Multiple Mitochondrial Dysfunctions Syndrome 6

Genetic MONDO:0054785 Pathograph 25 Show in embeddings browser MONDO:0017338

Multiple mitochondrial dysfunctions syndrome 6 (MMDS6; MONDO:0054785; OMIM #617954) is an ultra-rare autosomal-recessive childhood-onset mitochondrial neurodegeneration caused by biallelic variants in PMPCB (7q22.1), which encodes the catalytic beta subunit of the mitochondrial processing peptidase (MPP). MPP is the essential protease that cleaves the N-terminal presequences of the majority of nuclear-encoded mitochondrial precursor proteins after matrix import. Unlike the Fe-S-scaffold forms of the MMDS series, PMPCB is a presequence protease rather than an iron-sulfur assembly factor; it reaches the shared iron-sulfur/respiratory-chain phenotype indirectly, in significant part through failure to mature frataxin (a sensitive MPP substrate and a core Fe-S biogenesis factor). Reduced MPP activity leads to accumulation of the frataxin processing intermediate, impaired iron-sulfur cluster biogenesis, decreased activity of Fe-S-containing respiratory chain complexes, and neurodegeneration in early childhood. The clinical picture is a Leigh-like syndrome of developmental regression with symmetrical basal-ganglia lesions and prominent cerebellar atrophy, ataxia, and variable dystonia and epilepsy, with onset typically by 12 months and frequent death in childhood. Only about six individuals from four to five families have been reported; all original cases carried missense variants (recurrent at residue Arg175), and one splice-site variant has since been described in a milder, adult-surviving patient. No disease-modifying therapy exists; management is supportive.

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8
Pathophys.
10
Phenotypes
25
Pathograph
1
Genes
2
Variants
4
Medical Actions
4
Differentials
2
Models
3
References
1
Deep Research
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
Mechanistic Nosology
mitochondrial disease
⚙

Pathophysiology

8
PMPCB Catalytic Subunit Deficiency
Biallelic PMPCB variants reduce PMPCB protein levels and the proteolytic activity of the mitochondrial processing peptidase (MPP). PMPCB is the catalytic beta subunit of MPP, a heterodimeric metalloendopeptidase that cleaves the N-terminal presequences of the majority of nuclear-encoded mitochondrial precursor proteins imported into the matrix. The alpha subunit (PMPCA) recognizes substrate while the beta subunit carries the catalytic metalloprotease site; both are required for processing.
PMPCB hgnc:9119 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PMPCB (hgnc:9119). hgnc:9119 is a gene from the HUGO Gene Nomenclature Committee.
mitochondrial protein processing GO:0034982 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial protein processing (GO:0034982). GO:0034982 is a biological process from the Gene Ontology. ↓ DECREASED
metalloendopeptidase activity GO:0004222 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased metalloendopeptidase activity (GO:0004222). GO:0004222 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Mitochondrial Presequence and Frataxin Processing
Show evidence (2 references)
PMID:29576218 SUPPORT Human Clinical
"PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins."
Establishes PMPCB as the catalytic subunit of MPP and the role of MPP in maturing mitochondrial precursor proteins.
PMID:38374165 SUPPORT Human Clinical
"The PMPCB gene codes for the catalytic β sub-unit of the mitochondrial processing protease (MPP). MPP consists of two subunits, α and β, encoded by separate genes"
Confirms the two-subunit MPP architecture and PMPCB as the catalytic beta subunit.
Impaired Mitochondrial Presequence and Frataxin Processing
Loss of MPP proteolytic activity impairs cleavage of imported mitochondrial precursor proteins. Frataxin, an especially sensitive MPP substrate, is not matured normally, so its processing intermediate accumulates in patient fibroblasts, induced pluripotent stem cells, and differentiated neuroepithelial stem cells. Because frataxin is a core factor for iron-sulfur cluster biogenesis, its failed maturation is the principal indirect route by which a protease defect produces the Fe-S phenotype shared with the rest of the MMDS series and with Friedreich ataxia.
mitochondrial protein processing GO:0034982 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial protein processing (GO:0034982). GO:0034982 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Iron-Sulfur Cluster Biogenesis
Show evidence (1 reference)
PMID:29576218 SUPPORT In Vitro
"showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction."
Patient-derived cells show reduced PMPCB and accumulation of the frataxin processing intermediate, the direct readout of impaired MPP processing.
Impaired Iron-Sulfur Cluster Biogenesis
Defective presequence/frataxin processing produces an early impairment of iron-sulfur (Fe-S) cluster biogenesis. Fe-S clusters are indispensable cofactors for a broad range of enzymes, including several respiratory chain complexes and cytosolic Fe-S-dependent enzymes.
iron-sulfur cluster assembly GO:0016226 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased iron-sulfur cluster assembly (GO:0016226). GO:0016226 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Yeast Mas1 patient-variant complementation Saccharomyces cerevisiae recapitulates The patient variants placed in the yeast MPP-beta ortholog reproduce the MPP-processing defect and the consequent Fe-S biogenesis impairment.
Downstream
Respiratory Chain and Fe-S Enzyme Dysfunction
Show evidence (1 reference)
PMID:29576218 SUPPORT Human Clinical
"biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood."
The authors' overall conclusion places dysregulated Fe-S biogenesis downstream of the MPP proteolytic defect and upstream of neurodegeneration.
Respiratory Chain and Fe-S Enzyme Dysfunction
Loss of Fe-S cluster supply decreases the activity of iron-sulfur cluster-containing respiratory chain complexes and disables mitochondrial and cytosolic Fe-S-dependent enzymes, documented in biopsy material from an affected individual. The result is impaired oxidative phosphorylation.
electron transport chain GO:0022900 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased electron transport chain (GO:0022900). GO:0022900 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Mitochondrial Bioenergetic Failure
Basal Ganglia and Cerebellar Neurodegeneration
Show evidence (1 reference)
PMID:29576218 SUPPORT Human Clinical
"Analysis of biopsy materials of an affected individual revealed changes and decreased activity in iron-sulfur cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes."
Direct human biopsy evidence of decreased Fe-S respiratory chain complex activity and Fe-S enzyme dysfunction.
Mitochondrial Bioenergetic Failure
In a zebrafish pmpcb-null model, loss of MPP activity lowers the mitochondrial membrane potential and reduces ATP synthesis. This model-organism evidence details the bioenergetic consequence of the catalytic deficiency; it corroborates but does not by itself establish the human phenotype.
Neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
oxidative phosphorylation GO:0006119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased oxidative phosphorylation (GO:0006119). GO:0006119 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Zebrafish pmpcb-null Zebrafish recapitulates The pmpcb-null larva reproduces the mitochondrial membrane-potential and ATP-synthesis deficit modeled by this node.
Downstream
Oxidative and ER Stress
Show evidence (1 reference)
PMID:41999531 SUPPORT Model Organism
"the decrease in mitochondrial membrane potential and insufficient ATP synthesis in pmpcb-/- zebrafish contributes to elevated reactive oxygen species (ROS) stress and endoplasmic reticulum (ER) stress and the consequent neural cell apoptosis."
Zebrafish pmpcb-null model shows decreased mitochondrial membrane potential and ATP synthesis, the bioenergetic failure downstream of respiratory chain dysfunction.
Oxidative and ER Stress
The bioenergetic failure raises reactive oxygen species and triggers endoplasmic reticulum stress in the zebrafish pmpcb-null model. This model-organism evidence corroborates the cellular stress response downstream of energy failure; it does not by itself establish the human phenotype.
Neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ↑ INCREASED response to endoplasmic reticulum stress GO:0034976 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to endoplasmic reticulum stress (GO:0034976). GO:0034976 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Neural Cell Apoptosis
Show evidence (1 reference)
PMID:41999531 SUPPORT Model Organism
"the decrease in mitochondrial membrane potential and insufficient ATP synthesis in pmpcb-/- zebrafish contributes to elevated reactive oxygen species (ROS) stress and endoplasmic reticulum (ER) stress and the consequent neural cell apoptosis."
The same zebrafish sentence places elevated ROS and ER stress downstream of the bioenergetic failure and upstream of neural apoptosis.
Neural Cell Apoptosis
ROS and ER stress drive apoptosis of neural cells in the zebrafish pmpcb-null model, the cellular death mechanism underlying the CNS degeneration. This model-organism evidence corroborates but does not by itself establish the human phenotype.
Neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Zebrafish pmpcb-null Zebrafish recapitulates Neural-cell apoptosis is directly observed in the pmpcb-null larva.
Downstream
Basal Ganglia and Cerebellar Neurodegeneration
Show evidence (1 reference)
PMID:41999531 SUPPORT Model Organism
"the decrease in mitochondrial membrane potential and insufficient ATP synthesis in pmpcb-/- zebrafish contributes to elevated reactive oxygen species (ROS) stress and endoplasmic reticulum (ER) stress and the consequent neural cell apoptosis."
The zebrafish sentence names neural cell apoptosis as the consequence of the ROS/ER stress, the cellular death step upstream of tissue neurodegeneration.
Basal Ganglia and Cerebellar Neurodegeneration
Progressive neurodegeneration with a predilection for the basal ganglia and cerebellum. Imaging shows symmetrical basal-ganglia lesions (Leigh-like pattern, e.g. putaminal atrophy and hyperintensity) and prominent cerebellar atrophy. This tissue-level degeneration is the proximate cause of the developmental regression, ataxia, dystonia, and epilepsy that define the clinical syndrome.
Neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Animal models
Zebrafish pmpcb-null Zebrafish partially recapitulates Reproduces the CNS-degeneration mechanism (reduced neural cells, uncompacted myelin) but not the region-specific human imaging phenotype.
Downstream
Developmental Regression
Global Developmental Delay
Ataxia
Dystonia
Seizures
Cerebellar Atrophy
Basal Ganglia Lesions
Dysarthria
Nystagmus
Death in Childhood
Show evidence (2 references)
PMID:29576218 SUPPORT Human Clinical
"We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy."
Establishes neurodegeneration with cerebellar atrophy as the human end-organ phenotype of PMPCB deficiency.
PMID:38374165 SUPPORT Human Clinical
"The described phenotype included typical Leigh-like features of developmental regression and basal ganglia lesions, often associated with febrile illness, and with prominent cerebellar atrophy and increased T2 signal of the cerebellar cortex."
Documents the basal-ganglia and cerebellar neurodegeneration pattern across reported PMPCB cases.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Multiple Mitochondrial Dysfunctions Syndrome 6 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Eye 1
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38374165 SUPPORT Human Clinical
"Neurological examination demonstrated upper, lower limb and truncal ataxia with dysarthria, and nystagmus."
Documents nystagmus on examination of a PMPCB patient.
Nervous System 8
Developmental Regression VERY_FREQUENT HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38374165 SUPPORT Human Clinical
"Clinical features included a Leigh-like syndrome of developmental regression, basal ganglia lesions and ataxia with or without dystonia and epilepsy."
Developmental regression is a defining Leigh-like feature across PMPCB cases.
Global Developmental Delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38374165 SUPPORT Human Clinical
"The onset of symptoms was by 12 months in each case and none of the children had obtained ambulation or speech."
Documents the severe global developmental impairment with failure to obtain ambulation or speech.
Ataxia FREQUENT HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38374165 SUPPORT Human Clinical
"Symptoms of dystonia, epilepsy and/or ataxia occurred in four."
Ataxia, with dystonia and/or epilepsy, occurred in four of the five originally reported PMPCB children.
PMID:38374165 SUPPORT Human Clinical
"Neurological examination demonstrated upper, lower limb and truncal ataxia with dysarthria, and nystagmus."
Documents ataxia (with dysarthria and nystagmus) on examination of a PMPCB patient.
Dystonia FREQUENT HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38374165 SUPPORT Human Clinical
"Symptoms of dystonia, epilepsy and/or ataxia occurred in four."
Dystonia occurred in four of the five originally reported PMPCB children.
Seizures FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38374165 SUPPORT Human Clinical
"Symptoms of dystonia, epilepsy and/or ataxia occurred in four."
Epilepsy occurred in four of the five originally reported PMPCB children.
Cerebellar Atrophy VERY_FREQUENT HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29576218 SUPPORT Human Clinical
"We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy."
Cerebellar atrophy is reported in the original PMPCB families.
PMID:38374165 SUPPORT Human Clinical
"prominent cerebellar atrophy and increased T2 signal of the cerebellar cortex"
The case-review paper describes prominent cerebellar atrophy as a characteristic feature of the reported PMPCB cases.
Basal Ganglia Lesions VERY_FREQUENT Bilateral basal ganglia lesions HP:0007146 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral basal ganglia lesions (HP:0007146). HP:0007146 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38374165 SUPPORT Human Clinical
"Clinical features included a Leigh-like syndrome of developmental regression, basal ganglia lesions and ataxia with or without dystonia and epilepsy."
Basal-ganglia lesions are described as a clinical feature of the Leigh-like syndrome across reported PMPCB cases.
PMID:38374165 SUPPORT Human Clinical
"MRI brain showed basal ganglia and cerebellar atrophy"
Documents basal-ganglia involvement on imaging in a PMPCB patient.
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38374165 SUPPORT Human Clinical
"Neurological examination demonstrated upper, lower limb and truncal ataxia with dysarthria, and nystagmus."
Documents dysarthria on examination of a PMPCB patient.
Other 1
Death in Childhood FREQUENT
Show evidence (1 reference)
PMID:38374165 SUPPORT Human Clinical
"Three of the five died in childhood and none was older than age six when described."
Records childhood death in three of the five originally reported PMPCB children (60% of the reported cohort).
🧬

