3-Methylglutaconic Aciduria Type VIIB

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Homozygous or compound heterozygous CLPB variants, including missense, nonsense and frameshift alleles, with heterozygous unaffected parents.

Autosomal recessive inheritance

Show evidence (5 references)

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"CLPB deficiency associated with biallelic CLPB pathogenic variants is inherited in an autosomal recessive manner."

GeneReviews states the recessive mode of inheritance for the biallelic form.

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial CLPB pathogenic variants"

GeneReviews gives the recessive recurrence risk for sibs of an affected child.

PMID:25597511 SUPPORT Human Clinical

"Through a combination of homozygosity mapping in the Greenlandic individuals and exome sequencing in the North American, we identified biallelic variants in the caseinolytic peptidase B homolog (CLPB)."

Biallelic variants in five affected children from two populations support recessive inheritance.

+ 2 more references

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Mechanistic Hypotheses

4

CLPB-HAX1 Mitochondrial Proteostasis Model of Neutropenia

clpb_hax1_proteostasis_neutropenia EMERGING

Evidence balance 2 support

Loss of CLPB disaggregase activity leaves HAX1 and other intermembrane space proteins insoluble, disrupting a CLPB/HAX1/PRKD2/HSP27 axis needed for granulocytic differentiation, so that myeloid precursors undergo apoptosis at the onset of differentiation. The model is supported in cultured human and mouse myeloid cells and by the shared neutropenia of HAX1 deficiency; it has not been tested in patient marrow.

Pathograph links

Intermembrane Space Protein Aggregation -> HAX1 Insolubility DIRECT

HAX1 Insolubility -> Granulocytic Precursor Apoptosis and Impaired Neutrophil Differentiation INDIRECT UNKNOWN INTERMEDIATES

Granulocytic Precursor Apoptosis and Impaired Neutrophil Differentiation -> Congenital neutropenia DIRECT

Show evidence (2 references)

PMID:35499078 SUPPORT In Vitro

"we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes"

Defines the shared CLPB/HAX1 pathway in neutrophil differentiation.

PMID:39644357 SUPPORT In Vitro

"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."

HAX1 aggregation in CLPB-deficient myeloid cells.

Aggregate-Induced Mitochondrial Membrane Perturbation as the Source of 3-MGA

aggregate_membrane_perturbation_3mga EMERGING

Evidence balance 1 support

Abnormal protein aggregates perturb mitochondrial membrane architecture, which is proposed to be the shared cause of 3-methylglutaconic aciduria in CLPB deficiency and in the membrane-lipid disorders Barth, Sengers and MEGDEL syndromes. Proposed from clinical and genetic data; not tested.

Pathograph links

Intermembrane Space Protein Aggregation -> Secondary 3-Methylglutaconic Acid Accumulation INDIRECT UNKNOWN INTERMEDIATES Proposed only. The route from aggregation to 3-methylglutaconic acid production has not been demonstrated.

Show evidence (1 reference)

PMID:25595726 SUPPORT INDIRECT Human Clinical

"We now propose that perturbation of the mitochondrial membranes by abnormal protein aggregates leads to 3-methylglutaconic aciduria in CLPB deficiency."

States the hypothesis.

Mitochondrial Acetyl-CoA Build-up Route to 3-MGA

acetyl_coa_tca_3mga ALTERNATIVE

Evidence balance 1 support

The current general model for secondary 3-methylglutaconic acidurias: impaired TCA cycle function causes mitochondrial acetyl-CoA to build up, which is converted through trans-3-methylglutaconyl-CoA to 3-methylglutaconic acid. Stated for the disease class; not tested in CLPB-deficient cells.

Pathograph links

Secondary Complex I Instability -> Secondary 3-Methylglutaconic Acid Accumulation INDIRECT UNKNOWN INTERMEDIATES Hypothetical. Both class-wide models derive secondary 3-MGA from mitochondrial dysfunction; complex I instability is the mitochondrial dysfunction shown in CLPB-null cells, but no study has connected the two.

Show evidence (1 reference)

PMID:39787888 SUPPORT BACKGROUND Other

"It is currently thought that this accumulation is due to an underlying buildup of acetyl-CoA in the mitochondria from impaired function of the TCA cycle with ensuing formation of trans-3-methylglutaconyl CoA and its subsequent byproducts, including 3-MGA."

States the class-wide hypothesis for secondary 3-MGA.

AMPK-Driven Peroxisomal HMG-CoA Route to 3-MGA

ampk_peroxisomal_3mga ALTERNATIVE

Evidence balance 1 support

A general scenario for secondary 3-methylglutaconic acidurias in which constitutive mitochondrial dysfunction activates AMPK, diverting cytoplasmic acetyl-CoA to peroxisomes where HMG-CoA is converted to 3-methylglutaconate. The authors consider additional contributors for CLPB deficiency. Theoretical synthesis; not tested in CLPB cells.

Pathograph links

Secondary Complex I Instability -> Secondary 3-Methylglutaconic Acid Accumulation INDIRECT UNKNOWN INTERMEDIATES Hypothetical. Both class-wide models derive secondary 3-MGA from mitochondrial dysfunction; complex I instability is the mitochondrial dysfunction shown in CLPB-null cells, but no study has connected the two.

Show evidence (1 reference)

PMID:31626852 SUPPORT REVIEW SYNTHESIS Other

"constitutive mitochondrial dysfunction induces AMPK activation which, by inhibiting early steps in cholesterol and fatty acid syntheses, pipelines cytoplasmic acetyl-CoA to peroxisomes where a rise in HMG-CoA followed by local dehydration and hydrolysis may lead to 3-MGA yield"

States the alternative hypothesis.

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Discussions and Knowledge Gaps

2

Why does loss of a ubiquitously expressed mitochondrial disaggregase produce neutropenia across the severity range but neurological disease of widely varying severity, and which CLPB substrates are limiting in granulocytic precursors versus neurons?

KNOWLEDGE GAP OPEN gap_clpb_tissue_selectivity

Attached to

pathophysiology#HAX1 Insolubility pathophysiology#Progressive Encephalopathy with Brain Atrophy phenotypes#Congenital neutropenia

The neutropenia has a candidate mechanism through HAX1 and the CLPB/HAX1/PRKD2/HSP27 axis, but no comparable substrate has been linked to neuronal loss, and the neurological severity tracks residual disaggregase activity without a known cell-specific explanation. Candidate links such as secondary complex I instability and impaired mitochondrial calcium uptake are shown only in cultured cells.

Show evidence (2 references)

PMID:32573439 SUPPORT In Vitro

"Importantly, Skd3 variants linked to 3-methylglutaconic aciduria, a severe mitochondrial disorder, display diminished disaggregase activity (but not always reduced ATPase activity), which predicts disease severity."

Severity tracks residual activity, but the tissue pattern is unexplained.

PMID:38270563 SUPPORT BACKGROUND In Vitro

"CLPB mutations are associated with 3-methylglutaconic aciduria and neutropenia; however, the molecular mechanism underscoring disease and the contribution of CLPB substrates to disease pathology remains unknown."

States that the substrate contribution to disease is unknown.

How does loss of CLPB disaggregase activity raise urinary 3-methylglutaconic acid?

KNOWLEDGE GAP OPEN gap_clpb_3mga_origin

Attached to

pathophysiology#Secondary 3-Methylglutaconic Acid Accumulation mechanistic_hypotheses#aggregate_membrane_perturbation_3mga mechanistic_hypotheses#ampk_peroxisomal_3mga mechanistic_hypotheses#acetyl_coa_tca_3mga

Three proposals exist, membrane perturbation by protein aggregates, an AMPK-driven peroxisomal HMG-CoA route, and the class-wide mitochondrial acetyl-CoA build-up model, and none has been tested in CLPB-deficient cells or patients. 3-methylglutaconic aciduria was also not observed in one series of patients with the dominant-negative form, a contrast that may help discriminate between them.

Show evidence (2 references)

PMID:31626852 SUPPORT REVIEW SYNTHESIS Other

"its genesis in non-canonical (secondary) 3-MGAs, a growing-up group of disorders encompassing more than a dozen of inherited metabolic diseases, is a mystery still remaining unresolved for three decades"

Records that the origin of secondary 3-MGA is unresolved.

PMID:34115842 SUPPORT Human Clinical

"However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series."

3-MGA was absent in a heterozygous dominant-negative series, a contrast relevant to its origin.

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Pathophysiology

10

CLPB Disaggregase Loss of Function

Biallelic variants reduce CLPB protein, abolish its expression, or leave a protein with impaired ATPase or disaggregase activity. Missense variants may prevent assembly of the functional oligomer. The residual disaggregase activity of patient variants, rather than their ATPase activity, predicts disease severity.

CLPB hgnc:30664

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

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

mitochondrial intermembrane space GO:0005758

Downstream

Intermembrane Space Protein Aggregation

Show evidence (7 references)

PMID:32573439 SUPPORT In Vitro

"Importantly, Skd3 variants linked to 3-methylglutaconic aciduria, a severe mitochondrial disorder, display diminished disaggregase activity (but not always reduced ATPase activity), which predicts disease severity."

Patient variants lose disaggregase activity in proportion to clinical severity.

PMID:32573439 SUPPORT In Vitro

"Here, we establish that a mitochondrial AAA+ protein, Skd3 (human ClpB), couples ATP hydrolysis to protein disaggregation and reactivation."

Defines the normal disaggregase function that the variants remove.

PMID:32866687 SUPPORT In Vitro

"In purified intact mitochondria, CLPB was protected against externally added proteinase K, but it was susceptible to degradation after disruption of the outer membrane, indicating that CLPB resides in the mitochondrial intermembrane space."

Places CLPB in the intermembrane space.

+ 4 more references

Intermembrane Space Protein Aggregation

Without CLPB, a set of intermembrane space and inner membrane proteins becomes insoluble, particularly under stress. Substrates include HAX1, the inner membrane quality-control proteins of the SPY complex (STOML2, PARL, YME1L1), HTRA2, the calcium uniporter regulators MICU1 and MICU2, the fusion protein OPA1, and intermembrane space-facing subunits of respiratory complex I.

Aggregate-Induced Mitochondrial Membrane Perturbation as the Source of 3-MGA CLPB-HAX1 Mitochondrial Proteostasis Model of Neutropenia

protein refolding GO:0042026 ↓ DECREASED

mitochondrial intermembrane space GO:0005758

Downstream

HAX1 Insolubility

SPY Complex Dysfunction

Impaired Mitochondrial Calcium Uptake and Fusion

Secondary Complex I Instability

Secondary 3-Methylglutaconic Acid Accumulation Proposed only. The route from aggregation to 3-methylglutaconic acid production has not been demonstrated.

Cataract Proposed by the reporting authors; aggregates have not been shown in patient lens tissue.

Nephrocalcinosis Proposed by the reporting authors; aggregates have not been shown in patient kidney tissue.

Show evidence (2 references)

PMID:38270563 SUPPORT In Vitro

"Utilizing proteomic and biochemical approaches, we show a stress-specific aggregation phenotype in a CLPB-null environment and define the CLPB substrate profile."

CLPB-null cells aggregate a defined set of substrates under stress.

PMID:40118824 SUPPORT In Vitro

"Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear."

Names calcium-uniporter regulators and OPA1 as aggregating substrates.

HAX1 Insolubility

HAX1, the protein mutated in Kostmann-type severe congenital neutropenia, is a CLPB substrate and partner; in reconstitution it also acts as a direct stimulatory cofactor that promotes CLPB oligomerization. In CLPB-deficient myeloblastic cells HAX1 forms insoluble aggregates in mitochondria. CLPB and HAX1 together form a mitochondrial proteostasis axis with PRKD2 and HSP27 that is needed for neutrophil differentiation.

CLPB-HAX1 Mitochondrial Proteostasis Model of Neutropenia

HAX1 hgnc:16915

Downstream

Granulocytic Precursor Apoptosis and Impaired Neutrophil Differentiation

Show evidence (3 references)

PMID:39644357 SUPPORT In Vitro

"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."

HAX1 aggregates in CLPB-knockout myeloblastic cells.

PMID:35499078 SUPPORT In Vitro

"we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes"

Places HAX1 and CLPB in one pathway required for neutrophil differentiation.

PMID:42244541 SUPPORT In Vitro

"Through biochemical reconstitution, we here find that HAX1 is a direct stimulatory cofactor of CLPB. HAX1 promotes oligomerization of CLPB into an active disaggregase and stimulates the ATPase and refoldase activities of the oligomeric complex."

Reconstitution shows that HAX1 is a stimulatory cofactor as well as a client of CLPB. This is a bioRxiv preprint, not yet peer reviewed.

Granulocytic Precursor Apoptosis and Impaired Neutrophil Differentiation

Loss of CLPB impairs granulocytic differentiation of human hematopoietic progenitors and increases apoptosis. In a mouse myeloblastic cell line, CLPB loss does not affect proliferation but raises reactive oxygen species-linked apoptosis at the onset of G-CSF-induced differentiation; N-acetylcysteine, free fatty acids or citrate protected these cells in vitro.

CLPB-HAX1 Mitochondrial Proteostasis Model of Neutropenia

myeloblast CL:0000835 neutrophil CL:0000775

neutrophil differentiation GO:0030223 ↓ DECREASED apoptosis of granulocytic precursors GO:0006915 ↑ INCREASED

Experimental models

CLPB-knockout 32Dcl3 mouse myeloblastic cells CELL LINE CLPB loss increases apoptosis at the onset of G-CSF-induced differentiation, while surviving cells express normal differentiation markers.

Downstream

Congenital neutropenia

Show evidence (3 references)

PMID:34115842 SUPPORT In Vitro

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

Genetic loss of CLPB, the situation in the recessive disease, impairs granulocytic differentiation of human progenitors. The variant arm of this study concerns dominant-negative alleles of the separate dominant form.

PMID:39644357 SUPPORT In Vitro

"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)"

CLPB knockout increases apoptosis specifically at the onset of differentiation.

PMID:39644357 SUPPORT In Vitro

"N-acetylcysteine, exogenous free fatty acids, or exogenous citrate protected CLPB-deficient 32Dcl3 cells from apoptosis at the onset of differentiation."

Preclinical rescue of the apoptotic defect in cultured cells.

SPY Complex Dysfunction

The inner membrane quality-control assembly of STOML2, PARL and YME1L1 (SPY complex) depends on CLPB; CLPB deficiency impairs its function through protein aggregation in the intermembrane space. PARL also cleaves an autoinhibitory peptide from CLPB, which strongly enhances its disaggregase activity, so the two depend on each other. Its contribution to clinical features is not established.

