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Inheritance

1

Autosomal recessive HP:0000007

Biallelic PEX19 variants are required. The original complementation-group-J patient was homozygous for a frameshift allele, and the most recently reported family was homozygous for a nonsense allele with both parents heterozygous. ClinGen's Peroxisomal Disorders expert panel classifies the PEX19 gene-disease relationship as Definitive with autosomal recessive inheritance.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:39757991 SUPPORT Human Clinical

"Alignment of Sanger sequencing data with reference genomic sequences revealed that the variants were present in a homozygous state in patients and in a heterozygous state in both parents, confirming an autosomal recessive pattern of inheritance"

Segregation in the PEX19 family establishes the recessive mode directly.

CGGV:assertion_fa073c77-0623-4e82-b5b2-9fcd0eb0dc6e-2023-04-27T160000.000Z SUPPORT Other

ClinGen records the mode of inheritance as autosomal recessive and the gene-disease relationship as Definitive.

PMID:20301621 SUPPORT INDIRECT Human Clinical

"At conception, each sib of an individual with biallelic ZSD-causing pathogenic variants has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."

The recurrence risk that follows from the recessive mode, which is what a family with an affected child is actually counselled on. Graded indirect because GeneReviews states it for the Zellweger spectrum as a class; the PEX19 family reported in 2025 segregated exactly this way, with both parents heterozygous.

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Pathophysiology

10

Biallelic PEX19 Loss of Function

Both PEX19 alleles carry variants that abolish or severely reduce functional Pex19p. Reported severe alleles are truncating: the original complementation-group-J patient was homozygous for a single-base insertion that frameshifts the codon for Met255 and replaces the C-terminus, including the CAAX box required for function, with an unrelated 24-residue tail; the most recent family was homozygous for a nonsense change in exon 4 predicted to trigger nonsense-mediated decay.

PEX19 hgnc:9713

Downstream

Failure of Cytosolic Membrane-Protein Targeting Loss of functional Pex19p removes the cytosolic receptor that peroxisomal membrane proteins depend on.

Show evidence (3 references)

PMID:10051604 SUPPORT Human Clinical

"This patient (PBDJ-01) possessed a homozygous, inactivating mutation: a 1-base insertion, A764, in a codon for Met255, resulted in a frameshift, inducing a 24-aa sequence entirely distinct from normal Pex19p."

The founding PEX19 allele, homozygous and inactivating in a patient with complementation-group-J Zellweger syndrome.

PMID:10051604 SUPPORT In Vitro

"These results demonstrate that PEX19 is the causative gene for CG-J PBD and suggest that the C-terminal part, including the CAAX homology box, is required for the biological function of Pex19p."

Assigns the gene to the complementation group and locates the essential region in the C-terminus that the patient allele destroys.

PMID:39757991 SUPPORT Human Clinical

"The identified mutation (c.367C > T; p. Gln123*) in a patient from family A is located in exon 4 of PEX19, which is predicted to cause premature termination of the mRNA transcript in domain 2"

A second, independent truncating allele in a separate family.

Failure of Cytosolic Membrane-Protein Targeting

Pex19p is a soluble protein, mostly cytosolic at steady state, that binds a broad range of peroxisomal membrane proteins through the regions those proteins use for peroxisomal targeting, and delivers them to the membrane. Farnesylation of its C-terminal CaaX motif reorganises the cargo-binding surface and strengthens the interaction, which is why alleles truncating that region are inactivating. When Pex19p is absent, newly synthesised membrane proteins are degraded or delivered to mitochondria instead.

peroxisomal membrane protein targeting GO:0045046 ⇓ LOSS OF FUNCTION

Downstream

Absence of Peroxisomal Membrane Compartments With no route for membrane proteins to reach a peroxisomal membrane, no such membrane is assembled. Kept DIRECT deliberately. Pex19p hands its cargo off at the membrane in partnership with Pex3p, so a named intermediate could be written in here - but which step that partnership performs is genuinely unsettled, with direct insertion into the peroxisomal membrane and budding of PMP-containing vesicles from the ER both still live models. Naming one would assert a mechanism the field has not agreed on; the edge records the dependency and this note records the dispute.

Show evidence (5 references)

PMID:28281558 SUPPORT In Vitro

"The transport of peroxisomal membrane proteins (PMPs) requires the soluble PEX19 protein as chaperone and import receptor."

States the function this node loses.

PMID:10704444 SUPPORT In Vitro

"Here, we show that PEX19 binds a broad spectrum of PMPs, displays saturable PMP binding, and interacts with regions of PMPs required for their targeting to peroxisomes."

Establishes the breadth of cargo and that PEX19 engages the targeting regions themselves, so its loss is not cargo-selective.

PMID:10704444 SUPPORT In Vitro

"This hypothesis is supported by the observation that the loss of PEX19 results in degradation of PMPs and/or mislocalization of PMPs to the mitochondrion."

The specific fate of the untargeted cargo asserted in this node's description.

+ 2 more references

Absence of Peroxisomal Membrane Compartments

Cells from complementation group J contain no peroxisomal membrane remnants. This is the feature that separates PEX19 disease from the matrix-import peroxisome biogenesis disorders, in which membrane "ghosts" persist and can be stained; PEX3 and PEX16 deficiency behave the same way.

peroxisome organization GO:0007031 ↓ DECREASED

Experimental models

CHO peroxisome-deficient mutant ZP119 (complementation group J) CELL LINE The mutant is devoid of peroxisomal membrane vesicles, which is this node's defining cellular phenotype, and stable expression of human PEX19 restores peroxisome biogenesis - so the line demonstrates the dependency rather than merely displaying it.

Downstream

Collapse of Peroxisomal Matrix Protein Import A matrix cannot be imported into a compartment that does not exist, so matrix import fails as a consequence of the membrane defect rather than in parallel with it.

Show evidence (4 references)

PMID:10051604 SUPPORT In Vitro

"In no CG-J mutant cell were peroxisomal ghosts found"

The absence of membrane remnants in group-J cells, which is the defining cellular phenotype of this node.

PMID:39757991 SUPPORT Human Clinical

"Pathogenic mutations in PEX3, PEX16 and PEX19 cause affected cells to be devoid of peroxisomes"

Groups PEX19 with the two other membrane-assembly genes and states the same cellular consequence.

PMID:39757991 SUPPORT Human Clinical

"the genes PEX 1, 2, 5-7, 10, 11β, 12-14 and 26 are essential for the import of matrix enzymes from the cytosol into peroxisomes, and PEX 3, 16, and 19 work for the biogenesis of peroxisomes and assembly of peroxisomal membranes"

The division of labour that puts this entry's gene in the membrane-assembly class rather than the matrix-import class.

+ 1 more reference

Collapse of Peroxisomal Matrix Protein Import

With no peroxisomal compartment, matrix enzymes remain in the cytosol, where they are degraded or left in unprocessed precursor form. Expressing wild-type PEX19 in group-J patient fibroblasts restores matrix protein import, which is what demonstrates that the matrix defect is downstream of the PEX19 lesion rather than a separate one.

protein import into peroxisome matrix GO:0016558 ↓ DECREASED

Experimental models

CHO peroxisome-deficient mutant ZP119 (complementation group J) CELL LINE The line was isolated as a matrix- and membrane-import double defect, which is the combination this entry's chain predicts: matrix import fails because there is no compartment to import into.

PBDJ-01 patient fibroblasts (complementation group J) PRIMARY CELL CULTURE Human PEX19 expression restores matrix protein import in cells carrying a patient's own PEX19 allele, establishing that the import collapse is downstream of the PEX19 lesion and not a separate defect.

Downstream

Accumulation of Very-Long-Chain Fatty Acids Peroxisomal beta-oxidation is lost with the matrix enzymes that carry it out.

Plasmalogen Deficiency Ether-lipid synthesis begins in the peroxisome and fails with it.

Craniofacial and Skeletal Dysmorphogenesis The dysmorphic and bone findings are consistently reported across the Zellweger spectrum and in the PEX19 cases specifically, but which metabolic arm produces them is not established, so this edge is drawn from the loss of peroxisomal function as a whole rather than from a named metabolite.

Congenital Structural Malformation Congenital malformations are part of the severe Zellweger phenotype and renal and cardiac defects were present in the reported PEX19 patients, but no mechanistic route from peroxisome loss to these particular malformations has been established; the edge records the association, not a worked-out mechanism.

Show evidence (2 references)

PMID:10051604 SUPPORT In Vitro

"HsPEX19 expression also restored peroxisomal protein import in fibroblasts from a patient (PBDJ-01) with Zellweger syndrome of CG-J."

Rescue of import by wild-type PEX19 in the patient's own cells places the import failure downstream of the PEX19 lesion.

PMID:10051604 SUPPORT In Vitro

"Moreover, Pex19p is apparently involved at the initial stage in peroxisome membrane assembly, before the import of matrix protein."

States the ordering this node depends on: membrane assembly first, matrix import after.

Accumulation of Very-Long-Chain Fatty Acids

Peroxisomes are where very-long-chain and branched-chain fatty acids are catabolised, so their absence lets these substrates accumulate. In this disorder that accumulation is usual but not invariable: the most recently reported PEX19 patient had an unremarkable very-long-chain fatty acid profile despite a homozygous nonsense allele, and normal plasma levels have been recorded in a handful of other peroxisome biogenesis disorder patients.

very long-chain fatty acid catabolism GO:0000038 ↓ DECREASED

Downstream

Progressive Hepatic Injury Liver disease is a core component of the severe Zellweger phenotype and developed in the longest-surviving reported PEX19 patient.

Impaired Neuronal Migration and Neurogenesis Neuronal migration defects are a defining congenital malformation of the severe end of the spectrum.

Show evidence (3 references)

PMID:39757991 SUPPORT Human Clinical

"Patients with PBD show elevated levels of VLCFAs."

The expected biochemical consequence in peroxisome biogenesis disorders.

PMID:39757991 REFUTE Human Clinical

"Metabolic profile including very long chain fatty acids (VLCFA) were unremarkable."

The PEX19-homozygous proband in this report had a normal very-long-chain fatty acid profile, which contradicts the claim that the accumulation is invariable in this disorder and is why the node's description hedges it.

DOI:10.1002/ajmg.a.33560 SUPPORT Human Clinical

"Plasma very long chain fatty acid analysis showed high C26:0 levels and increasedC26:0/C22:0 and C24:0/C22:0 ratios, which is consistent with a PBD."

The accumulation measured in a PEX19 patient specifically, which is what the node asserts; every other support for it here is spectrum-level. Quoted with the source's own missing space in "increasedC26:0" rather than corrected.

Plasmalogen Deficiency

The first steps of ether-lipid synthesis are peroxisomal, so plasmalogens fall when the compartment is lost. In Zellweger fibroblasts the plasmalogen fraction of phosphatidylethanolamine is roughly half of control while total phospholipid content and membrane fluidity are unchanged, so this is a selective lipid defect rather than general membrane damage.

ether lipid biosynthesis GO:0008611 ↓ DECREASED

Downstream

Impaired Neuronal Migration and Neurogenesis Plasmalogen loss is one of the two metabolic arms conventionally invoked for the brain phenotype of the Zellweger spectrum. No study cited here isolates its contribution in PEX19 disease specifically.

Show evidence (1 reference)

PMID:12457713 SUPPORT INDIRECT In Vitro

"In fibroblasts of CHRS patients, the plasmalogen fraction of phosphatidylethanolamine (PPE) was about half of that in control cells while total phospholipid (PL) content, individual PL and plasma membrane fluidity were normal."

Quantifies the deficit in Zellweger patient fibroblasts. Graded indirect because the cell strains are not identified as PEX19 group-J lines, so this supports the node through the shared Zellweger cellular phenotype rather than by measuring PEX19 cells.

Impaired Neuronal Migration and Neurogenesis

Cortical neurons fail to reach their destinations in the severe end of the Zellweger spectrum, producing the neuronal migration defect that underlies the neonatal seizures, the profound hypotonia and the absent developmental progress. Ventricular enlargement and hydrocephalus are reported alongside it in the PEX19 cases.

neuron migration GO:0001764 ↓ DECREASED

Downstream

Generalized Hypotonia

Hyporeflexia

Global Developmental Delay

Neonatal Seizures

Ventriculomegaly

Hydrocephalus

Feeding Difficulties GeneReviews reports the poor feeding of the affected newborn in the same breath as the hypotonia, so it is placed here rather than as an independent gastrointestinal finding.

Show evidence (2 references)

PMID:20301621 SUPPORT INDIRECT Human Clinical

"Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress."

The clinical outcome of the severe neurological phenotype. Graded indirect because GeneReviews describes the Zellweger spectrum as a class rather than the PEX19 subgroup.

PMID:39757991 SUPPORT Human Clinical

"Mutations in PEX19 have been associated with multisystem involvement, resulting in severe phenotypes, such as hypotonia, hydrocephalus, cardiac anomaly, genital abnormalities, dense bones, abnormal facial features, and early neonatal death"

The PEX19-specific phenotype summary, naming the hypotonia, hydrocephalus and neonatal death that hang off this node.

Progressive Hepatic Injury

Liver involvement is part of the severe Zellweger phenotype and was the late-emerging problem in the longest-surviving reported PEX19 patient, alongside renal tubular disease.

Downstream

Liver Dysfunction

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"One of the reported PEX19 cases with an insertion mutation c.763_764insA showed a less severe phenotype with milder biochemical abnormalities and survived for up to 16 months after developing liver dysfunction and renal tubular defects"

Liver dysfunction in a PEX19 patient specifically, with the survival that made it observable.

Craniofacial and Skeletal Dysmorphogenesis

The Zellweger facies and the bone findings. In the reported PEX19 patients this covers wide open fontanelles, dense bones and the characteristic facial features; which arm of the peroxisomal metabolic failure produces them is not worked out.

Downstream

Abnormal Facial Shape

Hypertelorism

Low-Set Ears

Depressed Nasal Bridge

Wide Anterior Fontanel

Increased Bone Density

Chondrodysplasia Punctata

Micrognathia

Show evidence (3 references)

PMID:39757991 SUPPORT Human Clinical

"These patients suffered severe clinical symptoms, such as hypotonia, hydrocephalus, cardiac anomaly, wide open fontanelles, facial dysmorphism, and dense bones"

The craniofacial and skeletal findings reported in previously published PEX19 patients.

PMID:20301621 SUPPORT INDIRECT Human Clinical

"They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling"

The GeneReviews congenital-malformation list, which is where the bone stippling of this node comes from. The quote stops before the source's bracketed gloss because the reference validator strips an unmatched bracketed span from the query side only, so a quote spanning it cannot verify; the full source phrase is "bony stippling [chondrodysplasia punctata] of the patella[e] and the long bones". Graded indirect: the chapter covers the spectrum, not PEX19.

DOI:10.1136/bcr-2022-252014 SUPPORT Human Clinical

"Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes..."

The dysmorphology of a second, independent PEX19 proband, which adds micrognathia to the craniofacial set this node carries.

Congenital Structural Malformation

Structural birth defects reported in this disorder. The renal cysts and neuronal migration defects of the severe Zellweger phenotype are long established; in the PEX19 patient reported in 2025 the malformations were unilateral renal agenesis, a cardiac septal defect and a patent ductus. No mechanistic account links peroxisome loss to these specific defects, and this node exists to carry the reported associations rather than to assert a pathway.

Downstream

Renal Cysts

Unilateral Renal Agenesis

Patent Ductus Arteriosus

Abnormal Cardiac Septum

Ventricular Septal Defect

Cryptorchidism

Hypospadias

Talipes Equinovarus

Cerebellar Vermis Hypoplasia

Corneal Opacity

Show evidence (3 references)

PMID:39757991 SUPPORT Human Clinical

"Antenatal scan showed polyhydramnios, kidney agenesis (single kidney), and ventriculomegaly."

The renal malformation in the PEX19 proband, detected antenatally.

PMID:39757991 SUPPORT Human Clinical

"ECHO showed an abnormal septal defect and patent ductus arteriosus as signs of developmental disability."

The cardiac malformations in the same patient.

DOI:10.1136/bcr-2022-252014 SUPPORT Human Clinical

"Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes..."

A second PEX19 proband, presenting as a multiple malformation syndrome, which is the source of the genital, limb, ocular, hindbrain and ventricular septal defects this node now carries. As with the 2025 case, no source proposes a route from peroxisome loss to any of them.

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Pathograph

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Phenotypes

29

Cardiovascular 3

Patent Ductus Arteriosus HP:0001643

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"ECHO showed an abnormal septal defect and patent ductus arteriosus as signs of developmental disability."

Echocardiographic finding in the PEX19-homozygous patient.

Abnormal Cardiac Septum Abnormal cardiac septum morphology HP:0001671

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"ECHO showed an abnormal septal defect and patent ductus arteriosus as signs of developmental disability."

Echocardiographic finding in the PEX19-homozygous patient.

Ventricular Septal Defect HP:0001629

Show evidence (1 reference)

DOI:10.1136/bcr-2022-252014 SUPPORT Human Clinical

"Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes..."

Echocardiographic finding in the p.Leu94Ter PEX19 neonate.

Digestive 3

Feeding Difficulties HP:0011968

Show evidence (2 references)

PMID:20301621 SUPPORT INDIRECT Human Clinical

"Affected newborns are hypotonic and feed poorly."

GeneReviews pairs the poor feeding with the hypotonia in the affected newborn. Graded indirect because the chapter covers the spectrum, not the PEX19 subgroup.

DOI:10.1002/ajmg.a.33560 SUPPORT Human Clinical

"We report on a female infant, born to a consanguineous parents (first degree cousins), who presented with inactivity, poor sucking, and hypotonia early in the neonatal period."

The same finding in a PEX19-homozygous patient, which is what lifts this above a spectrum-level claim.

Cholelithiasis HP:0001081

Unwired for the same reason as the renal tubular defect: the reporting paper describes the association with a peroxisome biogenesis disorder as previously unrecognised and offers no mechanism, and none of the other sources here mentions gallstones at all. It is a single-patient observation.

Show evidence (2 references)

DOI:10.1002/ajmg.a.33560 SUPPORT Human Clinical

"Abdominal ultrasound showed multiple gallstones."

The ultrasound finding in the PEX19-homozygous patient.

DOI:10.1002/ajmg.a.33560 SUPPORT Human Clinical

"Our patient showed a previously unrecognized association of gallstones and a renal tubular defect with a PBD."

Records that the paper treated the gallstones as a new association rather than an established feature.

Liver Dysfunction Decreased liver function HP:0001410

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"One of the reported PEX19 cases with an insertion mutation c.763_764insA showed a less severe phenotype with milder biochemical abnormalities and survived for up to 16 months after developing liver dysfunction and renal tubular defects"

Liver dysfunction in a PEX19 patient with sufficient survival to develop it.

Ear 1

Low-Set Ears HP:0000369

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"A detailed physical examination showed abnormal facial features with low-set ears, prominent premaxilla, and nose with a broad depressed nasal bridge."

Physical examination of the PEX19-homozygous patient.

Eye 2

Hypertelorism HP:0000316

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"She had dysmorphic features, such as hypertelorism, increased skin folds, prominent calcaneus, joint laxity, open tented mouth, and periorbital puffiness."

Physical examination of the PEX19-homozygous patient.

Corneal Opacity HP:0007957

Show evidence (1 reference)

DOI:10.1136/bcr-2022-252014 SUPPORT Human Clinical

"Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes..."

Physical examination of the p.Leu94Ter PEX19 neonate.

Genitourinary 5

Unilateral Renal Agenesis HP:0000122

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"Antenatal scan showed polyhydramnios, kidney agenesis (single kidney), and ventriculomegaly."

Antenatal finding in the PEX19-homozygous patient.

Renal Cysts HP:0000107

Show evidence (1 reference)

PMID:39757991 SUPPORT INDIRECT Human Clinical

"Patients with severe ZS experience profound neurological impairment, renal cysts, hepatic dysfunction, elevation of liver function enzymes, and polymicrogyria with frequent multisystem involvement."

Renal cysts in severe Zellweger syndrome. Graded indirect because the statement is about the severe Zellweger phenotype as a class, not about PEX19 patients.

Hypospadias HP:0000047

Show evidence (2 references)

DOI:10.1136/bcr-2022-252014 SUPPORT Human Clinical

"Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes..."

Physical examination of the p.Leu94Ter PEX19 neonate.