Genetic Associations

1
Autosomal Recessive PMPCB Deficiency
Gene: PMPCB hgnc:9119 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PMPCB (hgnc:9119). hgnc:9119 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Variants (2)
PMPCB p.Arg175 missense variants
Gene: PMPCB hgnc:9119 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in PMPCB (hgnc:9119). hgnc:9119 is a gene from the HUGO Gene Nomenclature Committee.
Missense variants at the recurrent residue Arg175 (p.Arg175Cys, seen in multiple unrelated individuals; p.Arg175His in another) are the most commonly reported PMPCB variants. Arg175 is a conserved residue that stabilizes the protein fold; the original cohort carried only missense variants.
Show evidence (1 reference)
PMID:38374165 SUPPORT Human Clinical
"This has been seen in two other individuals, p.Arg175His present in a third, indicating this is a common recurring site for variation."
Documents Arg175 as a recurrent PMPCB variation site (p.Arg175Cys and p.Arg175His).
PMPCB c.1330-2A>T splice variant
Gene: PMPCB hgnc:9119 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in PMPCB (hgnc:9119). hgnc:9119 is a gene from the HUGO Gene Nomenclature Committee.
The first reported PMPCB splice-site variant, c.1330-2A>T, causes skipping of exon 12 (confirmed by an exon-trapping minigene assay). In compound heterozygosity it was associated with a milder, adult-surviving phenotype, attributed to residual normally spliced PMPCB mRNA.
Show evidence (1 reference)
PMID:38374165 SUPPORT Human Clinical
"A minigene assay confirms this variant results in aberrant splicing and skipping of exon 12."
Functional confirmation that the c.1330-2A>T variant causes exon-12 skipping.
💊

Medical Actions

4
Supportive Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
No disease-modifying therapy exists. Management is symptomatic and supportive: seizure control, dystonia management, nutritional support, rehabilitation, and prompt treatment of intercurrent infections, which are documented precipitants of Leigh-like decompensation.
Anticonvulsant Therapy
Action: anticonvulsant agent therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is anticonvulsant agent therapy, annotated with Anticonvulsant Therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. Ontology label: Anticonvulsant Therapy NCIT:C64172
Platform: Small molecule
Seizure management with standard antiepileptic drugs. No PMPCB-specific pharmacogenomic interactions are known.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Physical Therapy and Rehabilitation
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Physical, occupational, and speech therapy for the motor, ataxic, and communication deficits arising from basal-ganglia and cerebellar degeneration.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Autosomal-recessive inheritance with 25% recurrence risk per pregnancy for carrier parents. Carrier and cascade testing available once the familial variants are known; reproductive options include prenatal diagnosis and preimplantation genetic testing.
🌍

Environmental Factors

1
Intercurrent febrile illness
exposure_term left unbound. ECTO has no clean single term for "intercurrent febrile illness / minor infection as a metabolic-decompensation trigger"; the concept is a nonspecific physiological stressor rather than a chemical or defined-agent exposure. The claim is nonetheless evidenced for PMPCB disease as cited below.
As in other Leigh-like mitochondrial disorders, febrile or intercurrent illness precipitates acute neurological decompensation and developmental regression in PMPCB disease. In the adult-surviving patient, regression followed an episode of otitis media; across reported cases the Leigh-like features are often associated with febrile illness. Prompt treatment of intercurrent infection is the corresponding clinical priority.
Show evidence (1 reference)
PMID:38374165 SUPPORT Human Clinical
"She was diagnosed with otitis media and subsequently admitted to hospital for five weeks with presumed encephalitis. She had regressed losing the ability to sit and speak"
Documents an intercurrent infection (otitis media) preceding acute regression in a PMPCB patient.
Mechanism Target:
TRIGGERS Developmental Regression — Febrile/intercurrent illness triggers the Leigh-like regression episodes characteristic of PMPCB disease.
Show evidence (1 reference)
PMID:38374165 SUPPORT Human Clinical
"The described phenotype included typical Leigh-like features of developmental regression and basal ganglia lesions, often associated with febrile illness, and with prominent cerebellar atrophy and increased T2 signal of the cerebellar cortex."
States that the regression/basal-ganglia phenotype is often associated with febrile illness, i.e. the exposure triggers the episodes.
🔬