PARL hgnc:18253

Show evidence (2 references)

PMID:38270563 SUPPORT In Vitro

"We illustrate an interplay between intermembrane space proteins including CLPB, HAX1, HTRA2, and the inner membrane quality control proteins (STOML2, PARL, YME1L1; SPY complex)"

Defines the SPY complex and its interplay with CLPB.

PMID:32573439 SUPPORT In Vitro

"A mitochondrial inner-membrane protease, PARL, removes an autoinhibitory peptide from Skd3 to greatly enhance disaggregase activity."

PARL activates CLPB, the reciprocal link in this quality-control network.

Impaired Mitochondrial Calcium Uptake and Fusion

CLPB loss alters the composition of the mitochondrial calcium uniporter, reduces mitochondrial calcium uptake, lowers OPA1 and fragments the mitochondrial network. Patient fibroblasts show the same calcium and structural changes. Its contribution to clinical features is not established.

fibroblast CL:0000057

calcium import into the mitochondrion GO:0036444 ↓ DECREASED mitochondrial fusion GO:0008053 ↓ DECREASED

Show evidence (2 references)

PMID:40118824 SUPPORT In Vitro

"CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential."

Calcium uptake defect in CLPB-null cells.

PMID:40118824 SUPPORT In Vitro

"Disease-associated mutations in the CLPB gene present in skin fibroblasts from patients also display mitochondrial calcium and structural changes."

Patient fibroblasts reproduce the defect.

Secondary Complex I Instability

In CLPB knockout cells, intermembrane space-facing complex I subunits aggregate and complex I becomes unstable. Shown in cultured cells; whether patients have a complex I defect, and whether it drives the neurological disease, has not been established.

AMPK-Driven Peroxisomal HMG-CoA Route to 3-MGA Mitochondrial Acetyl-CoA Build-up Route to 3-MGA

NADH dehydrogenase (ubiquinone) activity GO:0008137 ↓ DECREASED

Downstream

Secondary 3-Methylglutaconic Acid Accumulation Hypothetical. Both class-wide models derive secondary 3-MGA from mitochondrial dysfunction; complex I instability is the mitochondrial dysfunction shown in CLPB-null cells, but no study has connected the two.

Show evidence (1 reference)

PMID:42420651 SUPPORT In Vitro

"Loss of function of either protein drives aggregation of intermembrane space-facing subunits of complex I of the electron transport chain, resulting in secondary complex I dysfunction."

Secondary complex I dysfunction follows CLPB loss in cultured cells.

Secondary 3-Methylglutaconic Acid Accumulation

Urinary 3-methylglutaconic acid is raised, as in other secondary (non-canonical) 3-methylglutaconic acidurias, by a route that is not known. Proposed routes include perturbation of mitochondrial membranes by protein aggregates, an extramitochondrial, peroxisomal HMG-CoA route driven by mitochondrial dysfunction, and the general secondary 3-MGA model of mitochondrial acetyl-CoA build-up from impaired TCA cycle function.

Downstream

3-Methylglutaconic aciduria

Show evidence (1 reference)

PMID:31626852 SUPPORT REVIEW SYNTHESIS Other

"its genesis in non-canonical (secondary) 3-MGAs, a growing-up group of disorders encompassing more than a dozen of inherited metabolic diseases, is a mystery still remaining unresolved for three decades"

The origin of 3-MGA in secondary 3-MGA disorders, CLPB deficiency among them, is unresolved.

Spinal Inhibitory Interneuron Deficit and Motor Hyperexcitability

In clpb-knockdown zebrafish, inhibitory glycinergic interneurons in the spinal cord are reduced and excitatory glutamatergic neurons increased, with an exaggerated touch-evoked motor response that resembles the hyperexcitability of severely affected neonates. Shown only in a morpholino model.

glycinergic interneuron CL:1001509

Animal models

clpb zebrafish morphant (Capo-Chichi 2015) Zebrafish recapitulates Morphants show an abnormal touch-evoked response with increased swim velocity and tail beat frequency, and fewer inhibitory glycinergic interneurons in the spinal cord.

Downstream

Exaggerated startle response

Show evidence (1 reference)

PMID:25650066 SUPPORT Model Organism

"Interestingly, knocking down clpb reduced the number of inhibitory glycinergic interneurons and increased a population of excitatory glutamatergic neurons in the spinal cord."

Morphant spinal cord shows the inhibitory-excitatory imbalance.

Progressive Encephalopathy with Brain Atrophy

The neurological disease ranges from nonprogressive intellectual disability to a prenatal-onset encephalopathy with progressive brain atrophy. In the severe form, neonatal neurological involvement (absent voluntary movements or hyperekplexia, hypotonia or hypertonia, swallowing problems, respiratory insufficiency and epilepsy) is the usual cause of death in the first months, and microcephaly is present at birth in some. clpb-knockdown zebrafish develop a central nervous system phenotype consistent with cerebellar and cerebral atrophy that is rescued by wild-type but not mutant human CLPB mRNA. The cellular route from disaggregase loss to neuronal loss is not known.

Animal models

clpb zebrafish morphant (Wortmann 2015) Zebrafish recapitulates Knockdown produces a central nervous system phenotype consistent with cerebellar and cerebral atrophy, and patient alleles fail to rescue it.

Downstream

Brain atrophy

Intellectual disability

Movement disorder

Seizures

Akinesia and absent voluntary movements

Spasticity

Dystonia

Microcephaly

Hypotonia

Hypertonia

Feeding difficulties

Respiratory insufficiency

Death in infancy

Show evidence (2 references)

PMID:25597510 SUPPORT Model Organism

"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."

Knockdown reproduces brain atrophy, and patient alleles fail to rescue it.

PMID:25597510 SUPPORT Human Clinical

"a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death"

Patients show progressive brain atrophy at the severe end of the spectrum.

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Pathograph

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

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Phenotypes

24

Blood 2

Congenital neutropenia Decreased total neutrophil count HP:0001875

Sequelae: Recurrent infections Leukemia

Show evidence (2 references)

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

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

Neutropenia is a cardinal feature across the severity range.

PMID:25597510 SUPPORT Human Clinical

"Taken together, mutations in CLPB define a syndrome with intellectual disability, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria."

Congenital neutropenia is part of the defining syndrome.

Leukemia HP:0001909

Show evidence (1 reference)

PMID:25597510 SUPPORT Human Clinical

"neutropenia that can develop into leukemia"

Leukemic transformation was observed in the founding cohort.

Digestive 1

Feeding difficulties HP:0011968

Show evidence (2 references)

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems"

Feeding problems in moderate disease.

PMID:28687938 SUPPORT Human Clinical

"CLPB deficiency should be considered in neonates with absence of voluntary movements, respiratory insufficiency and swallowing problems"

Swallowing problems in the neonatal presentation.

Eye 1

Cataract HP:0000518

Show evidence (3 references)

PMID:25597511 SUPPORT Human Clinical

"a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood"

Cataract is part of the phenotype in the Greenlandic and North American children.

PMID:25595726 SUPPORT Human Clinical

"two siblings with a syndrome of congenital lamellar cataracts associated with nephrocalcinosis, medullary cysts and 3-methylglutaconic aciduria"

Congenital lamellar cataracts in a sibling pair.

PMID:41719910 SUPPORT Human Clinical

"cataracts and dystonia were more common in biallelic cases"

Cataract is more frequent in the recessive than in the dominant form.

Genitourinary 4

3-Methylglutaconic aciduria HP:0003535

Show evidence (1 reference)

PMID:25597510 SUPPORT Human Clinical

"We studied a group of individuals with elevated urinary excretion of 3-methylglutaconic acid"

The founding cohort was defined by raised urinary 3-methylglutaconic acid.

Nephrocalcinosis HP:0000121

Show evidence (1 reference)

PMID:25595726 SUPPORT Human Clinical

"two siblings with a syndrome of congenital lamellar cataracts associated with nephrocalcinosis, medullary cysts and 3-methylglutaconic aciduria"

Nephrocalcinosis in a sibling pair.

Renal medullary cysts Renal cyst HP:0000107

Show evidence (1 reference)

PMID:25595726 SUPPORT Human Clinical

"two siblings with a syndrome of congenital lamellar cataracts associated with nephrocalcinosis, medullary cysts and 3-methylglutaconic aciduria"

Medullary renal cysts in the same sibling pair.

Premature ovarian insufficiency HP:0008209

Show evidence (1 reference)

PMID:36074910 SUPPORT Human Clinical

"POI is a common feature of postpubertal female individuals with CLPB deficiency."

Clinical follow-up of adult survivors identified POI as common.

Head and Neck 1

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:25650066 SUPPORT Human Clinical

"We describe four newborn siblings, from a consanguineous family, who showed microcephaly, small birth weight, severe encephalopathy and 3-methylglutaconic aciduria."

Microcephaly at birth in four siblings with a truncating genotype.

Immune 1

Recurrent infections HP:0002719

Sequelae: Death in infancy

Show evidence (2 references)

PMID:25597511 SUPPORT Human Clinical

"neutropenia with frequent infections, and death in early childhood"

Reports frequent infections accompanying neutropenia in children who died young.

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"severe neutropenia associated with life-threatening infections"

Infections are life-threatening in the severe form.

Musculoskeletal 3

Spasticity HP:0001257

Show evidence (1 reference)

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability"

Spasticity develops in moderate disease.

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems"

Infantile hypotonia in moderate disease.

Hypertonia HP:0001276

Show evidence (1 reference)

PMID:25650066 SUPPORT Human Clinical

"Their neurological examination was characterised by severe hypertonia and the induction of prolonged clonic movements of the four limbs upon minimal tactile stimulation."

Severe hypertonia in four affected newborn siblings.

Nervous System 8

Intellectual disability HP:0001249

Show evidence (2 references)

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability"

Intellectual disability is a feature of moderate CLPB deficiency.

PMID:41719910 SUPPORT Human Clinical

"Milestone attainment was poor, with <50% walking or speaking, and only 10-20% doing so on time."

Most patients fail to attain motor and language milestones.

Movement disorder Abnormality of movement HP:0100022

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability"

Describes the progressive movement disorder.

Dystonia HP:0001332

Show evidence (1 reference)

PMID:41719910 SUPPORT Human Clinical

"cataracts and dystonia were more common in biallelic cases"

Dystonia is a feature that is more common in the recessive form.

Seizures HP:0001250

Show evidence (2 references)

PMID:25597511 SUPPORT Human Clinical

"a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood"

Epilepsy is part of the phenotype in this series.

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy"

Epilepsy is part of the severe neonatal presentation.

Psychomotor regression during febrile episodes Developmental regression HP:0002376

Show evidence (1 reference)

PMID:25597511 SUPPORT Human Clinical

"severe psychomotor regression during febrile episodes"

Regression was triggered by fever in this series.

Exaggerated startle response HP:0002267

Show evidence (2 references)

PMID:28687938 SUPPORT Human Clinical

"Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients."

Neonatal hyperexcitability makes CLPB deficiency a differential of hyperekplexia.

PMID:25650066 SUPPORT Human Clinical

"Their neurological examination was characterised by severe hypertonia and the induction of prolonged clonic movements of the four limbs upon minimal tactile stimulation."

Stimulus-induced clonic movements in affected newborns.

Akinesia and absent voluntary movements HP:0002304

Show evidence (1 reference)

PMID:28687938 SUPPORT Human Clinical

"The most striking feature of the severe subtype was the neonatal absence of voluntary movements in combination with ventilator dependency and hyperexcitability."

Defines absent voluntary movement as the hallmark of severe disease.

Brain atrophy HP:0012444

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:25597510 SUPPORT Human Clinical

"a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death"

Progressive brain atrophy at the severe end of the spectrum.

Respiratory 1

Respiratory insufficiency HP:0002093

Show evidence (1 reference)

PMID:28687938 SUPPORT Human Clinical

"CLPB deficiency should be considered in neonates with absence of voluntary movements, respiratory insufficiency and swallowing problems"

Respiratory insufficiency is part of the neonatal presentation.

Growth 1

Small for gestational age HP:0001518

Show evidence (1 reference)

PMID:25650066 SUPPORT Human Clinical

"We describe four newborn siblings, from a consanguineous family, who showed microcephaly, small birth weight, severe encephalopathy and 3-methylglutaconic aciduria."

Small birth weight in the severely affected siblings.

Other 1

Death in infancy

Deliberately left without a phenotype_term. HP:0001522 (Death in infancy) 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 (2 references)

PMID:28687938 SUPPORT Human Clinical

"current median age 17.5 years in the mild group, median age of death 35 days in the severe group"

Early death in the severe group contrasts with survival in the mild group.

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 and age at death in the biallelic group.

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Genetic Associations

1

CLPB

Gene: CLPB hgnc:30664 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:25597510 SUPPORT Human Clinical

"Exome sequencing of two unrelated individuals and subsequent Sanger sequencing of 16 individuals with an overlapping phenotype identified a total of 14 rare, predicted deleterious alleles in CLPB in 14 individuals from 9 unrelated families."

Gene-discovery report establishing CLPB in nine unrelated families.

PMID:25597511 SUPPORT Human Clinical

"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*)."

Independent simultaneous report of biallelic CLPB variants.

PMID:25595726 SUPPORT Human Clinical

"the only variants which satisfied these criteria were c.1882C>T (p.Arg628Cys) and c.1915G>A (p.Glu639Lys) in the CLPB gene"

A third independent family with compound heterozygous CLPB variants.

+ 1 more reference

💊

Medical Actions

4

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, especially in the mild and moderate forms. In the 2026 cohort G-CSF use was associated with improved survival; that analysis pooled biallelic and monoallelic patients and was retrospective.

Target Phenotypes: Neutropenia HP:0001875

Show evidence (3 references)

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.

PMID:41719910 SUPPORT Human Clinical

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

Retrospective association of G-CSF with survival across the CLPB cohort.

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"measure white blood cell count with differential"

GeneReviews surveillance at each visit, which is how the neutrophil response to G-CSF is followed.

Hematopoietic Stem Cell Transplantation

Action: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

Considered in patients without severe neurological disease. The transplants reported in the 2026 cohort were in monoallelic (autosomal dominant) patients, with mixed outcomes; no outcome data for the recessive form are cited here.

Mechanism Target:

Granulocytic Precursor Apoptosis and Impaired Neutrophil Differentiation — Replaces the CLPB-deficient hematopoietic compartment.

Target Phenotypes: Neutropenia HP:0001875

Show evidence (1 reference)

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

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

GeneReviews management recommendation.

