modifying therapy exists; management is supportive/symptomatic.

Pharmacotherapy: granulocyte colony-stimulating factor (G-CSF) corrects neutropenia—"Administration of granulocyte colony-stimulating factor successfully maintained neutrophil counts above 0.5 × 10⁹/L and significantly reduced the frequency of respiratory tract infections" (PMID: 41560087). Antiepileptics manage seizures; symptomatic agents address the movement disorder. Pharmacogenomics: none established.

Surgical: cataract extraction for visual rehabilitation. Supportive/rehabilitative: neonatal respiratory and feeding support in severe disease; developmental, physical, occupational, and speech therapy; endocrine/fertility care (hormone replacement) for POI (PMID: 36074910).

Caveat on G-CSF: residual malignancy risk persists—"While some patients benefit from granulocyte colony-stimulating factor treatment, they may still face an increased risk of bone marrow failure, myelodysplastic syndrome and acute leukaemia"—mandating hematologic surveillance (PMID: 38589208). Hematopoietic stem cell transplantation is considered in severe-congenital-neutropenia disorders but is not an established cure for the multisystem CLPB phenotype.

Advanced/experimental therapeutics: no approved gene, cell, or RNA-based therapy; no disease-specific clinical trials with NCT identifiers were identified. Suggested NCIT terms: C1725 (G-CSF), C15329 (Cataract Surgery), C264 (Anticonvulsant Agent), C15431 (Supportive Care), C15431 (symptom management).

Section 13 — Prevention

Because MGCA7A is a monogenic CLPB disorder with no environmental cause, prevention is entirely genetic:

Primary/genetic prevention: genetic counseling with recurrence-risk assessment (25% for carrier couples in AR families; low—but non-zero via germline mosaicism—for de novo dominant cases); carrier testing (targeted founder-variant testing in the Greenlandic/Inuit population); cascade testing of relatives; and reproductive options including prenatal diagnosis and preimplantation genetic testing (PGT) once familial variants are known (PMID: 25597511, PMID: 34140661).
Secondary prevention: early diagnosis via urinary organic-acid screening + NGS and prompt supportive care (PMID: 41560087).
Tertiary prevention: infection prophylaxis and leukemia/MDS surveillance (PMID: 38589208).

Immunization / public-health / environmental interventions: not applicable (no infectious or environmental etiology).

Section 14 — Other Species / Natural Disease

Taxonomy / orthologs: CLPB is evolutionarily conserved; a functional ortholog exists in zebrafish (Danio rerio, NCBI Taxon 7955) (used as a disease model, below). Bacterial/yeast ClpB/Hsp104 family members are the ancestral disaggregases, underscoring deep conservation of the disaggregase mechanism.

Naturally occurring disease in other species: no naturally occurring CLPB-deficiency disease has been catalogued in companion animals or wildlife (no OMIA entry identified). Zoonotic potential / cross-species transmission: not applicable (non-infectious genetic disorder).

Comparative biology: the conservation of the disaggregase from bacteria/yeast (Hsp104) through zebrafish to humans makes the mechanism broadly tractable, but no natural animal disease model is reported.

Section 15 — Model Organisms

Zebrafish (Danio rerio) morphant is the principal in vivo model: "Suppression of clpb in zebrafish embryos induced a central nervous system phenotype that was consistent with cerebellar and cerebral atrophy that could be rescued by wild-type, but not mutant, human CLPB mRNA" (PMID: 25597510). This both recapitulates the CNS atrophy and provides a variant-pathogenicity rescue assay. Its limitation is that it models mainly the neurological component, not the full multisystem syndrome.

In vitro / cellular models: - Recombinant SKD3 ATPase/disaggregase activity assays (PMID: 32573439, PMID: 35247700). - Patient fibroblasts and liver showing markedly decreased CLPB protein (PMID: 25597511). - HEK-293/BT-549 cell fractionation establishing IMS localization and ATP-dependent complexes (PMID: 32866687). - CLPB-knockout human cell lines demonstrating reduced solubility of mitochondrial proteins including HAX1 (PMID: 32573439).

No published mouse knock-in recapitulating the human genotype–phenotype spectrum was identified—a key gap. Resources: ZFIN (zebrafish), Cellosaurus (HEK-293/BT-549).