Diagnosis

4
Molecular Genetic Testing
Definitive diagnosis rests on identifying biallelic pathogenic PMPCB variants by exome sequencing or a mitochondrial/nuclear gene panel, with confirmation of biparental inheritance. No GeneReviews chapter exists for PMPCB/MMDS6.
molecular genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29576218 SUPPORT Human Clinical
"We identified biallelic variants in PMPCB in individuals of four families"
Diagnosis is established by identifying biallelic PMPCB variants, as in the original four-family cohort.
Brain MRI
Brain MRI shows the Leigh-like pattern: symmetrical basal-ganglia signal change (putaminal atrophy and hyperintensity) with prominent cerebellar atrophy and increased T2 signal of the cerebellar cortex.
brain magnetic resonance imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:38374165 SUPPORT Human Clinical
"MRI brain showed basal ganglia and cerebellar atrophy"
Brain MRI documents the basal-ganglia and cerebellar findings used to support the diagnosis.
Frataxin Processing / MPP Functional Assay
In research settings, accumulation of the frataxin processing intermediate in patient-derived cells is a sensitive functional readout of impaired MPP activity and supports the diagnosis at the mechanistic level.
frataxin processing / MPP functional assay NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29576218 SUPPORT In Vitro
"accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction."
Accumulation of the frataxin processing intermediate in patient cells is a sensitive functional readout of PMPCB/MPP deficiency.
Mitochondrial Respiratory Chain Enzyme Testing
Assay of respiratory chain enzyme activities in biopsy tissue can show decreased activity of iron-sulfur cluster-containing complexes, reflecting the Fe-S biogenesis defect. Not disease-specific.
Show evidence (1 reference)
PMID:29576218 SUPPORT Human Clinical
"decreased activity in iron-sulfur cluster-containing respiratory chain complexes"
Biopsy shows decreased Fe-S respiratory chain complex activity, a diagnostic biochemical correlate of the mechanism.
📈

Progression

2
Classic early-onset
Age: Onset by 12 months; death before age six
Symptom onset by 12 months with severe global impairment (no ambulation or speech), progressive regression, and death in childhood before age six.
Show evidence (2 references)
PMID:38374165 SUPPORT Human Clinical
"The onset of symptoms was by 12 months in each case and none of the children had obtained ambulation or speech."
Documents the infantile onset and severe impairment of the classic course.
PMID:38374165 SUPPORT Human Clinical
"Three of the five died in childhood and none was older than age six when described."
Documents childhood death as the terminal outcome of the classic course.
Adult-surviving
Age: Survival into adulthood (reported at 39 years)
A milder course associated with a splice-site variant retaining residual normally spliced PMPCB, with survival into adulthood.
Show evidence (1 reference)
PMID:38374165 SUPPORT Human Clinical
"We report the first splice site variant in the PMPCB gene in a 39-year old individual who experienced developmental regression and ataxia following otitis media in childhood."
Documents the milder adult-surviving course driven by the splice variant.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Ultra-rare. Approximately six individuals from four to five families reported as of 2024. No prevalence estimate or registry exists.
Show evidence (1 reference)
PMID:38374165 SUPPORT Human Clinical
"To our knowledge she is only the sixth person to be described with MMD syndrome 6 due to pathogenic variants in the PMPCB gene"
Establishes the ultra-rare case count for MMDS6 at the time of the most recent report.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Multiple Mitochondrial Dysfunctions Syndrome 6:

Friedreich Ataxia
Overlapping Features Shares ataxia and impaired frataxin/Fe-S biology, but is caused by a GAA repeat expansion in FXN with characteristic cardiac involvement and later onset. PMPCB disease reaches frataxin dysfunction indirectly (failed processing) and presents as an infantile Leigh-like syndrome. Repeat-expansion testing distinguishes the two.
Leigh Syndrome (Other Causes)
Overlapping Features PMPCB disease presents as a Leigh-like syndrome; over 100 nuclear genes cause Leigh syndrome, so genetic testing is required to identify PMPCB as the cause.
Other Multiple Mitochondrial Dysfunctions Syndromes
Overlapping Features MMDS types 1-5 and 9 (NFU1, BOLA3, IBA57, ISCA2, ISCA1, FDXR and others) are direct Fe-S cluster assembly defects sharing the Fe-S/respiratory-chain phenotype; PMPCB (MMDS6) reaches it indirectly via a presequence-protease defect.
🐁

Animal Models

2
Zebrafish pmpcb-null
Zebrafish larvae with functional pmpcb deficiency show reduced neural cells, uncompacted myelin, and dysfunctional locomotor behavior, driven by decreased mitochondrial membrane potential, insufficient ATP synthesis, elevated ROS and ER stress, neural-cell apoptosis, and impaired WNT/beta-catenin signaling. Rescue with a WNT agonist (BIO), creatine, the ER-stress scavenger 4-phenylbutyric acid, or glial-driven pmpcb re-expression mitigates the CNS defects. Recapitulates the CNS-degeneration mechanism but not the specific basal-ganglia/cerebellar human imaging phenotype.
Reduced neural cell number Uncompacted myelin Locomotor dysfunction Decreased mitochondrial membrane potential Neural cell apoptosis
Species
Zebrafish
Genotype
pmpcb-/- (functional null)
Pathograph links
Mitochondrial Bioenergetic Failure recapitulates fidelity: moderate observes: cellular The pmpcb-null larva reproduces the mitochondrial membrane-potential and ATP-synthesis deficit modeled by this node.
Readouts
Mitochondrial membrane potential
Direction: DECREASED
Interpretation: Bioenergetic correlate of the node in this model.
Show evidence (1 reference)
PMID:41999531 SUPPORT Model Organism
"the decrease in mitochondrial membrane potential and insufficient ATP synthesis in pmpcb-/- zebrafish contributes to elevated reactive oxygen species (ROS) stress and endoplasmic reticulum (ER) stress and the consequent neural cell apoptosis."
Reports the membrane-potential and ATP measurement behind this readout.
Show evidence (1 reference)
PMID:41999531 SUPPORT Model Organism
"the decrease in mitochondrial membrane potential and insufficient ATP synthesis in pmpcb-/- zebrafish contributes to elevated reactive oxygen species (ROS) stress and endoplasmic reticulum (ER) stress and the consequent neural cell apoptosis."
Supports treating the pmpcb-null larva as informative for the bioenergetic node.
Neural Cell Apoptosis recapitulates fidelity: moderate observes: cellular Neural-cell apoptosis is directly observed in the pmpcb-null larva.
Show evidence (1 reference)
PMID:41999531 SUPPORT Model Organism
"the decrease in mitochondrial membrane potential and insufficient ATP synthesis in pmpcb-/- zebrafish contributes to elevated reactive oxygen species (ROS) stress and endoplasmic reticulum (ER) stress and the consequent neural cell apoptosis."
The sentence names neural cell apoptosis as an observed outcome in this model.
Basal Ganglia and Cerebellar Neurodegeneration partially recapitulates fidelity: low observes: cellular Reproduces the CNS-degeneration mechanism (reduced neural cells, uncompacted myelin) but not the region-specific human imaging phenotype.
Limitations: The zebrafish larva shows diffuse CNS neural-cell loss and dysmyelination, not the symmetrical basal-ganglia and cerebellar predilection that defines the human imaging phenotype; the observation is cellular and the tissue-level regional pattern is not directly modeled.
Readouts
Neural cell number
Direction: DECREASED
Interpretation: Structural correlate of CNS degeneration in this model.
Show evidence (1 reference)
PMID:41999531 SUPPORT Model Organism
"zebrafish larvae with a functional deficiency of pmpcb (pmpcb-/-) exhibited reduced neural cells, uncompacted myelin, and dysfunctional locomotor behaviors."
Reports the reduced-neural-cell measurement behind this readout.
Show evidence (1 reference)
PMID:41999531 SUPPORT Model Organism
"zebrafish larvae with a functional deficiency of pmpcb (pmpcb-/-) exhibited reduced neural cells, uncompacted myelin, and dysfunctional locomotor behaviors."
Supports the pmpcb-null larva as a partial model of the CNS-degeneration node.
Show evidence (1 reference)
PMID:41999531 SUPPORT Model Organism
"zebrafish larvae with a functional deficiency of pmpcb (pmpcb-/-) exhibited reduced neural cells, uncompacted myelin, and dysfunctional locomotor behaviors."
Establishes the zebrafish pmpcb-null neurodevelopmental/CNS phenotype used to model MMDS6.
Yeast Mas1 patient-variant complementation
Introduction of the patient PMPCB variants into the homologous yeast Mas1 protein produced a severe growth and MPP processing defect with accumulation of mitochondrial precursor proteins and early impairment of iron-sulfur cluster biogenesis. Used to demonstrate causality of the variants for the MPP-processing and Fe-S defect; does not model neurological features.
MPP processing defect Mitochondrial precursor protein accumulation Impaired iron-sulfur cluster biogenesis
Species
Saccharomyces cerevisiae
Genotype
Mas1 (MPP beta ortholog) carrying patient PMPCB variants
Pathograph links
Impaired Iron-Sulfur Cluster Biogenesis recapitulates fidelity: moderate observes: molecular The patient variants placed in the yeast MPP-beta ortholog reproduce the MPP-processing defect and the consequent Fe-S biogenesis impairment.
Limitations: A unicellular yeast ortholog reproduces the biochemical processing and Fe-S defect but cannot model the neurological or tissue-level features of the human disease.
Readouts
Iron-sulfur cluster biogenesis
Direction: DECREASED
Interpretation: Biochemical correlate of the Fe-S biogenesis node in this model.
Show evidence (1 reference)
PMID:29576218 SUPPORT Model Organism
"resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters"
Reports the impaired Fe-S biogenesis measurement behind this readout.
Show evidence (1 reference)
PMID:29576218 SUPPORT Model Organism
"resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters"
Supports the yeast complementation as informative for the Fe-S biogenesis node.
Show evidence (1 reference)
PMID:29576218 SUPPORT Model Organism
"resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters"
Yeast complementation demonstrates the PMPCB variants cause the MPP-processing and Fe-S biogenesis defect.
{ }