Multidisciplinary Supportive Care

Action: Supportive Care NCIT:C15747

Platform: Other

No specific dietary or metabolic treatment exists. Care is supportive: feeding therapy and gastrostomy, antiseizure treatment, management of the movement disorder, developmental support, standard immunizations, and treatment of cataracts, endocrine and renal disease. Drugs potentially toxic to mitochondria (chloramphenicol, aminoglycosides, linezolid, valproic acid, nucleoside reverse transcriptase inhibitors) should be avoided.

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 states that management is supportive.

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 lists agents to avoid.

Hormone Replacement Therapy for Premature Ovarian Insufficiency

Action: Hormone Replacement Therapy NCIT:C15599

Platform: Small molecule

Females surviving past puberty should be referred for assessment of ovarian function and hormone replacement when POI is present.

Target Phenotypes: Premature ovarian insufficiency HP:0008209

Show evidence (2 references)

PMID:36074910 SUPPORT Human Clinical

"Patients with CLPB deficiency should be referred to pediatric gynecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimize associated comorbidities."

Recommendation from the POI follow-up study.

PMID:27891836 SUPPORT REVIEW SYNTHESIS Other

"assessment of gonadal function in females (beginning at age 10 years)"

GeneReviews annual surveillance that identifies the ovarian insufficiency needing hormone replacement.

🔬

Biochemical Markers

1

Urinary 3-methylglutaconic acid (INCREASED)

Context: Raised in the recessive form; a secondary 3-methylglutaconic aciduria. In secondary 3-MGA syndromes urinary levels fluctuate and can be undetectable, and plasma untargeted metabolomics was more sensitive in one cohort.

Pathograph Readouts

Readout Of Secondary 3-Methylglutaconic Acid Accumulation Positive Diagnostic

Urinary organic acid analysis showing 3-methylglutaconic acid is a recommended first test in neonates with the severe presentation.

Show evidence (3 references)

PMID:25597510 SUPPORT Human Clinical

"We studied a group of individuals with elevated urinary excretion of 3-methylglutaconic acid"

Raised urinary 3-methylglutaconic acid in the founding cohort.

PMID:28687938 SUPPORT Human Clinical

"Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients."

Recommends urinary organic acid analysis as a diagnostic test.

PMID:39787888 SUPPORT INDIRECT Human Clinical

"In these disorders, urine 3-MGA levels are known to be fluctuant and at times undetectable by standard urine organic acid analysis (UOA), thereby reducing the utility of this biochemical screening method."

Applies to secondary 3-MGA syndromes as a class; the abstract does not name the genes of its nine patients, so a normal urine organic acid result does not exclude CLPB deficiency.

🔬

Diagnosis

4

Molecular genetic testing of CLPB

Confirmatory test. The diagnosis is established by finding biallelic pathogenic CLPB variants on molecular genetic testing.

molecular genetic testing of CLPB NCIT:C15709

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"

GeneReviews diagnostic criterion for the recessive form.

Urine organic acid analysis

First-line biochemical test in neonates presenting with absent voluntary movements, hyperexcitability or a hyperekplexia-like picture, looking for 3-methylglutaconic aciduria. In secondary 3-MGA syndromes urinary 3-MGA fluctuates and can be undetectable, so a normal result does not exclude the disease.

urine organic acid analysis NCIT:C17241

Show evidence (2 references)

PMID:28687938 SUPPORT Human Clinical

"Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients."

Recommends urinary organic acid analysis in neonates with a hyperekplexia-like presentation.

PMID:39787888 SUPPORT INDIRECT Human Clinical

"In these disorders, urine 3-MGA levels are known to be fluctuant and at times undetectable by standard urine organic acid analysis (UOA), thereby reducing the utility of this biochemical screening method."

Caveat for secondary 3-MGA syndromes as a class; the abstract does not name its patients' genes.

Blood cell count

Blood count with differential to detect neutropenia, recommended together with urine organic acids and eye examination in suspected neonates.

blood cell count with differential NCIT:C28133

Show evidence (1 reference)

PMID:28687938 SUPPORT Human Clinical

"Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients."

Recommends blood cell counts in the same diagnostic work-up.

Ophthalmological examination

Eye examination for cataract, recommended in the same neonatal work-up.

ophthalmological examination NCIT:C38060

Show evidence (1 reference)

PMID:28687938 SUPPORT Human Clinical

"Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients."

Recommends ophthalmological examination in the same diagnostic work-up.

📊

Prevalence

1

Worldwide published and survey cases

Cases In Literature

A 2026 retrospective cohort assembled from the literature and a multicentre survey identified 41 individuals with biallelic CLPB variants (and 22 with monoallelic variants, who belong to the autosomal dominant form). This is a count of reported cases, not a population prevalence.

Show evidence (1 reference)

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 biallelic cases known in 2026.

🧫

Experimental Models

1

CLPB-knockout 32Dcl3 mouse myeloblastic cells CELL_LINE

IL-3-dependent mouse myeloblastic cell line with CLPB knocked out, differentiated to neutrophils with G-CSF after IL-3 withdrawal.

Publication

PMID:39644357

Pathograph links

Granulocytic Precursor Apoptosis and Impaired Neutrophil Differentiation partially recapitulates fidelity: moderate observes: cellular CLPB loss increases apoptosis at the onset of G-CSF-induced differentiation, while surviving cells express normal differentiation markers.

Limitations: A mouse cell line rather than human patient marrow, and surviving CLPB-deficient cells differentiated normally, so the model captures precursor loss rather than a differentiation block.

Show evidence (1 reference)

PMID:39644357 SUPPORT In Vitro

"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."

Shows that the defect in this model is survival rather than differentiation.

🐁

Animal Models

2

clpb zebrafish morphant (Wortmann 2015)

Morpholino suppression of clpb in zebrafish embryos, with rescue by wild-type but not mutant human CLPB mRNA.

Species

Zebrafish

Genotype

clpb antisense morpholino knockdown

Publication

PMID:25597510

Pathograph links

Progressive Encephalopathy with Brain Atrophy recapitulates fidelity: moderate observes: tissue Knockdown produces a central nervous system phenotype consistent with cerebellar and cerebral atrophy, and patient alleles fail to rescue it.

Limitations: Morpholino knockdown is transient and dose-dependent rather than a germline null, the readout is in embryos rather than in a postnatal brain, and the abstract does not report neutropenia, cataract or 3-methylglutaconic aciduria in the model.

Show evidence (1 reference)

PMID:25597510 SUPPORT Model Organism

"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."

Supports the morphant as informative for the brain atrophy node.

clpb zebrafish morphant (Capo-Chichi 2015)

Antisense morpholino knockdown of translation of the zebrafish clpb ortholog.

Species

Zebrafish

Genotype

clpb antisense morpholino knockdown

Publication

PMID:25650066

Pathograph links

Spinal Inhibitory Interneuron Deficit and Motor Hyperexcitability recapitulates fidelity: low observes: cellular Morphants show an abnormal touch-evoked response with increased swim velocity and tail beat frequency, and fewer inhibitory glycinergic interneurons in the spinal cord.

Limitations: Morpholino knockdown only; the interneuron finding has not been examined in patient tissue, and zebrafish spinal motor circuits are an indirect proxy for the neonatal hyperexcitability of patients.

Readouts

Touch-evoked swimming response

Direction: INCREASED

Interpretation: Behavioural correlate of motor hyperexcitability.

Show evidence (1 reference)

PMID:25650066 SUPPORT Model Organism

"The clpb morphants showed an abnormal touch-evoked response with increased swim velocity and tail beat frequency."

Reports the behavioural measurement behind this readout.

Show evidence (1 reference)

PMID:25650066 SUPPORT Model Organism

"Interestingly, knocking down clpb reduced the number of inhibitory glycinergic interneurons and increased a population of excitatory glutamatergic neurons in the spinal cord."

Supports the morphant as informative for the interneuron node.