PMID:39757991 SUPPORT INDIRECT Human Clinical

"Mutations in PEX19 have been associated with multisystem involvement, resulting in severe phenotypes, such as hypotonia, hydrocephalus, cardiac anomaly, genital abnormalities, dense bones, abnormal facial features, and early neonatal death"

The PEX19-specific phenotype summary names genital abnormalities without specifying them, which is the general claim this specific finding falls under.

Cryptorchidism HP:0000028

Show evidence (1 reference)

DOI:10.1136/bcr-2022-252014 SUPPORT Human Clinical

"Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes..."

Physical examination of the p.Leu94Ter PEX19 neonate.

Renal Tubular Dysfunction HP:0000124

Deliberately not wired to a pathophysiology node, for the reason the source itself gives: the report that described it called the association with a peroxisome biogenesis disorder previously unrecognised, and no cited source proposes a route from peroxisome loss to tubular injury. It is also not a congenital malformation, so it does not belong on that node either.

Show evidence (3 references)

DOI:10.1002/ajmg.a.33560 SUPPORT Human Clinical

"At 1 year of age she developed metabolic acidosis with normal anion gap, proteinuria, aminoaciduria, and glucosuria consistent with a renal tubular defect."

The tubular defect described directly in a PEX19-homozygous patient.

PMID:39757991 SUPPORT Human Clinical

"One of the reported PEX19 cases with an insertion mutation c.763_764insA showed a less severe phenotype with milder biochemical abnormalities and survived for up to 16 months after developing liver dysfunction and renal tubular defects"

The same finding in a second PEX19 patient with enough survival to develop it.

DOI:10.1002/ajmg.a.33560 SUPPORT Human Clinical

"Our patient showed a previously unrecognized association of gallstones and a renal tubular defect with a PBD."

The source's own statement that this association was previously unrecognised, which is why the finding is carried without a mechanistic edge.

Head and Neck 4

Abnormal Facial Shape HP:0001999

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"These patients suffered severe clinical symptoms, such as hypotonia, hydrocephalus, cardiac anomaly, wide open fontanelles, facial dysmorphism, and dense bones"

Facial dysmorphism in previously published PEX19 patients.

Depressed Nasal Bridge HP:0005280

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"A detailed physical examination showed abnormal facial features with low-set ears, prominent premaxilla, and nose with a broad depressed nasal bridge."

Physical examination of the PEX19-homozygous patient.

Wide Anterior Fontanel HP:0000260

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"These patients suffered severe clinical symptoms, such as hypotonia, hydrocephalus, cardiac anomaly, wide open fontanelles, facial dysmorphism, and dense bones"

Wide open fontanelles in previously published PEX19 patients.

Micrognathia HP:0000347

Show evidence (1 reference)

DOI:10.1136/bcr-2022-252014 SUPPORT Human Clinical

"Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes..."

Physical examination of the p.Leu94Ter PEX19 neonate.

Limbs 1

Talipes Equinovarus HP:0001762

Show evidence (1 reference)

DOI:10.1136/bcr-2022-252014 SUPPORT Human Clinical

"Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes..."

Physical examination of the p.Leu94Ter PEX19 neonate.

Musculoskeletal 3

Generalized Hypotonia HP:0001290

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"The proband had generalized hypotonia with poor reflexes and open anterior fontanelle."

Direct observation in the PEX19-homozygous patient.

Increased Bone Density Increased bone mineral density HP:0011001

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"These patients suffered severe clinical symptoms, such as hypotonia, hydrocephalus, cardiac anomaly, wide open fontanelles, facial dysmorphism, and dense bones"

Dense bones in previously published PEX19 patients.

Chondrodysplasia Punctata Calcific stippling of infantile cartilaginous skeleton HP:0005841

HPO carries no term labelled "chondrodysplasia punctata": an OLS search of hp for that string returns nothing bearing the name, and a search for "calcific stippling" returns site-specific terms (shoulder, humeral epiphyses, elbow, carpal bones) plus this one and HP:0002832 "Calcific stippling". HP:0002832 is defined as calcification "in soft tissues within or surrounding bones", which is not what chondrodysplasia punctata is; HP:0010655 "Epiphyseal stippling" is restricted to epiphyses and so does not cover the patella, which is cartilaginous at birth. This term covers the infantile cartilaginous skeleton as a whole, which is what the source describes.

Show evidence (1 reference)

PMID:20301621 SUPPORT INDIRECT Human Clinical

"They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling"

The GeneReviews congenital-malformation list. The quote stops before the source's bracketed gloss, which the reference validator strips from the query side only; the source reads "bony stippling [chondrodysplasia punctata] of the patella[e] and the long bones". Graded indirect because the chapter covers the Zellweger spectrum as a class.

Nervous System 6

Hyporeflexia HP:0001265

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"The proband had generalized hypotonia with poor reflexes and open anterior fontanelle."

Same examination of the PEX19-homozygous patient.

Global Developmental Delay HP:0001263

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"The generalized clinical characteristics of patients, in this study, included dysmorphic features, hypertelorism, pronounced epicanthal folds, scaphocephaly, hypotonia accompanied by ventriculomegaly, open anterior fontanelle, and neurodevelopmental delay."

This sentence aggregates the study's two probands, only one of whom carried the PEX19 variant, so it supports the feature for this disorder without being an isolated PEX19 observation.

Neonatal Seizures HP:0032807

Show evidence (1 reference)

PMID:20301621 SUPPORT INDIRECT Human Clinical

"neuronal migration defects associated with neonatal-onset seizures"

GeneReviews lists neonatal-onset seizures among the congenital malformations of the severe Zellweger phenotype. Graded indirect: the chapter covers the spectrum as a class, not the PEX19 subgroup.

Ventriculomegaly HP:0002119

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"Antenatal scan showed polyhydramnios, kidney agenesis (single kidney), and ventriculomegaly."

Antenatal finding in the PEX19-homozygous patient.

Hydrocephalus HP:0000238

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"Mutations in PEX19 have been associated with multisystem involvement, resulting in severe phenotypes, such as hypotonia, hydrocephalus, cardiac anomaly, genital abnormalities, dense bones, abnormal facial features, and early neonatal death"

PEX19-specific phenotype summary naming hydrocephalus.

Cerebellar Vermis Hypoplasia HP:0001320

Show evidence (1 reference)

DOI:10.1136/bcr-2022-252014 SUPPORT Human Clinical

"Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes..."

Neuroimaging finding in the p.Leu94Ter PEX19 neonate.

Prenatal and Birth 1

Polyhydramnios HP:0001561

Deliberately not wired to a pathophysiology node. Polyhydramnios in this setting is usually attributed to impaired fetal swallowing from the neurological impairment, but none of the cited sources says so for this disorder, and inventing that edge would assert a mechanism no reference here supports.

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"Antenatal scan showed polyhydramnios, kidney agenesis (single kidney), and ventriculomegaly."

Antenatal finding in the PEX19-homozygous patient.

🧬

Genetic Associations

1

PEX19

Gene: PEX19 hgnc:9713 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (6 references)

CGGV:assertion_fa073c77-0623-4e82-b5b2-9fcd0eb0dc6e-2023-04-27T160000.000Z SUPPORT Other

ClinGen classifies the gene-disease relationship as Definitive.

PMID:39757991 SUPPORT Human Clinical

"Patients with missense mutations (p.Ala85Val and p.Ser54Leu) had late-onset mild clinical symptoms with long-term survival"

The mild end of the PEX19 allelic series, which is why this entry's description says the reported phenotype is wider than the "Zellweger" label implies.

PMID:28281558 SUPPORT In Vitro

"Farnesylation at a C-terminal CaaX motif in PEX19 enhances the PMP interaction, but the underlying molecular mechanisms are unknown."

The C-terminal modification whose loss explains why the frameshift allele that replaces the CAAX box is inactivating.

+ 3 more references

💊

Medical Actions

4

Supportive and Symptomatic Management

Action: Supportive Care NCIT:C15747

Platform: Other

There is no disease-modifying therapy. Management of the Zellweger spectrum is symptomatic and multidisciplinary, including gastrostomy feeding for caloric intake, hearing aids, cataract surgery and refractive correction, and fat-soluble vitamin supplementation.

Show evidence (1 reference)

PMID:20301621 SUPPORT INDIRECT Human Clinical

"The focus is on symptomatic therapy and may include gastrostomy to provide adequate calories, hearing aids, cataract removal, glasses to correct refractive errors, supplementation of fat-soluble vitamins, and cholic acid supplementation"

The GeneReviews management list for the spectrum. Graded indirect because no management study addresses the PEX19 subgroup.

Cholic Acid Supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: cholic acid CHEBI:16359

Platform: Small molecule

Cholic acid supplementation is listed among the symptomatic measures used across the Zellweger spectrum.

Show evidence (1 reference)

PMID:20301621 SUPPORT INDIRECT Human Clinical

"supplementation of fat-soluble vitamins, and cholic acid supplementation"

GeneReviews lists cholic acid supplementation in the management of the spectrum. Graded indirect for the same reason as the other treatment records.

Adrenal Replacement Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: corticosteroid CHEBI:50858

Platform: Small molecule

Adrenal insufficiency is monitored for and treated with replacement therapy across the Zellweger spectrum.

Show evidence (1 reference)

PMID:20301621 SUPPORT INDIRECT Human Clinical

"early intervention services for developmental delay and intellectual disability; adrenal replacement therapy"

GeneReviews lists adrenal replacement therapy in the management of the spectrum. Graded indirect for the same reason as the other treatment records.

Anti-Seizure Medication

Action: Pharmacotherapy NCIT:C15986

Agent: anti-seizure medication NCIT:C264

Platform: Small molecule

Seizures at the severe end of the spectrum are managed pharmacologically.

Show evidence (1 reference)

PMID:20301621 SUPPORT INDIRECT Human Clinical

"anti-seizure medication, early intervention services for developmental delay and intellectual disability"

GeneReviews lists anti-seizure medication in the management of the spectrum. Graded indirect for the same reason as the other treatment records.

🔬

Biochemical Markers

1

Very-long-chain fatty acids

Show evidence (3 references)

PMID:39757991 SUPPORT Human Clinical

"Patients with PBD show elevated levels of VLCFAs."

The expected direction of the marker in this disease class.

PMID:39757991 SUPPORT Human Clinical

"Although, normal plasma VLCFAs have also been reported in a few patients"

Records that the marker can be normal, which is the caveat this record exists to carry.

DOI:10.1002/ajmg.a.33560 SUPPORT Human Clinical

"Plasma very long chain fatty acid analysis showed high C26:0 levels and increasedC26:0/C22:0 and C24:0/C22:0 ratios, which is consistent with a PBD."

The marker measured and elevated in a PEX19 patient, which is the positive case this record previously carried only at the level of the disease class. Quoted with the source's own missing space in "increasedC26:0".

🔬

Diagnosis

4

Plasma very-long-chain fatty acid screening

Biochemical screening of plasma very-long-chain fatty acids is the conventional entry point to a Zellweger spectrum diagnosis, but it can be normal in PEX19 disease and did not raise the diagnosis in the 2025 proband, who was first labelled with a connective tissue disorder and then with acrocallosal syndrome.

Show evidence (1 reference)

PMID:39757991 SUPPORT Human Clinical

"The absence of the corpus callosum and widely spaced eyes (hypertelorism) have led neonatologists to misdiagnose these patients with acrocallosal syndrome."

Documents the misdiagnosis route that biochemical screening failed to correct in this report.

Molecular confirmation by exome sequencing

Identification of biallelic pathogenic variants in a Zellweger-spectrum PEX gene establishes the diagnosis; in the reported PEX19 family it was whole-exome sequencing, confirmed by Sanger sequencing across the pedigree, that made it.

Show evidence (2 references)

PMID:20301621 SUPPORT INDIRECT Human Clinical

"The diagnosis of ZSD is established in a proband with the suggestive clinical and biochemical findings above by identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes."

The diagnostic standard for the spectrum. Graded indirect because GeneReviews states it for the ZSD-PEX genes as a group.

PMID:39757991 SUPPORT Human Clinical

"WES identified a homozygous nonsense variant (c.367C > T; p. Gln123*) in exon 4 of PEX19 in a female patient (IV-1) from family A"

The route by which the PEX19 diagnosis was actually made.

Peroxisomal functional studies in cultured fibroblasts

The fibroblast panel that establishes a peroxisome biogenesis defect and then localises it: plasmalogen biosynthesis and peroxisomal fatty acid alpha- and beta-oxidation to confirm the disorder, catalase and peroxisomal-membrane-protein immunofluorescence to ask whether any peroxisomal structure remains, and complementation assay or PEX cDNA transfection to assign the gene. The immunofluorescence step is the one that discriminates this entry's gene: absent membrane remnants point at PEX3, PEX16 or PEX19, whereas the matrix-import disorders leave stainable ghosts. This is the route by which the 2010 PEX19 patient was diagnosed, and it remains usable where plasma screening is normal.

Show evidence (4 references)

DOI:10.1002/ajmg.a.33560 SUPPORT In Vitro

"Studies in fibroblasts including plasmalogen biosynthesis, peroxisomal fatty acid alfa and beta oxidation confirmed the diagnosis of PBD."

The functional panel that confirmed the diagnosis in a PEX19 patient.

DOI:10.1002/ajmg.a.33560 SUPPORT In Vitro

"Immunofluoresence microscopy revealed the absence of peroxisomes in fibroblasts."

The immunofluorescence step, and the result that in this gene is diagnostic rather than merely confirmatory.

PMID:39757991 SUPPORT Human Clinical

"Pathogenic mutations in PEX3, PEX16 and PEX19 cause affected cells to be devoid of peroxisomes"

Why the absent-remnant result narrows the candidate genes to three rather than simply confirming a peroxisome biogenesis disorder.

+ 1 more reference

Carrier and prenatal testing

Once the two pathogenic variants are known in an affected family member, at-risk relatives can be carrier tested and a subsequent pregnancy can be tested by DNA analysis. Where the variants are not known but the biochemical defect has been confirmed in cultured fibroblasts from the affected family member, prenatal biochemical testing is the alternative route - which matters in this gene, because the plasma screen can be normal while the fibroblast studies are not.

No PEX19-specific prenatal or carrier-testing series exists; this record is the spectrum-level standard applied to a gene whose reported case base is a handful of families. The 2025 Saudi report is the only one here that tested parents, and it did so to confirm segregation rather than for reproductive counselling.

Show evidence (2 references)

PMID:20301621 SUPPORT INDIRECT Human Clinical

"Carrier testing for at-risk relatives is possible if the pathogenic variants have been identified in an affected family member."

The carrier-testing offer, conditional on the variants being known. Graded indirect because GeneReviews states it for the Zellweger spectrum as a class.

PMID:20301621 SUPPORT INDIRECT Human Clinical

"Prenatal testing for a pregnancy at increased risk is possible by DNA testing if both ZSD-related pathogenic variants have been identified in an affected family member, or by biochemical testing if the biochemical defects have been confirmed in cultured fibroblasts from an affected family member."

The two prenatal routes and the condition each requires. Graded indirect for the same reason.

📈

Progression

2

Severe Zellweger-end presentation

Truncating PEX19 alleles have been associated with the severe end of the spectrum, including early neonatal death. Early death is recorded here rather than as a phenotype because the HPO mortality terms sit outside the branch this schema's PhenotypeTerm enum is drawn from.

Show evidence (3 references)

PMID:39757991 SUPPORT Human Clinical

"Mutations in PEX19 have been associated with multisystem involvement, resulting in severe phenotypes, such as hypotonia, hydrocephalus, cardiac anomaly, genital abnormalities, dense bones, abnormal facial features, and early neonatal death"

Names early neonatal death as part of the severe PEX19 phenotype.

PMID:20301621 SUPPORT INDIRECT Human Clinical

"Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress."

The survival expectation at the severe end of the spectrum. Graded indirect because GeneReviews describes the spectrum as a class.

DOI:10.1002/ajmg.a.33560 SUPPORT Human Clinical

"The patient had a stormy course with multiple admissions to the pediatric intensive care unit with pneumonia, liver impairment, sepsis, and epilepsy."

The clinical course of the c.320delA homozygote, which is the most fully described PEX19 case. Severe and multisystem, but with survival past the first year, so the severe end of this gene's range is not uniformly neonatally lethal.

Attenuated PEX19 presentations

The PEX19 allelic series is not uniformly severe. Two missense alleles gave late-onset disease with long-term survival, and one reported insertion allele, c.763_764insA, allowed survival to 16 months with liver and renal tubular disease emerging over that period.

Show evidence (2 references)

PMID:39757991 SUPPORT Human Clinical

"Patients with missense mutations (p.Ala85Val and p.Ser54Leu) had late-onset mild clinical symptoms with long-term survival"

The mild end of the reported PEX19 allelic series.

PMID:39757991 SUPPORT Human Clinical

"One of the reported PEX19 cases with an insertion mutation c.763_764insA showed a less severe phenotype with milder biochemical abnormalities and survived for up to 16 months after developing liver dysfunction and renal tubular defects"

The course of the original complementation-group-J patient's allele.

📊

Prevalence

1

Worldwide

Cases In Literature Not yet documented

No population estimate exists for the PEX19 subgroup specifically. The 2025 review that assembled the published PEX19 mutation spectrum found only eight prior studies, and describes PEX19 as among the least common causes of Zellweger spectrum disease; more than 90% of Zellweger spectrum cases are accounted for by PEX1, PEX6, PEX10, PEX12 and PEX26.

Show evidence (3 references)

PMID:39757991 SUPPORT Human Clinical

"Mutations in PEX19 gene are one of the least common causes of ZS disorders"

States the rarity of this genetic subgroup within the Zellweger spectrum.

PMID:39757991 SUPPORT Human Clinical

"There are very few reported cases of PEX19 gene mutations and only eight studies have been published, of which four had missense, two nonsense, and two had frameshift mutations diagnosed with developmental disorder, ZS, PBDs, and myoclonic epilepsy"

Gives the size of the published case base, which is the reason this entry carries no phenotype frequency bands.

PMID:21031596 SUPPORT INDIRECT In Vitro

"The assignment of over 600 fibroblast cell lines to different genetic complementation groups provides the most comprehensive and representative overview of the frequency distribution of the different PEX gene defects."

The largest systematic complementation survey of the spectrum, and the reference source for how the PEX gene defects are distributed. Cited for the existence of that denominator, not for a PEX19 share: the per-gene breakdown is in the paper's tables, and the cached record carries only the abstract, so no PEX19 percentage is quoted here.

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Clinical Trials

2

NCT01668186 NOT_APPLICABLE RECRUITING

A longitudinal observational natural history study of peroxisome biogenesis disorders, following patients in Canada, the US and internationally, and banking clinical data in a peroxisomal disorder databank and biobank. It is the only registered study whose enrolment criteria this entry's patients would meet as a group; it is not PEX19-specific and no PEX19 result has been reported from it.

Show evidence (1 reference)

clinicaltrials:NCT01668186 SUPPORT INDIRECT Human Clinical

"Our aims are to further define this population clinically, biochemically and genetically."

The study's own statement of its aims, which is why it is recorded here: the natural history of this disorder is not systematically described, and this is the study addressing that.

NCT06190626 NOT_APPLICABLE RECRUITING

A longitudinal observational study of retinal degeneration in a Zellweger spectrum cohort, defining its course, the tests that best monitor it, and prognosis for vision loss.

Show evidence (1 reference)

clinicaltrials:NCT06190626 SUPPORT INDIRECT Human Clinical

"The goal of this observational study is to define the course of the retinal degeneration in a ZSD patient cohort."

The study's stated goal.

🧫

Experimental Models

2

CHO peroxisome-deficient mutant ZP119 (complementation group J) CELL_LINE

A chemically derived Chinese hamster ovary mutant defective in import of both matrix and membrane proteins, later shown to be PEX19-deficient and assigned to the same complementation group as the human CG-J patients. It is the cell line the human PEX19 cDNA was cloned on, by screening a liver cDNA library for restoration of peroxisomes; the sibling mutant ZP165 belongs to the same group. It is a mammalian somatic-cell system rather than an animal model, which is why it sits here and not in `animal_models`.

Organism

Chinese hamster NCBITaxon:10029

Cell source

immortalized rodent cell line

Culture

2D monolayer

Publication

PMID:10051604

Pathograph links

Absence of Peroxisomal Membrane Compartments recapitulates fidelity: moderate observes: cellular The mutant is devoid of peroxisomal membrane vesicles, which is this node's defining cellular phenotype, and stable expression of human PEX19 restores peroxisome biogenesis - so the line demonstrates the dependency rather than merely displaying it.