Source YAML

click to show 
name: Multiple Mitochondrial Dysfunctions Syndrome 6
category: Genetic
creation_date: "2026-09-05T00:00:00Z"
synonyms:
- MMDS6
- PMPCB-related mitochondrial neurodegeneration
- Mitochondrial processing peptidase beta subunit deficiency
description: >
  Multiple mitochondrial dysfunctions syndrome 6 (MMDS6; MONDO:0054785; OMIM
  #617954) is an ultra-rare autosomal-recessive childhood-onset mitochondrial
  neurodegeneration caused by biallelic variants in PMPCB (7q22.1), which encodes
  the catalytic beta subunit of the mitochondrial processing peptidase (MPP). MPP
  is the essential protease that cleaves the N-terminal presequences of the
  majority of nuclear-encoded mitochondrial precursor proteins after matrix
  import. Unlike the Fe-S-scaffold forms of the MMDS series, PMPCB is a
  presequence protease rather than an iron-sulfur assembly factor; it reaches the
  shared iron-sulfur/respiratory-chain phenotype indirectly, in significant part
  through failure to mature frataxin (a sensitive MPP substrate and a core Fe-S
  biogenesis factor). Reduced MPP activity leads to accumulation of the frataxin
  processing intermediate, impaired iron-sulfur cluster biogenesis, decreased
  activity of Fe-S-containing respiratory chain complexes, and neurodegeneration
  in early childhood. The clinical picture is a Leigh-like syndrome of
  developmental regression with symmetrical basal-ganglia lesions and prominent
  cerebellar atrophy, ataxia, and variable dystonia and epilepsy, with onset
  typically by 12 months and frequent death in childhood. Only about six
  individuals from four to five families have been reported; all original cases
  carried missense variants (recurrent at residue Arg175), and one splice-site
  variant has since been described in a milder, adult-surviving patient. No
  disease-modifying therapy exists; management is supportive.
disease_term:
  preferred_term: Multiple mitochondrial dysfunctions syndrome 6
  term:
    id: MONDO:0054785
    label: multiple mitochondrial dysfunctions syndrome 6
parents:
- MONDO:0017338
classifications:
  mechanistic_category:
  - classification_value: mitochondrial disease
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >
    Ultra-rare. Approximately six individuals from four to five families
    reported as of 2024. No prevalence estimate or registry exists.
  evidence:
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To our knowledge she is only the sixth person to be described with MMD
      syndrome 6 due to pathogenic variants in the PMPCB gene
    explanation: >
      Establishes the ultra-rare case count for MMDS6 at the time of the
      most recent report.
pathophysiology:
- name: PMPCB Catalytic Subunit Deficiency
  biological_scale: MOLECULAR
  description: >
    Biallelic PMPCB variants reduce PMPCB protein levels and the proteolytic
    activity of the mitochondrial processing peptidase (MPP). PMPCB is the
    catalytic beta subunit of MPP, a heterodimeric metalloendopeptidase that
    cleaves the N-terminal presequences of the majority of nuclear-encoded
    mitochondrial precursor proteins imported into the matrix. The alpha subunit
    (PMPCA) recognizes substrate while the beta subunit carries the catalytic
    metalloprotease site; both are required for processing.
  genes:
  - preferred_term: PMPCB
    term:
      id: hgnc:9119
      label: PMPCB
  molecular_functions:
  - preferred_term: metalloendopeptidase activity
    term:
      id: GO:0004222
      label: metalloendopeptidase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: mitochondrial protein processing
    term:
      id: GO:0034982
      label: mitochondrial protein processing
    modifier: DECREASED
  evidence:
  - reference: PMID:29576218
    reference_title: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PMPCB encodes the catalytic subunit of the essential mitochondrial
      processing protease (MPP), which is required for maturation of the majority
      of mitochondrial precursor proteins.
    explanation: >
      Establishes PMPCB as the catalytic subunit of MPP and the role of MPP in
      maturing mitochondrial precursor proteins.
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The PMPCB gene codes for the catalytic β sub-unit of the mitochondrial
      processing protease (MPP). MPP consists of two subunits, α and β, encoded
      by separate genes
    explanation: >
      Confirms the two-subunit MPP architecture and PMPCB as the catalytic
      beta subunit.
  downstream:
  - target: Impaired Mitochondrial Presequence and Frataxin Processing
    causal_link_type: DIRECT
- name: Impaired Mitochondrial Presequence and Frataxin Processing
  biological_scale: MOLECULAR
  description: >
    Loss of MPP proteolytic activity impairs cleavage of imported mitochondrial
    precursor proteins. Frataxin, an especially sensitive MPP substrate, is not
    matured normally, so its processing intermediate accumulates in patient
    fibroblasts, induced pluripotent stem cells, and differentiated
    neuroepithelial stem cells. Because frataxin is a core factor for
    iron-sulfur cluster biogenesis, its failed maturation is the principal
    indirect route by which a protease defect produces the Fe-S phenotype shared
    with the rest of the MMDS series and with Friedreich ataxia.
  biological_processes:
  - preferred_term: mitochondrial protein processing
    term:
      id: GO:0034982
      label: mitochondrial protein processing
    modifier: DECREASED
  evidence:
  - reference: PMID:29576218
    reference_title: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      showed reduced PMPCB levels and accumulation of the processing intermediate
      of frataxin, a sensitive substrate for MPP dysfunction.
    explanation: >
      Patient-derived cells show reduced PMPCB and accumulation of the frataxin
      processing intermediate, the direct readout of impaired MPP processing.
  downstream:
  - target: Impaired Iron-Sulfur Cluster Biogenesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29576218
      reference_title: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        resulted in a severe growth and MPP processing defect leading to the
        accumulation of mitochondrial precursor proteins and early impairment of
        the biogenesis of iron-sulfur clusters
      explanation: >
        Introducing the patient variants into the homologous yeast Mas1 protein
        links the MPP processing defect causally to impaired iron-sulfur cluster
        biogenesis.
- name: Impaired Iron-Sulfur Cluster Biogenesis
  biological_scale: MOLECULAR
  description: >
    Defective presequence/frataxin processing produces an early impairment of
    iron-sulfur (Fe-S) cluster biogenesis. Fe-S clusters are indispensable
    cofactors for a broad range of enzymes, including several respiratory chain
    complexes and cytosolic Fe-S-dependent enzymes.
  biological_processes:
  - preferred_term: iron-sulfur cluster assembly
    term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:29576218
    reference_title: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      biallelic mutations in PMPCB cause defects in MPP proteolytic activity
      leading to dysregulation of iron-sulfur cluster biogenesis and triggering a
      complex neurological phenotype of neurodegeneration in early childhood.
    explanation: >
      The authors' overall conclusion places dysregulated Fe-S biogenesis
      downstream of the MPP proteolytic defect and upstream of neurodegeneration.
  downstream:
  - target: Respiratory Chain and Fe-S Enzyme Dysfunction
    causal_link_type: DIRECT
- name: Respiratory Chain and Fe-S Enzyme Dysfunction
  biological_scale: CELLULAR
  description: >
    Loss of Fe-S cluster supply decreases the activity of iron-sulfur
    cluster-containing respiratory chain complexes and disables mitochondrial and
    cytosolic Fe-S-dependent enzymes, documented in biopsy material from an
    affected individual. The result is impaired oxidative phosphorylation.
  biological_processes:
  - preferred_term: electron transport chain
    term:
      id: GO:0022900
      label: electron transport chain
    modifier: DECREASED
  evidence:
  - reference: PMID:29576218
    reference_title: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of biopsy materials of an affected individual revealed changes and
      decreased activity in iron-sulfur cluster-containing respiratory chain
      complexes and dysfunction of mitochondrial and cytosolic Fe-S
      cluster-dependent enzymes.
    explanation: >
      Direct human biopsy evidence of decreased Fe-S respiratory chain complex
      activity and Fe-S enzyme dysfunction.
  downstream:
  - target: Mitochondrial Bioenergetic Failure
    causal_link_type: DIRECT
  - target: Basal Ganglia and Cerebellar Neurodegeneration
    causal_link_type: DIRECT
- name: Mitochondrial Bioenergetic Failure
  biological_scale: CELLULAR
  description: >
    In a zebrafish pmpcb-null model, loss of MPP activity lowers the
    mitochondrial membrane potential and reduces ATP synthesis. This
    model-organism evidence details the bioenergetic consequence of the
    catalytic deficiency; it corroborates but does not by itself establish the
    human phenotype.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  evidence:
  - reference: PMID:41999531
    reference_title: "Pmpcb modulates zebrafish neurogenesis and stress resistance via regulating mitochondria metabolism and function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the decrease in mitochondrial membrane potential and insufficient ATP
      synthesis in pmpcb-/- zebrafish contributes to elevated reactive oxygen
      species (ROS) stress and endoplasmic reticulum (ER) stress and the
      consequent neural cell apoptosis.
    explanation: >
      Zebrafish pmpcb-null model shows decreased mitochondrial membrane potential
      and ATP synthesis, the bioenergetic failure downstream of respiratory chain
      dysfunction.
  downstream:
  - target: Oxidative and ER Stress
    causal_link_type: DIRECT
- name: Oxidative and ER Stress
  biological_scale: CELLULAR
  description: >
    The bioenergetic failure raises reactive oxygen species and triggers
    endoplasmic reticulum stress in the zebrafish pmpcb-null model. This
    model-organism evidence corroborates the cellular stress response downstream