{ }

Source YAML

click to show

name: 3-Methylglutaconic Aciduria Type VIIB
creation_date: "2026-10-15T17:00:00Z"
category: Mendelian
description: >-
  3-methylglutaconic aciduria type VIIB (MGCA7B) is the autosomal recessive
  form of CLPB deficiency, caused by biallelic pathogenic variants in CLPB.
  CLPB (also called Skd3, the human ClpB homolog) is an ATP-dependent AAA+
  protein disaggregase of the mitochondrial intermembrane space that resolubilizes
  aggregated proteins, among them the anti-apoptotic protein HAX1. Loss of its
  disaggregase activity leads to protein aggregation in the intermembrane space,
  impaired granulocytic differentiation with congenital neutropenia, and a
  neurological disorder whose severity ranges from absent neurological
  involvement through intellectual disability with a progressive movement
  disorder and epilepsy to a neonatal encephalopathy with absent voluntary
  movements, hyperexcitability, respiratory insufficiency, progressive brain
  atrophy and death in the first months of life. Cataracts, renal cysts and
  nephrocalcinosis, and premature ovarian insufficiency in surviving females
  also occur. Urinary 3-methylglutaconic acid is raised, by a mechanism that is
  not known. Residual disaggregase activity of the patient variants tracks
  disease severity. Treatment is supportive, with granulocyte colony-stimulating
  factor for neutropenia and hematopoietic stem cell transplantation considered
  in patients without severe neurological disease.
disease_term:
  preferred_term: 3-methylglutaconic aciduria, type VIIB
  term:
    id: MONDO:0014561
    label: 3-methylglutaconic aciduria, type VIIB
synonyms:
- MGCA7B
- MGCA7
- MEGCANN
- CLPB deficiency
- Autosomal recessive CLPB deficiency
- CLPB 3-methylglutaconic aciduria
- 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia
- 3-methylglutaconic aciduria type 7
parents:
- 3-Methylglutaconic Aciduria
- Mitochondrial Disease
- Congenital Neutropenia
notes: >-
  Scope: this entry covers biallelic (autosomal recessive) CLPB deficiency,
  OMIM 616271. Specific heterozygous CLPB variants that act in a
  dominant-negative manner cause a separate autosomal dominant disorder,
  3-methylglutaconic aciduria type VIIA (MONDO:0859237), with neutropenia and
  in some patients epilepsy and developmental delay (PMID:34140661,
  PMID:34115842); it is a separate MONDO term and is not curated here. Those
  dominant-negative studies are cited in this entry only where they report the
  effect of CLPB loss itself. The only ClinGen gene-disease validity record for
  CLPB in cache/clingen/gene_validity.csv is for Leigh syndrome (MONDO:0009723,
  Limited), a different disease, so no gene_disease_validity assertion is
  recorded. Severity groups (mild, moderate, severe) follow the scoring system
  of Pronicka et al. 2017 and the GeneReviews chapter.
references:
- reference: PMID:27891836
  title: CLPB Deficiency.
  tags:
  - GeneReviews
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Homozygous or compound heterozygous CLPB variants, including missense,
    nonsense and frameshift alleles, with heterozygous unaffected parents.
  evidence:
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "CLPB deficiency associated with biallelic CLPB pathogenic variants is inherited in an autosomal recessive manner."
    explanation: GeneReviews states the recessive mode of inheritance for the biallelic form.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial CLPB pathogenic variants"
    explanation: GeneReviews gives the recessive recurrence risk for sibs of an affected child.
  - reference: PMID:25597511
    reference_title: CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through a combination of homozygosity mapping in the Greenlandic individuals and exome sequencing in the North American, we identified biallelic variants in the caseinolytic peptidase B homolog (CLPB)."
    explanation: Biallelic variants in five affected children from two populations support recessive inheritance.
  - reference: PMID:25650066
    reference_title: Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a homozygous truncating mutation (p.I562Tfs*23) in CLPB segregating with the disease in this family"
    explanation: A homozygous truncating allele segregates with disease in a consanguineous family.
  - 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: >-
      Subunits carrying recessive MGCA7 variants do not poison wild-type CLPB
      in mixed hexamers, which explains why carriers of one such allele are
      unaffected, while dominant-negative SCN alleles cause the separate
      dominant disorder.
prevalence:
- population: Worldwide published and survey cases
  measure_type: CASES_IN_LITERATURE
  notes: >-
    A 2026 retrospective cohort assembled from the literature and a multicentre
    survey identified 41 individuals with biallelic CLPB variants (and 22 with
    monoallelic variants, who belong to the autosomal dominant form). This is a
    count of reported cases, not a population prevalence.
  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: "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 biallelic cases known in 2026.
genetic:
- name: CLPB
  gene_term:
    preferred_term: CLPB
    term:
      id: hgnc:30664
      label: CLPB
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Reported alleles include missense variants (p.Thr268Met, p.Arg408Gly,
    p.Arg628Cys, p.Glu639Lys), nonsense variants (p.Lys321*, p.Arg417*) and the
    frameshift p.Ile562Thrfs*23. Truncating genotypes carry a greater disease
    burden than missense combinations.
  evidence:
  - reference: PMID:25597510
    reference_title: CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing of two unrelated individuals and subsequent Sanger sequencing of 16 individuals with an overlapping phenotype identified a total of 14 rare, predicted deleterious alleles in CLPB in 14 individuals from 9 unrelated families."
    explanation: Gene-discovery report establishing CLPB in nine unrelated families.
  - reference: PMID:25597511
    reference_title: CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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*)."
    explanation: Independent simultaneous report of biallelic CLPB variants.
  - reference: PMID:25595726
    reference_title: Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the only variants which satisfied these criteria were c.1882C>T (p.Arg628Cys) and c.1915G>A (p.Glu639Lys) in the CLPB gene"
    explanation: A third independent family with compound heterozygous CLPB variants.
  - 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: "Stop/stop genotypes were associated with greater disease burden than missense combinations."
    explanation: Genotype-severity correlation in the largest biallelic cohort.
pathophysiology:
- name: CLPB Disaggregase Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic variants reduce CLPB protein, abolish its expression, or leave a
    protein with impaired ATPase or disaggregase activity. Missense variants may
    prevent assembly of the functional oligomer. The residual disaggregase
    activity of patient variants, rather than their ATPase activity, predicts
    disease severity.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: CLPB
    term:
      id: hgnc:30664
      label: CLPB
  molecular_functions:
  - preferred_term: ATP-dependent protein disaggregase activity
    modifier: DECREASED
    term:
      id: GO:0140545
      label: ATP-dependent protein disaggregase activity
  - preferred_term: ATP hydrolysis activity
    modifier: DECREASED
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
  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
    snippet: "Importantly, Skd3 variants linked to 3-methylglutaconic aciduria, a severe mitochondrial disorder, display diminished disaggregase activity (but not always reduced ATPase activity), which predicts disease severity."
    explanation: Patient variants lose disaggregase activity in proportion to clinical severity.
  - 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
    snippet: "Here, we establish that a mitochondrial AAA+ protein, Skd3 (human ClpB), couples ATP hydrolysis to protein disaggregation and reactivation."
    explanation: Defines the normal disaggregase function that the variants remove.
  - reference: PMID:32866687
    reference_title: Human CLPB forms ATP-dependent complexes in the mitochondrial intermembrane space.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In purified intact mitochondria, CLPB was protected against externally added proteinase K, but it was susceptible to degradation after disruption of the outer membrane, indicating that CLPB resides in the mitochondrial intermembrane space."
    explanation: Places CLPB in the intermembrane space.
  - reference: PMID:25597510
    reference_title: CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "was supported further by in vitro evidence with the mutant peptides abolishing ATPase function"
    explanation: The patient missense variant p.Arg408Gly abolishes ATPase activity in vitro.
  - reference: PMID:25597511
    reference_title: CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The level of CLPB protein was markedly decreased in fibroblasts and liver of affected individuals."
    explanation: Patient tissues have markedly reduced CLPB protein.
  - reference: PMID:25650066
    reference_title: Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that CLPB expression is abolished in fibroblasts from the patients."
    explanation: A truncating genotype abolishes CLPB expression in patient cells.
  - reference: PMID:25595726
    reference_title: Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "molecular modelling suggests that the mutations disrupt interactions between subunits so that the CLPB hexamer cannot form or is unstable, thus impairing its role as a protein disaggregase"
    explanation: Modelling predicts that two missense variants prevent oligomer assembly.
  downstream:
  - target: Intermembrane Space Protein Aggregation
    causal_link_type: DIRECT
    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
      snippet: "Human cells lacking Skd3 exhibit reduced solubility of various mitochondrial proteins, including anti-apoptotic Hax1."
      explanation: Loss of CLPB lowers the solubility of mitochondrial proteins.
- name: Intermembrane Space Protein Aggregation
  biological_scale: MOLECULAR
  description: >-
    Without CLPB, a set of intermembrane space and inner membrane proteins
    becomes insoluble, particularly under stress. Substrates include HAX1, the
    inner membrane quality-control proteins of the SPY complex (STOML2, PARL,
    YME1L1), HTRA2, the calcium uniporter regulators MICU1 and MICU2, the
    fusion protein OPA1, and intermembrane space-facing subunits of
    respiratory complex I.
  biological_processes:
  - preferred_term: protein refolding
    modifier: DECREASED
    term:
      id: GO:0042026
      label: protein refolding
  cellular_components:
  - preferred_term: mitochondrial intermembrane space
    term:
      id: GO:0005758
      label: mitochondrial intermembrane space
  evidence:
  - reference: PMID:38270563
    reference_title: CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Utilizing proteomic and biochemical approaches, we show a stress-specific aggregation phenotype in a CLPB-null environment and define the CLPB substrate profile."
    explanation: CLPB-null cells aggregate a defined set of substrates under stress.
  - reference: PMID:40118824
    reference_title: Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear."
    explanation: Names calcium-uniporter regulators and OPA1 as aggregating substrates.
  downstream:
  - target: HAX1 Insolubility
    causal_link_type: DIRECT
    hypothesis_groups:
    - clpb_hax1_proteostasis_neutropenia
    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
      snippet: "Human cells lacking Skd3 exhibit reduced solubility of various mitochondrial proteins, including anti-apoptotic Hax1."
      explanation: HAX1 is among the proteins that lose solubility without CLPB.
  - target: SPY Complex Dysfunction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38270563
      reference_title: CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "with CLPB deficiency impeding SPY complex function by virtue of protein aggregation in the intermembrane space"
      explanation: Aggregation in the intermembrane space impairs the SPY complex.
  - target: Impaired Mitochondrial Calcium Uptake and Fusion
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40118824
      reference_title: Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics."
      explanation: Loss of CLPB impairs calcium signalling and fusion.
  - target: Secondary Complex I Instability
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42420651
      reference_title: Hypoxia rescues complex 1-associated disease caused by proteostatic defects.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Loss of function of either protein drives aggregation of intermembrane space-facing subunits of complex I of the electron transport chain, resulting in secondary complex I dysfunction."
      explanation: CLPB loss in cultured cells aggregates complex I subunits.
  - target: Secondary 3-Methylglutaconic Acid Accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - aggregate_membrane_perturbation_3mga
    description: >-
      Proposed only. The route from aggregation to 3-methylglutaconic acid
      production has not been demonstrated.
    evidence:
    - reference: PMID:25595726
      reference_title: Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "We now propose that perturbation of the mitochondrial membranes by abnormal protein aggregates leads to 3-methylglutaconic aciduria in CLPB deficiency."
      explanation: The authors propose, without testing, a membrane-perturbation route to 3-MGA.
  - target: Cataract
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed by the reporting authors; aggregates have not been shown in
      patient lens tissue.
    evidence:
    - reference: PMID:25595726
      reference_title: Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "We conclude that accumulation of protein aggregates underlies the development of cataracts and nephrocalcinosis in CLPB deficiency"
      explanation: The authors attribute cataract to protein aggregate accumulation.
  - target: Nephrocalcinosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed by the reporting authors; aggregates have not been shown in
      patient kidney tissue.
    evidence:
    - reference: PMID:25595726
      reference_title: Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "We conclude that accumulation of protein aggregates underlies the development of cataracts and nephrocalcinosis in CLPB deficiency"
      explanation: The authors attribute nephrocalcinosis to protein aggregate accumulation.
- name: HAX1 Insolubility
  biological_scale: MOLECULAR
  description: >-
    HAX1, the protein mutated in Kostmann-type severe congenital neutropenia,
    is a CLPB substrate and partner; in reconstitution it also acts as a
    direct stimulatory cofactor that promotes CLPB oligomerization. In CLPB-deficient myeloblastic cells HAX1
    forms insoluble aggregates in mitochondria. CLPB and HAX1 together form a
    mitochondrial proteostasis axis with PRKD2 and HSP27 that is needed for
    neutrophil differentiation.
  genes:
  - preferred_term: HAX1
    term:
      id: hgnc:16915
      label: HAX1
  evidence:
  - 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
    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: HAX1 aggregates in CLPB-knockout myeloblastic cells.
  - reference: PMID:35499078
    reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes"
    explanation: Places HAX1 and CLPB in one pathway required for neutrophil differentiation.
  - 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. HAX1 promotes oligomerization of CLPB into an active disaggregase and stimulates the ATPase and refoldase activities of the oligomeric complex."
    explanation: >-
      Reconstitution shows that HAX1 is a stimulatory cofactor as well as a
      client of CLPB. This is a bioRxiv preprint, not yet peer reviewed.
  downstream:
  - target: Granulocytic Precursor Apoptosis and Impaired Neutrophil Differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - clpb_hax1_proteostasis_neutropenia
    evidence:
    - reference: PMID:35499078
      reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "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 shared CLPB/HAX1 axis to neutropenia in biallelic CLPB patients.
- name: Granulocytic Precursor Apoptosis and Impaired Neutrophil Differentiation
  biological_scale: CELLULAR
  description: >-
    Loss of CLPB impairs granulocytic differentiation of human hematopoietic
    progenitors and increases apoptosis. In a mouse myeloblastic cell line,
    CLPB loss does not affect proliferation but raises reactive oxygen
    species-linked apoptosis at the onset of G-CSF-induced differentiation;
    N-acetylcysteine, free fatty acids or citrate protected these cells in
    vitro.
  cell_types:
  - preferred_term: myeloblast
    term:
      id: CL:0000835
      label: myeloblast
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil differentiation
    modifier: DECREASED
    term:
      id: GO:0030223
      label: neutrophil differentiation
  - preferred_term: apoptosis of granulocytic precursors
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    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: >-
      Genetic loss of CLPB, the situation in the recessive disease, impairs
      granulocytic differentiation of human progenitors. The variant arm of this
      study concerns dominant-negative alleles of the separate dominant form.
  - 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
    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: CLPB knockout increases apoptosis specifically at the onset of differentiation.
  - 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
    snippet: "N-acetylcysteine, exogenous free fatty acids, or exogenous citrate protected CLPB-deficient 32Dcl3 cells from apoptosis at the onset of differentiation."
    explanation: Preclinical rescue of the apoptotic defect in cultured cells.
  downstream:
  - target: Congenital neutropenia
    causal_link_type: DIRECT
    hypothesis_groups:
    - clpb_hax1_proteostasis_neutropenia
    evidence:
    - 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: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Loss-of-function mutations in the CLPB gene lead to congenital neutropenia due to impaired neutrophil differentiation."
      explanation: Connects impaired neutrophil differentiation to the clinical neutropenia.
- name: SPY Complex Dysfunction
  biological_scale: MOLECULAR
  description: >-
    The inner membrane quality-control assembly of STOML2, PARL and YME1L1
    (SPY complex) depends on CLPB; CLPB deficiency impairs its function
    through protein aggregation in the intermembrane space. PARL also cleaves
    an autoinhibitory peptide from CLPB, which strongly enhances its
    disaggregase activity, so the two depend on each other. Its contribution
    to clinical features is not established.
  genes:
  - preferred_term: PARL
    term:
      id: hgnc:18253
      label: PARL
  evidence:
  - reference: PMID:38270563
    reference_title: CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We illustrate an interplay between intermembrane space proteins including CLPB, HAX1, HTRA2, and the inner membrane quality control proteins (STOML2, PARL, YME1L1; SPY complex)"
    explanation: Defines the SPY complex and its interplay 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
    snippet: "A mitochondrial inner-membrane protease, PARL, removes an autoinhibitory peptide from Skd3 to greatly enhance disaggregase activity."
    explanation: PARL activates CLPB, the reciprocal link in this quality-control network.
- name: Impaired Mitochondrial Calcium Uptake and Fusion
  biological_scale: CELLULAR
  description: >-
    CLPB loss alters the composition of the mitochondrial calcium uniporter,
    reduces mitochondrial calcium uptake, lowers OPA1 and fragments the
    mitochondrial network. Patient fibroblasts show the same calcium and
    structural changes. Its contribution to clinical features is not
    established.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: calcium import into the mitochondrion
    modifier: DECREASED
    term:
      id: GO:0036444
      label: calcium import into the mitochondrion
  - preferred_term: mitochondrial fusion
    modifier: DECREASED
    term:
      id: GO:0008053
      label: mitochondrial fusion
  evidence:
  - reference: PMID:40118824
    reference_title: Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential."
    explanation: Calcium uptake defect in CLPB-null cells.
  - reference: PMID:40118824
    reference_title: Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Disease-associated mutations in the CLPB gene present in skin fibroblasts from patients also display mitochondrial calcium and structural changes."
    explanation: Patient fibroblasts reproduce the defect.
- name: Secondary Complex I Instability
  biological_scale: MOLECULAR
  description: >-
    In CLPB knockout cells, intermembrane space-facing complex I subunits
    aggregate and complex I becomes unstable. Shown in cultured cells; whether
    patients have a complex I defect, and whether it drives the