Limitations: A rodent somatic-cell mutant, not a patient genotype: it carries whatever lesion the mutagenesis produced rather than a reported human PEX19 allele, and a cultured fibroblast-like cell reports none of the developmental, hepatic or neurological biology that makes this a disease.

Show evidence (2 references)

PMID:10051604 SUPPORT In Vitro

"In no CG-J mutant cell were peroxisomal ghosts found"

The absence of membrane remnants in the group-J cells this line belongs to.

+ 1 more reference

Collapse of Peroxisomal Matrix Protein Import recapitulates fidelity: moderate observes: cellular The line was isolated as a matrix- and membrane-import double defect, which is the combination this entry's chain predicts: matrix import fails because there is no compartment to import into.

Limitations: Same rodent-somatic-cell caveat. The line cannot separate the two defects in time, so it shows the combination rather than the ordering the edge asserts.

Show evidence (1 reference)

PMID:10051604 SUPPORT In Vitro

"We have isolated a human PEX19 cDNA (HsPEX19) by functional complementation of peroxisome deficiency of a mutant Chinese hamster ovary cell line, ZP119, defective in import of both matrix and membrane proteins."

States the import defect and that human PEX19 complements it.

PBDJ-01 patient fibroblasts (complementation group J) PRIMARY_CELL_CULTURE

Skin fibroblasts from the original complementation-group-J Zellweger patient, who is homozygous for a 1-base insertion at A764 that frameshifts the C-terminal CAAX region. Transfection with human PEX19 restores peroxisomal protein import in these cells and in no other complementation group, which is the experiment that made PEX19 the causative gene for this disorder.

Organism

human NCBITaxon:9606

Cell source

patient-derived primary culture

Culture

2D monolayer

Publication

PMID:10051604

Pathograph links

Collapse of Peroxisomal Matrix Protein Import rescues fidelity: high observes: cellular Human PEX19 expression restores matrix protein import in cells carrying a patient's own PEX19 allele, establishing that the import collapse is downstream of the PEX19 lesion and not a separate defect.

Limitations: A cultured skin fibroblast reports the cellular arm of the disorder only. It carries one allele from one patient, so it says nothing about the allelic series, and nothing about why the same cellular defect produces phenotypes ranging from neonatal death to long-term survival.

Show evidence (1 reference)

PMID:10051604 SUPPORT In Vitro

"HsPEX19 expression also restored peroxisomal protein import in fibroblasts from a patient (PBDJ-01) with Zellweger syndrome of CG-J."

The complementation result in patient cells, which is the basis for treating matrix-import failure as a consequence of the PEX19 lesion.

{ }

Source YAML

click to show

name: Peroxisome Biogenesis Disorder 12A (Zellweger)
creation_date: "2026-09-09T00:00:00Z"
category: Mendelian
description: >-
  Peroxisome biogenesis disorder 12A is the severe, Zellweger-end presentation of
  PEX19 deficiency, historically complementation group J (also numbered group 14) of
  the peroxisome biogenesis disorders.

  PEX19 is not part of the matrix-import machinery. It is a soluble, predominantly
  cytosolic chaperone and import receptor for peroxisomal membrane proteins (PMPs):
  it binds newly made PMPs in the cytosol, recognises the targeting regions within
  them, and delivers them to the peroxisomal membrane, with farnesylation of its
  C-terminal CaaX motif reshaping the cargo-binding surface and strengthening that
  interaction. That places PEX19 one step earlier than every other PEX gene this KB
  curates as its own entry. PEX1, PEX6, PEX12 and PEX26 fail at receptor recycling
  and PEX13 at receptor docking; in those the peroxisomal membrane is still built and
  the cells retain the import-incompetent membrane remnants called "peroxisomal
  ghosts". In PEX19 disease there are no ghosts: with the membrane
  receptor gone, PMPs are degraded or mislocalise to mitochondria and no peroxisomal
  membrane compartment is assembled at all. PEX3 and PEX16 are the other two genes
  that behave this way.

  The downstream consequence nevertheless converges on the same clinical picture,
  because a cell with no peroxisomal membrane also has no peroxisomal matrix.
  Very-long-chain fatty acid beta-oxidation and ether-lipid (plasmalogen) synthesis
  both fail, and the developing brain, liver and skeleton are injured, producing the
  cerebro-hepato-renal presentation Zellweger described.