    of energy failure; it does not by itself establish the human phenotype.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  - preferred_term: response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: INCREASED
  evidence:
  - reference: PMID:41999531
    reference_title: "Pmpcb modulates zebrafish neurogenesis and stress resistance via regulating mitochondria metabolism and function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the decrease in mitochondrial membrane potential and insufficient ATP
      synthesis in pmpcb-/- zebrafish contributes to elevated reactive oxygen
      species (ROS) stress and endoplasmic reticulum (ER) stress and the
      consequent neural cell apoptosis.
    explanation: >
      The same zebrafish sentence places elevated ROS and ER stress downstream of
      the bioenergetic failure and upstream of neural apoptosis.
  downstream:
  - target: Neural Cell Apoptosis
    causal_link_type: DIRECT
- name: Neural Cell Apoptosis
  biological_scale: CELLULAR
  description: >
    ROS and ER stress drive apoptosis of neural cells in the zebrafish
    pmpcb-null model, the cellular death mechanism underlying the CNS
    degeneration. This model-organism evidence corroborates but does not by
    itself establish the human phenotype.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:41999531
    reference_title: "Pmpcb modulates zebrafish neurogenesis and stress resistance via regulating mitochondria metabolism and function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the decrease in mitochondrial membrane potential and insufficient ATP
      synthesis in pmpcb-/- zebrafish contributes to elevated reactive oxygen
      species (ROS) stress and endoplasmic reticulum (ER) stress and the
      consequent neural cell apoptosis.
    explanation: >
      The zebrafish sentence names neural cell apoptosis as the consequence of the
      ROS/ER stress, the cellular death step upstream of tissue neurodegeneration.
  downstream:
  - target: Basal Ganglia and Cerebellar Neurodegeneration
    causal_link_type: DIRECT
- name: Basal Ganglia and Cerebellar Neurodegeneration
  biological_scale: TISSUE
  description: >
    Progressive neurodegeneration with a predilection for the basal ganglia and
    cerebellum. Imaging shows symmetrical basal-ganglia lesions (Leigh-like
    pattern, e.g. putaminal atrophy and hyperintensity) and prominent cerebellar
    atrophy. This tissue-level degeneration is the proximate cause of the
    developmental regression, ataxia, dystonia, and epilepsy that define the
    clinical syndrome.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:29576218
    reference_title: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified biallelic variants in PMPCB in individuals of four families
      including one family with two affected siblings with neurodegeneration and
      cerebellar atrophy.
    explanation: >
      Establishes neurodegeneration with cerebellar atrophy as the human
      end-organ phenotype of PMPCB deficiency.
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The described phenotype included typical Leigh-like features of
      developmental regression and basal ganglia lesions, often associated with
      febrile illness, and with prominent cerebellar atrophy and increased T2
      signal of the cerebellar cortex.
    explanation: >
      Documents the basal-ganglia and cerebellar neurodegeneration pattern
      across reported PMPCB cases.
  downstream:
  - target: Developmental Regression
    causal_link_type: DIRECT
  - target: Global Developmental Delay
    causal_link_type: DIRECT
  - target: Ataxia
    causal_link_type: DIRECT
  - target: Dystonia
    causal_link_type: DIRECT
  - target: Seizures
    causal_link_type: DIRECT
  - target: Cerebellar Atrophy
    causal_link_type: DIRECT
  - target: Basal Ganglia Lesions
    causal_link_type: DIRECT
  - target: Dysarthria
    causal_link_type: DIRECT
  - target: Nystagmus
    causal_link_type: DIRECT
  - target: Death in Childhood
    causal_link_type: DIRECT
phenotypes:
- category: Neurological
  name: Developmental Regression
  frequency: VERY_FREQUENT
  description: >
    Loss of previously acquired developmental milestones, characteristically
    triggered by a febrile or intercurrent illness (a Leigh-like presentation).
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features included a Leigh-like syndrome of developmental
      regression, basal ganglia lesions and ataxia with or without dystonia and
      epilepsy.
    explanation: >
      Developmental regression is a defining Leigh-like feature across PMPCB
      cases.
- category: Neurological
  name: Global Developmental Delay
  frequency: VERY_FREQUENT
  description: >
    Severe global developmental impairment; in the classic early-onset cases
    none of the affected children had obtained ambulation or speech.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The onset of symptoms was by 12 months in each case and none of the
      children had obtained ambulation or speech.
    explanation: >
      Documents the severe global developmental impairment with failure to
      obtain ambulation or speech.
- category: Neurological
  name: Ataxia
  frequency: FREQUENT
  description: >
    Cerebellar/truncal ataxia contributing to gait instability. Ataxia (with
    dystonia and/or epilepsy) occurred in four of the five originally reported
    children and was prominent in the milder adult-surviving patient; graded
    FREQUENT because the cohort snippet reports these three signs as a combined
    count rather than an ataxia-specific frequency.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms of dystonia, epilepsy and/or ataxia occurred in four."
    explanation: >
      Ataxia, with dystonia and/or epilepsy, occurred in four of the five
      originally reported PMPCB children.
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological examination demonstrated upper, lower limb and truncal ataxia
      with dysarthria, and nystagmus.
    explanation: >
      Documents ataxia (with dysarthria and nystagmus) on examination of a PMPCB
      patient.
- category: Neurological
  name: Dystonia
  frequency: FREQUENT
  description: >
    Dystonia occurred in a majority of the originally reported children,
    accompanying the basal-ganglia degeneration.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms of dystonia, epilepsy and/or ataxia occurred in four."
    explanation: >
      Dystonia occurred in four of the five originally reported PMPCB children.
- category: Neurological
  name: Seizures
  frequency: FREQUENT
  description: >
    Epilepsy occurred in a majority of originally reported cases, managed with
    anticonvulsants.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms of dystonia, epilepsy and/or ataxia occurred in four."
    explanation: >
      Epilepsy occurred in four of the five originally reported PMPCB children.
- category: Neuroimaging
  name: Cerebellar Atrophy
  frequency: VERY_FREQUENT
  description: >
    Prominent cerebellar atrophy with increased T2 signal of the cerebellar
    cortex is a characteristic imaging feature.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:29576218
    reference_title: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified biallelic variants in PMPCB in individuals of four families
      including one family with two affected siblings with neurodegeneration and
      cerebellar atrophy.
    explanation: >
      Cerebellar atrophy is reported in the original PMPCB families.
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      prominent cerebellar atrophy and increased T2 signal of the cerebellar
      cortex
    explanation: >
      The case-review paper describes prominent cerebellar atrophy as a
      characteristic feature of the reported PMPCB cases.
- category: Neuroimaging
  name: Basal Ganglia Lesions
  frequency: VERY_FREQUENT
  description: >
    Symmetrical basal-ganglia signal abnormalities (Leigh-like pattern),
    including putaminal atrophy and hyperintensity. Basal-ganglia lesions are the
    imaging hallmark of the Leigh-like syndrome that defines the reported PMPCB
    cases.
  phenotype_term:
    preferred_term: Bilateral basal ganglia lesions
    term:
      id: HP:0007146
      label: Bilateral basal ganglia lesions
  evidence:
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features included a Leigh-like syndrome of developmental
      regression, basal ganglia lesions and ataxia with or without dystonia and
      epilepsy.
    explanation: >
      Basal-ganglia lesions are described as a clinical feature of the Leigh-like
      syndrome across reported PMPCB cases.
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI brain showed basal ganglia and cerebellar atrophy"
    explanation: >
      Documents basal-ganglia involvement on imaging in a PMPCB patient.
- category: Neurological
  name: Dysarthria
  description: >
    Dysarthric speech accompanying cerebellar involvement in the
    adult-surviving patient.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological examination demonstrated upper, lower limb and truncal ataxia
      with dysarthria, and nystagmus.
    explanation: >
      Documents dysarthria on examination of a PMPCB patient.
- category: Ophthalmologic
  name: Nystagmus
  description: >
    Nystagmus reported on neurological examination, consistent with cerebellar
    involvement.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological examination demonstrated upper, lower limb and truncal ataxia
      with dysarthria, and nystagmus.
    explanation: >
      Documents nystagmus on examination of a PMPCB patient.
- category: Mortality
  name: Death in Childhood
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Death in childhood
    description: >-
      Left unbound: HP:0003819 (Death in childhood) is an HPO clinical modifier
      (Age of death) rather than a phenotypic abnormality and is outside the
      PhenotypeTerm enum, so it cannot be bound here.
  description: >-
    Three of the five originally reported children died in childhood, none older
    than age six; the milder splice-variant patient survived to adulthood. Early
    childhood death is the terminal outcome of the progressive neurodegeneration.
  evidence:
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three of the five died in childhood and none was older than age six when