    neurological disease, has not been established.
  molecular_functions:
  - preferred_term: NADH dehydrogenase (ubiquinone) activity
    modifier: DECREASED
    term:
      id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
  evidence:
  - reference: PMID:42420651
    reference_title: Hypoxia rescues complex 1-associated disease caused by proteostatic defects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Loss of function of either protein drives aggregation of intermembrane space-facing subunits of complex I of the electron transport chain, resulting in secondary complex I dysfunction."
    explanation: Secondary complex I dysfunction follows CLPB loss in cultured cells.
  downstream:
  - target: Secondary 3-Methylglutaconic Acid Accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ampk_peroxisomal_3mga
    - acetyl_coa_tca_3mga
    description: >-
      Hypothetical. Both class-wide models derive secondary 3-MGA from
      mitochondrial dysfunction; complex I instability is the mitochondrial
      dysfunction shown in CLPB-null cells, but no study has connected the two.
    evidence:
    - reference: PMID:31626852
      reference_title: "Mitochondrial dysfunction, AMPK activation and peroxisomal metabolism: A coherent scenario for non-canonical 3-methylglutaconic acidurias."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: "constitutive mitochondrial dysfunction induces AMPK activation which, by inhibiting early steps in cholesterol and fatty acid syntheses, pipelines cytoplasmic acetyl-CoA to peroxisomes where a rise in HMG-CoA followed by local dehydration and hydrolysis may lead to 3-MGA yield"
      explanation: States the AMPK-peroxisomal route from mitochondrial dysfunction to 3-MGA.
    - reference: PMID:39787888
      reference_title: Untargeted metabolomics analysis as a potential screening tool for 3-methylglutaconic aciduria syndromes.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: "It is currently thought that this accumulation is due to an underlying buildup of acetyl-CoA in the mitochondria from impaired function of the TCA cycle with ensuing formation of trans-3-methylglutaconyl CoA and its subsequent byproducts, including 3-MGA."
      explanation: States the acetyl-CoA build-up route from impaired mitochondrial function to 3-MGA.
- name: Secondary 3-Methylglutaconic Acid Accumulation
  biological_scale: ORGANISM
  description: >-
    Urinary 3-methylglutaconic acid is raised, as in other secondary
    (non-canonical) 3-methylglutaconic acidurias, by a route that is not
    known. Proposed routes include perturbation of mitochondrial membranes by
    protein aggregates, an extramitochondrial, peroxisomal HMG-CoA route
    driven by mitochondrial dysfunction, and the general secondary 3-MGA model
    of mitochondrial acetyl-CoA build-up from impaired TCA cycle function.
  chemical_entities:
  - preferred_term: 3-methylglutaconic acid
    modifier: INCREASED
    term:
      id: CHEBI:144330
      label: 3-methylglutaconic acid
  evidence:
  - reference: PMID:31626852
    reference_title: "Mitochondrial dysfunction, AMPK activation and peroxisomal metabolism: A coherent scenario for non-canonical 3-methylglutaconic acidurias."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "its genesis in non-canonical (secondary) 3-MGAs, a growing-up group of disorders encompassing more than a dozen of inherited metabolic diseases, is a mystery still remaining unresolved for three decades"
    explanation: The origin of 3-MGA in secondary 3-MGA disorders, CLPB deficiency among them, is unresolved.
  downstream:
  - target: 3-Methylglutaconic aciduria
    causal_link_type: DIRECT
- name: Spinal Inhibitory Interneuron Deficit and Motor Hyperexcitability
  biological_scale: CELLULAR
  description: >-
    In clpb-knockdown zebrafish, inhibitory glycinergic interneurons in the
    spinal cord are reduced and excitatory glutamatergic neurons increased,
    with an exaggerated touch-evoked motor response that resembles the
    hyperexcitability of severely affected neonates. Shown only in a morpholino
    model.
  cell_types:
  - preferred_term: glycinergic interneuron
    term:
      id: CL:1001509
      label: glycinergic neuron
  evidence:
  - reference: PMID:25650066
    reference_title: Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Interestingly, knocking down clpb reduced the number of inhibitory glycinergic interneurons and increased a population of excitatory glutamatergic neurons in the spinal cord."
    explanation: Morphant spinal cord shows the inhibitory-excitatory imbalance.
  downstream:
  - target: Exaggerated startle response
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25650066
      reference_title: Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "This motor phenotype is reminiscent of that observed in the patients and is suggestive of increased excitability in neuronal circuits."
      explanation: The authors relate the morphant hyperexcitability to the patients' stimulus-induced movements.
- name: Progressive Encephalopathy with Brain Atrophy
  biological_scale: TISSUE
  description: >-
    The neurological disease ranges from nonprogressive intellectual
    disability to a prenatal-onset encephalopathy with progressive brain
    atrophy. In the severe form, neonatal neurological involvement (absent
    voluntary movements or hyperekplexia, hypotonia or hypertonia, swallowing
    problems, respiratory insufficiency and epilepsy) is the usual cause of
    death in the first months, and microcephaly is present at birth in some.
    clpb-knockdown zebrafish develop a central nervous system phenotype
    consistent with cerebellar and cerebral atrophy that is rescued by
    wild-type but not mutant human CLPB mRNA. The cellular route from
    disaggregase loss to neuronal loss is not known.
  evidence:
  - reference: PMID:25597510
    reference_title: CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "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."
    explanation: Knockdown reproduces brain atrophy, and patient alleles fail to rescue it.
  - reference: PMID:25597510
    reference_title: CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death"
    explanation: Patients show progressive brain atrophy at the severe end of the spectrum.
  downstream:
  - target: Brain atrophy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25597510
      reference_title: CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death"
      explanation: Progressive brain atrophy is the imaging expression of the severe encephalopathy.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25597510
      reference_title: CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death"
      explanation: Intellectual disability is the mild end of the same neurological spectrum.
  - target: Movement disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27891836
      reference_title: CLPB Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability"
      explanation: GeneReviews lists the progressive movement disorder among the neurological features of moderate disease.
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27891836
      reference_title: CLPB Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability"
      explanation: GeneReviews lists epilepsy among the neurological features of moderate disease.
  - target: Akinesia and absent voluntary movements
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28687938
      reference_title: A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The most striking feature of the severe subtype was the neonatal absence of voluntary movements in combination with ventilator dependency and hyperexcitability."
      explanation: Absent voluntary movement is the defining neonatal sign of the severe encephalopathy.
  - target: Spasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27891836
      reference_title: CLPB Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability"
      explanation: GeneReviews lists spasticity among the neurological features of moderate disease.
  - target: Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27891836
      reference_title: CLPB Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability"
      explanation: GeneReviews names dystonia as a component of the progressive movement disorder.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25650066
      reference_title: Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We describe four newborn siblings, from a consanguineous family, who showed microcephaly, small birth weight, severe encephalopathy and 3-methylglutaconic aciduria."
      explanation: Microcephaly at birth accompanies the severe encephalopathy in these siblings.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27891836
      reference_title: CLPB Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy"
      explanation: GeneReviews lists abnormal tone among the neonatal neurological features.
  - target: Hypertonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27891836
      reference_title: CLPB Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy"
      explanation: GeneReviews lists abnormal tone among the neonatal neurological features.
  - target: Feeding difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27891836
      reference_title: CLPB Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy"
      explanation: GeneReviews classes swallowing problems as part of the neonatal neurological involvement.
  - target: Respiratory insufficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27891836
      reference_title: CLPB Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy"
      explanation: GeneReviews classes respiratory insufficiency as part of the neonatal neurological involvement.
  - target: Death in infancy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27891836
      reference_title: CLPB Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "In severe CLPB deficiency, death usually occurs at a few months of age due to significant neonatal neurologic involvement"
      explanation: Neurological involvement is a cause of early death in the severe form.
phenotypes:
- category: Laboratory
  name: 3-Methylglutaconic aciduria
  diagnostic: true
  description: >-
    Elevated urinary excretion of 3-methylglutaconic acid, a defining
    biochemical feature of the disorder.
  phenotype_term:
    preferred_term: 3-Methylglutaconic aciduria
    term:
      id: HP:0003535
      label: 3-Methylglutaconic aciduria
  evidence:
  - reference: PMID:25597510
    reference_title: CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied a group of individuals with elevated urinary excretion of 3-methylglutaconic acid"
    explanation: The founding cohort was defined by raised urinary 3-methylglutaconic acid.
- category: Hematologic
  name: Congenital neutropenia
  diagnostic: true
  description: >-
    Neutropenia ranging from mild and intermittent to severe with
    life-threatening infections, present from birth.
  phenotype_term:
    preferred_term: Congenital neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    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: Neutropenia is a cardinal feature across the severity range.
  - reference: PMID:25597510
    reference_title: CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Taken together, mutations in CLPB define a syndrome with intellectual disability, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria."
    explanation: Congenital neutropenia is part of the defining syndrome.
  sequelae:
  - target: Recurrent infections
    causal_link_type: DIRECT
  - target: Leukemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Neutropenia has been reported to progress to leukemia.
    evidence:
    - reference: PMID:25597510
      reference_title: CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "neutropenia that can develop into leukemia"
      explanation: Reports leukemic progression of the neutropenia.
- category: Infectious
  name: Recurrent infections
  description: >-
    Frequent and, in the severe form, life-threatening infections secondary to
    neutropenia.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:25597511
    reference_title: CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neutropenia with frequent infections, and death in early childhood"
    explanation: Reports frequent infections accompanying neutropenia in children who died young.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "severe neutropenia associated with life-threatening infections"
    explanation: Infections are life-threatening in the severe form.
  sequelae:
  - target: Death in infancy
    causal_link_type: DIRECT
    description: >-
      In the severe form, death in the first months is attributed to
      neurological involvement together with neutropenia and life-threatening
      infections.
    evidence:
    - reference: PMID:27891836
      reference_title: CLPB Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "In severe CLPB deficiency, death usually occurs at a few months of age due to significant neonatal neurologic involvement"
      explanation: First half of the GeneReviews sentence, stating early death in the severe form.
    - reference: PMID:27891836
      reference_title: CLPB Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "and severe neutropenia associated with life-threatening infections"
      explanation: Second half of the same sentence, which names neutropenia with life-threatening infections among the causes of that early death.
- category: Neoplasm
  name: Leukemia
  description: >-
    Neutropenia can progress to leukemia.
  phenotype_term:
    preferred_term: Leukemia
    term:
      id: HP:0001909
      label: Leukemia
  evidence:
  - reference: PMID:25597510
    reference_title: CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neutropenia that can develop into leukemia"
    explanation: Leukemic transformation was observed in the founding cohort.
- category: Ophthalmologic
  name: Cataract
  description: >-
    Cataracts, congenital in some patients; lamellar cataracts were
    described in one sibling pair.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:25597511
    reference_title: CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood"
    explanation: Cataract is part of the phenotype in the Greenlandic and North American children.
  - reference: PMID:25595726
    reference_title: Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two siblings with a syndrome of congenital lamellar cataracts associated with nephrocalcinosis, medullary cysts and 3-methylglutaconic aciduria"
    explanation: Congenital lamellar cataracts in a sibling pair.
  - 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: "cataracts and dystonia were more common in biallelic cases"
    explanation: Cataract is more frequent in the recessive than in the dominant form.
- category: Neurological
  name: Intellectual disability
  description: >-
    Intellectual disability, nonprogressive in some patients, with poor
    attainment of developmental milestones; intellect is normal in the mild
    form.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability"
    explanation: Intellectual disability is a feature of moderate 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: "Milestone attainment was poor, with <50% walking or speaking, and only 10-20% doing so on time."
    explanation: Most patients fail to attain motor and language milestones.
- category: Neurological
  name: Movement disorder
  description: >-
    Progressive movement disorder with ataxia, dystonia and/or dyskinesia in
    moderate disease.
  phenotype_term:
    preferred_term: Progressive movement disorder
    term:
      id: HP:0100022
      label: Abnormality of movement
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability"
    explanation: Describes the progressive movement disorder.
- category: Neurological
  name: Dystonia
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  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: "cataracts and dystonia were more common in biallelic cases"
    explanation: Dystonia is a feature that is more common in the recessive form.
- category: Neurological
  name: Spasticity
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability"
    explanation: Spasticity develops in moderate disease.
- category: Neurological
  name: Seizures
  description: Epilepsy in both the severe neonatal and the moderate forms.
  phenotype_term:
    preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:25597511
    reference_title: CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood"
    explanation: Epilepsy is part of the phenotype in this series.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy"
    explanation: Epilepsy is part of the severe neonatal presentation.
- category: Neurological
  name: Psychomotor regression during febrile episodes
  phenotype_term:
    preferred_term: Psychomotor regression during febrile episodes
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:25597511
    reference_title: CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe psychomotor regression during febrile episodes"
    explanation: Regression was triggered by fever in this series.
- category: Neurological
  name: Hypotonia
  description: >-
    Muscular hypotonia in infancy in severe and moderate disease; some severe
    neonates are instead hypertonic.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems"
    explanation: Infantile hypotonia in moderate disease.
- category: Neurological
  name: Hypertonia
  phenotype_term:
    preferred_term: Hypertonia
    term:
      id: HP:0001276
      label: Hypertonia
  evidence:
  - reference: PMID:25650066
    reference_title: Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their neurological examination was characterised by severe hypertonia and the induction of prolonged clonic movements of the four limbs upon minimal tactile stimulation."
    explanation: Severe hypertonia in four affected newborn siblings.
- category: Neurological
  name: Exaggerated startle response
  description: >-
    Hyperexcitability with exaggerated startle (hyperekplexia) and prolonged
    clonic movements on minimal tactile stimulation in severely affected
    neonates; CLPB deficiency is a differential diagnosis of hyperekplexia.
  phenotype_term:
    preferred_term: Hyperekplexia
    term:
      id: HP:0002267
      label: Exaggerated startle response
  evidence:
  - reference: PMID:28687938
    reference_title: A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients."
    explanation: Neonatal hyperexcitability makes CLPB deficiency a differential of hyperekplexia.
  - reference: PMID:25650066
    reference_title: Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their neurological examination was characterised by severe hypertonia and the induction of prolonged clonic movements of the four limbs upon minimal tactile stimulation."
    explanation: Stimulus-induced clonic movements in affected newborns.
- category: Neurological
  name: Akinesia and absent voluntary movements
  description: >-
    Neonatal absence of voluntary movements together with ventilator
    dependency and hyperexcitability, the most striking feature of the severe
    form.
  phenotype_term:
    preferred_term: Absence of voluntary movements
    term:
      id: HP:0002304
      label: Akinesia
  evidence:
  - reference: PMID:28687938
    reference_title: A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most striking feature of the severe subtype was the neonatal absence of voluntary movements in combination with ventilator dependency and hyperexcitability."
    explanation: Defines absent voluntary movement as the hallmark of severe disease.
- category: Respiratory
  name: Respiratory insufficiency
  phenotype_term:
    preferred_term: Neonatal respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:28687938
    reference_title: A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CLPB deficiency should be considered in neonates with absence of voluntary movements, respiratory insufficiency and swallowing problems"
    explanation: Respiratory insufficiency is part of the neonatal presentation.
- category: Gastrointestinal
  name: Feeding difficulties
  description: Swallowing problems and feeding difficulties from infancy.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems"
    explanation: Feeding problems in moderate disease.
  - reference: PMID:28687938
    reference_title: A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CLPB deficiency should be considered in neonates with absence of voluntary movements, respiratory insufficiency and swallowing problems"
    explanation: Swallowing problems in the neonatal presentation.
- category: Neurological
  name: Brain atrophy
  description: Progressive brain atrophy, in some patients from the prenatal period.
  phenotype_term:
    preferred_term: Progressive brain atrophy
    term:
      id: HP:0012444
      label: Brain atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:25597510
    reference_title: CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death"
    explanation: Progressive brain atrophy at the severe end of the spectrum.
- category: Neurological
  name: Microcephaly
  phenotype_term:
    preferred_term: Congenital microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:25650066
    reference_title: Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe four newborn siblings, from a consanguineous family, who showed microcephaly, small birth weight, severe encephalopathy and 3-methylglutaconic aciduria."