Mechanistic Model / Interpretation (Synthesis)

The pathophysiology is best understood as a single enzymatic lesion radiating into tissue-specific failures. The proximal, best-demonstrated arm is the CLPB→HAX1→neutropenia axis: loss of the IMS disaggregase renders anti-apoptotic HAX1 insoluble and mis-assembled, phenocopying the HAX1-mutant Kostmann neutropenia. The remaining arms (brain atrophy, cataract, POI) are inferred to arise from generalized IMS proteostatic stress in highly mitochondria-dependent tissues. Severity is encoded at the genotype: variants that abolish refoldase activity (NMD/stop-stop, ankyrin-domain disruption) produce lethal neonatal disease, whereas partially functional missense alleles allow survival into adulthood. Critically, disaggregase (refoldase) activity—not ATPase activity—is the quantitative determinant of severity, which reframes the protein's function (refolding, not merely ATP hydrolysis) as the therapeutically relevant target.

Evidence Base

PMID	Title (abbrev.)	Evidence type	Supports
25597510	CLPB mutations cause 3-MGA, brain atrophy, neutropenia, cataracts	Human genetics + zebrafish	Gene discovery; zebrafish CNS model
25597511	CLPB variants w/ cataract, neutropenia, epilepsy, MGA	Human genetics	Independent confirmation; Greenlandic founder; variants
34140661	Neutropenia & ID are hallmarks of biallelic & de novo CLPB deficiency	Human genetics + complexome	Dominant-negative subset; HAX1 assembly
32573439	Skd3 is a potent mito disaggregase inactivated by MGA mutations	In vitro + human KO cells	PARL activation; HAX1 solubility; severity predictor
32866687	CLPB forms ATP-dependent complexes in the IMS	Cell biology	Subcellular localization
35247700	SKD3 assembles into nucleotide-stabilized dodecamers	Structural	Double-hexamer architecture; AML link
37041140	Structural basis of impaired disaggregase in oxidation-sensitive SKD3 mutant	Structural	Y272C/Cys267 disulfide mechanism
28687938	Scoring system predicting clinical course (31 patients)	Clinical cohort	Severity stratification; survival; temporal course
41719910	Genotype to outcome: zygosity-specific insights (63 cases)	Clinical cohort	Survival by zygosity; structural predictors
36074910	Premature ovarian insufficiency in CLPB deficiency	Clinical + multi-omics	POI; RNAseq/proteomics validation
41560087	CLPB deficiency-associated congenital neutropenia (case report)	Case report	G-CSF efficacy
38589208	Congenital neutropenia syndromes: differential diagnosis	Review	Residual leukemia/MDS risk; differential
32219827	Clinical/genetic analysis of an infant with MGCA7	Case report	Biochemical + NGS diagnosis
37906145	Child with MGCA7 due to novel CLPB variants	Case report	Urinary 3-MGA hallmark
23296368	Inborn errors with 3-MGA-uria: classification & nomenclature	Review	3-MGA-uria as diagnostic key
23355087	3-MGA-uria: lessons from 50 genes and 977 patients	Large review	Differential (TAZ, SERAC1, OPA3, DNAJC19, TMEM70)
31048321	Targeting mitochondrial structure sensitizes AML to venetoclax	Functional genomics	Context — CLPB/mito chaperone in AML

Evidence-source breakdown: Human clinical genetics and cohorts provide the strongest evidence for gene–disease relationship, phenotype, and prognosis. Mechanistic claims rest on in vitro biochemistry and human knockout-cell/complexome studies (strong for the HAX1 branch). Animal-model evidence is limited to the zebrafish morphant.

Limitations and Knowledge Gaps

Rarity limits statistics. Fewer than ~100 patients worldwide; largest cohort 63. Prevalence/incidence, penetrance, and expressivity are described qualitatively, not with confidence intervals.
Mechanistic gaps for non-hematologic branches. The HAX1–neutropenia link is biochemically demonstrated; the pathways to brain atrophy, cataract, and POI are inferred from shared mitochondrial stress, not directly shown. Specific IMS clients and apoptotic effectors in neurons, lens, and ovary are undefined.
Origin of 3-MGA-uria unknown. As in other mitochondrial 3-MGA-urias (except AUH), the biochemical origin of the excreted acid is unestablished; it is a nonspecific marker, not a direct CLPB readout.
No disease-modifying therapy or validated progression biomarker. G-CSF addresses only neutropenia and does not abolish malignancy risk; variant class/structural prediction is the only deployed prognostic tool.
Limited animal models. The zebrafish morphant captures CNS atrophy but not the full syndrome; no mouse knock-in recapitulating the human spectrum was identified.
Modifier genes and epigenetics underlying the wide severity range are essentially unstudied; founder data outside Greenland/Inuit are sparse.