  Two things are specific to this locus and are curated here rather than inherited
  from the spectrum. First, PEX19 is among the rarest causes of Zellweger spectrum
  disease - the 2025 review that assembled its mutation spectrum found only eight
  published studies, against PEX1 and PEX26 which alone account for about 70% and
  10% of Zellweger spectrum cases - so the phenotype here is described from case
  reports rather than from a series, and this entry carries no frequency bands.
  Second, the reported PEX19 phenotype is unusually wide for a gene labelled by its
  severe end: two missense alleles gave late-onset disease with long-term survival,
  one reported insertion allele allowed survival to 16 months with liver and renal
  tubular disease emerging over that time, and the most recently reported patient
  had an unremarkable plasma very-long-chain fatty acid profile despite a homozygous
  nonsense allele. A normal metabolic screen therefore does not exclude this
  diagnosis.
disease_term:
  preferred_term: peroxisome biogenesis disorder 12A (Zellweger)
  term:
    id: MONDO:0013951
    label: peroxisome biogenesis disorder 12A (Zellweger)
synonyms:
- PBD12A
- peroxisome biogenesis disorder, complementation group J
- peroxisome biogenesis disorder, complementation group 14
- CG-J
- PEX19-related Zellweger syndrome
parents:
- Peroxisome Biogenesis Disorder
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic PEX19 variants are required. The original complementation-group-J
    patient was homozygous for a frameshift allele, and the most recently reported
    family was homozygous for a nonsense allele with both parents heterozygous.
    ClinGen's Peroxisomal Disorders expert panel classifies the PEX19 gene-disease
    relationship as Definitive with autosomal recessive inheritance.
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alignment of Sanger sequencing data with reference genomic sequences revealed that the variants were present in a homozygous state in patients and in a heterozygous state in both parents, confirming an autosomal recessive pattern of inheritance
    explanation: >-
      Segregation in the PEX19 family establishes the recessive mode directly.
  - reference: CGGV:assertion_fa073c77-0623-4e82-b5b2-9fcd0eb0dc6e-2023-04-27T160000.000Z
    reference_title: "PEX19 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX19 | HGNC:9713 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: >-
      ClinGen records the mode of inheritance as autosomal recessive and the
      gene-disease relationship as Definitive.
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      At conception, each sib of an individual with biallelic ZSD-causing pathogenic variants has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
    explanation: >-
      The recurrence risk that follows from the recessive mode, which is what a family
      with an affected child is actually counselled on. Graded indirect because
      GeneReviews states it for the Zellweger spectrum as a class; the PEX19 family
      reported in 2025 segregated exactly this way, with both parents heterozygous.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population estimate exists for the PEX19 subgroup specifically. The 2025
    review that assembled the published PEX19 mutation spectrum found only eight
    prior studies, and describes PEX19 as among the least common causes of Zellweger
    spectrum disease; more than 90% of Zellweger spectrum cases are accounted for by
    PEX1, PEX6, PEX10, PEX12 and PEX26.
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in PEX19 gene are one of the least common causes of ZS disorders"
    explanation: >-
      States the rarity of this genetic subgroup within the Zellweger spectrum.
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There are very few reported cases of PEX19 gene mutations and only eight studies have been published, of which four had missense, two nonsense, and two had frameshift mutations diagnosed with developmental disorder, ZS, PBDs, and myoclonic epilepsy
    explanation: >-
      Gives the size of the published case base, which is the reason this entry
      carries no phenotype frequency bands.
  - reference: PMID:21031596
    reference_title: "Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      The assignment of over 600 fibroblast cell lines to different genetic complementation groups provides the most comprehensive and representative overview of the frequency distribution of the different PEX gene defects.
    explanation: >-
      The largest systematic complementation survey of the spectrum, and the reference
      source for how the PEX gene defects are distributed. Cited for the existence of
      that denominator, not for a PEX19 share: the per-gene breakdown is in the paper's
      tables, and the cached record carries only the abstract, so no PEX19 percentage
      is quoted here.
progression:
- phase: Severe Zellweger-end presentation
  notes: >-
    Truncating PEX19 alleles have been associated with the severe end of the
    spectrum, including early neonatal death. Early death is recorded here rather
    than as a phenotype because the HPO mortality terms sit outside the branch this
    schema's PhenotypeTerm enum is drawn from.
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in PEX19 have been associated with multisystem involvement, resulting in severe phenotypes, such as hypotonia, hydrocephalus, cardiac anomaly, genital abnormalities, dense bones, abnormal facial features, and early neonatal death
    explanation: Names early neonatal death as part of the severe PEX19 phenotype.
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress.
    explanation: >-
      The survival expectation at the severe end of the spectrum. Graded indirect
      because GeneReviews describes the spectrum as a class.
  - reference: DOI:10.1002/ajmg.a.33560
    reference_title: "A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had a stormy course with multiple admissions to the pediatric intensive care unit with pneumonia, liver impairment, sepsis, and epilepsy.
    explanation: >-
      The clinical course of the c.320delA homozygote, which is the most fully described
      PEX19 case. Severe and multisystem, but with survival past the first year, so the
      severe end of this gene's range is not uniformly neonatally lethal.
- phase: Attenuated PEX19 presentations
  notes: >-
    The PEX19 allelic series is not uniformly severe. Two missense alleles gave
    late-onset disease with long-term survival, and one reported insertion allele,
    c.763_764insA, allowed survival to 16 months with liver and renal tubular disease
    emerging over that period.
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with missense mutations (p.Ala85Val and p.Ser54Leu) had late-onset mild clinical symptoms with long-term survival
    explanation: The mild end of the reported PEX19 allelic series.
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One of the reported PEX19 cases with an insertion mutation c.763_764insA showed a less severe phenotype with milder biochemical abnormalities and survived for up to 16 months after developing liver dysfunction and renal tubular defects
    explanation: >-
      The course of the original complementation-group-J patient's allele.
pathophysiology:
- name: Biallelic PEX19 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Both PEX19 alleles carry variants that abolish or severely reduce functional
    Pex19p. Reported severe alleles are truncating: the original
    complementation-group-J patient was homozygous for a single-base insertion that
    frameshifts the codon for Met255 and replaces the C-terminus, including the CAAX
    box required for function, with an unrelated 24-residue tail; the most recent
    family was homozygous for a nonsense change in exon 4 predicted to trigger
    nonsense-mediated decay.
  genes:
  - preferred_term: PEX19
    term:
      id: hgnc:9713
      label: PEX19
  downstream:
  - target: Failure of Cytosolic Membrane-Protein Targeting
    causal_link_type: DIRECT
    description: >-
      Loss of functional Pex19p removes the cytosolic receptor that peroxisomal
      membrane proteins depend on.
  evidence:
  - reference: PMID:10051604
    reference_title: "Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This patient (PBDJ-01) possessed a homozygous, inactivating mutation: a 1-base insertion, A764, in a codon for Met255, resulted in a frameshift, inducing a 24-aa sequence entirely distinct from normal Pex19p.
    explanation: >-
      The founding PEX19 allele, homozygous and inactivating in a patient with
      complementation-group-J Zellweger syndrome.
  - reference: PMID:10051604
    reference_title: "Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results demonstrate that PEX19 is the causative gene for CG-J PBD and suggest that the C-terminal part, including the CAAX homology box, is required for the biological function of Pex19p.
    explanation: >-
      Assigns the gene to the complementation group and locates the essential region
      in the C-terminus that the patient allele destroys.
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identified mutation (c.367C > T; p. Gln123*) in a patient from family A is located in exon 4 of PEX19, which is predicted to cause premature termination of the mRNA transcript in domain 2
    explanation: >-
      A second, independent truncating allele in a separate family.
- name: Failure of Cytosolic Membrane-Protein Targeting
  biological_scale: MOLECULAR
  description: >-
    Pex19p is a soluble protein, mostly cytosolic at steady state, that binds a broad
    range of peroxisomal membrane proteins through the regions those proteins use for
    peroxisomal targeting, and delivers them to the membrane. Farnesylation of its
    C-terminal CaaX motif reorganises the cargo-binding surface and strengthens the
    interaction, which is why alleles truncating that region are inactivating. When
    Pex19p is absent, newly synthesised membrane proteins are degraded or delivered
    to mitochondria instead.
  biological_processes:
  - preferred_term: peroxisomal membrane protein targeting
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0045046
      label: protein import into peroxisome membrane
  downstream:
  - target: Absence of Peroxisomal Membrane Compartments
    causal_link_type: DIRECT
    description: >-
      With no route for membrane proteins to reach a peroxisomal membrane, no such
      membrane is assembled. Kept DIRECT deliberately. Pex19p hands its cargo off at
      the membrane in partnership with Pex3p, so a named intermediate could be written
      in here - but which step that partnership performs is genuinely unsettled, with
      direct insertion into the peroxisomal membrane and budding of PMP-containing
      vesicles from the ER both still live models. Naming one would assert a mechanism
      the field has not agreed on; the edge records the dependency and this note
      records the dispute.
    evidence:
    - reference: DOI:10.1002/1873-3468.13340
      reference_title: "The peroxisome biogenesis factors Pex3 and Pex19: multitasking proteins with disputed functions"
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Although these peroxins have been extensively studied, no consensus has been reached yet on how they operate.
      explanation: >-
        States that the Pex3/Pex19 mechanism is unresolved, which is why this edge is
        left as a dependency rather than being decomposed into named steps.
    - reference: DOI:10.1002/1873-3468.13340
      reference_title: "The peroxisome biogenesis factors Pex3 and Pex19: multitasking proteins with disputed functions"
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Here, we discuss two major models of their function, namely, in direct insertion of proteins into the peroxisomal membrane or in formation of PMP‐containing vesicles from the endoplasmic reticulum (ER).
      explanation: >-
        Names the two competing models, so a reader can see what the unnamed
        intermediate step would have to choose between.
  evidence:
  - reference: PMID:28281558
    reference_title: "Allosteric modulation of peroxisomal membrane protein recognition by farnesylation of the peroxisomal import receptor PEX19."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The transport of peroxisomal membrane proteins (PMPs) requires the soluble PEX19 protein as chaperone and import receptor.
    explanation: >-
      States the function this node loses.
  - reference: PMID:10704444
    reference_title: "PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we show that PEX19 binds a broad spectrum of PMPs, displays saturable PMP binding, and interacts with regions of PMPs required for their targeting to peroxisomes.
    explanation: >-
      Establishes the breadth of cargo and that PEX19 engages the targeting regions
      themselves, so its loss is not cargo-selective.
  - reference: PMID:10704444
    reference_title: "PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This hypothesis is supported by the observation that the loss of PEX19 results in degradation of PMPs and/or mislocalization of PMPs to the mitochondrion.
    explanation: >-
      The specific fate of the untargeted cargo asserted in this node's description.
  - reference: PMID:28281558
    reference_title: "Allosteric modulation of peroxisomal membrane protein recognition by farnesylation of the peroxisomal import receptor PEX19."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutations of PEX19 residues that either mediate farnesyl contacts or are directly involved in PMP recognition abolish cargo binding and cannot complement a ΔPEX19 phenotype in human Zellweger patient fibroblasts.
    explanation: >-
      Ties the cargo-recognition surface, and its dependence on farnesylation, to
      failure to rescue patient cells, which is what makes this the disease-relevant
      step.
  - reference: DOI:10.1083/jcb.200304111
    reference_title: "PEX19 is a predominantly cytosolic chaperone and import receptor for class 1 peroxisomal membrane proteins"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results show that PEX19 functions as both a chaperone and an import receptor for newly synthesized PMPs.
    explanation: >-
      Establishes that PEX19 carries two separable jobs, cytosolic stabilisation of
      newly made membrane proteins and receptor-mediated delivery, so its loss removes
      both at once rather than only the targeting step this node is named for.
- name: Absence of Peroxisomal Membrane Compartments
  biological_scale: CELLULAR
  description: >-
    Cells from complementation group J contain no peroxisomal membrane remnants. This
    is the feature that separates PEX19 disease from the matrix-import peroxisome
    biogenesis disorders, in which membrane "ghosts" persist and can be stained; PEX3
    and PEX16 deficiency behave the same way.
  biological_processes:
  - preferred_term: peroxisome organization
    modifier: DECREASED
    term:
      id: GO:0007031
      label: peroxisome organization
  downstream:
  - target: Collapse of Peroxisomal Matrix Protein Import
    causal_link_type: DIRECT
    description: >-
      A matrix cannot be imported into a compartment that does not exist, so matrix
      import fails as a consequence of the membrane defect rather than in parallel
      with it.
  evidence:
  - reference: PMID:10051604
    reference_title: "Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In no CG-J mutant cell were peroxisomal ghosts found"
    explanation: >-
      The absence of membrane remnants in group-J cells, which is the defining
      cellular phenotype of this node.
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic mutations in PEX3, PEX16 and PEX19 cause affected cells to be devoid of peroxisomes"
    explanation: >-
      Groups PEX19 with the two other membrane-assembly genes and states the same
      cellular consequence.
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the genes PEX 1, 2, 5-7, 10, 11β, 12-14 and 26 are essential for the import of matrix enzymes from the cytosol into peroxisomes, and PEX 3, 16, and 19 work for the biogenesis of peroxisomes and assembly of peroxisomal membranes
    explanation: >-
      The division of labour that puts this entry's gene in the membrane-assembly
      class rather than the matrix-import class.
  - reference: DOI:10.1002/ajmg.a.33560
    reference_title: "A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunofluoresence microscopy revealed the absence of peroxisomes in fibroblasts.
    explanation: >-
      The same cellular phenotype observed directly in fibroblasts from a
      PEX19-homozygous patient, independently of the original complementation-group-J
      cell panel.
- name: Collapse of Peroxisomal Matrix Protein Import
  biological_scale: CELLULAR
  description: >-
    With no peroxisomal compartment, matrix enzymes remain in the cytosol, where they
    are degraded or left in unprocessed precursor form. Expressing wild-type PEX19 in
    group-J patient fibroblasts restores matrix protein import, which is what
    demonstrates that the matrix defect is downstream of the PEX19 lesion rather than
    a separate one.
  biological_processes:
  - preferred_term: protein import into peroxisome matrix
    modifier: DECREASED
    term:
      id: GO:0016558
      label: protein import into peroxisome matrix
  downstream:
  - target: Accumulation of Very-Long-Chain Fatty Acids
    causal_link_type: DIRECT
    description: >-
      Peroxisomal beta-oxidation is lost with the matrix enzymes that carry it out.
  - target: Plasmalogen Deficiency
    causal_link_type: DIRECT
    description: >-
      Ether-lipid synthesis begins in the peroxisome and fails with it.
  - target: Craniofacial and Skeletal Dysmorphogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The dysmorphic and bone findings are consistently reported across the Zellweger
      spectrum and in the PEX19 cases specifically, but which metabolic arm produces
      them is not established, so this edge is drawn from the loss of peroxisomal
      function as a whole rather than from a named metabolite.
  - target: Congenital Structural Malformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Congenital malformations are part of the severe Zellweger phenotype and renal
      and cardiac defects were present in the reported PEX19 patients, but no
      mechanistic route from peroxisome loss to these particular malformations has
      been established; the edge records the association, not a worked-out mechanism.
  evidence:
  - reference: PMID:10051604
    reference_title: "Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      HsPEX19 expression also restored peroxisomal protein import in fibroblasts from a patient (PBDJ-01) with Zellweger syndrome of CG-J.
    explanation: >-
      Rescue of import by wild-type PEX19 in the patient's own cells places the
      import failure downstream of the PEX19 lesion.
  - reference: PMID:10051604
    reference_title: "Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, Pex19p is apparently involved at the initial stage in peroxisome membrane assembly, before the import of matrix protein.
    explanation: >-
      States the ordering this node depends on: membrane assembly first, matrix
      import after.
- name: Accumulation of Very-Long-Chain Fatty Acids
  biological_scale: ORGANISM
  description: >-
    Peroxisomes are where very-long-chain and branched-chain fatty acids are
    catabolised, so their absence lets these substrates accumulate. In this disorder
    that accumulation is usual but not invariable: the most recently reported PEX19
    patient had an unremarkable very-long-chain fatty acid profile despite a
    homozygous nonsense allele, and normal plasma levels have been recorded in a
    handful of other peroxisome biogenesis disorder patients.
  biological_processes:
  - preferred_term: very long-chain fatty acid catabolism
    modifier: DECREASED
    term:
      id: GO:0000038
      label: very long-chain fatty acid metabolic process
  downstream:
  - target: Progressive Hepatic Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Liver disease is a core component of the severe Zellweger phenotype and
      developed in the longest-surviving reported PEX19 patient.
  - target: Impaired Neuronal Migration and Neurogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Neuronal migration defects are a defining congenital malformation of the severe
      end of the spectrum.
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with PBD show elevated levels of VLCFAs."
    explanation: >-
      The expected biochemical consequence in peroxisome biogenesis disorders.
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Metabolic profile including very long chain fatty acids (VLCFA) were unremarkable."
    explanation: >-
      The PEX19-homozygous proband in this report had a normal very-long-chain fatty
      acid profile, which contradicts the claim that the accumulation is invariable
      in this disorder and is why the node's description hedges it.
  - reference: DOI:10.1002/ajmg.a.33560
    reference_title: "A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plasma very long chain fatty acid analysis showed high C26:0 levels and increasedC26:0/C22:0 and C24:0/C22:0 ratios, which is consistent with a PBD.
    explanation: >-
      The accumulation measured in a PEX19 patient specifically, which is what the
      node asserts; every other support for it here is spectrum-level. Quoted with the
      source's own missing space in "increasedC26:0" rather than corrected.
- name: Plasmalogen Deficiency
  biological_scale: MOLECULAR
  description: >-
    The first steps of ether-lipid synthesis are peroxisomal, so plasmalogens fall
    when the compartment is lost. In Zellweger fibroblasts the plasmalogen fraction of
    phosphatidylethanolamine is roughly half of control while total phospholipid
    content and membrane fluidity are unchanged, so this is a selective lipid defect
    rather than general membrane damage.
  biological_processes:
  - preferred_term: ether lipid biosynthesis
    modifier: DECREASED
    term:
      id: GO:0008611
      label: ether lipid biosynthetic process
  downstream:
  - target: Impaired Neuronal Migration and Neurogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Plasmalogen loss is one of the two metabolic arms conventionally invoked for the
      brain phenotype of the Zellweger spectrum. No study cited here isolates its
      contribution in PEX19 disease specifically.
  evidence:
  - reference: PMID:12457713
    reference_title: "Plasmalogen content and beta-adrenoceptor signalling in fibroblasts from patients with Zellweger syndrome. Effects of hexadecylglycerol."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      In fibroblasts of CHRS patients, the plasmalogen fraction of phosphatidylethanolamine (PPE) was about half of that in control cells while total phospholipid (PL) content, individual PL and plasma membrane fluidity were normal.
    explanation: >-
      Quantifies the deficit in Zellweger patient fibroblasts. Graded indirect
      because the cell strains are not identified as PEX19 group-J lines, so this
      supports the node through the shared Zellweger cellular phenotype rather than
      by measuring PEX19 cells.
- name: Impaired Neuronal Migration and Neurogenesis
  biological_scale: TISSUE
  description: >-
    Cortical neurons fail to reach their destinations in the severe end of the
    Zellweger spectrum, producing the neuronal migration defect that underlies the
    neonatal seizures, the profound hypotonia and the absent developmental progress.
    Ventricular enlargement and hydrocephalus are reported alongside it in the PEX19
    cases.
  biological_processes:
  - preferred_term: neuron migration
    modifier: DECREASED
    term:
      id: GO:0001764
      label: neuron migration
  downstream:
  - target: Generalized Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hyporeflexia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Neonatal Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ventriculomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hydrocephalus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Feeding Difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      GeneReviews reports the poor feeding of the affected newborn in the same breath
      as the hypotonia, so it is placed here rather than as an independent
      gastrointestinal finding.
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress.
    explanation: >-
      The clinical outcome of the severe neurological phenotype. Graded indirect
      because GeneReviews describes the Zellweger spectrum as a class rather than the
      PEX19 subgroup.
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in PEX19 have been associated with multisystem involvement, resulting in severe phenotypes, such as hypotonia, hydrocephalus, cardiac anomaly, genital abnormalities, dense bones, abnormal facial features, and early neonatal death
    explanation: >-
      The PEX19-specific phenotype summary, naming the hypotonia, hydrocephalus and
      neonatal death that hang off this node.
- name: Progressive Hepatic Injury
  biological_scale: TISSUE
  description: >-
    Liver involvement is part of the severe Zellweger phenotype and was the
    late-emerging problem in the longest-surviving reported PEX19 patient, alongside
    renal tubular disease.
  downstream:
  - target: Liver Dysfunction
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One of the reported PEX19 cases with an insertion mutation c.763_764insA showed a less severe phenotype with milder biochemical abnormalities and survived for up to 16 months after developing liver dysfunction and renal tubular defects
    explanation: >-
      Liver dysfunction in a PEX19 patient specifically, with the survival that made
      it observable.
- name: Craniofacial and Skeletal Dysmorphogenesis
  biological_scale: TISSUE
  description: >-
    The Zellweger facies and the bone findings. In the reported PEX19 patients this
    covers wide open fontanelles, dense bones and the characteristic facial features;
    which arm of the peroxisomal metabolic failure produces them is not worked out.
  downstream:
  - target: Abnormal Facial Shape
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Low-Set Ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Depressed Nasal Bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Wide Anterior Fontanel
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Increased Bone Density
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Chondrodysplasia Punctata
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Micrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients suffered severe clinical symptoms, such as hypotonia, hydrocephalus, cardiac anomaly, wide open fontanelles, facial dysmorphism, and dense bones
    explanation: >-
      The craniofacial and skeletal findings reported in previously published PEX19
      patients.
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling
    explanation: >-
      The GeneReviews congenital-malformation list, which is where the bone stippling
      of this node comes from. The quote stops before the source's bracketed gloss
      because the reference validator strips an unmatched bracketed span from the
      query side only, so a quote spanning it cannot verify; the full source phrase is
      "bony stippling [chondrodysplasia punctata] of the patella[e] and the long
      bones". Graded indirect: the chapter covers the spectrum, not PEX19.
  - reference: DOI:10.1136/bcr-2022-252014
    reference_title: "Novel mutation causing Zellweger syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes equinovarus, hypoplastic inferior cerebellar vermis, poor reflexes, hypotonia and ventricular septal defect.
    explanation: >-
      The dysmorphology of a second, independent PEX19 proband, which adds micrognathia
      to the craniofacial set this node carries.
- name: Congenital Structural Malformation
  biological_scale: TISSUE
  description: >-
    Structural birth defects reported in this disorder. The renal cysts and neuronal
    migration defects of the severe Zellweger phenotype are long established; in the
    PEX19 patient reported in 2025 the malformations were unilateral renal agenesis, a
    cardiac septal defect and a patent ductus. No mechanistic account links peroxisome
    loss to these specific defects, and this node exists to carry the reported
    associations rather than to assert a pathway.
  downstream:
  - target: Renal Cysts
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Unilateral Renal Agenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Patent Ductus Arteriosus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal Cardiac Septum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ventricular Septal Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cryptorchidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypospadias
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Talipes Equinovarus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cerebellar Vermis Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Corneal Opacity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antenatal scan showed polyhydramnios, kidney agenesis (single kidney), and ventriculomegaly."
    explanation: >-
      The renal malformation in the PEX19 proband, detected antenatally.
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ECHO showed an abnormal septal defect and patent ductus arteriosus as signs of developmental disability."
    explanation: >-
      The cardiac malformations in the same patient.
  - reference: DOI:10.1136/bcr-2022-252014
    reference_title: "Novel mutation causing Zellweger syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes equinovarus, hypoplastic inferior cerebellar vermis, poor reflexes, hypotonia and ventricular septal defect.
    explanation: >-
      A second PEX19 proband, presenting as a multiple malformation syndrome, which is
      the source of the genital, limb, ocular, hindbrain and ventricular septal defects
      this node now carries. As with the 2025 case, no source proposes a route from
      peroxisome loss to any of them.
phenotypes:
- category: Neurologic
  name: Generalized Hypotonia
  description: >-
    Profound generalised hypotonia from birth, present in the reported PEX19 proband
    and listed among the severe features of previously published PEX19 patients.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband had generalized hypotonia with poor reflexes and open anterior fontanelle."
    explanation: Direct observation in the PEX19-homozygous patient.
- category: Neurologic
  name: Hyporeflexia
  description: >-
    Poor neonatal reflexes accompanying the hypotonia.
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband had generalized hypotonia with poor reflexes and open anterior fontanelle."
    explanation: Same examination of the PEX19-homozygous patient.
- category: Neurologic
  name: Global Developmental Delay
  description: >-
    Neurodevelopmental delay was among the shared clinical characteristics of the two
    probands in the 2025 Saudi report, one of whom carried the PEX19 allele.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The generalized clinical characteristics of patients, in this study, included dysmorphic features, hypertelorism, pronounced epicanthal folds, scaphocephaly, hypotonia accompanied by ventriculomegaly, open anterior fontanelle, and neurodevelopmental delay.
    explanation: >-
      This sentence aggregates the study's two probands, only one of whom carried the
      PEX19 variant, so it supports the feature for this disorder without being an
      isolated PEX19 observation.
- category: Neurologic
  name: Neonatal Seizures
  description: >-
    Neonatal-onset seizures accompany the neuronal migration defect at the severe end
    of the Zellweger spectrum. Not reported in the PEX19 proband described in 2025.
  phenotype_term:
    preferred_term: Neonatal seizure
    term:
      id: HP:0032807
      label: Neonatal seizure
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "neuronal migration defects associated with neonatal-onset seizures"
    explanation: >-
      GeneReviews lists neonatal-onset seizures among the congenital malformations of
      the severe Zellweger phenotype. Graded indirect: the chapter covers the spectrum
      as a class, not the PEX19 subgroup.
- category: Neurologic
  name: Ventriculomegaly
  description: >-
    Enlarged cerebral ventricles, detected on the antenatal scan of the PEX19 proband.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antenatal scan showed polyhydramnios, kidney agenesis (single kidney), and ventriculomegaly."
    explanation: Antenatal finding in the PEX19-homozygous patient.
- category: Neurologic
  name: Hydrocephalus
  description: >-
    Reported among the severe features of previously published PEX19 patients.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in PEX19 have been associated with multisystem involvement, resulting in severe phenotypes, such as hypotonia, hydrocephalus, cardiac anomaly, genital abnormalities, dense bones, abnormal facial features, and early neonatal death
    explanation: PEX19-specific phenotype summary naming hydrocephalus.
- category: Craniofacial
  name: Abnormal Facial Shape
  description: >-
    The dysmorphic Zellweger facies, reported across the published PEX19 cases.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients suffered severe clinical symptoms, such as hypotonia, hydrocephalus, cardiac anomaly, wide open fontanelles, facial dysmorphism, and dense bones
    explanation: Facial dysmorphism in previously published PEX19 patients.
- category: Craniofacial
  name: Hypertelorism
  description: >-
    Widely spaced eyes, present in the PEX19 proband and one of the features that led
    to the initial misdiagnosis.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had dysmorphic features, such as hypertelorism, increased skin folds, prominent calcaneus, joint laxity, open tented mouth, and periorbital puffiness.
    explanation: Physical examination of the PEX19-homozygous patient.
- category: Craniofacial
  name: Low-Set Ears
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A detailed physical examination showed abnormal facial features with low-set ears, prominent premaxilla, and nose with a broad depressed nasal bridge.
    explanation: Physical examination of the PEX19-homozygous patient.
- category: Craniofacial
  name: Depressed Nasal Bridge
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A detailed physical examination showed abnormal facial features with low-set ears, prominent premaxilla, and nose with a broad depressed nasal bridge.
    explanation: Physical examination of the PEX19-homozygous patient.
- category: Craniofacial
  name: Wide Anterior Fontanel
  description: >-
    Wide open fontanelles, reported both in the 2025 PEX19 proband and in earlier
    published PEX19 patients.
  phenotype_term:
    preferred_term: Wide anterior fontanel
    term:
      id: HP:0000260
      label: Wide anterior fontanel
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients suffered severe clinical symptoms, such as hypotonia, hydrocephalus, cardiac anomaly, wide open fontanelles, facial dysmorphism, and dense bones
    explanation: Wide open fontanelles in previously published PEX19 patients.
- category: Skeletal
  name: Increased Bone Density
  description: >-
    Dense bones, reported among the severe features of previously published PEX19
    patients. Bound to the generic increased-bone-mineral-density term because the
    reports describe density rather than a named sclerosing pattern.
  phenotype_term:
    preferred_term: Dense bones
    term:
      id: HP:0011001
      label: Increased bone mineral density
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients suffered severe clinical symptoms, such as hypotonia, hydrocephalus, cardiac anomaly, wide open fontanelles, facial dysmorphism, and dense bones
    explanation: Dense bones in previously published PEX19 patients.
- category: Cardiovascular
  name: Patent Ductus Arteriosus
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ECHO showed an abnormal septal defect and patent ductus arteriosus as signs of developmental disability."
    explanation: Echocardiographic finding in the PEX19-homozygous patient.
- category: Cardiovascular
  name: Abnormal Cardiac Septum
  description: >-
    A septal defect was reported on echocardiography without the chamber being