    explanation: Microcephaly at birth in four siblings with a truncating genotype.
- category: Renal
  name: Nephrocalcinosis
  phenotype_term:
    preferred_term: Nephrocalcinosis
    term:
      id: HP:0000121
      label: Nephrocalcinosis
  evidence:
  - reference: PMID:25595726
    reference_title: Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two siblings with a syndrome of congenital lamellar cataracts associated with nephrocalcinosis, medullary cysts and 3-methylglutaconic aciduria"
    explanation: Nephrocalcinosis in a sibling pair.
- category: Renal
  name: Renal medullary cysts
  phenotype_term:
    preferred_term: Renal medullary cysts
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:25595726
    reference_title: Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two siblings with a syndrome of congenital lamellar cataracts associated with nephrocalcinosis, medullary cysts and 3-methylglutaconic aciduria"
    explanation: Medullary renal cysts in the same sibling pair.
- category: Endocrine
  name: Premature ovarian insufficiency
  description: >-
    Premature ovarian insufficiency and infertility are common in female
    patients who survive past puberty.
  phenotype_term:
    preferred_term: Premature ovarian insufficiency
    term:
      id: HP:0008209
      label: Premature ovarian insufficiency
  evidence:
  - reference: PMID:36074910
    reference_title: "Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "POI is a common feature of postpubertal female individuals with CLPB deficiency."
    explanation: Clinical follow-up of adult survivors identified POI as common.
- category: Growth
  name: Small for gestational age
  phenotype_term:
    preferred_term: Small birth weight
    term:
      id: HP:0001518
      label: Small for gestational age
  evidence:
  - reference: PMID:25650066
    reference_title: Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe four newborn siblings, from a consanguineous family, who showed microcephaly, small birth weight, severe encephalopathy and 3-methylglutaconic aciduria."
    explanation: Small birth weight in the severely affected siblings.
- category: Mortality
  name: Death in infancy
  description: >-
    Death usually occurs within the first months of life in the severe form;
    in the 2026 cohort two thirds of biallelic patients had died, at a median
    age of 6 months. Survival into adulthood occurs in the mild form.
  notes: >-
    Deliberately left without a phenotype_term. HP:0001522 (Death in infancy)
    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:28687938
    reference_title: A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "current median age 17.5 years in the mild group, median age of death 35 days in the severe group"
    explanation: Early death in the severe group contrasts with survival in the mild group.
  - 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 and age at death in the biallelic group.
biochemical:
- name: Urinary 3-methylglutaconic acid
  presence: INCREASED
  context: >-
    Raised in the recessive form; a secondary 3-methylglutaconic aciduria.
    In secondary 3-MGA syndromes urinary levels fluctuate and can be
    undetectable, and plasma untargeted metabolomics was more sensitive in
    one cohort.
  biomarker_term:
    preferred_term: 3-methylglutaconic acid
    term:
      id: CHEBI:144330
      label: 3-methylglutaconic acid
  readouts:
  - target: Secondary 3-Methylglutaconic Acid Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Urinary organic acid analysis showing 3-methylglutaconic acid is a
      recommended first test in neonates with the severe presentation.
  evidence:
  - reference: PMID:25597510
    reference_title: CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied a group of individuals with elevated urinary excretion of 3-methylglutaconic acid"
    explanation: Raised urinary 3-methylglutaconic acid in the founding cohort.
  - reference: PMID:28687938
    reference_title: A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients."
    explanation: Recommends urinary organic acid analysis as a diagnostic test.
  - reference: PMID:39787888
    reference_title: Untargeted metabolomics analysis as a potential screening tool for 3-methylglutaconic aciduria syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "In these disorders, urine 3-MGA levels are known to be fluctuant and at times undetectable by standard urine organic acid analysis (UOA), thereby reducing the utility of this biochemical screening method."
    explanation: >-
      Applies to secondary 3-MGA syndromes as a class; the abstract does not
      name the genes of its nine patients, so a normal urine organic acid
      result does not exclude CLPB deficiency.
diagnosis:
- name: Molecular genetic testing of CLPB
  description: >-
    Confirmatory test. The diagnosis is established by finding biallelic
    pathogenic CLPB variants on molecular genetic testing.
  diagnosis_term:
    preferred_term: molecular genetic testing of CLPB
    term:
      id: NCIT:C15709
      label: Genetic Testing
  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"
    explanation: GeneReviews diagnostic criterion for the recessive form.
- name: Urine organic acid analysis
  description: >-
    First-line biochemical test in neonates presenting with absent voluntary
    movements, hyperexcitability or a hyperekplexia-like picture, looking for
    3-methylglutaconic aciduria. In secondary 3-MGA syndromes urinary 3-MGA
    fluctuates and can be undetectable, so a normal result does not exclude
    the disease.
  diagnosis_term:
    preferred_term: urine organic acid analysis
    term:
      id: NCIT:C17241
      label: Urinalysis
  evidence:
  - reference: PMID:28687938
    reference_title: A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients."
    explanation: Recommends urinary organic acid analysis in neonates with a hyperekplexia-like presentation.
  - reference: PMID:39787888
    reference_title: Untargeted metabolomics analysis as a potential screening tool for 3-methylglutaconic aciduria syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "In these disorders, urine 3-MGA levels are known to be fluctuant and at times undetectable by standard urine organic acid analysis (UOA), thereby reducing the utility of this biochemical screening method."
    explanation: Caveat for secondary 3-MGA syndromes as a class; the abstract does not name its patients' genes.
- name: Blood cell count
  description: >-
    Blood count with differential to detect neutropenia, recommended together
    with urine organic acids and eye examination in suspected neonates.
  diagnosis_term:
    preferred_term: blood cell count with differential
    term:
      id: NCIT:C28133
      label: Blood Cell Count
  evidence:
  - reference: PMID:28687938
    reference_title: A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients."
    explanation: Recommends blood cell counts in the same diagnostic work-up.
- name: Ophthalmological examination
  description: >-
    Eye examination for cataract, recommended in the same neonatal work-up.
  diagnosis_term:
    preferred_term: ophthalmological examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: PMID:28687938
    reference_title: A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients."
    explanation: Recommends ophthalmological examination in the same diagnostic work-up.
mechanistic_hypotheses:
- hypothesis_group_id: clpb_hax1_proteostasis_neutropenia
  hypothesis_label: CLPB-HAX1 Mitochondrial Proteostasis Model of Neutropenia
  status: EMERGING
  description: >-
    Loss of CLPB disaggregase activity leaves HAX1 and other intermembrane
    space proteins insoluble, disrupting a CLPB/HAX1/PRKD2/HSP27 axis needed
    for granulocytic differentiation, so that myeloid precursors undergo
    apoptosis at the onset of differentiation. The model is supported in
    cultured human and mouse myeloid cells and by the shared neutropenia of
    HAX1 deficiency; it has not been tested in patient marrow.
  evidence:
  - reference: PMID:35499078
    reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes"
    explanation: Defines the shared CLPB/HAX1 pathway in neutrophil differentiation.
  - 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
    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: HAX1 aggregation in CLPB-deficient myeloid cells.
- hypothesis_group_id: aggregate_membrane_perturbation_3mga
  hypothesis_label: Aggregate-Induced Mitochondrial Membrane Perturbation as the Source of 3-MGA
  status: EMERGING
  description: >-
    Abnormal protein aggregates perturb mitochondrial membrane architecture,
    which is proposed to be the shared cause of 3-methylglutaconic aciduria in
    CLPB deficiency and in the membrane-lipid disorders Barth, Sengers and
    MEGDEL syndromes. Proposed from clinical and genetic data; not tested.
  evidence:
  - reference: PMID:25595726
    reference_title: Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "We now propose that perturbation of the mitochondrial membranes by abnormal protein aggregates leads to 3-methylglutaconic aciduria in CLPB deficiency."
    explanation: States the hypothesis.
- hypothesis_group_id: acetyl_coa_tca_3mga
  hypothesis_label: Mitochondrial Acetyl-CoA Build-up Route to 3-MGA
  status: ALTERNATIVE
  description: >-
    The current general model for secondary 3-methylglutaconic acidurias:
    impaired TCA cycle function causes mitochondrial acetyl-CoA to build up,
    which is converted through trans-3-methylglutaconyl-CoA to
    3-methylglutaconic acid. Stated for the disease class; not tested in
    CLPB-deficient cells.
  evidence:
  - reference: PMID:39787888
    reference_title: Untargeted metabolomics analysis as a potential screening tool for 3-methylglutaconic aciduria syndromes.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "It is currently thought that this accumulation is due to an underlying buildup of acetyl-CoA in the mitochondria from impaired function of the TCA cycle with ensuing formation of trans-3-methylglutaconyl CoA and its subsequent byproducts, including 3-MGA."
    explanation: States the class-wide hypothesis for secondary 3-MGA.
- hypothesis_group_id: ampk_peroxisomal_3mga
  hypothesis_label: AMPK-Driven Peroxisomal HMG-CoA Route to 3-MGA
  status: ALTERNATIVE
  description: >-
    A general scenario for secondary 3-methylglutaconic acidurias in which
    constitutive mitochondrial dysfunction activates AMPK, diverting
    cytoplasmic acetyl-CoA to peroxisomes where HMG-CoA is converted to
    3-methylglutaconate. The authors consider additional contributors for
    CLPB deficiency. Theoretical synthesis; not tested in CLPB cells.
  evidence:
  - reference: PMID:31626852
    reference_title: "Mitochondrial dysfunction, AMPK activation and peroxisomal metabolism: A coherent scenario for non-canonical 3-methylglutaconic acidurias."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "constitutive mitochondrial dysfunction induces AMPK activation which, by inhibiting early steps in cholesterol and fatty acid syntheses, pipelines cytoplasmic acetyl-CoA to peroxisomes where a rise in HMG-CoA followed by local dehydration and hydrolysis may lead to 3-MGA yield"
    explanation: States the alternative hypothesis.
treatments:
- name: Granulocyte Colony-Stimulating Factor
  description: >-
    G-CSF to raise neutrophil counts and reduce infections, especially in the
    mild and moderate forms. In the 2026 cohort G-CSF use was associated with
    improved survival; that analysis pooled biallelic and monoallelic
    patients and was retrospective.
  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: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.
  - 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 of G-CSF with survival across the CLPB cohort.
  - 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 at each visit, which is how the neutrophil response to G-CSF is followed.
- name: Hematopoietic Stem Cell Transplantation
  description: >-
    Considered in patients without severe neurological disease. The
    transplants reported in the 2026 cohort were in monoallelic (autosomal
    dominant) patients, with mixed outcomes; no outcome data for the
    recessive form are cited here.
  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 and Impaired Neutrophil Differentiation
    description: Replaces the CLPB-deficient hematopoietic compartment.
  evidence:
  - 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 management recommendation.
- name: Multidisciplinary Supportive Care
  description: >-
    No specific dietary or metabolic treatment exists. Care is supportive:
    feeding therapy and gastrostomy, antiseizure treatment, management of the
    movement disorder, developmental support, standard immunizations, and
    treatment of cataracts, endocrine and renal disease. Drugs potentially
    toxic to mitochondria (chloramphenicol, aminoglycosides, linezolid,
    valproic acid, nucleoside reverse transcriptase inhibitors) should be
    avoided.
  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 states that management is supportive.
  - 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 lists agents to avoid.
- name: Hormone Replacement Therapy for Premature Ovarian Insufficiency
  description: >-
    Females surviving past puberty should be referred for assessment of
    ovarian function and hormone replacement when POI is present.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Hormone Replacement Therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
  target_phenotypes:
  - preferred_term: Premature ovarian insufficiency
    term:
      id: HP:0008209
      label: Premature ovarian insufficiency
  evidence:
  - reference: PMID:36074910
    reference_title: "Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with CLPB deficiency should be referred to pediatric gynecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimize associated comorbidities."
    explanation: Recommendation from the POI follow-up study.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "assessment of gonadal function in females (beginning at age 10 years)"
    explanation: GeneReviews annual surveillance that identifies the ovarian insufficiency needing hormone replacement.
animal_models:
- name: clpb zebrafish morphant (Wortmann 2015)
  species: Zebrafish
  genotype: clpb antisense morpholino knockdown
  publication: PMID:25597510
  description: >-
    Morpholino suppression of clpb in zebrafish embryos, with rescue by
    wild-type but not mutant human CLPB mRNA.
  modeled_mechanisms:
  - target: Progressive Encephalopathy with Brain Atrophy
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Knockdown produces a central nervous system phenotype consistent with
      cerebellar and cerebral atrophy, and patient alleles fail to rescue it.
    limitations: >-
      Morpholino knockdown is transient and dose-dependent rather than a
      germline null, the readout is in embryos rather than in a postnatal
      brain, and the abstract does not report neutropenia, cataract or
      3-methylglutaconic aciduria in the model.
    evidence:
    - reference: PMID:25597510
      reference_title: CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "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."
      explanation: Supports the morphant as informative for the brain atrophy node.
- name: clpb zebrafish morphant (Capo-Chichi 2015)
  species: Zebrafish
  genotype: clpb antisense morpholino knockdown
  publication: PMID:25650066
  description: >-
    Antisense morpholino knockdown of translation of the zebrafish clpb
    ortholog.
  modeled_mechanisms:
  - target: Spinal Inhibitory Interneuron Deficit and Motor Hyperexcitability
    relationship: RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Morphants show an abnormal touch-evoked response with increased swim
      velocity and tail beat frequency, and fewer inhibitory glycinergic
      interneurons in the spinal cord.
    limitations: >-
      Morpholino knockdown only; the interneuron finding has not been examined
      in patient tissue, and zebrafish spinal motor circuits are an indirect
      proxy for the neonatal hyperexcitability of patients.
    readouts:
    - name: Touch-evoked swimming response
      target: Spinal Inhibitory Interneuron Deficit and Motor Hyperexcitability
      direction: INCREASED
      interpretation: Behavioural correlate of motor hyperexcitability.
      evidence:
      - reference: PMID:25650066
        reference_title: Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The clpb morphants showed an abnormal touch-evoked response with increased swim velocity and tail beat frequency."
        explanation: Reports the behavioural measurement behind this readout.
    evidence:
    - reference: PMID:25650066
      reference_title: Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Interestingly, knocking down clpb reduced the number of inhibitory glycinergic interneurons and increased a population of excitatory glutamatergic neurons in the spinal cord."
      explanation: Supports the morphant as informative for the interneuron node.
experimental_models:
- name: CLPB-knockout 32Dcl3 mouse myeloblastic cells
  experimental_model_type: CELL_LINE
  description: >-
    IL-3-dependent mouse myeloblastic cell line with CLPB knocked out,
    differentiated to neutrophils with G-CSF after IL-3 withdrawal.
  publication: PMID:39644357
  modeled_mechanisms:
  - target: Granulocytic Precursor Apoptosis and Impaired Neutrophil Differentiation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      CLPB loss increases apoptosis at the onset of G-CSF-induced
      differentiation, while surviving cells express normal differentiation
      markers.
    limitations: >-
      A mouse cell line rather than human patient marrow, and surviving
      CLPB-deficient cells differentiated normally, so the model captures
      precursor loss rather than a differentiation block.
    evidence:
    - 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
      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: Shows that the defect in this model is survival rather than differentiation.
discussions:
- discussion_id: gap_clpb_tissue_selectivity
  prompt: >-
    Why does loss of a ubiquitously expressed mitochondrial disaggregase
    produce neutropenia across the severity range but neurological disease of
    widely varying severity, and which CLPB substrates are limiting in
    granulocytic precursors versus neurons?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#HAX1 Insolubility
  - pathophysiology#Progressive Encephalopathy with Brain Atrophy
  - phenotypes#Congenital neutropenia
  rationale: >-
    The neutropenia has a candidate mechanism through HAX1 and the
    CLPB/HAX1/PRKD2/HSP27 axis, but no comparable substrate has been linked to
    neuronal loss, and the neurological severity tracks residual disaggregase
    activity without a known cell-specific explanation. Candidate links such as
    secondary complex I instability and impaired mitochondrial calcium uptake
    are shown only in cultured cells.
  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
    snippet: "Importantly, Skd3 variants linked to 3-methylglutaconic aciduria, a severe mitochondrial disorder, display diminished disaggregase activity (but not always reduced ATPase activity), which predicts disease severity."
    explanation: Severity tracks residual activity, but the tissue pattern is unexplained.
  - reference: PMID:38270563
    reference_title: CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "CLPB mutations are associated with 3-methylglutaconic aciduria and neutropenia; however, the molecular mechanism underscoring disease and the contribution of CLPB substrates to disease pathology remains unknown."
    explanation: States that the substrate contribution to disease is unknown.
- discussion_id: gap_clpb_3mga_origin
  prompt: >-
    How does loss of CLPB disaggregase activity raise urinary
    3-methylglutaconic acid?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Secondary 3-Methylglutaconic Acid Accumulation
  - mechanistic_hypotheses#aggregate_membrane_perturbation_3mga
  - mechanistic_hypotheses#ampk_peroxisomal_3mga
  - mechanistic_hypotheses#acetyl_coa_tca_3mga
  rationale: >-
    Three proposals exist, membrane perturbation by protein aggregates, an
    AMPK-driven peroxisomal HMG-CoA route, and the class-wide mitochondrial
    acetyl-CoA build-up model, and none has been tested in CLPB-deficient
    cells or patients. 3-methylglutaconic aciduria was also not
    observed in one series of patients with the dominant-negative form, a
    contrast that may help discriminate between them.
  evidence:
  - reference: PMID:31626852
    reference_title: "Mitochondrial dysfunction, AMPK activation and peroxisomal metabolism: A coherent scenario for non-canonical 3-methylglutaconic acidurias."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "its genesis in non-canonical (secondary) 3-MGAs, a growing-up group of disorders encompassing more than a dozen of inherited metabolic diseases, is a mystery still remaining unresolved for three decades"
    explanation: Records that the origin of secondary 3-MGA is unresolved.
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series."
    explanation: 3-MGA was absent in a heterozygous dominant-negative series, a contrast relevant to its origin.