Proposed Follow-up Experiments / Actions

Generate a mouse (or iPSC-organoid) allelic series spanning null, hypomorphic missense, and dominant-negative CLPB variants to test the "residual refoldase activity sets severity" model in vivo and to model the brain/lens/ovary branches directly.
Define the IMS client interactome by proximity-labeling (BioID/APEX) proteomics in CLPB-knockout vs. rescued human neurons, lens epithelium, and granulosa cells—to find tissue-specific aggregation-prone clients beyond HAX1.
Develop a quantitative variant-function assay (recombinant SKD3 disaggregase activity ± PARL processing) as a clinical-grade functional classifier to resolve VUS and refine prognosis (PMID: 41719910).
Establish a prospective natural-history registry with standardized neuro-imaging, CBC, ophthalmologic, and endocrine endpoints to generate confidence-bounded prevalence, penetrance, and progression data and to support trial design.
Test chaperone/proteostasis-restoring or HAX1-stabilizing strategies (e.g., molecules enhancing residual disaggregase function) in patient-derived cells as disease-modifying proof-of-concept.
Pharmacovigilance for leukemia/MDS in G-CSF-treated patients via longitudinal bone-marrow surveillance cohorts to quantify malignant-transformation hazard specific to CLPB deficiency.
Expand founder-variant carrier screening in Greenlandic/Inuit populations and investigate additional geographic founder alleles to inform targeted reproductive genetic services.

Report compiled from 12 confirmed findings across 17 reviewed primary and review articles. Evidence sources are distinguished as human clinical genetics/cohorts, in vitro biochemistry, human knockout-cell and complexome studies, structural biology, and a zebrafish morphant model. All mechanistic and clinical claims are cited to PMID with verbatim abstract support where available.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	17
Resolved	17
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	22
Quoted claims found in source	21
Quoted claims not found in source	1
References weighed for topical relevance	17
On topic	14
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

PMID:41560087: "Administration of granulocyte colony-stimulating factor successfully maintained neutrophil counts above 0.5 × 10⁹/L and significantly reduced the frequency of respiratory tract infections"
closest text in source: "OUTCOMES: Administration of granulocyte colony-stimulating factor successfully maintained neutrophil counts above 0.5 × 109/L and significantly reduced the frequency of respiratory tract infections"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	27
Resolved	25
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	24
Terms named correctly	12
Terms named as a different term	12

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0001875 (2 mentions) - the report calls it "Lab abnormality", "neutropenia"; HP calls it Decreased total neutrophil count
HP:0001249 (1 mention) - the report calls it "Clinical sign"; HP calls it Intellectual disability
HP:0002059 (1 mention) - the report calls it "Imaging"; HP calls it Cerebral atrophy
HP:0001272 (1 mention) - the report calls it "Imaging"; HP calls it Cerebellar atrophy
HP:0000518 (1 mention) - the report calls it "Physical"; HP calls it Cataract
HP:0003535 (2 mentions) - the report calls it "Lab abnormality", "3-MGA-uria"; HP calls it 3-Methylglutaconic aciduria
HP:0100022 (1 mention) - the report calls it "Clinical sign"; HP calls it Abnormality of movement
HP:0001250 (1 mention) - the report calls it "Clinical sign"; HP calls it Seizure
HP:0032322 (1 mention) - the report calls it "Clinical sign"; HP calls it Healthy
HP:0008209 (1 mention) - the report calls it "Clinical sign"; HP calls it Premature ovarian insufficiency
HP:0002093 (1 mention) - the report calls it "Clinical sign"; HP calls it Respiratory insufficiency
CHEBI:28123 (1 mention) - the report calls it "3-methylglutaconic acid"; CHEBI calls it diethanolamine

Terms named inconsistently

The report gives these identifiers more than one name of its own:

HP:0001875 - called "Lab abnormality", "neutropenia"
HP:0003535 - called "Lab abnormality", "3-MGA-uria"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Prevalence

Experimental Models

Source YAML

References & Deep Research

References

Deep Research

3-Methylglutaconic Aciduria Type VIIA (MGCA7A): A Comprehensive Disease Characterization Report

Summary

Section 1 — Disease Information

Section 2 — Etiology

Section 3 — Phenotypes

Section 4 — Genetic / Molecular Information

Section 5 — Environmental Information

Section 6 — Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Detail

Section 7 — Anatomical Structures Affected

Section 8 — Temporal Development

Section 9 — Inheritance and Population

Section 10 — Diagnostics

Section 11 — Outcome / Prognosis

Section 12 — Treatment

Section 13 — Prevention

Section 14 — Other Species / Natural Disease

Section 15 — Model Organisms

Mechanistic Model / Interpretation (Synthesis)

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Terms named inconsistently

Prefixes with no resolver