    specified, so the binding is the generic septal-morphology term rather than an
    atrial or ventricular one.
  phenotype_term:
    preferred_term: Abnormal cardiac septum morphology
    term:
      id: HP:0001671
      label: Abnormal cardiac septum morphology
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ECHO showed an abnormal septal defect and patent ductus arteriosus as signs of developmental disability."
    explanation: Echocardiographic finding in the PEX19-homozygous patient.
- category: Renal
  name: Unilateral Renal Agenesis
  description: >-
    A single kidney on antenatal scan in the PEX19 proband.
  phenotype_term:
    preferred_term: Unilateral renal agenesis
    term:
      id: HP:0000122
      label: Unilateral renal agenesis
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antenatal scan showed polyhydramnios, kidney agenesis (single kidney), and ventriculomegaly."
    explanation: Antenatal finding in the PEX19-homozygous patient.
- category: Renal
  name: Renal Cysts
  description: >-
    Renal cysts are a congenital malformation of the severe Zellweger phenotype. Not
    reported in the PEX19 proband described in 2025, whose renal finding was agenesis.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Patients with severe ZS experience profound neurological impairment, renal cysts, hepatic dysfunction, elevation of liver function enzymes, and polymicrogyria with frequent multisystem involvement.
    explanation: >-
      Renal cysts in severe Zellweger syndrome. Graded indirect because the statement
      is about the severe Zellweger phenotype as a class, not about PEX19 patients.
- category: Prenatal
  name: Polyhydramnios
  description: >-
    Excess amniotic fluid on the antenatal scan of the PEX19 proband.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  notes: >-
    Deliberately not wired to a pathophysiology node. Polyhydramnios in this setting
    is usually attributed to impaired fetal swallowing from the neurological
    impairment, but none of the cited sources says so for this disorder, and inventing
    that edge would assert a mechanism no reference here supports.
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antenatal scan showed polyhydramnios, kidney agenesis (single kidney), and ventriculomegaly."
    explanation: Antenatal finding in the PEX19-homozygous patient.
- category: Skeletal
  name: Chondrodysplasia Punctata
  description: >-
    Punctate calcific stippling of the infantile cartilaginous skeleton, classically
    of the patellae and the long bones, and one of the defining radiographic findings
    of the severe Zellweger phenotype. Not reported in either of the two PEX19
    probands described in 2023 and 2025, neither of whom had a skeletal survey
    reported.
  phenotype_term:
    preferred_term: Chondrodysplasia punctata of the patellae and long bones
    term:
      id: HP:0005841
      label: Calcific stippling of infantile cartilaginous skeleton
  notes: >-
    HPO carries no term labelled "chondrodysplasia punctata": an OLS search of hp for
    that string returns nothing bearing the name, and a search for "calcific
    stippling" returns site-specific terms (shoulder, humeral epiphyses, elbow, carpal
    bones) plus this one and HP:0002832 "Calcific stippling". HP:0002832 is defined as
    calcification "in soft tissues within or surrounding bones", which is not what
    chondrodysplasia punctata is; HP:0010655 "Epiphyseal stippling" is restricted to
    epiphyses and so does not cover the patella, which is cartilaginous at birth. This
    term covers the infantile cartilaginous skeleton as a whole, which is what the
    source describes.
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling
    explanation: >-
      The GeneReviews congenital-malformation list. The quote stops before the
      source's bracketed gloss, which the reference validator strips from the query
      side only; the source reads "bony stippling [chondrodysplasia punctata] of the
      patella[e] and the long bones". Graded indirect because the chapter covers the
      Zellweger spectrum as a class.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: >-
    Poor feeding from the first days of life, reported for the severe Zellweger
    newborn as a class and observed as poor sucking in the PEX19-homozygous infant
    described in 2010.
  phenotype_term:
    preferred_term: Poor feeding
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Affected newborns are hypotonic and feed poorly.
    explanation: >-
      GeneReviews pairs the poor feeding with the hypotonia in the affected newborn.
      Graded indirect because the chapter covers the spectrum, not the PEX19
      subgroup.
  - reference: DOI:10.1002/ajmg.a.33560
    reference_title: "A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a female infant, born to a consanguineous parents (first degree cousins), who presented with inactivity, poor sucking, and hypotonia early in the neonatal period.
    explanation: >-
      The same finding in a PEX19-homozygous patient, which is what lifts this above
      a spectrum-level claim.
- category: Craniofacial
  name: Micrognathia
  description: >-
    A small mandible, in the multiple-malformation presentation of the second reported
    PEX19 proband.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: DOI:10.1136/bcr-2022-252014
    reference_title: "Novel mutation causing Zellweger syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes equinovarus, hypoplastic inferior cerebellar vermis, poor reflexes, hypotonia and ventricular septal defect.
    explanation: >-
      Physical examination of the p.Leu94Ter PEX19 neonate.
- category: Ophthalmologic
  name: Corneal Opacity
  description: >-
    Corneal clouding at birth in the second reported PEX19 proband. Distinct from the
    cataract and retinal dystrophy that GeneReviews describes at the attenuated end of
    the spectrum, neither of which is reported in a PEX19 patient.
  phenotype_term:
    preferred_term: Corneal cloudiness
    term:
      id: HP:0007957
      label: Corneal opacity
  evidence:
  - reference: DOI:10.1136/bcr-2022-252014
    reference_title: "Novel mutation causing Zellweger syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes equinovarus, hypoplastic inferior cerebellar vermis, poor reflexes, hypotonia and ventricular septal defect.
    explanation: >-
      Physical examination of the p.Leu94Ter PEX19 neonate.
- category: Genitourinary
  name: Hypospadias
  description: >-
    One of the genital abnormalities named in the PEX19 phenotype summary and observed
    directly in the second reported proband.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: DOI:10.1136/bcr-2022-252014
    reference_title: "Novel mutation causing Zellweger syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes equinovarus, hypoplastic inferior cerebellar vermis, poor reflexes, hypotonia and ventricular septal defect.
    explanation: >-
      Physical examination of the p.Leu94Ter PEX19 neonate.
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Mutations in PEX19 have been associated with multisystem involvement, resulting in severe phenotypes, such as hypotonia, hydrocephalus, cardiac anomaly, genital abnormalities, dense bones, abnormal facial features, and early neonatal death
    explanation: >-
      The PEX19-specific phenotype summary names genital abnormalities without
      specifying them, which is the general claim this specific finding falls under.
- category: Genitourinary
  name: Cryptorchidism
  description: >-
    Undescended testis in the second reported PEX19 proband, alongside the hypospadias.
  phenotype_term:
    preferred_term: Undescended testis
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: DOI:10.1136/bcr-2022-252014
    reference_title: "Novel mutation causing Zellweger syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes equinovarus, hypoplastic inferior cerebellar vermis, poor reflexes, hypotonia and ventricular septal defect.
    explanation: >-
      Physical examination of the p.Leu94Ter PEX19 neonate.
- category: Skeletal
  name: Talipes Equinovarus
  description: >-
    Congenital clubfoot in the second reported PEX19 proband.
  phenotype_term:
    preferred_term: Congenital talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: DOI:10.1136/bcr-2022-252014
    reference_title: "Novel mutation causing Zellweger syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes equinovarus, hypoplastic inferior cerebellar vermis, poor reflexes, hypotonia and ventricular septal defect.
    explanation: >-
      Physical examination of the p.Leu94Ter PEX19 neonate.
- category: Neurologic
  name: Cerebellar Vermis Hypoplasia
  description: >-
    Hypoplasia of the inferior cerebellar vermis on neuroimaging of the second
    reported PEX19 proband. A hindbrain developmental defect, distinct from the
    cortical migration defect the other neurological findings hang off.
  phenotype_term:
    preferred_term: Hypoplastic inferior cerebellar vermis
    term:
      id: HP:0001320
      label: Cerebellar vermis hypoplasia
  evidence:
  - reference: DOI:10.1136/bcr-2022-252014
    reference_title: "Novel mutation causing Zellweger syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes equinovarus, hypoplastic inferior cerebellar vermis, poor reflexes, hypotonia and ventricular septal defect.
    explanation: >-
      Neuroimaging finding in the p.Leu94Ter PEX19 neonate.
- category: Cardiovascular
  name: Ventricular Septal Defect
  description: >-
    A ventricular septal defect in the second reported PEX19 proband. Recorded
    separately from "Abnormal Cardiac Septum" because that record exists precisely
    because the 2025 report did not say which septum was involved, and this one does.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: DOI:10.1136/bcr-2022-252014
    reference_title: "Novel mutation causing Zellweger syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a neonate born with multiple anomalies—wide anterior and posterior fontanelle, metopic suture, flat nasal bridge, hypertelorism, low set dysplastic ears, corneal cloudiness, micrognathia, webbed neck, simian crease, undescended testis, hypospadias, congenital talipes equinovarus, hypoplastic inferior cerebellar vermis, poor reflexes, hypotonia and ventricular septal defect.
    explanation: >-
      Echocardiographic finding in the p.Leu94Ter PEX19 neonate.
- category: Renal
  name: Renal Tubular Dysfunction
  description: >-
    A proximal tubular defect - metabolic acidosis with a normal anion gap,
    proteinuria, aminoaciduria and glucosuria - emerging in the first year in the
    PEX19-homozygous patient reported in 2010, and named again among the late
    complications of the longest-surviving reported PEX19 case.
  phenotype_term:
    preferred_term: Renal tubular defect
    term:
      id: HP:0000124
      label: Renal tubular dysfunction
  notes: >-
    Deliberately not wired to a pathophysiology node, for the reason the source itself
    gives: the report that described it called the association with a peroxisome
    biogenesis disorder previously unrecognised, and no cited source proposes a route
    from peroxisome loss to tubular injury. It is also not a congenital malformation,
    so it does not belong on that node either.
  evidence:
  - reference: DOI:10.1002/ajmg.a.33560
    reference_title: "A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 1 year of age she developed metabolic acidosis with normal anion gap, proteinuria, aminoaciduria, and glucosuria consistent with a renal tubular defect.
    explanation: >-
      The tubular defect described directly in a PEX19-homozygous patient.
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One of the reported PEX19 cases with an insertion mutation c.763_764insA showed a less severe phenotype with milder biochemical abnormalities and survived for up to 16 months after developing liver dysfunction and renal tubular defects
    explanation: >-
      The same finding in a second PEX19 patient with enough survival to develop it.
  - reference: DOI:10.1002/ajmg.a.33560
    reference_title: "A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patient showed a previously unrecognized association of gallstones and a renal tubular defect with a PBD.
    explanation: >-
      The source's own statement that this association was previously unrecognised,
      which is why the finding is carried without a mechanistic edge.
- category: Gastrointestinal
  name: Cholelithiasis
  description: >-
    Multiple gallstones on abdominal ultrasound in the PEX19-homozygous patient
    reported in 2010, with haemoglobinopathy and other causes excluded.
  phenotype_term:
    preferred_term: Gallstones
    term:
      id: HP:0001081
      label: Cholelithiasis
  notes: >-
    Unwired for the same reason as the renal tubular defect: the reporting paper
    describes the association with a peroxisome biogenesis disorder as previously
    unrecognised and offers no mechanism, and none of the other sources here mentions
    gallstones at all. It is a single-patient observation.
  evidence:
  - reference: DOI:10.1002/ajmg.a.33560
    reference_title: "A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abdominal ultrasound showed multiple gallstones.
    explanation: >-
      The ultrasound finding in the PEX19-homozygous patient.
  - reference: DOI:10.1002/ajmg.a.33560
    reference_title: "A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patient showed a previously unrecognized association of gallstones and a renal tubular defect with a PBD.
    explanation: >-
      Records that the paper treated the gallstones as a new association rather than
      an established feature.
- category: Hepatic
  name: Liver Dysfunction
  description: >-
    Impaired liver function, which emerged over the first year in the
    longest-surviving reported PEX19 patient.
  phenotype_term:
    preferred_term: Decreased liver function
    term:
      id: HP:0001410
      label: Decreased liver function
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One of the reported PEX19 cases with an insertion mutation c.763_764insA showed a less severe phenotype with milder biochemical abnormalities and survived for up to 16 months after developing liver dysfunction and renal tubular defects
    explanation: Liver dysfunction in a PEX19 patient with sufficient survival to develop it.
genetic:
- name: PEX19
  gene_term:
    preferred_term: PEX19
    term:
      id: hgnc:9713
      label: PEX19
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    PEX19 encodes the 299-residue cytosolic chaperone and import receptor for
    peroxisomal membrane proteins, with three conserved domains and a C-terminal CAAX
    box that is farnesylated. Reported disease alleles include truncating variants at
    both ends of the severity range and missense variants associated with late-onset,
    mildly affected, long-surviving patients, so genotype does track phenotype to some
    degree within this gene.
  evidence:
  - reference: CGGV:assertion_fa073c77-0623-4e82-b5b2-9fcd0eb0dc6e-2023-04-27T160000.000Z
    reference_title: "PEX19 / peroxisome biogenesis disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PEX19 | HGNC:9713 | peroxisome biogenesis disorder | MONDO:0019234 | AR | Definitive"
    explanation: ClinGen classifies the gene-disease relationship as Definitive.
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with missense mutations (p.Ala85Val and p.Ser54Leu) had late-onset mild clinical symptoms with long-term survival
    explanation: >-
      The mild end of the PEX19 allelic series, which is why this entry's description
      says the reported phenotype is wider than the "Zellweger" label implies.
  - reference: PMID:28281558
    reference_title: "Allosteric modulation of peroxisomal membrane protein recognition by farnesylation of the peroxisomal import receptor PEX19."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Farnesylation at a C-terminal CaaX motif in PEX19 enhances the PMP interaction, but the underlying molecular mechanisms are unknown.
    explanation: >-
      The C-terminal modification whose loss explains why the frameshift allele that
      replaces the CAAX box is inactivating.
  - reference: DOI:10.1002/ajmg.a.33560
    reference_title: "A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was assigned to the PEX19 complementation group. Subsequent mutation analysis of the PEX19 gene revealed homozygosity for a c.320delA frameshift mutation.
    explanation: >-
      A third truncating allele, c.320delA, reached through complementation-group
      assignment rather than sequencing first. It is the earliest frameshift in the
      reported series and sits at the severe end.
  - reference: DOI:10.1136/bcr-2022-252014
    reference_title: "Novel mutation causing Zellweger syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical exome sequencing yielded the diagnosis of Zellweger syndrome with a rare mutation in PEX-19 gene.
    explanation: >-
      A fourth reported PEX19 proband, diagnosed by clinical exome sequencing.
  - reference: PMID:21031596
    reference_title: "Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      We did not identify any novel genetic complementation group, suggesting that all PEX gene defects resulting in peroxisome deficiency are currently known.
    explanation: >-
      The systematic complementation survey found no further group, which is what makes
      the twelve or thirteen known PEX genes, PEX19 among them, a closed set rather
      than a running list. Graded indirect: the finding is about the gene set, not
      about PEX19.
biochemical:
- name: Very-long-chain fatty acids
  notes: >-
    Plasma very-long-chain fatty acids are the standard first-line screen for the
    Zellweger spectrum and are usually elevated. A normal profile does not exclude
    PEX19 disease: the 2025 PEX19-homozygous proband screened normal, and normal
    plasma levels have been recorded in a small number of other peroxisome biogenesis
    disorder patients.
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with PBD show elevated levels of VLCFAs."
    explanation: The expected direction of the marker in this disease class.
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although, normal plasma VLCFAs have also been reported in a few patients"
    explanation: >-
      Records that the marker can be normal, which is the caveat this record exists to
      carry.
  - reference: DOI:10.1002/ajmg.a.33560
    reference_title: "A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plasma very long chain fatty acid analysis showed high C26:0 levels and increasedC26:0/C22:0 and C24:0/C22:0 ratios, which is consistent with a PBD.
    explanation: >-
      The marker measured and elevated in a PEX19 patient, which is the positive case
      this record previously carried only at the level of the disease class. Quoted
      with the source's own missing space in "increasedC26:0".
diagnosis:
- name: Plasma very-long-chain fatty acid screening
  description: >-
    Biochemical screening of plasma very-long-chain fatty acids is the conventional
    entry point to a Zellweger spectrum diagnosis, but it can be normal in PEX19
    disease and did not raise the diagnosis in the 2025 proband, who was first
    labelled with a connective tissue disorder and then with acrocallosal syndrome.
  evidence:
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The absence of the corpus callosum and widely spaced eyes (hypertelorism) have led neonatologists to misdiagnose these patients with acrocallosal syndrome.
    explanation: >-
      Documents the misdiagnosis route that biochemical screening failed to correct in
      this report.
- name: Molecular confirmation by exome sequencing
  description: >-
    Identification of biallelic pathogenic variants in a Zellweger-spectrum PEX gene
    establishes the diagnosis; in the reported PEX19 family it was whole-exome
    sequencing, confirmed by Sanger sequencing across the pedigree, that made it.
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The diagnosis of ZSD is established in a proband with the suggestive clinical and biochemical findings above by identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes.
    explanation: >-
      The diagnostic standard for the spectrum. Graded indirect because GeneReviews
      states it for the ZSD-PEX genes as a group.
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES identified a homozygous nonsense variant (c.367C > T; p. Gln123*) in exon 4 of PEX19 in a female patient (IV-1) from family A
    explanation: The route by which the PEX19 diagnosis was actually made.
- name: Peroxisomal functional studies in cultured fibroblasts
  description: >-
    The fibroblast panel that establishes a peroxisome biogenesis defect and then
    localises it: plasmalogen biosynthesis and peroxisomal fatty acid alpha- and
    beta-oxidation to confirm the disorder, catalase and peroxisomal-membrane-protein
    immunofluorescence to ask whether any peroxisomal structure remains, and
    complementation assay or PEX cDNA transfection to assign the gene. The
    immunofluorescence step is the one that discriminates this entry's gene: absent
    membrane remnants point at PEX3, PEX16 or PEX19, whereas the matrix-import
    disorders leave stainable ghosts. This is the route by which the 2010 PEX19 patient
    was diagnosed, and it remains usable where plasma screening is normal.
  evidence:
  - reference: DOI:10.1002/ajmg.a.33560
    reference_title: "A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Studies in fibroblasts including plasmalogen biosynthesis, peroxisomal fatty acid alfa and beta oxidation confirmed the diagnosis of PBD.
    explanation: >-
      The functional panel that confirmed the diagnosis in a PEX19 patient.
  - reference: DOI:10.1002/ajmg.a.33560
    reference_title: "A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunofluoresence microscopy revealed the absence of peroxisomes in fibroblasts.
    explanation: >-
      The immunofluorescence step, and the result that in this gene is diagnostic
      rather than merely confirmatory.
  - reference: PMID:39757991
    reference_title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic mutations in PEX3, PEX16 and PEX19 cause affected cells to be devoid of peroxisomes"
    explanation: >-
      Why the absent-remnant result narrows the candidate genes to three rather than
      simply confirming a peroxisome biogenesis disorder.
  - reference: PMID:21031596
    reference_title: "Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      The assignment of over 600 fibroblast cell lines to different genetic complementation groups provides the most comprehensive and representative overview of the frequency distribution of the different PEX gene defects.
    explanation: >-
      Establishes complementation grouping of cultured fibroblasts as the systematic
      route to the gene. Graded indirect because the survey covers the spectrum.
- name: Carrier and prenatal testing
  description: >-
    Once the two pathogenic variants are known in an affected family member, at-risk
    relatives can be carrier tested and a subsequent pregnancy can be tested by DNA
    analysis. Where the variants are not known but the biochemical defect has been
    confirmed in cultured fibroblasts from the affected family member, prenatal
    biochemical testing is the alternative route - which matters in this gene, because
    the plasma screen can be normal while the fibroblast studies are not.
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Carrier testing for at-risk relatives is possible if the pathogenic variants have been identified in an affected family member.
    explanation: >-
      The carrier-testing offer, conditional on the variants being known. Graded
      indirect because GeneReviews states it for the Zellweger spectrum as a class.
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Prenatal testing for a pregnancy at increased risk is possible by DNA testing if both ZSD-related pathogenic variants have been identified in an affected family member, or by biochemical testing if the biochemical defects have been confirmed in cultured fibroblasts from an affected family member.
    explanation: >-
      The two prenatal routes and the condition each requires. Graded indirect for the
      same reason.
  notes: >-
    No PEX19-specific prenatal or carrier-testing series exists; this record is the
    spectrum-level standard applied to a gene whose reported case base is a handful of
    families. The 2025 Saudi report is the only one here that tested parents, and it
    did so to confirm segregation rather than for reproductive counselling.
treatments:
- name: Supportive and Symptomatic Management
  description: >-
    There is no disease-modifying therapy. Management of the Zellweger spectrum is
    symptomatic and multidisciplinary, including gastrostomy feeding for caloric
    intake, hearing aids, cataract surgery and refractive correction, and fat-soluble
    vitamin supplementation.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The focus is on symptomatic therapy and may include gastrostomy to provide adequate calories, hearing aids, cataract removal, glasses to correct refractive errors, supplementation of fat-soluble vitamins, and cholic acid supplementation
    explanation: >-
      The GeneReviews management list for the spectrum. Graded indirect because no
      management study addresses the PEX19 subgroup.
  notes: >-
    No PEX19-specific management evidence exists. Every treatment record in this entry
    is drawn from the GeneReviews chapter covering the Zellweger spectrum as a class
    and is graded INDIRECT for that reason.
- name: Cholic Acid Supplementation
  description: >-
    Cholic acid supplementation is listed among the symptomatic measures used across
    the Zellweger spectrum.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cholic acid
      term:
        id: CHEBI:16359
        label: cholic acid
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      supplementation of fat-soluble vitamins, and cholic acid supplementation
    explanation: >-
      GeneReviews lists cholic acid supplementation in the management of the spectrum.
      Graded indirect for the same reason as the other treatment records.
  notes: >-
    The description deliberately says only what the cited snippet says. The usual
    rationale for cholic acid here - suppressing the toxic C27 bile-acid intermediates
    that accumulate when peroxisomal bile-acid synthesis fails - is the standard
    account of the drug in this disease class, but the cached GeneReviews record lists
    the intervention without explaining it, and nothing else cited here explains it
    either, so it is recorded as unsourced context rather than asserted.
- name: Adrenal Replacement Therapy
  description: >-
    Adrenal insufficiency is monitored for and treated with replacement therapy across
    the Zellweger spectrum.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  notes: >-
    The agent is bound at class level only. GeneReviews names the intervention
    ("adrenal replacement therapy") and not the drug, and no source cited here names
    one for a PEX19 patient, so the specific glucocorticoid is not recorded. The class
    binding is the clinical content of the phrase rather than an additional claim; a
    named agent would need its own source.
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      early intervention services for developmental delay and intellectual disability; adrenal replacement therapy
    explanation: >-
      GeneReviews lists adrenal replacement therapy in the management of the spectrum.
      Graded indirect for the same reason as the other treatment records.
- name: Anti-Seizure Medication
  description: >-
    Seizures at the severe end of the spectrum are managed pharmacologically.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anti-seizure medication
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  notes: >-
    Bound at class level because that is the level GeneReviews states it at; it names
    no agent and no regimen, and neither does any PEX19 case report cited here.
  evidence:
  - reference: PMID:20301621
    reference_title: "Zellweger Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      anti-seizure medication, early intervention services for developmental delay and intellectual disability
    explanation: >-
      GeneReviews lists anti-seizure medication in the management of the spectrum.
      Graded indirect for the same reason as the other treatment records.
clinical_trials:
- name: NCT01668186
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    A longitudinal observational natural history study of peroxisome biogenesis
    disorders, following patients in Canada, the US and internationally, and banking
    clinical data in a peroxisomal disorder databank and biobank. It is the only
    registered study whose enrolment criteria this entry's patients would meet as a
    group; it is not PEX19-specific and no PEX19 result has been reported from it.
  evidence:
  - reference: clinicaltrials:NCT01668186
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Our aims are to further define this population clinically, biochemically and genetically.
    explanation: >-
      The study's own statement of its aims, which is why it is recorded here: the
      natural history of this disorder is not systematically described, and this is the
      study addressing that.
- name: NCT06190626
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    A longitudinal observational study of retinal degeneration in a Zellweger spectrum
    cohort, defining its course, the tests that best monitor it, and prognosis for
    vision loss.
  evidence:
  - reference: clinicaltrials:NCT06190626
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The goal of this observational study is to define the course of the retinal degeneration in a ZSD patient cohort.
    explanation: >-
      The study's stated goal.
  notes: >-
    Retinal degeneration belongs to the attenuated end of the Zellweger spectrum, where
    patients survive long enough for it to develop. No published PEX19 patient is
    reported to have it, so this trial is recorded as relevant to the disorder's class
    rather than to any observed PEX19 finding, and no `target_phenotypes` are bound.
experimental_models:
- name: CHO peroxisome-deficient mutant ZP119 (complementation group J)
  experimental_model_type: CELL_LINE
  description: >-
    A chemically derived Chinese hamster ovary mutant defective in import of both
    matrix and membrane proteins, later shown to be PEX19-deficient and assigned to the
    same complementation group as the human CG-J patients. It is the cell line the
    human PEX19 cDNA was cloned on, by screening a liver cDNA library for restoration
    of peroxisomes; the sibling mutant ZP165 belongs to the same group. It is a
    mammalian somatic-cell system rather than an animal model, which is why it sits
    here and not in `animal_models`.
  organism:
    preferred_term: Chinese hamster
    term:
      id: NCBITaxon:10029
      label: Cricetulus griseus
  cell_source: immortalized rodent cell line
  culture_system: 2D monolayer
  publication: PMID:10051604
  modeled_mechanisms:
  - target: Absence of Peroxisomal Membrane Compartments
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The mutant is devoid of peroxisomal membrane vesicles, which is this node's
      defining cellular phenotype, and stable expression of human PEX19 restores
      peroxisome biogenesis - so the line demonstrates the dependency rather than
      merely displaying it.
    limitations: >-
      A rodent somatic-cell mutant, not a patient genotype: it carries whatever lesion
      the mutagenesis produced rather than a reported human PEX19 allele, and a
      cultured fibroblast-like cell reports none of the developmental, hepatic or
      neurological biology that makes this a disease.
    evidence:
    - reference: PMID:10051604
      reference_title: "Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In no CG-J mutant cell were peroxisomal ghosts found
      explanation: >-
        The absence of membrane remnants in the group-J cells this line belongs to.
    - reference: PMID:10051604
      reference_title: "Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        A stable transformant of ZP119 with HsPEX19 was morphologically and biochemically restored for peroxisome biogenesis.
      explanation: >-
        The rescue that makes the phenotype attributable to PEX19 rather than to the
        line's background.
  - target: Collapse of Peroxisomal Matrix Protein Import
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The line was isolated as a matrix- and membrane-import double defect, which is
      the combination this entry's chain predicts: matrix import fails because there is
      no compartment to import into.
    limitations: >-
      Same rodent-somatic-cell caveat. The line cannot separate the two defects in
      time, so it shows the combination rather than the ordering the edge asserts.
    evidence:
    - reference: PMID:10051604
      reference_title: "Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We have isolated a human PEX19 cDNA (HsPEX19) by functional complementation of peroxisome deficiency of a mutant Chinese hamster ovary cell line, ZP119, defective in import of both matrix and membrane proteins.
      explanation: >-
        States the import defect and that human PEX19 complements it.
- name: PBDJ-01 patient fibroblasts (complementation group J)
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Skin fibroblasts from the original complementation-group-J Zellweger patient, who
    is homozygous for a 1-base insertion at A764 that frameshifts the C-terminal CAAX
    region. Transfection with human PEX19 restores peroxisomal protein import in these
    cells and in no other complementation group, which is the experiment that made
    PEX19 the causative gene for this disorder.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: patient-derived primary culture
  culture_system: 2D monolayer
  publication: PMID:10051604
  modeled_mechanisms:
  - target: Collapse of Peroxisomal Matrix Protein Import
    relationship: RESCUES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Human PEX19 expression restores matrix protein import in cells carrying a
      patient's own PEX19 allele, establishing that the import collapse is downstream
      of the PEX19 lesion and not a separate defect.
    limitations: >-
      A cultured skin fibroblast reports the cellular arm of the disorder only. It
      carries one allele from one patient, so it says nothing about the allelic series,
      and nothing about why the same cellular defect produces phenotypes ranging from
      neonatal death to long-term survival.
    evidence:
    - reference: PMID:10051604
      reference_title: "Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        HsPEX19 expression also restored peroxisomal protein import in fibroblasts from a patient (PBDJ-01) with Zellweger syndrome of CG-J.
      explanation: >-
        The complementation result in patient cells, which is the basis for treating
        matrix-import failure as a consequence of the PEX19 lesion.
references:
- reference: PMID:20301621
  title: "Zellweger Spectrum Disorder."
  tags:
  - GeneReviews
- reference: PMID:10051604
  title: "Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly."
- reference: PMID:10704444
  title: "PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis."
- reference: PMID:28281558
  title: "Allosteric modulation of peroxisomal membrane protein recognition by farnesylation of the peroxisomal import receptor PEX19."
- reference: PMID:39757991
  title: "Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families."
- reference: PMID:12457713
  title: "Plasmalogen content and beta-adrenoceptor signalling in fibroblasts from patients with Zellweger syndrome. Effects of hexadecylglycerol."
- reference: PMID:21031596
  title: "Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder."
- reference: DOI:10.1002/ajmg.a.33560
  title: "A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder"
- reference: DOI:10.1136/bcr-2022-252014
  title: "Novel mutation causing Zellweger syndrome"
- reference: DOI:10.1002/1873-3468.13340
  title: "The peroxisome biogenesis factors Pex3 and Pex19: multitasking proteins with disputed functions"
- reference: DOI:10.1083/jcb.200304111
  title: "PEX19 is a predominantly cytosolic chaperone and import receptor for class 1 peroxisomal membrane proteins"
notes: >-
  Ten things about this entry are deliberate.

  First, **it is a standalone entry rather than a subtype of
  `Peroxisome_Biogenesis_Disorder`.** That file carries no `has_subtypes` block at
  all, and PBD 1B, 2B, 3A, 4A, 4B, 11A and 11B are each their own file; PBD2B was
  curated standalone in #11030 on the reasoning that the A/B split is a mechanistic
  claim about residual peroxin function rather than a severity label. That reasoning
  holds here and is if anything stronger: PEX19 is not a matrix-import gene at all,
  so its mechanism diverges from the PEX1/PEX6/PEX12/PEX26 entries at the first step
  rather than at the last.

  Second, **the mechanistic claim that distinguishes this entry is the absence of
  peroxisomal membrane ghosts**, and it is carried by two independent citations
  rather than asserted in prose alone: the 1999 complementation-group-J report states
  that no peroxisomal ghosts were found in any group-J mutant cell, and the 2025
  review states that PEX3, PEX16 and PEX19 mutations leave cells devoid of
  peroxisomes. This is the feature that separates PEX19 from every other PEX gene
  curated here as its own entry.

  Third, **no phenotype carries a `frequency` band.** The published PEX19 case base
  is eight studies. There is no denominator from which a frequency could be read, and
  fabricating one from a spectrum-level source would attribute PEX1-dominated
  statistics to this gene.

  Fourth, **the normal very-long-chain fatty acid profile is curated as content, not
  omitted.** The 2025 proband was homozygous for a nonsense PEX19 allele and screened
  normal for VLCFA. That observation is carried twice: as a `REFUTE` evidence item on
  the accumulation node, because it contradicts the claim that accumulation is
  invariable, and as a caveat on the biochemical marker and the screening diagnosis
  record. A curator reading only the node description would otherwise take the
  accumulation as obligate.

  Fifth, **the causal edges into the malformation and dysmorphology nodes are marked
  `INDIRECT` and say in their own `description` that the route is not worked out.**
  Renal agenesis, the septal defect and the patent ductus were observed in the PEX19
  proband and cardiac anomaly appears in the PEX19 phenotype summary, but no cited
  source proposes a mechanism connecting peroxisome loss to them. The nodes exist to
  attach the reported findings, not to assert a pathway.

  Sixth, **early neonatal death is recorded in `progression`, not as a phenotype.**
  `HP:0003811` Neonatal death and `HP:0001522` Death in infancy both sit under the
  HPO mortality branch, which is outside `HP:0000118` and therefore outside this
  schema's `PhenotypeTerm` dynamic enum; binding either fails validation. The
  observation is carried by a `progression` phase instead, alongside the attenuated
  PEX19 courses that show it is not universal in this gene.

  Seventh, **three phenotypes are deliberately unwired**, each with its reason in its
  own `notes`. `Polyhydramnios` has no incoming edge because the usual explanation,
  impaired fetal swallowing, is not stated for this disorder in any cited source.
  `Renal Tubular Dysfunction` and `Cholelithiasis` have none because the paper that
  reported them says in as many words that the association with a peroxisome biogenesis
  disorder was previously unrecognised, and offers no route from peroxisome loss to
  either. Every other phenotype is the target of exactly one pathophysiology node.

  Eighth, **the deep-research provider substituted a different disease on the
  first two attempts, and the query that fixed it is recorded here.** A `falcon`
  run against the plain entry name returned a report about *PEX3* - that is
  peroxisome biogenesis disorder 10A, the neighbouring membrane-assembly gene -
  with `PEX3` mentioned 95 times against 5 for `PEX19`. A retry appending
  `--var 'disease_name=...'` to `just research-disorder` reproduced that report
  byte-for-byte, because the override does not reach the client through the
  recipe's trailing arguments. What worked was temporarily replacing the entry's
  own `name:` field, which is what the recipe reads, with a disambiguated string
  naming PBD12A, OMIM 614886, *PEX19*, complementation group J, and an explicit
  "not the PEX3-associated PBD10A". That run returned the right disease
  (`PEX19=85`, `PEX3=15`, report OMIM 614886 matching MONDO's) and is the report
  committed here; the substituted report was discarded rather than mined. Note
  that `just preflight-dr` reports `SKIP` for this entry in every case, because
  MONDO records no causal gene for `MONDO:0013951` - the gene comes from its
  parent term - so the gene check has to be done by hand.

  Ninth, **the one figure a reviewer asked for is the one that cannot be quoted.**
  Ebberink's complementation survey of more than 600 patient cell lines is the natural
  denominator for a statement of how rare the PEX19 group is, and the falcon report
  committed alongside this entry does carry a per-gene share, reading "In a
  613-cell-line ZSD series, only 4/613 (0.65%) were assigned to PEX19". That number is
  in no committed *source*. The DOI form of the paper (`DOI:10.1002/humu.21388`)
  fetches to a 403 at the publisher and caches with `content_type: unavailable` and an
  empty body; refetching by PMID recovers `PMID:21031596`, whose PubMed abstract is
  what is cited here, but the per-gene breakdown is in the paper's tables and not in
  the abstract, which says only "over 600". So the survey is cited for the existence
  and authority of its frequency distribution, and `prevalence` stays
  `NOT_YET_DOCUMENTED`. Quoting the percentage would have put a number in this entry
  that no reader could check against anything in this repository.

  Tenth, **the PEX3/PEX16 step is deliberately not written into the pathograph.** It
  would be easy to decompose the edge from membrane-protein targeting to absent
  peroxisomes into "PEX19 delivers cargo to PEX3, which inserts it", and that sentence
  appears in plenty of reviews. The Pex3/Pex19 review cited on that edge states that no
  consensus exists on how the two operate, and names direct membrane insertion and
  ER-derived vesicle budding as both still live. The edge therefore stays `DIRECT`,
  with the dispute recorded on it as evidence rather than resolved by fiat.

  Two limitations worth flagging for anyone extending this. The plasmalogen node is
  supported by a Zellweger-fibroblast study whose cell strains are not identified as
  group-J, so it is graded `directness: INDIRECT`; a PEX19-specific plasmalogen
  measurement would be a real improvement. And there is still no `animal_models`
  section, but the earlier statement of why was narrower than the search behind it.
  What was searched was a PubMed title search for the gene combined with mouse, mice or
  knockout, which returns no `Pex19` knockout mouse; that is a claim about mice, not
  about model organisms. Non-mammalian and cell-based systems do exist, and two of them
  are now curated in `experimental_models` from sources already cited here - the CHO
  group-J mutants ZP119/ZP165 and the PBDJ-01 patient fibroblast line. A *Pichia
  pastoris* `pex19` mutant is cited in the literature and its paper is cached here
  (`DOI:10.1091/mbc.10.6.1745`), but a yeast deletion strain is neither an animal model
  nor a disease-relevant NAM, so it is left uncurated. The review that catalogues
  peroxisome-deficient invertebrate and vertebrate models
  (`DOI:10.3389/fphys.2013.00335`) caches with an empty body, so the *Drosophila*,
  *C. elegans* and zebrafish work it covers cannot be quoted from anything committed
  here and is not asserted.

📚

References & Deep Research

References

11

PMID:20301621

Zellweger Spectrum Disorder.

No top-level findings curated for this source.

PMID:10051604

Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly.

No top-level findings curated for this source.

PMID:10704444

PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis.

No top-level findings curated for this source.

PMID:28281558

Allosteric modulation of peroxisomal membrane protein recognition by farnesylation of the peroxisomal import receptor PEX19.

No top-level findings curated for this source.

PMID:39757991

Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families.

No top-level findings curated for this source.

PMID:12457713

Plasmalogen content and beta-adrenoceptor signalling in fibroblasts from patients with Zellweger syndrome. Effects of hexadecylglycerol.

No top-level findings curated for this source.

PMID:21031596

Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder.

No top-level findings curated for this source.

DOI:10.1002/ajmg.a.33560

A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder

No top-level findings curated for this source.

DOI:10.1136/bcr-2022-252014

Novel mutation causing Zellweger syndrome

No top-level findings curated for this source.

DOI:10.1002/1873-3468.13340

The peroxisome biogenesis factors Pex3 and Pex19: multitasking proteins with disputed functions

No top-level findings curated for this source.

DOI:10.1083/jcb.200304111

PEX19 is a predominantly cytosolic chaperone and import receptor for class 1 peroxisomal membrane proteins

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 (2)

Record notes

Ten things about this entry are deliberate. First, **it is a standalone entry rather than a subtype of `Peroxisome_Biogenesis_Disorder`.** That file carries no `has_subtypes` block at all, and PBD 1B, 2B, 3A, 4A, 4B, 11A and 11B are each their own file; PBD2B was curated standalone in #11030 on the reasoning that the A/B split is a mechanistic claim about residual peroxin function rather than a severity label. That reasoning holds here and is if anything stronger: PEX19 is not a matrix-import gene at all, so its mechanism diverges from the PEX1/PEX6/PEX12/PEX26 entries at the first step rather than at the last. Second, **the mechanistic claim that distinguishes this entry is the absence of peroxisomal membrane ghosts**, and it is carried by two independent citations rather than asserted in prose alone: the 1999 complementation-group-J report states that no peroxisomal ghosts were found in any group-J mutant cell, and the 2025 review states that PEX3, PEX16 and PEX19 mutations leave cells devoid of peroxisomes. This is the feature that separates PEX19 from every other PEX gene curated here as its own entry. Third, **no phenotype carries a `frequency` band.** The published PEX19 case base is eight studies. There is no denominator from which a frequency could be read, and fabricating one from a spectrum-level source would attribute PEX1-dominated statistics to this gene. Fourth, **the normal very-long-chain fatty acid profile is curated as content, not omitted.** The 2025 proband was homozygous for a nonsense PEX19 allele and screened normal for VLCFA. That observation is carried twice: as a `REFUTE` evidence item on the accumulation node, because it contradicts the claim that accumulation is invariable, and as a caveat on the biochemical marker and the screening diagnosis record. A curator reading only the node description would otherwise take the accumulation as obligate. Fifth, **the causal edges into the malformation and dysmorphology nodes are marked `INDIRECT` and say in their own `description` that the route is not worked out.** Renal agenesis, the septal defect and the patent ductus were observed in the PEX19 proband and cardiac anomaly appears in the PEX19 phenotype summary, but no cited source proposes a mechanism connecting peroxisome loss to them. The nodes exist to attach the reported findings, not to assert a pathway. Sixth, **early neonatal death is recorded in `progression`, not as a phenotype.** `HP:0003811` Neonatal death and `HP:0001522` Death in infancy both sit under the HPO mortality branch, which is outside `HP:0000118` and therefore outside this schema's `PhenotypeTerm` dynamic enum; binding either fails validation. The observation is carried by a `progression` phase instead, alongside the attenuated PEX19 courses that show it is not universal in this gene. Seventh, **three phenotypes are deliberately unwired**, each with its reason in its own `notes`. `Polyhydramnios` has no incoming edge because the usual explanation, impaired fetal swallowing, is not stated for this disorder in any cited source. `Renal Tubular Dysfunction` and `Cholelithiasis` have none because the paper that reported them says in as many words that the association with a peroxisome biogenesis disorder was previously unrecognised, and offers no route from peroxisome loss to either. Every other phenotype is the target of exactly one pathophysiology node. Eighth, **the deep-research provider substituted a different disease on the first two attempts, and the query that fixed it is recorded here.** A `falcon` run against the plain entry name returned a report about *PEX3* - that is peroxisome biogenesis disorder 10A, the neighbouring membrane-assembly gene - with `PEX3` mentioned 95 times against 5 for `PEX19`. A retry appending `--var 'disease_name=...'` to `just research-disorder` reproduced that report byte-for-byte, because the override does not reach the client through the recipe's trailing arguments. What worked was temporarily replacing the entry's own `name:` field, which is what the recipe reads, with a disambiguated string naming PBD12A, OMIM 614886, *PEX19*, complementation group J, and an explicit "not the PEX3-associated PBD10A". That run returned the right disease (`PEX19=85`, `PEX3=15`, report OMIM 614886 matching MONDO's) and is the report committed here; the substituted report was discarded rather than mined. Note that `just preflight-dr` reports `SKIP` for this entry in every case, because MONDO records no causal gene for `MONDO:0013951` - the gene comes from its parent term - so the gene check has to be done by hand. Ninth, **the one figure a reviewer asked for is the one that cannot be quoted.** Ebberink's complementation survey of more than 600 patient cell lines is the natural denominator for a statement of how rare the PEX19 group is, and the falcon report committed alongside this entry does carry a per-gene share, reading "In a 613-cell-line ZSD series, only 4/613 (0.65%) were assigned to PEX19". That number is in no committed *source*. The DOI form of the paper (`DOI:10.1002/humu.21388`) fetches to a 403 at the publisher and caches with `content_type: unavailable` and an empty body; refetching by PMID recovers `PMID:21031596`, whose PubMed abstract is what is cited here, but the per-gene breakdown is in the paper's tables and not in the abstract, which says only "over 600". So the survey is cited for the existence and authority of its frequency distribution, and `prevalence` stays `NOT_YET_DOCUMENTED`. Quoting the percentage would have put a number in this entry that no reader could check against anything in this repository. Tenth, **the PEX3/PEX16 step is deliberately not written into the pathograph.** It would be easy to decompose the edge from membrane-protein targeting to absent peroxisomes into "PEX19 delivers cargo to PEX3, which inserts it", and that sentence appears in plenty of reviews. The Pex3/Pex19 review cited on that edge states that no consensus exists on how the two operate, and names direct membrane insertion and ER-derived vesicle budding as both still live. The edge therefore stays `DIRECT`, with the dispute recorded on it as evidence rather than resolved by fiat. Two limitations worth flagging for anyone extending this. The plasmalogen node is supported by a Zellweger-fibroblast study whose cell strains are not identified as group-J, so it is graded `directness: INDIRECT`; a PEX19-specific plasmalogen measurement would be a real improvement. And there is still no `animal_models` section, but the earlier statement of why was narrower than the search behind it. What was searched was a PubMed title search for the gene combined with mouse, mice or knockout, which returns no `Pex19` knockout mouse; that is a claim about mice, not about model organisms. Non-mammalian and cell-based systems do exist, and two of them are now curated in `experimental_models` from sources already cited here - the CHO group-J mutants ZP119/ZP165 and the PBDJ-01 patient fibroblast line. A *Pichia pastoris* `pex19` mutant is cited in the literature and its paper is cached here (`DOI:10.1091/mbc.10.6.1745`), but a yeast deletion strain is neither an animal model nor a disease-relevant NAM, so it is left uncurated. The review that catalogues peroxisome-deficient invertebrate and vertebrate models (`DOI:10.3389/fphys.2013.00335`) caches with an empty body, so the *Drosophila*, *C. elegans* and zebrafish work it covers cannot be quoted from anything committed here and is not asserted.

Create: Peroxisome Biogenesis Disorder 12A (Zellweger), PEX19 · 2026-09-09T18:13:27Z · View source

New standalone entry for MONDO:0013951 (OMIM 614886, PEX19, complementation group J). Decided DISEASE rather than a has_subtypes row on Peroxisome_Biogenesis_Disorder.yaml, which carries no has_subtypes block at all, following the PBD2B precedent from #11030; the case is stronger here because PEX19 is a peroxisomal membrane protein import receptor rather than a matrix-import peroxin, so its mechanism diverges from the sibling entries at the first step. Ten pathophysiology nodes, eighteen phenotypes, all wired except Polyhydramnios which is deliberately unwired with its reason in notes. Evidence from PMID:10051604 (the founding complementation-group-J report), PMID:10704444, PMID:28281558, PMID:39757991 (the 2025 Saudi PEX19 family), PMID:12457713 and GeneReviews PMID:20301621, plus the ClinGen PEX19 Definitive assertion. Early neonatal death is recorded in progression rather than as a phenotype because HPO mortality terms fall outside the PhenotypeTerm dynamic enum. The normal VLCFA profile of the 2025 proband is curated as a REFUTE evidence item on the accumulation node rather than omitted. Deep research: the first falcon run substituted PEX3 (PBD10A) for PEX19 and was discarded; a re-run with a disambiguating disease_name is recorded in the entry notes. Validated with just validate, validate-terms, count-verified-snippets 59/59, check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms, check-folded-hyphens, validate-disorders and the whole-KB snippet checks.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 44 citations 2026-09-09T11:35:55.218576

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Peroxisome biogenesis disorder 12A (PBD12A, Zellweger syndrome, OMIM 614886) caused by biallelic PEX19 variants, historically peroxisome biogenesis disorder complementation group J - not the PEX3-associated PBD10A
MONDO ID: MONDO:0013951 (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Peroxisome biogenesis disorder 12A (PBD12A, Zellweger syndrome, OMIM 614886) caused by biallelic PEX19 variants, historically peroxisome biogenesis disorder complementation group J - not the PEX3-associated PBD10A covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
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Screening:
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11. Outcome/Prognosis

Survival and Mortality:
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Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
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Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
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Prediction:
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12. Treatment

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Supportive and Rehabilitative:
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Experimental:
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For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
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Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
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Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
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Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
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Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Peroxisome biogenesis disorder 12A due to PEX19

Scope and evidence standard

This report concerns PBD12A/Zellweger syndrome caused by biallelic PEX19 variants, historically complementation group J. It does not concern PEX3-associated PBD10A. The distinction is important because older complementation-group nomenclature varies among laboratories.

The PEX19-specific human evidence is exceptionally small: three primary case publications describe four molecularly confirmed children and one highly suggestive, untested sibling. Consequently, percentages calculated from these patients would be unstable and ascertainment-biased. Statements below are labeled PEX19-specific where directly demonstrated; otherwise they are identified as Zellweger-spectrum (ZSD) extrapolation.