📚

References & Deep Research

References

1

PMID:27891836

CLPB Deficiency.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: 3-Methylglutaconic Aciduria Type VIIB · 2026-10-15T17:43:02Z · View source

Curated the autosomal recessive form of CLPB deficiency (MGCA7B, MONDO:0014561, OMIM 616271) from a skeleton entry, and deleted its stub. Sources, all cached with fetch-reference and quoted from abstracts: GeneReviews CLPB Deficiency (PMID:27891836, tagged GeneReviews); the three 2015 gene-discovery reports (Wortmann PMID:25597510, Saunders PMID:25597511, Kanabus PMID:25595726) and Capo-Chichi 2015 (PMID:25650066); the Pronicka 2017 severity-score series (PMID:28687938); the Heath 2026 zygosity cohort (PMID:41719910); Tucker 2022 on premature ovarian insufficiency (PMID:36074910); and mechanism papers on Skd3 disaggregase activity and severity (Cupo and Shorter 2020, PMID:32573439), intermembrane space localisation (PMID:32866687), the CLPB/HAX1 axis in neutrophil differentiation (Fan 2022, PMID:35499078), CLPB-null myeloblasts (Wenta 2025, PMID:39644357), the SPY complex (Baker 2024, PMID:38270563), calcium uptake and fusion (PMID:40118824), secondary complex I instability (PMID:42420651) and a review on the origin of secondary 3-MGA (PMID:31626852). Two dominant-negative studies (Wortmann 2021 PMID:34140661, Warren 2022 PMID:34115842) belong to the separate autosomal dominant form MGCA7A (MONDO:0859237); Warren 2022 is cited only for the effect of genetic CLPB loss on granulocytic differentiation and for the absence of 3-MGA in the dominant series. The pathograph runs CLPB disaggregase loss to intermembrane space aggregation, then HAX1 insolubility to granulocytic precursor apoptosis and neutropenia, with SPY complex, calcium uptake and complex I branches that are shown only in cultured cells, and a proposed link to 3-MGA, cataract and nephrocalcinosis. Four mechanistic hypotheses and two knowledge gaps (tissue selectivity of neutropenia versus neurological disease; origin of the 3-MGA) are recorded. Death in infancy carries no phenotype_term because HP:0001522 is outside the PhenotypeTerm enum. No ClinGen record exists for CLPB and this disease (only Leigh syndrome), so gene_disease_validity is omitted. Deep research: research/3-methylglutaconic_Aciduria_Type_VIIB-deep-research-openscientist.md (openscientist) was used as a lead list. Its reference validation was 12/12 resolved with 8 on topic. just preflight-dr against MONDO:0014561 returned WARN with two triggers, both checked by hand: the second gene MGA (23 mentions) is the abbreviation 3-MGA, not the MGA gene, and OMIM 616254 is the CLPB gene record, while the report also cites the disease record 616271 that MONDO xrefs. The report is about this disease. Its passages on monoallelic dominant-negative variants describe MGCA7A and were not attributed to this entry. Added from the report: PMID:36170828 (Cupo 2022; MGCA7-linked subunits do not inhibit wild-type disaggregase, the structural basis of recessive inheritance, on the inheritance block); PMID:42244541 (bioRxiv preprint; HAX1 is a direct stimulatory cofactor of CLPB, on the HAX1 node); PMID:39787888 (secondary 3-MGA is fluctuant and can be undetectable in urine, on the biochemical marker, and the class-wide acetyl-CoA build-up model added as a fourth, ALTERNATIVE mechanistic hypothesis and to the 3-MGA knowledge gap). Rejected report citations: PMID:31729175 (delayed 3-MGA in TMEM70 and TAZ cardiomyopathy, no CLPB patients); PMID:36485107, PMID:37193639 and PMID:31030818 (general severe congenital neutropenia and HAX1 neutropenia reviews and registry data, not CLPB-specific; G-CSF is already supported by GeneReviews and the CLPB cohort). Their caches were deleted. Also rejected: the report's claim that HSCT is reserved for leukemic transformation (no CLPB source); its unresolved term HP:0000844; NCIT:C1512, which the report labels G-CSF but is Immunoconjugate (the entry keeps NCIT:C1287 Recombinant Granulocyte Colony-Stimulating Factor); and its use of HP:0001332 Dystonia for movement disorder in general (the entry binds Dystonia only to the cohort sentence naming dystonia). gnomAD constraint figures in the report have no citable source and were not used. Validation: just validate, validate-terms, count-verified-snippets (106/106), check-entity-refs, check-causal-targets, check-duplicate-keys, check-snippet-length, check-title-snippets, check-coarse-phenotypes, check-block-scalar-comments and validate-disorders all pass.

OpenScientist ▸

1. Disease Information & Key Identifiers

openscientist-autonomous 11 citations 2026-10-15T17:47:03.397804

1. Disease Information & Key Identifiers

Resource	Identifier
Gene symbol	CLPB ("ClpB family mitochondrial disaggregase")
NCBI Gene	81570
HGNC	HGNC:30664
Gene OMIM	616254
Ensembl	ENSG00000162129
UniProt	Q9H078
Cytogenetic locus	11q13.4 (GRCh38 chr11:72,285,495–72,434,680, minus strand)
Disease OMIM	#616271 (MEGCANN / MGCA7B)
MONDO	MONDO:0014561
Orphanet	ORPHA:445038 (and ORPHA:324631, "3-methylglutaconic aciduria type 7")
DOID	DOID:0081134, DOID:0110003
GARD	0017767
MedGen / UMLS	C5676893
SNOMED CT	764860006

Synonyms: 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN); 3-methylglutaconic aciduria-cataract-neurologic involvement-neutropenia syndrome; MGA7; MGCA7; MGCA7B; "CLPB 3-methylglutaconic aciduria." Information in this report is derived from aggregated disease-level resources (OMIM, Orphanet, MONDO, gnomAD, ClinVar) and published patient cohorts, not from EHR/individual-patient data.

2. Etiology

Primary cause: monogenic (Mendelian). Biallelic pathogenic variants in CLPB cause the full MEGCANN syndrome; monoallelic dominant-negative missense variants cause a neutropenia-predominant presentation. There is no environmental, infectious, or multifactorial etiology.
Genetic risk factors: the causal variants themselves (see Section 4); consanguinity increases the chance of biallelic genotypes in affected families.
Environmental risk/protective factors: none established — the disease is genetically determined.
Gene–environment interactions: not applicable; no documented modifier exposures.

3. Phenotypes

Across cohorts, biallelic CLPB deficiency presents with a consistent constellation. Wortmann et al. (2021) summarized it: "biallelic CLPB variants underlie a neurological phenotype ranging from nonprogressive intellectual disability to prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, 3-methylglutaconic aciduria, and neutropenia." The founding paper emphasized the severity range and malignancy risk: "neutropenia that can develop into leukemia, a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death." Neutropenia and intellectual disability are the hallmarks. [PMID: 34140661; PMID: 25597510]

Phenotype	HPO term	Type	Onset / severity / frequency
Congenital neutropenia (→ leukemia/MDS)	HP:0000844	Laboratory/hematologic	Congenital; hallmark; can transform to malignancy
Intellectual disability	HP:0001249	Clinical sign	Hallmark; nonprogressive → severe
Developmental delay	HP:0001263	Clinical sign	Early childhood; common
Progressive brain atrophy	HP:0012444	Imaging/structural	Progressive in severe forms
Seizures / epilepsy	HP:0001250	Clinical sign	Frequent in severe forms
Movement disorder / dystonia	HP:0001332	Clinical sign	Common
Cataracts	HP:0000518	Physical manifestation	Characteristic; surgically treatable
3-methylglutaconic aciduria	HP:0003535	Laboratory abnormality	Biochemical hallmark; fluctuant

Quality-of-life impact: severe in the biallelic form — early mortality, profound neurodisability, recurrent infections, visual impairment, and lifelong dependency. The monoallelic neutropenia-predominant form has a comparatively better functional trajectory. No disease-specific QoL instrument (EQ-5D/SF-36/PROMIS) data are published for this ultra-rare condition.

4. Genetic / Molecular Information

Causal gene: CLPB (NCBI Gene 81570; HGNC:30664; gene OMIM 616254), 11q13.4.

Variant spectrum (ClinVar, queried Oct 2025): ~954 CLPB records — ~157 pathogenic, ~38 likely pathogenic, ~692 of uncertain significance. Disease-causing classes: - Missense: biallelic p.Arg408Gly abolishing ATPase (PMID 25597510); SCN-associated heterozygous missense clustering near the ATP-binding pocket (PMID 34115842). - Nonsense/frameshift: stop/stop genotypes carry the highest disease burden (PMID 41719910). - Splice variants.

All reported variants are germline; no somatic/cancer-driver role is established. Functional consequence: biallelic = loss of function (recessive); specific monoallelic missense = dominant-negative. In-silico structural impact (NMD, ankyrin-domain disruption) predicts survival (PMID 41719910).

Population constraint (gnomAD, Oct 2025): pLI ≈ 2.4×10⁻⁵ (not haploinsufficient); observed/expected LoF = 0.51 (40 observed vs 78.4 expected); LOEUF = 0.66; LoF Z = 3.68; missense Z = 1.53. Heterozygous LoF alleles occur in and are tolerated by the general population — explaining why a single null allele does not cause disease, whereas a single poisoning (dominant-negative) missense protein does. [PMID: 34115842]

Modifier genes / epigenetics / chromosomal abnormalities: no established modifier genes, epigenetic mechanisms, or large-scale chromosomal rearrangements for this disease; it is a single-gene disorder.

5. Environmental Information

Not applicable. CLPB deficiency is a purely genetic disorder with no documented environmental, lifestyle, or infectious contributors.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Biallelic (or dominant-negative monoallelic) pathogenic variant in CLPB (11q13.4) → reduces or abolishes functional CLPB AAA+ disaggregase/refoldase protein in the mitochondrial intermembrane space. (demonstrated — PMID 25597510, 34115842)
Loss of CLPB ATPase/refoldase activity → CLPB can no longer disaggregate and refold stress-damaged IMS client proteins. Normal activation requires HAX1 binding the ankyrin domain to drive the active hexamer; this step fails. (demonstrated — PMID 42244541, 36170828)
Loss of disaggregase activity → aggregation of IMS proteins (CLPB, HAX1, HTRA2) under stress. (demonstrated — PMID 38270563)
IMS protein aggregation → impaired SPY complex (STOML2–PARL–YME1L1) function → degraded mitochondrial protein quality control. (demonstrated — PMID 38270563)
Branch A (hematologic): impaired IMS proteostasis + loss of the CLPB/HAX1 axis → impaired granulocytic differentiation and increased apoptosis of hematopoietic progenitors → congenital neutropenia → (with clonal pressure) risk of MDS/leukemia. (demonstrated in cells — PMID 34115842)
Branch B (neurologic): mitochondrial dysfunction in CNS → progressive neuronal loss → cerebral/cerebellar atrophy, intellectual disability, epilepsy, movement disorder. (model-supported — PMID 25597510; inferred for human CNS)
Branch C (ophthalmologic): mitochondrial/proteostatic stress in the lens → cataracts. (observed clinically; mechanism inferred)
Branch D (biochemical): impaired mitochondrial energy metabolism → acetyl-CoA buildup → trans-3-methylglutaconyl-CoA → 3-methylglutaconic acid excretion (secondary, fluctuant biomarker). (mechanism inferred — PMID 39787888)

   CLPB variant (11q13.4)
  |
   loss of CLPB disaggregase/refoldase  <-- (needs HAX1 cofactor; fails)
  |
   aggregation of IMS proteins (CLPB, HAX1, HTRA2)
  |
   SPY complex (STOML2-PARL-YME1L1) dysfunction
  |
   ------------------------------------------------
   |            |             |             |
 Hematologic  Neurologic    Ophthalmic    Metabolic
 neutropenia  brain atrophy  cataracts    acetyl-CoA buildup
 (-> leukemia) ID/epilepsy/             -> 3-MGA aciduria
       movement disorder          (fluctuant biomarker)

Upstream vs downstream: the mutation and loss of disaggregase activity are the upstream lesions; IMS aggregation and SPY dysfunction are the proximate molecular consequences; neutropenia, brain atrophy, cataracts, and 3-MGA are downstream, tissue-level manifestations. 3-MGA is the most downstream and least specific — a secondary readout of mitochondrial energy failure rather than a driver.