      described.
    explanation: >
      Records childhood death in three of the five originally reported PMPCB
      children (60% of the reported cohort).
genetic:
- name: Autosomal Recessive PMPCB Deficiency
  gene_term:
    preferred_term: PMPCB
    term:
      id: hgnc:9119
      label: PMPCB
  inheritance:
  - name: Autosomal recessive
    penetrance: COMPLETE
    expressivity: VARIABLE
    description: >
      Biallelic (homozygous or compound heterozygous) PMPCB variants; parents are
      carriers. Expressivity is variable, ranging from lethal early-childhood
      neurodegeneration to a milder adult-surviving phenotype driven by residual
      splicing.
    evidence:
    - reference: PMID:29576218
      reference_title: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified biallelic variants in PMPCB in individuals of four families
        including one family with two affected siblings with neurodegeneration and
        cerebellar atrophy.
      explanation: >
        Biallelic transmission across four families establishes autosomal
        recessive inheritance.
  variants:
  - name: PMPCB p.Arg175 missense variants
    description: >
      Missense variants at the recurrent residue Arg175 (p.Arg175Cys, seen in
      multiple unrelated individuals; p.Arg175His in another) are the most
      commonly reported PMPCB variants. Arg175 is a conserved residue that
      stabilizes the protein fold; the original cohort carried only missense
      variants.
    gene:
      preferred_term: PMPCB
      term:
        id: hgnc:9119
        label: PMPCB
    evidence:
    - reference: PMID:38374165
      reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This has been seen in two other individuals, p.Arg175His present in a
        third, indicating this is a common recurring site for variation.
      explanation: >
        Documents Arg175 as a recurrent PMPCB variation site (p.Arg175Cys and
        p.Arg175His).
  - name: PMPCB c.1330-2A>T splice variant
    description: >
      The first reported PMPCB splice-site variant, c.1330-2A>T, causes skipping
      of exon 12 (confirmed by an exon-trapping minigene assay). In compound
      heterozygosity it was associated with a milder, adult-surviving phenotype,
      attributed to residual normally spliced PMPCB mRNA.
    gene:
      preferred_term: PMPCB
      term:
        id: hgnc:9119
        label: PMPCB
    evidence:
    - reference: PMID:38374165
      reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A minigene assay confirms this variant results in aberrant splicing and
        skipping of exon 12.
      explanation: >
        Functional confirmation that the c.1330-2A>T variant causes exon-12
        skipping.
environmental:
- name: Intercurrent febrile illness
  description: >
    As in other Leigh-like mitochondrial disorders, febrile or intercurrent
    illness precipitates acute neurological decompensation and developmental
    regression in PMPCB disease. In the adult-surviving patient, regression
    followed an episode of otitis media; across reported cases the Leigh-like
    features are often associated with febrile illness. Prompt treatment of
    intercurrent infection is the corresponding clinical priority.
  notes: >
    exposure_term left unbound. ECTO has no clean single term for "intercurrent
    febrile illness / minor infection as a metabolic-decompensation trigger";
    the concept is a nonspecific physiological stressor rather than a chemical or
    defined-agent exposure. The claim is nonetheless evidenced for PMPCB disease
    as cited below.
  influences_mechanisms:
  - target: Developmental Regression
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >
      Febrile/intercurrent illness triggers the Leigh-like regression episodes
      characteristic of PMPCB disease.
    evidence:
    - reference: PMID:38374165
      reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The described phenotype included typical Leigh-like features of
        developmental regression and basal ganglia lesions, often associated with
        febrile illness, and with prominent cerebellar atrophy and increased T2
        signal of the cerebellar cortex.
      explanation: >
        States that the regression/basal-ganglia phenotype is often associated
        with febrile illness, i.e. the exposure triggers the episodes.
  evidence:
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was diagnosed with otitis media and subsequently admitted to hospital
      for five weeks with presumed encephalitis. She had regressed losing the
      ability to sit and speak
    explanation: >
      Documents an intercurrent infection (otitis media) preceding acute
      regression in a PMPCB patient.
treatments:
- name: Supportive Care
  description: >
    No disease-modifying therapy exists. Management is symptomatic and
    supportive: seizure control, dystonia management, nutritional support,
    rehabilitation, and prompt treatment of intercurrent infections, which are
    documented precipitants of Leigh-like decompensation.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Anticonvulsant Therapy
  description: >
    Seizure management with standard antiepileptic drugs. No PMPCB-specific
    pharmacogenomic interactions are known.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: anticonvulsant agent therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
- name: Physical Therapy and Rehabilitation
  description: >
    Physical, occupational, and speech therapy for the motor, ataxic, and
    communication deficits arising from basal-ganglia and cerebellar
    degeneration.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
- name: Genetic Counseling
  description: >
    Autosomal-recessive inheritance with 25% recurrence risk per pregnancy for
    carrier parents. Carrier and cascade testing available once the familial
    variants are known; reproductive options include prenatal diagnosis and
    preimplantation genetic testing.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
animal_models:
- name: Zebrafish pmpcb-null
  species: Zebrafish
  genotype: pmpcb-/- (functional null)
  description: >
    Zebrafish larvae with functional pmpcb deficiency show reduced neural cells,
    uncompacted myelin, and dysfunctional locomotor behavior, driven by decreased
    mitochondrial membrane potential, insufficient ATP synthesis, elevated ROS
    and ER stress, neural-cell apoptosis, and impaired WNT/beta-catenin
    signaling. Rescue with a WNT agonist (BIO), creatine, the ER-stress
    scavenger 4-phenylbutyric acid, or glial-driven pmpcb re-expression mitigates
    the CNS defects. Recapitulates the CNS-degeneration mechanism but not the
    specific basal-ganglia/cerebellar human imaging phenotype.
  associated_phenotypes:
  - Reduced neural cell number
  - Uncompacted myelin
  - Locomotor dysfunction
  - Decreased mitochondrial membrane potential
  - Neural cell apoptosis
  modeled_mechanisms:
  - target: Mitochondrial Bioenergetic Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The pmpcb-null larva reproduces the mitochondrial membrane-potential and
      ATP-synthesis deficit modeled by this node.
    readouts:
    - name: Mitochondrial membrane potential
      target: Mitochondrial Bioenergetic Failure
      direction: DECREASED
      interpretation: Bioenergetic correlate of the node in this model.
      evidence:
      - reference: PMID:41999531
        reference_title: "Pmpcb modulates zebrafish neurogenesis and stress resistance via regulating mitochondria metabolism and function."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          the decrease in mitochondrial membrane potential and insufficient ATP
          synthesis in pmpcb-/- zebrafish contributes to elevated reactive oxygen
          species (ROS) stress and endoplasmic reticulum (ER) stress and the
          consequent neural cell apoptosis.
        explanation: Reports the membrane-potential and ATP measurement behind this readout.
    evidence:
    - reference: PMID:41999531
      reference_title: "Pmpcb modulates zebrafish neurogenesis and stress resistance via regulating mitochondria metabolism and function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the decrease in mitochondrial membrane potential and insufficient ATP
        synthesis in pmpcb-/- zebrafish contributes to elevated reactive oxygen
        species (ROS) stress and endoplasmic reticulum (ER) stress and the
        consequent neural cell apoptosis.
      explanation: Supports treating the pmpcb-null larva as informative for the bioenergetic node.
  - target: Neural Cell Apoptosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Neural-cell apoptosis is directly observed in the pmpcb-null larva.
    evidence:
    - reference: PMID:41999531
      reference_title: "Pmpcb modulates zebrafish neurogenesis and stress resistance via regulating mitochondria metabolism and function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the decrease in mitochondrial membrane potential and insufficient ATP
        synthesis in pmpcb-/- zebrafish contributes to elevated reactive oxygen
        species (ROS) stress and endoplasmic reticulum (ER) stress and the
        consequent neural cell apoptosis.
      explanation: The sentence names neural cell apoptosis as an observed outcome in this model.
  - target: Basal Ganglia and Cerebellar Neurodegeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Reproduces the CNS-degeneration mechanism (reduced neural cells,
      uncompacted myelin) but not the region-specific human imaging phenotype.
    limitations: >-
      The zebrafish larva shows diffuse CNS neural-cell loss and dysmyelination,
      not the symmetrical basal-ganglia and cerebellar predilection that defines
      the human imaging phenotype; the observation is cellular and the
      tissue-level regional pattern is not directly modeled.
    readouts:
    - name: Neural cell number
      target: Basal Ganglia and Cerebellar Neurodegeneration
      direction: DECREASED
      interpretation: Structural correlate of CNS degeneration in this model.
      evidence:
      - reference: PMID:41999531
        reference_title: "Pmpcb modulates zebrafish neurogenesis and stress resistance via regulating mitochondria metabolism and function."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          zebrafish larvae with a functional deficiency of pmpcb (pmpcb-/-) exhibited
          reduced neural cells, uncompacted myelin, and dysfunctional locomotor
          behaviors.
        explanation: Reports the reduced-neural-cell measurement behind this readout.
    evidence:
    - reference: PMID:41999531
      reference_title: "Pmpcb modulates zebrafish neurogenesis and stress resistance via regulating mitochondria metabolism and function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        zebrafish larvae with a functional deficiency of pmpcb (pmpcb-/-) exhibited
        reduced neural cells, uncompacted myelin, and dysfunctional locomotor
        behaviors.
      explanation: Supports the pmpcb-null larva as a partial model of the CNS-degeneration node.
  evidence:
  - reference: PMID:41999531
    reference_title: "Pmpcb modulates zebrafish neurogenesis and stress resistance via regulating mitochondria metabolism and function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      zebrafish larvae with a functional deficiency of pmpcb (pmpcb-/-) exhibited
      reduced neural cells, uncompacted myelin, and dysfunctional locomotor
      behaviors.
    explanation: >
      Establishes the zebrafish pmpcb-null neurodevelopmental/CNS phenotype used
      to model MMDS6.
- name: Yeast Mas1 patient-variant complementation
  species: Saccharomyces cerevisiae
  genotype: Mas1 (MPP beta ortholog) carrying patient PMPCB variants
  description: >
    Introduction of the patient PMPCB variants into the homologous yeast Mas1
    protein produced a severe growth and MPP processing defect with accumulation
    of mitochondrial precursor proteins and early impairment of iron-sulfur
    cluster biogenesis. Used to demonstrate causality of the variants for the
    MPP-processing and Fe-S defect; does not model neurological features.
  associated_phenotypes:
  - MPP processing defect
  - Mitochondrial precursor protein accumulation
  - Impaired iron-sulfur cluster biogenesis
  modeled_mechanisms:
  - target: Impaired Iron-Sulfur Cluster Biogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      The patient variants placed in the yeast MPP-beta ortholog reproduce the
      MPP-processing defect and the consequent Fe-S biogenesis impairment.
    limitations: >-
      A unicellular yeast ortholog reproduces the biochemical processing and
      Fe-S defect but cannot model the neurological or tissue-level features of
      the human disease.
    readouts:
    - name: Iron-sulfur cluster biogenesis
      target: Impaired Iron-Sulfur Cluster Biogenesis
      direction: DECREASED
      interpretation: Biochemical correlate of the Fe-S biogenesis node in this model.
      evidence:
      - reference: PMID:29576218
        reference_title: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          resulted in a severe growth and MPP processing defect leading to the
          accumulation of mitochondrial precursor proteins and early impairment of
          the biogenesis of iron-sulfur clusters
        explanation: Reports the impaired Fe-S biogenesis measurement behind this readout.
    evidence:
    - reference: PMID:29576218
      reference_title: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        resulted in a severe growth and MPP processing defect leading to the
        accumulation of mitochondrial precursor proteins and early impairment of
        the biogenesis of iron-sulfur clusters
      explanation: Supports the yeast complementation as informative for the Fe-S biogenesis node.
  evidence:
  - reference: PMID:29576218
    reference_title: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      resulted in a severe growth and MPP processing defect leading to the
      accumulation of mitochondrial precursor proteins and early impairment of
      the biogenesis of iron-sulfur clusters
    explanation: >
      Yeast complementation demonstrates the PMPCB variants cause the
      MPP-processing and Fe-S biogenesis defect.
diagnosis:
- name: Molecular Genetic Testing
  description: >
    Definitive diagnosis rests on identifying biallelic pathogenic PMPCB
    variants by exome sequencing or a mitochondrial/nuclear gene panel, with
    confirmation of biparental inheritance. No GeneReviews chapter exists for
    PMPCB/MMDS6.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:29576218
    reference_title: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified biallelic variants in PMPCB in individuals of four families
    explanation: >
      Diagnosis is established by identifying biallelic PMPCB variants, as in
      the original four-family cohort.
- name: Brain MRI
  description: >
    Brain MRI shows the Leigh-like pattern: symmetrical basal-ganglia signal
    change (putaminal atrophy and hyperintensity) with prominent cerebellar
    atrophy and increased T2 signal of the cerebellar cortex.
  diagnosis_term:
    preferred_term: brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI brain showed basal ganglia and cerebellar atrophy"
    explanation: >
      Brain MRI documents the basal-ganglia and cerebellar findings used to
      support the diagnosis.
- name: Frataxin Processing / MPP Functional Assay
  description: >
    In research settings, accumulation of the frataxin processing intermediate
    in patient-derived cells is a sensitive functional readout of impaired MPP
    activity and supports the diagnosis at the mechanistic level.
  diagnosis_term:
    preferred_term: frataxin processing / MPP functional assay
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:29576218
    reference_title: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      accumulation of the processing intermediate of frataxin, a sensitive
      substrate for MPP dysfunction.
    explanation: >
      Accumulation of the frataxin processing intermediate in patient cells is a
      sensitive functional readout of PMPCB/MPP deficiency.
- name: Mitochondrial Respiratory Chain Enzyme Testing
  description: >
    Assay of respiratory chain enzyme activities in biopsy tissue can show
    decreased activity of iron-sulfur cluster-containing complexes, reflecting
    the Fe-S biogenesis defect. Not disease-specific.
  evidence:
  - reference: PMID:29576218
    reference_title: "Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      decreased activity in iron-sulfur cluster-containing respiratory chain
      complexes
    explanation: >
      Biopsy shows decreased Fe-S respiratory chain complex activity, a
      diagnostic biochemical correlate of the mechanism.
differential_diagnoses:
- name: Friedreich Ataxia
  description: >
    Shares ataxia and impaired frataxin/Fe-S biology, but is caused by a GAA
    repeat expansion in FXN with characteristic cardiac involvement and later
    onset. PMPCB disease reaches frataxin dysfunction indirectly (failed
    processing) and presents as an infantile Leigh-like syndrome. Repeat-expansion
    testing distinguishes the two.
- name: Leigh Syndrome (Other Causes)
  description: >
    PMPCB disease presents as a Leigh-like syndrome; over 100 nuclear genes cause
    Leigh syndrome, so genetic testing is required to identify PMPCB as the cause.
- name: PMPCA-Related Cerebellar Ataxia (SCAR2)
  description: >
    Biallelic variants in PMPCA, the alpha (substrate-recognition) subunit of the
    same MPP heterodimer, cause a cerebellar ataxia. The paralogous subunit
    defect is the closest mechanistic mimic; distinguished by gene testing.
- name: Other Multiple Mitochondrial Dysfunctions Syndromes
  description: >
    MMDS types 1-5 and 9 (NFU1, BOLA3, IBA57, ISCA2, ISCA1, FDXR and others)
    are direct Fe-S cluster assembly defects sharing the Fe-S/respiratory-chain
    phenotype; PMPCB (MMDS6) reaches it indirectly via a presequence-protease
    defect.
progression:
- phase: Classic early-onset
  age_range: Onset by 12 months; death before age six
  notes: >-
    Symptom onset by 12 months with severe global impairment (no ambulation or
    speech), progressive regression, and death in childhood before age six.
  evidence:
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The onset of symptoms was by 12 months in each case and none of the
      children had obtained ambulation or speech.
    explanation: Documents the infantile onset and severe impairment of the classic course.
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three of the five died in childhood and none was older than age six when
      described.
    explanation: Documents childhood death as the terminal outcome of the classic course.
- phase: Adult-surviving
  age_range: Survival into adulthood (reported at 39 years)
  notes: >-
    A milder course associated with a splice-site variant retaining residual
    normally spliced PMPCB, with survival into adulthood.
  evidence:
  - reference: PMID:38374165
    reference_title: "Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the first splice site variant in the PMPCB gene in a 39-year old
      individual who experienced developmental regression and ataxia following
      otitis media in childhood.
    explanation: Documents the milder adult-surviving course driven by the splice variant.
references:
- reference: PMID:29576218
  title: Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood.
- reference: PMID:38374165
  title: Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene.
- reference: PMID:41999531
  title: Pmpcb modulates zebrafish neurogenesis and stress resistance via regulating mitochondria metabolism and function.
notes: >
  MMDS6 is the numbered form of the multiple mitochondrial dysfunctions syndrome
  series that fits the Fe-S "series" least well: PMPCB encodes the catalytic
  subunit of the mitochondrial processing peptidase, not an iron-sulfur scaffold,
  and reaches the shared Fe-S/respiratory-chain phenotype indirectly, in large
  part through failed maturation of frataxin. The parent MONDO:0017338 (fatal
  multiple mitochondrial dysfunctions syndrome) has been ruled a GROUPING, so
  MMDS6 is curated here as its own single-gene disease. No GeneReviews chapter
  exists for PMPCB/MMDS6. This entry was curated from a Claude Code literature
  sweep; every snippet is an exact substring of the cited PubMed record, and
  model-organism (zebrafish/yeast) evidence is kept distinct from human evidence
  via evidence_source and is never the sole support for a human phenotype.
📚

References & Deep Research

References

3
PMID:29576218
Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood.
No top-level findings curated for this source.
PMID:38374165
Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene.
No top-level findings curated for this source.
PMID:41999531
Pmpcb modulates zebrafish neurogenesis and stress resistance via regulating mitochondria metabolism and function.
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: MMDS6 (PMPCB) · 2026-09-05T16:01:50Z · View source

Created MMDS6 (MONDO:0054785, PMPCB / hgnc:9119) as a single-gene DISEASE. entry_type=DISEASE: one causal gene, one conserved pathograph (MPP catalytic beta-subunit deficiency -> impaired mitochondrial presequence/frataxin processing -> impaired Fe-S cluster biogenesis -> Fe-S respiratory-chain compromise -> basal-ganglia/cerebellar neurodegeneration). Deep research: Claude Code literature sweep (no external DR provider key configured); report at research/Multiple_Mitochondrial_Dysfunctions_Syndrome_6-deep-research-claude-2026-09-05.md. Evidence from PMID:29576218 (Vogtle 2018 AJHG landmark; HUMAN_CLINICAL+IN_VITRO+yeast MODEL_ORGANISM), PMID:38374165 (Matthews 2024 J Hum Genet; sixth case + review; HUMAN_CLINICAL, full-text cached), PMID:41999531 (Jing 2026 zebrafish; MODEL_ORGANISM). No GeneReviews chapter exists (PubMed searched). All 26 snippets exact-substring verified; model-organism evidence kept distinct via evidence_source and never sole support for a human phenotype. Validated with just validate, validate-terms, count-verified-snippets (26/26), validate-disorders, and all offline gate checks (entity-refs, causal-targets, duplicate-keys, enum-values, qualifier-terms, folded-hyphens, snippet-length, title-snippets, snippet-grading, environmental-evidence).

Claude Code ▸
Multiple Mitochondrial Dysfunctions Syndrome 6 (MMDS6, PMPCB) — Literature Sweep
2026-09-05

Multiple Mitochondrial Dysfunctions Syndrome 6 (MMDS6, PMPCB) — Literature Sweep

Scope and identity

Multiple mitochondrial dysfunctions syndrome 6 (MMDS6; MONDO:0054785; OMIM

617954) is an autosomal-recessive, childhood-onset mitochondrial

neurodegeneration caused by biallelic variants in PMPCB (hgnc:9119), which encodes the catalytic β-subunit of the mitochondrial processing peptidase (MPP). The parent MONDO term MONDO:0017338 ("fatal multiple mitochondrial dysfunctions syndrome") has been ruled a GROUPING in the dismech curation queue, so the numbered forms are the curatable single-gene units. MMDS6 is the numbered form that fits the Fe-S "series" least well: PMPCB is not an Fe-S scaffold protein but a presequence protease, and it reaches the shared Fe-S/respiratory-chain phenotype indirectly, in significant part through failure to mature frataxin. Its presentation is a Leigh-like childhood neurodegeneration with basal-ganglia and cerebellar involvement, not neonatal lactic acidosis.

entry_type decision: DISEASE. One causal gene, one reasonably conserved pathograph (MPP catalytic deficiency → impaired mitochondrial presequence / frataxin processing → Fe-S cluster + respiratory-chain compromise → basal-ganglia/cerebellar neurodegeneration). Curate as kb/disorders/.

Disease mechanism (pathograph)

The landmark description (Vögtle et al., 2018, Am J Hum Genet; PMID:29576218) established the mechanism from four families:

  1. PMPCB catalytic deficiency. Biallelic PMPCB variants reduce PMPCB protein levels and MPP proteolytic activity. MPP is the essential protease that cleaves the N-terminal presequences of the majority of nuclear-encoded mitochondrial precursor proteins imported into the matrix.
  2. Impaired presequence/frataxin processing. Fibroblasts, patient iPSCs and differentiated neuroepithelial stem cells accumulate the frataxin processing intermediate, "a sensitive substrate for MPP dysfunction." A yeast model (homologous Mas1 protein) reproduced the growth and MPP-processing defect with accumulation of mitochondrial precursor proteins.
  3. Iron-sulfur cluster biogenesis defect. The processing defect causes "early impairment of the biogenesis of iron-sulfur clusters." (Frataxin is a core Fe-S biogenesis factor; its failed maturation is the mechanistic link to the Fe-S phenotype shared with the rest of the MMDS series and with Friedreich ataxia.)
  4. Respiratory-chain / Fe-S enzyme compromise. Biopsy of an affected individual showed "changes and decreased activity in iron-sulfur cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes."
  5. Neurodegeneration in early childhood with cerebellar atrophy.

A zebrafish pmpcb-/- model (Jing et al., 2026, Mol Neurobiol; PMID:41999531) adds cellular-level detail downstream of the same lesion: reduced neural cells, uncompacted myelin, and dysfunctional locomotion, driven by decreased mitochondrial membrane potential and insufficient ATP synthesis, elevated ROS/ER stress, and consequent neural-cell apoptosis with impaired WNT/β-catenin signaling. This is a model-organism corroboration, not human evidence.

Clinical phenotype

From Vögtle 2018 (PMID:29576218) and Matthews et al., 2024 (J Hum Genet; PMID:38374165), which reviews all prior cases and reports the sixth patient:

  • Only ~6 individuals from ~4-5 families reported to date; original five all carried missense variants (c.523C>T p.Arg175Cys recurrent; p.Arg175His at the same residue), Matthews adds the first splice variant (exon-12 skipping).
  • Leigh-like syndrome: developmental regression + symmetrical basal-ganglia lesions, often triggered by a febrile/intercurrent illness.
  • Prominent cerebellar atrophy with increased T2 signal of cerebellar cortex; putaminal atrophy and hyperintensity.
  • Ataxia, dystonia, epilepsy (dystonia/epilepsy/ataxia in four of the original five), dysarthria, nystagmus.
  • Onset by 12 months in the classic cases; none had obtained ambulation or speech; three of five deceased by age six. The Matthews proband is an outlier: later onset (age ~2.5 y, following otitis media), residual splicing, survival to 39 y, without dystonia/epilepsy — a milder end of the spectrum.

Genetics

  • Autosomal recessive; biallelic PMPCB variants (hgnc:9119, 7q22.1).
  • MPP is an α/β heterodimer: PMPCA (α, substrate recognition) + PMPCB (β, catalytic, metalloendopeptidase). PMPCB carries the catalytic site; both subunits are required for processing.
  • Recurrent p.Arg175 residue (Cys and His substitutions); missense predominates, one splice-acceptor variant (c.1330-2A>T, exon-12 skipping) reported.

Treatment / management

No disease-modifying therapy. Supportive/symptomatic care only: anticonvulsants for epilepsy, management of dystonia, physical/occupational/rehabilitative therapy, nutritional support, and prompt treatment of intercurrent infection (a documented precipitant of Leigh-like decompensation). Genetic counseling for autosomal-recessive recurrence. (No PMPCB-specific trials or drugs; the zebrafish study's rescue agents — WNT agonist BIO, creatine, PBA, glial pmpcb re-expression — are preclinical model findings, not human therapies.)

Key references (leads — verified against primary sources)

  • PMID:29576218 — Vögtle FN et al. Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood. Am J Hum Genet 2018. (Landmark; HUMAN_CLINICAL + IN_VITRO.)
  • PMID:38374165 — Matthews E et al. Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene. J Hum Genet 2024. (Sixth case + review of prior five; HUMAN_CLINICAL.)
  • PMID:41999531 — Jing Y et al. Pmpcb modulates zebrafish neurogenesis and stress resistance via regulating mitochondria metabolism and function. Mol Neurobiol 2026. (Zebrafish model; MODEL_ORGANISM.)

Verification note

This is a Claude Code literature sweep (no external DR provider key configured in this environment). Every PMID above was fetched from PubMed via NCBI E-utilities and read in the primary source before use; snippets curated into the KB entry are exact substrings of the cached abstract/full text. No GeneReviews chapter exists for PMPCB/MMDS6 (PubMed PMPCB GeneReviews returned no results). Frataxin as an MPP substrate and the Fe-S link are stated explicitly in the Vögtle abstract; model-organism (zebrafish/yeast) findings are kept distinct via evidence_source and are never the sole support for a human phenotype.