Domain	PEX19-specific evidence	Zellweger-spectrum extrapolation	Key sources
Identity	Peroxisome biogenesis disorder 12A (PBD12A; Zellweger phenotype), OMIM 614886, MONDO:0013951, caused by biallelic PEX19 variants; historically complementation group J. It is distinct from PEX3-associated PBD10A.	Part of the autosomal-recessive Zellweger spectrum of peroxisome-biogenesis disorders.	Open Targets disease–gene evidence (OpenTargets Search: peroxisome biogenesis disorder 12A,Zellweger syndrome-PEX19); Matsuzono et al., 1999, DOI: 10.1073/pnas.96.5.2116, PMID: 10051604 (matsuzono1999humanpex19cdna pages 1-2, matsuzono1999humanpex19cdna pages 5-6)
Known human variants and cases	c.763_764insA (historically A764 insertion; C-terminal frameshift): homozygous in two brothers who died at 3 and 21 days. c.320delA, p.Lys107SerfsTer13: homozygous in one girl who died at 16 months. p.Leu94Ter (reported genomic coordinate chr1:g.160283009A>T): homozygous in a male neonate; a similarly affected sibling was not molecularly confirmed. Thus, the primary literature describes four genetically confirmed children plus one highly suggestive sibling.	No reliable population variant spectrum, recurrent founder allele, or genotype-specific frequency has been established because the reported cohort is extremely small.	Mohamed et al., 2010, DOI: 10.1002/ajmg.a.33560 (mohamed2010amutationin pages 3-4, mohamed2010amutationin pages 1-2); Adiyapatham & Murugesan, accepted 9 March 2023, DOI: 10.1136/bcr-2022-252014 (adiyapatham2023novelmutationcausing pages 1-2, adiyapatham2023novelmutationcausing pages 2-3)
Inheritance and risk	Autosomal recessive. Reported variants were homozygous; consanguinity was present in the 2010 and 2023 families, and both parents of the c.320delA patient were carriers.	For two carrier parents, Mendelian recurrence risk is 25% affected, 50% carrier, and 25% unaffected/non-carrier per pregnancy. Penetrance of biallelic null alleles appears high, but cannot be quantified. No anticipation, sex bias, protective allele, or established modifier is known.	Human segregation and family evidence (adiyapatham2023novelmutationcausing pages 1-2, mohamed2010amutationin pages 1-2)
Core phenotype	Antenatal or neonatal multisystem disease: profound hypotonia, weak cry/poor feeding and reflexes, seizures, craniofacial dysmorphism and large fontanelles/metopic suture; hydrocephalus, cerebral white-matter abnormalities, ventriculomegaly/colpocephaly or cerebellar-vermis hypoplasia; congenital heart defects; genital anomalies; corneal opacity; skeletal abnormalities or talipes. The longer-surviving child developed liver disease, global developmental delay, recurrent infection, renal tubular dysfunction and gallstones.	Other ZSD manifestations—sensorineural hearing loss, retinal degeneration, adrenal insufficiency, leukodystrophy, osteopenia/fractures and nephrolithiasis—are clinically relevant surveillance targets but have not all been demonstrated in PEX19 cases.	PEX19 cases (adiyapatham2023novelmutationcausing pages 2-3, mohamed2010amutationin pages 1-2, mohamed2010amutationin pages 2-3); broader ZSD review (argyriou2016peroxisomebiogenesisdisorders pages 9-10, argyriou2016peroxisomebiogenesisdisorders pages 7-9)
Diagnostic biomarkers	In the c.320delA patient: elevated plasma C26:0, C26:0/C22:0 and C24:0/C22:0 ratios; deficient fibroblast C26:0 and pristanate β-oxidation, phytanate α-oxidation, DHAPAT activity and plasmalogens; abnormal acyl-CoA oxidase/thiolase processing; and absent peroxisomes by immunofluorescence. Routine ammonia, lactate and organic acids were normal in the 2023 neonate, illustrating that normal routine metabolic tests do not exclude PBD12A.	Recommended ZSD testing includes plasma VLCFAs, phytanic/pristanic and pipecolic acids, C27 bile-acid intermediates and erythrocyte plasmalogens, followed by fibroblast functional studies and molecular confirmation.	Mohamed et al. (mohamed2010amutationin pages 1-2, mohamed2010amutationin pages 2-3); 2023 case (adiyapatham2023novelmutationcausing pages 1-2); aggregate diagnostic evidence (ebberink2011geneticclassificationand pages 1-2, argyriou2016peroxisomebiogenesisdisorders pages 10-16)
Molecular mechanism	PEX19 is a predominantly cytosolic chaperone/import receptor that binds membrane-peroxisomal targeting signals, stabilizes newly synthesized peroxisomal membrane proteins and delivers them to PEX3/PEX16 for membrane insertion. Loss causes PMP degradation or mitochondrial mistargeting, failed peroxisomal membrane assembly and loss of matrix-protein import. Wild-type PEX19 restored peroxisomes in CG-J fibroblasts and CHO mutants. PEX19-deficient human cells also show defective ether-lipid-dependent GPI-anchor remodeling.	Downstream accumulation of VLCFAs, branched fatty acids and toxic bile-acid intermediates, together with reduced plasmalogens/DHA and altered redox homeostasis, is the accepted ZSD mechanism linking peroxisome failure to brain, liver, kidney, eye and skeletal injury. Exact causal contributions to each PEX19 phenotype remain incompletely resolved.	Human/cellular studies: DOI 10.1083/jcb.200304111 (jones2004pex19isa pages 2-3, jones2004pex19isa pages 1-2); CG-J rescue (matsuzono1999humanpex19cdna pages 3-3, matsuzono1999humanpex19cdna pages 5-6); GPI remodeling, DOI 10.1194/jlr.M021204 (kanzawa2012defectivelipidremodeling pages 1-2)
Prognosis	All four molecularly confirmed children died early: 3 days, 21 days, approximately 15 days, and 16 months. Respiratory failure, severe infection/sepsis, coagulopathy and liver failure contributed. No PEX19-specific survival curve or 5-/10-year survival estimate exists.	Severe Zellweger syndrome generally causes death during infancy; survival into later childhood or adulthood pertains mainly to hypomorphic PEX variants and milder ZSD, not yet established for PEX19.	Human cases (mohamed2010amutationin pages 3-4, mohamed2010amutationin pages 1-2, adiyapatham2023novelmutationcausing pages 1-2); broader ZSD prognosis (argyriou2016peroxisomebiogenesisdisorders pages 7-9)
Treatment and current applications	No curative or PEX19-targeted treatment is established. Reported care was supportive: ventilation/respiratory support, antiseizure treatment, nutrition, infection management, comfort/palliative care and genetic counseling. No PEX19-specific gene, RNA or cell therapy trial was identified.	ZSD-wide interventions remain supportive or investigational. Betaine was studied only in selected PEX1 genotypes; hydroxychloroquine only in PEX1/PEX6/PEX26 disease. Bile-acid therapy may improve hepatobiliary biomarkers or histology without proven alteration of overall course. Recruiting studies include the PBD natural-history cohort NCT01668186 and retinopathy study NCT06190626; neither reports PEX19-specific outcomes.	Clinical records and review evidence (NCT01668186 chunk 1, NCT01838941 chunk 1, NCT00004442 chunk 1, argyriou2016peroxisomebiogenesisdisorders pages 18-20)
Epidemiology	PEX19-specific prevalence, incidence, carrier frequency, sex ratio and geographic distribution are unknown. In a 613-cell-line ZSD series, only 4/613 (0.65%) were assigned to PEX19, versus 3/613 to PEX3; the cohort was over 90% Western European and is not population based.	Overall ZSD birth incidence is commonly estimated near 1:50,000, with reported geographic variation as low as approximately 1:500,000 in Japan; these figures must not be presented as PBD12A incidence.	Aggregate fibroblast cohort (ebberink2011geneticclassificationand pages 3-4, ebberink2011geneticclassificationand pages 2-3); ZSD estimates (adiyapatham2023novelmutationcausing pages 1-2, argyriou2016peroxisomebiogenesisdisorders pages 7-9)
Evidence limitations	Evidence rests on three case publications, patient fibroblasts and experimental models. Phenotype percentages calculated from four confirmed patients would be unstable and ascertainment-biased. Allele frequencies and modern ACMG/AMP classifications were not consistently reported; the 2023 paper’s 0.002% figure came from an internal database rather than a specified population database.	Most diagnostic, surveillance and treatment recommendations necessarily derive from ZSD as a whole. No PEX19-specific natural-history cohort, randomized trial, standardized quality-of-life analysis, single-cell/spatial study or validated prognostic biomarker is available in the retrieved evidence.	Case-count and cohort limitations (adiyapatham2023novelmutationcausing pages 1-2, ebberink2011geneticclassificationand pages 1-2, ebberink2011geneticclassificationand pages 3-4); current study scope (NCT06190626 chunk 1, NCT03440905 chunk 1)

Table: Compact evidence map separating findings demonstrated in PEX19-associated PBD12A from broader Zellweger-spectrum extrapolations. It highlights the exceptionally small human case base and consequent limits on frequencies, prognosis and treatment inference.

1. Disease information

Definition

PBD12A is an autosomal-recessive, congenital peroxisome-biogenesis disorder in which biallelic loss-of-function variants in PEX19 prevent normal assembly of the peroxisomal membrane. This secondarily disrupts import of peroxisomal matrix enzymes and multiple lipid-metabolic pathways. Reported patients have had the severe neonatal Zellweger syndrome/cerebrohepatorenal syndrome phenotype rather than an attenuated ZSD phenotype. Open Targets independently links PEX19 (ENSG00000162735) to MONDO:0013951, citing the foundational and cohort literature (PMIDs 10051604 and 20683989) (OpenTargets Search: peroxisome biogenesis disorder 12A,Zellweger syndrome-PEX19).

Identifiers and synonyms

OMIM disease: 614886, peroxisome biogenesis disorder 12A (Zellweger).
MONDO: MONDO:0013951.
Gene: PEX19, peroxisomal biogenesis factor 19; the retrieved sources identify NM_002857.2 as a historical transcript reference (ebberink2011geneticclassificationand pages 2-3).
Synonyms: PBD12A; PEX19 deficiency; PEX19-related Zellweger syndrome; Zellweger spectrum disorder due to PEX19; peroxisome biogenesis disorder complementation group J/CG-J.
Not synonymous with: PEX3-associated PBD10A. PEX3 and PEX19 were separate complementation groups in the 613-cell-line series (ebberink2011geneticclassificationand pages 3-4).
Orphanet: a PEX19-specific ORPHA identifier was not established in the retrieved evidence; the condition is generally indexed under Zellweger spectrum disorder.
ICD-10: no specific PEX19 code; broader coding commonly falls under E71.5, disorders of peroxisomal function.
ICD-11/MeSH/SNOMED CT: broader Zellweger syndrome or peroxisomal-disorder concepts should be used with a PEX19 molecular qualifier; no uniquely validated PBD12A code was recovered.

The evidence includes individual case records and patient fibroblasts, plus aggregated disease-level resources and ZSD cohorts. It is not derived from an EHR population.

2. Etiology, risk, and protective factors

The initiating cause is germline biallelic PEX19 loss of function. All reported disease alleles are truncating frameshift or nonsense variants. Homozygosity and parental carrier status where tested support autosomal-recessive inheritance (matsuzono1999humanpex19cdna pages 3-5, mohamed2010amutationin pages 1-2).

Genetic risk factors are carriage of two pathogenic alleles and parental relatedness. The 2010 parents were first cousins; the 2023 family reported third-degree consanguinity and recurrence in two siblings (adiyapatham2023novelmutationcausing pages 1-2, mohamed2010amutationin pages 1-2). Family history is therefore a risk indicator, not a mechanistic environmental factor.

No susceptibility loci, validated modifier genes, protective alleles, founder effects, or epigenetic risk factors are known. No toxin, diet, infection, lifestyle, age, or sex exposure causes this Mendelian disorder. Infection can worsen an affected infant’s course but is a complication rather than the etiology. No demonstrated gene–environment interaction modifies penetrance. Residual PEX19 function is a plausible genotype–severity determinant, but this inference rests principally on the c.320delA patient’s longer survival and residual fibroblast activity, not a sufficiently large genotype–phenotype series (mohamed2010amutationin pages 2-3, mohamed2010amutationin pages 3-4).

3. Phenotypes

PEX19-specific clinical spectrum

All confirmed cases had antenatal or neonatal onset and severe multisystem disease.

Neuromuscular: neonatal hypotonia, inactivity, poor suck, weak cry, poor primitive reflexes, apnea/poor respiratory drive, seizures and profound developmental impairment. Suggested terms: HP:0001252 Hypotonia, HP:0001263 Global developmental delay, HP:0001250 Seizure, HP:0001284 Areflexia, HP:0002104 Apnea (adiyapatham2023novelmutationcausing pages 1-2, mohamed2010amutationin pages 1-2).
Brain: hydrocephalus in the original brothers; cerebral atrophy/diffuse demyelination in the c.320delA girl; ventriculomegaly, colpocephaly and inferior cerebellar-vermis hypoplasia in the 2023 child. Suggested terms: HP:0000238 Hydrocephalus, HP:0002119 Ventriculomegaly, HP:0001272 Cerebellar hypoplasia, HP:0002059 Cerebral atrophy (adiyapatham2023novelmutationcausing pages 2-3, mohamed2010amutationin pages 2-3).
Craniofacial: large anterior/posterior fontanelles, prominent metopic suture, broad or flat nasal bridge, hypertelorism, low-set dysplastic ears and micro/retrognathia. Suggested terms: HP:0000239 Large fontanelle, HP:0000316 Hypertelorism, HP:0000347 Micrognathia, HP:0000431 Wide nasal bridge (adiyapatham2023novelmutationcausing pages 1-2, adiyapatham2023novelmutationcausing pages 2-3).
Ocular: corneal clouding/opacity was reported in the 2023 proband. Suggested term: HP:0007957 Corneal opacity. Retinal degeneration is important in broader ZSD but has not been demonstrated in this tiny PEX19 series (adiyapatham2023novelmutationcausing pages 1-2, argyriou2016peroxisomebiogenesisdisorders pages 9-10).
Cardiac: double-outlet right ventricle in the original family, ASD/PDA in the 2010 patient, and perimembranous VSD in the 2023 family. Suggested terms: HP:0001719 Double outlet right ventricle, HP:0001631 ASD, HP:0001643 PDA, HP:0001629 VSD (adiyapatham2023novelmutationcausing pages 2-3, mohamed2010amutationin pages 1-2).
Hepatobiliary: neonatal liver-enzyme and bilirubin abnormalities, later liver failure, and multiple gallstones in the longest survivor. Suggested terms: HP:0001392 Abnormal liver function, HP:0002904 Hyperbilirubinemia, HP:0001081 Cholelithiasis, HP:0001399 Hepatic failure (mohamed2010amutationin pages 1-2, mohamed2010amutationin pages 2-3).
Renal: the c.320delA child developed proximal tubular dysfunction with normal-anion-gap acidosis, proteinuria, aminoaciduria and glucosuria at one year. Suggested terms: HP:0000124 Renal tubular dysfunction, HP:0001997 Gout is inappropriate; use HP terms for metabolic acidosis, proteinuria, aminoaciduria and glucosuria individually (mohamed2010amutationin pages 1-2).
Skeletal/limb: dense bones in the original brothers and bilateral congenital talipes equinovarus in the 2023 child. Suggested terms: HP:0011001 Increased bone mineral density and HP:0001762 Talipes equinovarus (adiyapatham2023novelmutationcausing pages 2-3, mohamed2010amutationin pages 3-4).
Genital: hypospadias and cryptorchidism/undescended testis. Suggested terms: HP:0000047 Hypospadias, HP:0000028 Cryptorchidism (adiyapatham2023novelmutationcausing pages 1-2).
Laboratory/cellular: elevated C26:0 and VLCFA ratios, markedly reduced plasmalogens and deficient peroxisomal oxidation/ether-lipid synthesis; absent peroxisomes by fibroblast immunofluorescence. Suggested HPO concepts include HP:0008167 Very-long-chain fatty acid accumulation and HP:0010964 Abnormality of glycolipid metabolism, supplemented by assay-specific LOINC codes (mohamed2010amutationin pages 1-2, mohamed2010amutationin pages 2-3).

Frequencies cannot be responsibly assigned. Apparent recurrence of hypotonia, dysmorphism, brain and cardiac abnormalities reflects fewer than five confirmed patients. Quality-of-life instruments have not been applied specifically to PEX19 disease. Functional impact was catastrophic: respiratory dependence, poor feeding, refractory epilepsy, repeated intensive-care admissions and death in infancy. A broader caregiver survey enrolled 92 ZSD/peroxisomal-disease families and assessed Family Quality of Life and Pediatric Inventory for Parents domains, but reported no PEX19 subgroup (NCT03440905) (NCT03440905 chunk 1).

4. Genetic and molecular information

Causal gene and variants

PEX19 encodes a 299-amino-acid, predominantly cytosolic peroxin with a C-terminal CaaX prenylation motif (matsuzono1999humanpex19cdna pages 1-2).

c.763_764insA—historically described as A764 insertion in the Met255 codon—causes a C-terminal frameshift and abnormal 24-residue tail. It was homozygous in two brothers who died at 3 and 21 days. Wild-type PEX19, but not the mutant construct, rescued their cellular defect (matsuzono1999humanpex19cdna pages 3-5, mohamed2010amutationin pages 3-4).
c.320delA, p.Lys107SerfsTer13—homozygous in a girl; both parents were carriers. She survived 16 months. Fibroblast DHAPAT activity was 0.6 nmol/hour/mg versus 0.29 and 0.39 in the original cases, providing limited evidence that residual activity tracked a less immediately lethal course (mohamed2010amutationin pages 1-2, mohamed2010amutationin pages 3-4).
p.Leu94Ter—reported as chr1:g.160283009A>T in exon 3, transcript ENST00000368072.10—was homozygous in the 2023 neonate. The paper reported an internal-database frequency of 0.002%, but did not provide a gnomAD frequency; this should not be treated as a validated population allele frequency (adiyapatham2023novelmutationcausing pages 1-2).

All are germline predicted loss-of-function alleles. No somatic PBD12A mechanism is recognized. Modern ClinVar submission status and ACMG assertions were not available in the retrieved evidence; the variants have strong disease-level evidence from homozygosity, phenotype and, for the founding allele, functional complementation. No pathogenic missense allele, structural rearrangement, chromosomal abnormality, modifier gene or disease-specific methylation signature has been established.

5. Environmental information

Environmental, occupational, lifestyle and infectious causes are not applicable to disease initiation. The 2023 sibling developed Staphylococcus aureus infection and the 2010 child had recurrent pneumonia and sepsis, but these were downstream complications in medically fragile infants (adiyapatham2023novelmutationcausing pages 1-2, mohamed2010amutationin pages 1-2). No diet, smoking, alcohol, radiation or pollutant association, and no proven protective exposure, has been reported.

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic truncating PEX19 variants lead to absent or severely reduced functional PEX19.
Loss of PEX19 chaperone/receptor activity leads to failure to bind and stabilize newly synthesized class-1 peroxisomal membrane proteins in the cytosol (demonstrated in human cells) (jones2004pex19isa pages 2-3, jones2004pex19isa pages 1-2).
Failed PEX19–cargo delivery to PEX3/PEX16 leads to degradation or mitochondrial mistargeting of membrane proteins and failure of peroxisomal membrane assembly (demonstrated cellularly; details of direct versus ER-vesicular routes remain debated) (argyriou2016peroxisomebiogenesisdisorders pages 5-7, jansen2019theperoxisomebiogenesis pages 1-2).
Loss of a competent peroxisomal membrane leads to failure of matrix-enzyme import and functional absence of peroxisomes. Wild-type PEX19 restores catalase/PTS1 import and morphologic peroxisomes in CG-J fibroblasts and CHO mutants, directly validating this step (matsuzono1999humanpex19cdna pages 3-3, matsuzono1999humanpex19cdna pages 5-6).
Functional peroxisome loss results in impaired VLCFA and branched-chain fatty-acid oxidation, phytanic-acid α-oxidation, plasmalogen/ether-lipid synthesis and bile-acid intermediate metabolism; the c.320delA fibroblasts directly demonstrated these defects (mohamed2010amutationin pages 1-2, mohamed2010amutationin pages 2-3).
These metabolic defects lead to VLCFA and toxic intermediate accumulation plus plasmalogen and other lipid deficiency. Defective 1-alkyl-2-acyl GPI-anchor remodeling has been demonstrated in PEX19-deficient Zellweger cells (kanzawa2012defectivelipidremodeling pages 1-2).
Abnormal membrane lipids and metabolite toxicity result in disturbed neuronal migration/myelination, hepatocellular and renal-tubular dysfunction, ocular/skeletal abnormalities and impaired organ development; assignment of individual metabolites to individual PEX19 manifestations remains partly inferred from broader ZSD biology (argyriou2016peroxisomebiogenesisdisorders pages 10-16, argyriou2016peroxisomebiogenesisdisorders pages 7-9).
Multiorgan developmental dysfunction leads to neonatal hypotonia, seizures, respiratory failure, congenital malformations, liver disease and early death.