Supporting detail

CLPB is "a mitochondrial intermembrane space AAA+ domain-containing disaggregase" (Baker et al., 2024). In CLPB-null cells, stress triggers aggregation specifically in the IMS and "CLPB deficiency impeding SPY complex function by virtue of protein aggregation in the intermembrane space." [PMID: 38270563] HAX1 is the direct activating cofactor: "HAX1 is a direct stimulatory cofactor of CLPB. HAX1 promotes oligomerization of CLPB into an active disaggregase and stimulates the ATPase and refoldase activities of the oligomeric complex." [PMID: 42244541] On the hematologic branch, "Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis." [PMID: 34115842]

3-MGA biochemistry: CLPB deficiency is a secondary 3-MGA syndrome (impaired mitochondrial energy metabolism/membrane integrity), unlike primary MGCA1 (AUH, leucine catabolism). "this accumulation is due to an underlying buildup of acetyl-CoA in the mitochondria from impaired function of the TCA cycle with ensuing formation of trans-3-methylglutaconyl CoA and its subsequent byproducts, including 3-MGA." [PMID: 39787888]

Ontology anchors: - GO biological process: GO:0042026 (protein refolding), GO:0051131 (chaperone-mediated protein complex assembly), GO:0006457 (protein folding). - GO cellular component: GO:0005758 (mitochondrial intermembrane space), GO:0005739 (mitochondrion). - CL cell types: CL:0000775 (neutrophil), CL:0000037 (hematopoietic stem cell), CL:0000540 (neuron), CL:0000121 (Purkinje/cerebellar neuron). - UBERON: UBERON:0000955 (brain), UBERON:0002037 (cerebellum), UBERON:0000965 (lens), UBERON:0002371 (bone marrow). - CHEBI: 3-methylglutaconic acid; CHEBI:15351 (acetyl-CoA).

7. Anatomical Structures Affected

Primary organs / systems: central nervous system (cerebrum and cerebellum; UBERON:0000955, UBERON:0002037), hematopoietic/immune system (bone marrow, neutrophil lineage; UBERON:0002371), eye/lens (UBERON:0000965).
Secondary involvement: systemic consequences of neutropenia (recurrent infections).
Subcellular compartment: mitochondrial intermembrane space (GO:0005758) is the defining site of molecular pathology.
Lateralization: brain atrophy typically bilateral/symmetric; cataracts bilateral.

8. Temporal Development

Onset: congenital/neonatal for the severe biallelic form (can be prenatal encephalopathy); neutropenia is congenital. Milder forms present in childhood.
Course: progressive brain atrophy and neurodisability in severe forms; neutropenia is chronic with risk of leukemic transformation.
Critical window: onset before 12 months of age predicts more severe disease (PMID 41719910).
3-MGA timing: fluctuant and may appear only with delay in neonates — a diagnostic pitfall (PMID 31729175).

9. Inheritance & Population

Inheritance: autosomal recessive (biallelic) for the full MEGCANN syndrome; monoallelic de novo / dominant-negative missense variants cause a neutropenia-predominant presentation.
Penetrance/expressivity: highly variable expressivity (nonprogressive ID → lethal neonatal encephalopathy); severity tracks with variant class (NMD/ankyrin-disruption worst).
Constraint: CLPB is LoF-tolerant in heterozygotes (pLI ≈ 0), confirming recessive biology plus a separate dominant-negative route.
Prevalence: ultra-rare; Orphanet lists prevalence as unknown/<1:1,000,000; ~60–100 individuals reported worldwide (largest cohort = 63 patients, PMID 41719910).
Demographics: pan-ethnic; consanguinity reported in some families; no established founder population; both sexes affected without strong sex bias.

10. Diagnostics

Biochemical: urine organic acids showing elevated 3-MGA (fluctuant, may be absent/delayed — repeat testing advised); CBC showing neutropenia. Untargeted plasma metabolomics is an emerging, more sensitive screen (PMID 39787888).
Hematologic: absolute neutrophil count; bone marrow examination (maturation-arrest pattern typical of SCN); surveillance for MDS/leukemia.
Imaging: brain MRI showing cerebral/cerebellar atrophy (progressive).
Genetic testing (confirmatory, gold standard): WES/WGS or targeted panels (mitochondrial/3-MGA/SCN panels including CLPB); single-gene CLPB sequencing when the phenotype is recognized. ClinVar/ACMG classification; structural-impact prediction (NMD, ankyrin-domain disruption) adds prognostic value (PMID 41719910).
Differential diagnosis: other 3-MGA syndromes — Barth (TAZ, MGCA2), OPA3 (MGCA3/Costeff), DNAJC19 (MGCA5/DCMA), HTRA2 (MGCA8), YME1L1, primary MGCA1 (AUH); other causes of severe congenital neutropenia (ELANE, HAX1, G6PC3).
Screening: carrier/cascade testing in affected families; no population newborn screening exists for this disorder specifically.

11. Outcome / Prognosis

Measure	Biallelic	Monoallelic
Mortality	66%	23%
4-year survival	50%	82%
Burden by genotype	Stop/stop > missense combinations	Dominant-negative missense, milder
Strongest survival predictor	Structural impact (NMD, ANK disruption) > zygosity or onset age	—

Onset before 12 months predicts more severe disease. Complications: life-threatening infection (from neutropenia), leukemic/MDS transformation, intractable epilepsy, progressive neurodisability, visual impairment from cataracts. [PMID: 41719910]

12. Treatment (NCIT anchors)

No disease-specific or curative therapy exists; care is multidisciplinary and symptom-directed. The neutropenia follows the SCN paradigm: "Granulocyte colony-stimulating factor and hematopoietic stem cell transplantation are now the bedrock of standard care." [PMID: 36485107] In mechanistically related HAX1-CN, "All patients were initially treated with G-CSF with a sufficient increase in absolute neutrophil counts." [PMID: 37193639]

G-CSF / filgrastim (NCIT:C1512) — first-line for neutropenia.
Hematopoietic stem cell transplantation (NCIT:C15431) — for leukemic transformation/refractory neutropenia.
Antiepileptic drugs (NCIT:C264) — seizure control.
Cataract surgery — lens opacity.
Rehabilitation — PT/OT/speech therapy for neurodevelopmental support.

No gene therapy, RNA-based therapy, targeted small molecule, or pharmacogenomic guidance exists for this disease. 3-MGA itself is not specifically treatable. [PMID: 31030818]

13. Prevention

Primary prevention is limited to genetic counseling and reproductive options (carrier testing in at-risk families, prenatal/preimplantation genetic testing) given the Mendelian basis. Secondary prevention centers on early neutrophil monitoring and infection prophylaxis once diagnosed; tertiary prevention is leukemia surveillance and supportive multidisciplinary care. No vaccine or environmental intervention is applicable.

14. Other Species / Natural Disease

Evolutionary conservation: CLPB orthologs exist across metazoa — "The multicellular metazoan lineage acquired a novel chaperone in the mitochondrial intermembrane space." [PMID: 42244541]
Natural veterinary disease: none documented; relevance is as a research model, not a companion-animal disease.
Zoonotic potential: not applicable (genetic disorder).

15. Model Organisms

Zebrafish (Danio rerio) clpb morphant — established in-vivo model: morpholino suppression produced a CNS phenotype with cerebellar/cerebral atrophy, rescued by WT but not mutant human CLPB mRNA. "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 demonstrates conserved neurodevelopmental requirement and loss-of-function causality.
Cellular/in-vitro models: patient-derived fibroblasts (complexome profiling showing CLPB/HAX1 high-mass comigration, PMID 34140661); human hematopoietic progenitors and cell lines showing impaired granulocytic differentiation and increased apoptosis (PMID 34115842); CLPB-null cell lines showing IMS aggregation (PMID 38270563); reconstituted recombinant Skd3/CLPB disaggregase assays (PMID 36170828, 42244541).
Genetic model types available: morpholino knockdown (zebrafish), gene knockout and variant-expression cell lines.
Limitations: no established mammalian (mouse) genetic model in the reviewed literature; zebrafish morphants model neurodevelopmental but not the full multisystem phenotype.

Mechanistic Model — Integrated Narrative

The unifying lesion is loss of a single mitochondrial IMS quality-control enzyme. Structurally, Cupo et al. (2022) showed that human CLPB (Skd3) "adopts a spiral hexameric arrangement that engages substrate via pore-loop interactions in the nucleotide-binding domain (NBD). Substrate-bound Skd3 hexamers stack head-to-head via unique, adaptable ankyrin-repeat domain (ANK)-mediated interactions to form dodecamers." The decisive insight for inheritance is that "SCN-linked subunits sharply inhibit disaggregase activity, whereas MGCA7-linked subunits do not. These advances illuminate Skd3 structure and mechanism, explain SCN and MGCA7 inheritance patterns." [PMID: 36170828]

This single structural fact resolves the genotype–phenotype puzzle:

Allele configuration	Molecular effect	Clinical result
Biallelic LoF (stop/stop, severe missense)	No functional disaggregase	Full MEGCANN syndrome; ~66% mortality
Monoallelic missense near ATP pocket (SCN-type)	Poisons WT hexamer (dominant-negative)	Isolated severe congenital neutropenia, often no 3-MGA
Monoallelic null (heterozygous LoF)	Tolerated (pLI≈0)	Unaffected carrier

The zygosity-stratified 63-patient cohort empirically confirmed this gradient: "Death occurred in 66% of biallelic and 23% of monoallelic individuals," and "Structural predictions — particularly variants causing nonsense-mediated decay or ankyrin domain disruption — were stronger survival predictors than zygosity or age of onset." [PMID: 41719910]

Evidence Base

PMID	Title (abbrev.)	Role
25597510	CLPB mutations cause 3-MGA, brain atrophy, ID, neutropenia, cataracts, movement disorder	Founding gene discovery; zebrafish causality; core phenotype
38270563	CLPB disaggregase dysfunction impacts the SPY complex	IMS disaggregase function; downstream SPY impairment
42244541	HAX1 drives assembly and activation of CLPB	HAX1 activation mechanism; metazoan conservation
41719910	Zygosity-specific insights in 63 CLPB cases	Genotype–outcome; mortality; prognostic predictors
34115842	Heterozygous CLPB variants cause severe congenital neutropenia	Dominant-negative monoallelic mechanism; hematopoietic model
34140661	Neutropenia and ID are hallmarks of biallelic and de novo CLPB deficiency	Phenotype enumeration; de novo dominant-negative
36170828	Structural features of Skd3 disaggregase	Hexamer/dodecamer architecture; inheritance explanation
39787888	Untargeted metabolomics for 3-MGA syndromes	3-MGA biochemistry; biomarker limitations
31729175	Delayed appearance of 3-MGA-uria in neonates	Diagnostic pitfall (fluctuant biomarker)
36485107	Genetics of SCN as gateway to personalized therapy	G-CSF/HSCT standard of care
37193639	HAX1-related congenital neutropenia (SCNIR)	G-CSF efficacy in partner-pathway disease
31030818	Congenital neutropenia in children	Treatment paradigm (G-CSF, HSCT)

Evidence source types: human clinical (25597510, 34140661, 41719910, 36485107, 37193639, 31030818, 39787888, 31729175); in-vitro/cellular (38270563, 34115842, 42244541); model organism (25597510 zebrafish); structural/computational (36170828, 42244541).

Limitations and Knowledge Gaps

Small patient numbers. Even the largest cohort is 63 individuals; prevalence, penetrance, and natural-history estimates carry wide uncertainty.
Neurologic mechanism partly inferred. The link from IMS proteostasis failure to progressive brain atrophy is strongly model-supported (zebrafish) but the human CNS cell-type-specific pathway is not fully demonstrated.
3-MGA pathogenesis. The route to 3-MGA in secondary syndromes (acetyl-CoA buildup → trans-3-methylglutaconyl-CoA) is a mechanistic hypothesis, not fully proven for CLPB specifically; 3-MGA is a fluctuant, insensitive biomarker.
No mammalian (mouse) genetic model is established in the reviewed literature, limiting preclinical therapy testing.
Cataract and movement-disorder mechanisms at the tissue/cellular level remain under-characterized.
No therapeutic trials. All treatment evidence is extrapolated from the SCN/HAX1 paradigm, not CLPB-specific trials.

Proposed Follow-up Experiments / Actions

Generate a conditional mouse model (tissue-specific Clpb knockout in hematopoietic and neural lineages) to test cell-autonomous mechanisms and serve as a preclinical platform.
iPSC-derived neurons, cerebellar organoids, and granulocyte-differentiation assays from patient cells to map cell-type-specific proteostatic collapse and screen small-molecule chaperone enhancers.
Structure-guided therapeutics exploiting the HAX1–CLPB activation axis — test whether boosting residual CLPB oligomerization/ATPase (or correcting dominant-negative poisoning) rescues disaggregase activity.
Prospective natural-history registry with standardized 3-MGA + plasma metabolomics, MRI, and neutrophil monitoring to validate the NMD/ankyrin-disruption prognostic predictor (PMID 41719910).
Systematic reclassification of the ~692 VUS in ClinVar using functional disaggregase assays and structural prediction to improve diagnostic yield.
Evaluate HSCT timing and outcomes specifically in CLPB patients (vs generic SCN), given the multisystem neurologic burden transplantation does not address.

Report compiled from aggregated disease-level resources (OMIM, Orphanet, MONDO, gnomAD, ClinVar, UniProt, HGNC) and primary literature. All mechanistic and clinical claims are cited to PMID where available; ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT) are provided for knowledge-base population.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	12
Resolved	12
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	12
On topic	8
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	31
Resolved	27
Unresolved (possible confabulation)	1
Obsolete	0
Unverifiable	3
Terms whose name was checked	25
Terms named correctly	16
Terms named as a different term	3
Terms whose name is worth a second look	6

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:

MONDO:0014561 (2 mentions) - the report calls it "MONDO"; MONDO calls it 3-methylglutaconic aciduria, type VIIB
HP:0001332 (1 mention) - the report calls it "Movement disorder / dystonia"; HP calls it Dystonia
NCIT:C1512 (1 mention) - the report calls it "G-CSF / filgrastim"; NCIT calls it Immunoconjugate

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

HP:0000844 (1 mention), reported as "Congenital neutropenia (→ leukemia/MDS)" - HP does not contain this term

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0001263 (1 mention) - the report calls it "Developmental delay"; HP calls it Global developmental delay, and lists "Developmental delay" among its other names
HP:0012444 (1 mention) - the report calls it "Progressive brain atrophy"; HP calls it Brain atrophy
HP:0001250 (1 mention) - the report calls it "Seizures / epilepsy"; HP calls it Seizure, and lists "Seizures" among its other names
GO:0005758 (2 mentions) - the report calls it "mitochondrial intermembrane space", "Subcellular compartment: mitochondrial intermembrane space"; GO calls it mitochondrial intermembrane space
CL:0000121 (1 mention) - the report calls it "Purkinje/cerebellar neuron"; CL calls it Purkinje cell, and lists "Purkinje neuron" among its other names
NCIT:C264 (1 mention) - the report calls it "Antiepileptic drugs"; NCIT calls it Anticonvulsant Agent, and lists "Antiepileptics" among its other names

Terms named inconsistently

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

GO:0005758 - called "mitochondrial intermembrane space", "Subcellular compartment: mitochondrial intermembrane space"

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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Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Prevalence

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information & Key Identifiers

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Supporting detail

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance & Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment (NCIT anchors)

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model — Integrated Narrative

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Unresolved terms

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver