3-Methylglutaconic Aciduria Type VIIB

1. Disease Information & Key Identifiers

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]

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)

1. 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)
2. 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)
3. Loss of disaggregase activity → aggregation of IMS proteins (CLPB, HAX1, HTRA2) under stress. (demonstrated — PMID 38270563)
4. IMS protein aggregation → impaired SPY complex (STOML2–PARL–YME1L1) function → degraded mitochondrial protein quality control. (demonstrated — PMID 38270563)
5. 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)
6. 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)
7. Branch C (ophthalmologic): mitochondrial/proteostatic stress in the lens → cataracts. (observed clinically; mechanism inferred)
8. 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

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:

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

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

1. 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.
2. 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.
3. Structure-guided therapeutics exploiting the HAX1–CLPB activation axis — test whether boosting residual CLPB oligomerization/ATPase (or correcting dominant-negative poisoning) rescues disaggregase activity.
4. Prospective natural-history registry with standardized 3-MGA + plasma metabolomics, MRI, and neutrophil monitoring to validate the NMD/ankyrin-disruption prognostic predictor (PMID 41719910).
5. Systematic reclassification of the ~692 VUS in ClinVar using functional disaggregase assays and structural prediction to improve diagnostic yield.
6. 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

• OpenScientist final report
• OpenScientist final report

Reference Validation

Checked with linkml-reference-validator 0.3.0.

All extracted references resolved successfully.

Term Validation

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

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.