A branch of current research concerns peroxisome-independent PEX19 activity: farnesylated PEX19 sorts UBXD8 and a subset of proteins to ER/lipid droplets. PEX19-null cells accumulated excess triacylglycerol and failed to mobilize neutral-lipid stores. This may modify lipid homeostasis, but its contribution to PBD12A clinical disease is unproven (lyschik2022pex19coordinatesneutral pages 1-2).

Suggested ontology annotations include GO:0007031 peroxisome organization, GO:0016558 protein import into peroxisome matrix, GO:0016559 peroxisome membrane biogenesis, GO:0030259 lipid glycosylation, GO:0033540 fatty-acid beta-oxidation using acyl-CoA oxidase, and GO:0006631 fatty-acid metabolic process. Relevant compartments are GO:0005777 peroxisome, GO:0005778 peroxisomal membrane, cytosol, ER, mitochondrion and lipid droplet.

Relevant cells include neuron (CL:0000540), hepatocyte (CL:0000182), kidney proximal-tubule epithelial cell, retinal photoreceptor, oligodendrocyte and fibroblast (CL:0000057). Direct cell-type mechanisms have mostly been studied in fibroblasts; assignment to neurons, hepatocytes and renal cells is based on organ pathology.

Molecular profiling

PEX19-knockout cellular work used SILAC proteomics and lipidomics; data were deposited in PRIDE as PXD032200 (lyschik2022pex19coordinatesneutral pages 14-15). Yeast pex19Δ profiling found altered peroxisomal and zinc-regulatory proteins, while broader ZSD models suggest peroxins can accumulate on mitochondria and impair respiration. The latter was not specifically proven in a PEX19-patient fibroblast in the retrieved text (nuebel2020msp1atad1restoresmitochondrial pages 8-10, nuebel2020msp1atad1restoresmitochondrial pages 1-3). No disease-specific single-cell, spatial-transcriptomic, epigenomic or integrated human multi-omics study was found.

7. Anatomical structures affected

Primary systems are the central nervous system, liver, kidney, eye, heart, skeleton and male genital tract; respiratory dysfunction and recurrent infection are important secondary complications. Suggested UBERON annotations include brain (UBERON:0000955), cerebellum (UBERON:0002037), cerebral white matter, liver (UBERON:0002107), kidney (UBERON:0002113), renal tubule, eye (UBERON:0000970), cornea, heart (UBERON:0000948), bone, testis and penis.

Pathology is generally bilateral/systemic rather than lateralized. Brain imaging changes were diffuse or bilateral in the 2010 patient, while congenital cardiac and genital lesions need not be symmetric (mohamed2010amutationin pages 1-2). At the subcellular level, the defining structure is the peroxisome/peroxisomal membrane, with secondary ER, lipid-droplet and possibly mitochondrial disturbances.

8. Temporal development

Onset is congenital: reduced fetal movement, growth restriction, oligohydramnios or malformations may be prenatal; hypotonia, poor feeding, apnea and dysmorphism are evident immediately after birth (mohamed2010amutationin pages 1-2). The course is rapidly progressive, not relapsing-remitting. Early stages comprise respiratory/feeding and neurologic dysfunction; later survival may reveal epilepsy, severe developmental delay, recurrent infection, liver failure, gallstones and renal Fanconi-like dysfunction. No remission has been reported.

All genetically confirmed patients died between 3 days and 16 months. The prenatal and neonatal periods are critical for diagnosis and reproductive decision-making; whether presymptomatic treatment can alter PEX19 disease is unknown.

9. Inheritance and population

Inheritance is autosomal recessive. When both parents are heterozygous, each pregnancy has a 25% affected, 50% carrier and 25% unaffected/non-carrier probability. Penetrance of biallelic null alleles appears high, but cannot be quantified. Expressivity varies somewhat—particularly survival from days to 16 months—but remains severe. Anticipation is not expected. Germline mosaicism has not been reported but cannot be excluded after an apparently de novo result.

In the 613 unrelated ZSD fibroblast-line series, 4/613 (0.65%) were assigned to PEX19, compared with 3/613 assigned to PEX3. This was a referral cohort, over 90% Western European, and is neither prevalence nor incidence (ebberink2011geneticclassificationand pages 3-4, ebberink2011geneticclassificationand pages 2-3). Overall ZSD birth incidence is often estimated around 1:50,000, with reported regional estimates down to 1:500,000 in Japan; these must not be represented as PBD12A-specific rates (adiyapatham2023novelmutationcausing pages 1-2, argyriou2016peroxisomebiogenesisdisorders pages 7-9).

PEX19-specific prevalence, incidence, carrier frequency, founder variants, geographic distribution and sex ratio are unknown. Confirmed cases include males and a female; no sex-dependent risk is expected for an autosomal disorder.

10. Diagnostics

Recommended approach

Recognize a neonatal multisystem pattern: hypotonia, poor feeding/respiratory drive, seizures, dysmorphism, large fontanelles, neuronal-migration or white-matter abnormalities, hepatic dysfunction and congenital cardiac/genital/skeletal lesions.
Measure plasma C26:0, C24:0/C22:0 and C26:0/C22:0, phytanic and pristanic acids, pipecolic acid and C27 bile-acid intermediates; measure erythrocyte plasmalogens. Normal ammonia, lactate and urine organic acids do not exclude disease (adiyapatham2023novelmutationcausing pages 1-2, argyriou2016peroxisomebiogenesisdisorders pages 10-16).
Use fibroblast catalase/PMP immunofluorescence, VLCFA and pristanate β-oxidation, phytanate α-oxidation, DHAPAT/plasmalogen synthesis and acyl-CoA-oxidase/thiolase processing when biochemical or molecular findings are uncertain. PEX3, PEX16 and PEX19 defects are especially suggested when peroxisomal membrane remnants are absent (ebberink2011geneticclassificationand pages 1-2, mohamed2010amutationin pages 1-2).
Confirm two pathogenic PEX19 alleles and parental phase. A comprehensive ZSD/peroxisomal panel is efficient; rapid trio WES or WGS is appropriate in a critically ill infant with multiple anomalies. Exome sequencing diagnosed the 2023 case after routine metabolic tests were unrevealing (adiyapatham2023novelmutationcausing pages 1-2, adiyapatham2023novelmutationcausing pages 3-4).
If sequencing finds one or no allele, deletion/duplication analysis, genome sequencing and RNA studies can seek structural or splice variants. CMA and karyotyping do not detect most PEX19 sequence variants and were normal in the affected sibling described in 2023 (adiyapatham2023novelmutationcausing pages 1-2).

MRI can identify neuronal migration abnormalities, delayed myelination, ventriculomegaly, colpocephaly, cerebellar hypoplasia or diffuse demyelination. EEG assesses seizures. Echocardiography, ophthalmologic evaluation, hearing testing, abdominal/renal ultrasound and serial liver, adrenal and renal-tubular studies define organ involvement.

Differential diagnoses include other PEX-gene ZSDs—especially PEX3/PBD10A and PEX16 disease—single-enzyme peroxisomal disorders such as ACOX1 or HSD17B4 deficiency, rhizomelic chondrodysplasia punctata, mitochondrial disease, congenital infection, lysosomal disease and other multiple-malformation syndromes. Biochemistry establishes generalized peroxisomal dysfunction; genotype identifies PBD12A.

No validated population newborn screen exists specifically for PBD12A. Cascade carrier testing and targeted familial testing are clinically applicable.

11. Outcome and prognosis

The observed prognosis is extremely poor. The four confirmed patients died at approximately 3 days, 21 days, 15 days and 16 months; the untested recurrent sibling died at 15 days. Respiratory failure, pneumonia/sepsis, disseminated coagulopathy and liver failure contributed (adiyapatham2023novelmutationcausing pages 1-2, mohamed2010amutationin pages 3-4, mohamed2010amutationin pages 1-2).

There are no PEX19-specific survival curves, mortality rates or 5-/10-year survival estimates. Severe-ZSD literature indicates death usually in the first year, whereas childhood or adult survival largely concerns hypomorphic alleles in other PEX genes (argyriou2016peroxisomebiogenesisdisorders pages 7-9). No recovery has been documented. Likely adverse prognostic indicators are complete absence of peroxisomes, profoundly abnormal lipid metabolism, neonatal respiratory failure and severe liver/brain involvement; none is validated in a PEX19 prognostic model.

12. Treatment and real-world implementation

There is no approved curative or PEX19-directed therapy. Current care is multidisciplinary and supportive:

respiratory support and aspiration prevention;
individualized enteral nutrition and feeding assistance;
antiseizure medication—phenobarbital was used in the reported sibling;
management of cholestasis, coagulopathy and fat-soluble-vitamin deficiency;
treatment of infection;
renal electrolyte/bicarbonate replacement when tubular dysfunction occurs;
hearing, vision, developmental, physical, occupational and speech support;
orthopedic care and palliative-care involvement for severe neonatal disease (adiyapatham2023novelmutationcausing pages 1-2, mohamed2010amutationin pages 1-2).

Suggested NCIT intervention concepts include Supportive Care, Mechanical Ventilation, Enteral Nutrition, Anticonvulsant Therapy, Physical Therapy, Occupational Therapy, Speech Therapy, Genetic Counseling and Palliative Care.

ZSD-wide interventions should not be overgeneralized. Cholic/chenodeoxycholic/ursodeoxycholic-acid treatment has improved bile-acid biomarkers, hepatobiliary function or histology in individual cases but has not shown altered overall neurologic course (NCT00004442 chunk 1, argyriou2016peroxisomebiogenesisdisorders pages 16-18). A randomized DHA study in 48 ZSD patients showed no overall ERG or growth benefit (argyriou2016peroxisomebiogenesisdisorders pages 18-20). Betaine trial NCT01838941 enrolled 12 selected PEX1 patients, not PEX19 cases (NCT01838941 chunk 1). Hydroxychloroquine NCT03856866 enrolled only three PEX1/PEX6/PEX26 patients and cannot support PEX19 treatment (NCT03856866 chunk 1).

Current research infrastructure includes recruiting natural-history study NCT01668186, estimated enrollment 244 with annual follow-up up to ten years, and retinopathy study NCT06190626, begun December 18, 2023 with target enrollment 30 and completion planned for 2029. Neither reports a PEX19-specific result (NCT06190626 chunk 1, NCT01668186 chunk 1). No PEX19 gene-replacement, genome-editing, RNA, cell or transplantation trial was identified.

13. Prevention

The molecular event cannot be prevented by lifestyle or vaccination. Primary reproductive prevention consists of genetic counseling, carrier testing, preimplantation genetic testing, chorionic-villus or amniotic-fluid targeted testing, and use of donor gametes where desired. The 2023 parents were specifically counseled about targeted prenatal testing in later pregnancies (adiyapatham2023novelmutationcausing pages 2-3, adiyapatham2023novelmutationcausing pages 3-4).

Secondary prevention means early molecular diagnosis and anticipatory surveillance rather than prevention of onset. Tertiary prevention includes aspiration precautions, nutritional support, vaccination according to routine schedules, prompt infection treatment, seizure control, monitoring liver/coagulation/adrenal/renal status, and sensory/rehabilitative care. No disease-specific prophylactic medication is established.

14. Other species and natural disease

PEX19 is evolutionarily conserved across eukaryotes. Relevant taxa include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), Danio rerio (7955), Drosophila melanogaster (7227), Caenorhabditis elegans (6239), Saccharomyces cerevisiae (4932) and Pichia pastoris/Komagataella phaffii.

No naturally occurring veterinary PEX19-associated syndrome, breed predisposition, zoonotic potential or cross-species transmission was identified. The disease is genetic and noninfectious. Comparative work instead uses induced mutants to establish the conserved requirement for Pex19 in organelle biogenesis (snyder1999pex19pinteractswith pages 1-2, veldhoven2013peroxisomedeficientinvertebrate pages 9-10).

15. Model organisms and experimental systems

Human patient fibroblasts: highest disease relevance. CG-J fibroblasts lack functional peroxisomes; wild-type PEX19 restores catalase/PTS1 import and membrane assembly. Limitations are scarcity, severe/null genotypes and absence of tissue architecture (matsuzono1999humanpex19cdna pages 3-3, matsuzono1999humanpex19cdna pages 5-6).
Chinese hamster ovary ZP119/ZP165 cells: rescued by human PEX19 and useful for complementation, prenylation and membrane-assembly studies. They model cell biology, not clinical organ disease (matsuzono1999humanpex19cdna pages 1-2, matsuzono1999humanpex19cdna pages 5-6).
Human engineered PEX19-knockout cells: used to separate peroxisomal from lipid-droplet functions and for proteomics/lipidomics. Nonfarnesylated PEX19C296S restored catalase-positive peroxisomes in one modern study, contrasting with older experiments in which C296S did not rescue; differences in constructs and readouts indicate that the precise requirement for farnesylation remains context-dependent (matsuzono1999humanpex19cdna pages 3-5, lyschik2022pex19coordinatesneutral pages 1-2).
Pichia pastoris pex19Δ/pex19-112: defective in PTS1/PTS2 import with cytosolic matrix proteins and small Pex3-positive membrane remnants. It is powerful for genetics and interaction mapping but lacks mammalian organs and has different prenylation requirements (snyder1999pex19pinteractswith pages 1-2).
Drosophila S2 Pex19 RNAi: produces fewer, larger GFP-SKL-positive peroxisomes. It is a tractable morphology assay but is an incomplete knockdown in cultured insect cells (veldhoven2013peroxisomedeficientinvertebrate pages 10-11).
C. elegans Pex19 loss: associated with embryonic lethality, demonstrating developmental essentiality but preventing later-stage analysis (veldhoven2013peroxisomedeficientinvertebrate pages 9-10).
Zebrafish Pex19 morpholino: no obvious abnormality at 32 hours post-fertilization, but knockdown efficacy was not controlled; this negative result is not a validated disease model (veldhoven2013peroxisomedeficientinvertebrate pages 13-14).

No well-characterized Pex19-null mouse, patient-derived iPSC, organoid or humanized knock-in model was identified in the retrieved evidence. Generic Pex5/Pex13/Pex14 models illuminate ZSD neurodevelopment and metabolism but should not be annotated as PEX19-specific.

Recent developments and expert interpretation

The most important recent clinical development was the 2023 report of homozygous p.Leu94Ter, which expanded the phenotype to include corneal opacity, talipes and inferior vermian hypoplasia and showed the diagnostic utility of rapid exome sequencing when routine metabolic assays are normal (adiyapatham2023novelmutationcausing pages 1-2, adiyapatham2023novelmutationcausing pages 2-3). Current 2023–2024 mechanistic reviews retain PEX19’s receptor/chaperone role but emphasize that direct peroxisomal insertion and ER-derived vesicular routes may coexist; this uncertainty concerns trafficking detail, not the established causal relationship between PEX19 loss and membrane-biogenesis failure (rudowitz2023importandquality pages 1-2, jansen2019theperoxisomebiogenesis pages 1-2).

Representative direct abstract statements include:

“The patient was assigned to the PEX19 complementation group.” — Mohamed et al., 2010 (mohamed2010amutationin pages 1-2)

“Clinical exome sequencing yielded the diagnosis of Zellweger syndrome with a rare mutation in PEX-19 gene.” — Adiyapatham and Murugesan, 2023 (adiyapatham2023novelmutationcausing pages 1-2)

PEX19 “binds and stabilizes newly synthesized PMPs in the cytosol” and functions as “both a chaperone and an import receptor.” — Jones et al., 2004 (jones2004pex19isa pages 1-2)

The principal expert conclusion is therefore high-confidence disease causality but low-confidence phenotype frequency and intervention estimates. PEX19 loss clearly abolishes an early, indispensable stage of peroxisomal membrane construction. However, the field lacks a PEX19-specific natural-history cohort, standardized outcome measures, validated prognostic biomarkers and any genotype-targeted therapy.

References

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(NCT00004442 chunk 1): Study of Bile Acids in Patients With Peroxisomal Disorders. University of Cincinnati. ClinicalTrials.gov Identifier: NCT00004442
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(NCT03856866 chunk 1): Neal Sondheimer. Hydroxychloroquine Administration for Reduction of Pexophagy. The Hospital for Sick Children. 2019. ClinicalTrials.gov Identifier: NCT03856866
(snyder1999pex19pinteractswith pages 1-2): William B. Snyder, Klaas Nico Faber, Thibaut J. Wenzel, Antonius Koller, Georg H. Lüers, Linda Rangell, Gilbert A. Keller, and Suresh Subramani. Pex19p interacts with pex3p and pex10p and is essential for peroxisome biogenesis in pichia pastoris. Molecular biology of the cell, 10 6:1745-61, Jun 1999. URL: https://doi.org/10.1091/mbc.10.6.1745, doi:10.1091/mbc.10.6.1745. This article has 142 citations and is from a domain leading peer-reviewed journal.
(veldhoven2013peroxisomedeficientinvertebrate pages 9-10): Paul P. Van Veldhoven and Myriam Baes. Peroxisome deficient invertebrate and vertebrate animal models. Frontiers in Physiology, Nov 2013. URL: https://doi.org/10.3389/fphys.2013.00335, doi:10.3389/fphys.2013.00335. This article has 48 citations.
(veldhoven2013peroxisomedeficientinvertebrate pages 10-11): Paul P. Van Veldhoven and Myriam Baes. Peroxisome deficient invertebrate and vertebrate animal models. Frontiers in Physiology, Nov 2013. URL: https://doi.org/10.3389/fphys.2013.00335, doi:10.3389/fphys.2013.00335. This article has 48 citations.
(veldhoven2013peroxisomedeficientinvertebrate pages 13-14): Paul P. Van Veldhoven and Myriam Baes. Peroxisome deficient invertebrate and vertebrate animal models. Frontiers in Physiology, Nov 2013. URL: https://doi.org/10.3389/fphys.2013.00335, doi:10.3389/fphys.2013.00335. This article has 48 citations.
(rudowitz2023importandquality pages 1-2): Markus Rudowitz and Ralf Erdmann. Import and quality control of peroxisomal proteins. Journal of cell science, Aug 2023. URL: https://doi.org/10.1242/jcs.260999, doi:10.1242/jcs.260999. This article has 25 citations and is from a domain leading peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	14
Resolved	14
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	14
On topic	3
Off topic	1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

DOI:10.1136/bcr-2022-252014 (7 mentions) - Novel mutation causing Zellweger syndrome
shared terms: genetic

Weighed against this report's own most characteristic terms: pex19, disease, peroxisome, patient, include, peroxisomal, zsd, disorder, genetic, fibroblast, biogenesis, severe, pex19-specific, liver, membrane, infection, respiratory, neonatal, renal, phenotype.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

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

Outcome	Count
Terms checked	48
Resolved	47
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	0
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

Terms the report names something else

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

MONDO:0013951 (5 mentions) - the report calls it "if available"; MONDO calls it peroxisome biogenesis disorder 12A (Zellweger)

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0030259 (obsolete lipid glycosylation) (1 mention)

Ask OpenScientist

OpenScientist Report

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Progression

Prevalence

Clinical Trials

Experimental Models

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Peroxisome biogenesis disorder 12A due to PEX19

Scope and evidence standard

1. Disease information

Definition

Identifiers and synonyms

2. Etiology, risk, and protective factors

3. Phenotypes

PEX19-specific clinical spectrum

4. Genetic and molecular information

Causal gene and variants

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Molecular profiling

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Recommended approach

11. Outcome and prognosis

12. Treatment and real-world implementation

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Recent developments and expert interpretation

Artifacts

Reference Validation

References that may not be about this subject

Term Validation

Terms the report names something else

Obsolete terms