This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "peroxisomal_metabolic_failure#Toxic Fatty-Acid Accumulation with Ether-Lipid Deficiency").
THE TWO ARMS ARE NOT INTERCHANGEABLE, AND A CONFORMER MUST SAY WHICH IT ENTERS BY. The generalized biogenesis arm (PEX1, PEX6, PEX26 and the other ZSD-PEX genes; Zellweger spectrum disorder) knocks out every peroxisomal pathway at once, so accumulation and deficiency co-occur. The selective arms do not: - PEX7 (rhizomelic chondrodysplasia punctata type 1) fails only the PTS2 import
route, so plasmalogen synthesis and phytanic acid alpha-oxidation fail while
PTS1-dependent VLCFA beta-oxidation is preserved - VLCFAs are normal in RCDP.
- GNPAT and AGPS (RCDP types 2 and 3) fail plasmalogen synthesis alone, with no
fatty-acid accumulation at all.
- ABCD1 (X-linked adrenoleukodystrophy) fails only VLCFA import for
beta-oxidation; plasmalogens are secondarily, not primarily, reduced.
- PHYH (adult Refsum disease) fails only phytanic acid alpha-oxidation. A conforming entry should therefore attach at the specific sub-branch its biochemistry supports and must NOT inherit the full two-sided lesion of the biogenesis arm. Curating normal-range analytes as accumulated is the single most likely error when conforming to this module.
WORKED NEGATIVE EXAMPLE, because this error is easy to make: the central effector below asserts accumulation AND deficiency together, so a disorder with only the deficiency half should not attach to it. Rhizomelic_Chondrodysplasia_Punctata_Plasmalogen_Synthesis_Defect (GNPAT/AGPS) therefore conforms at the trigger node only - its own pathophysiology records that phytanic acid alpha-oxidation is preserved and plasma phytanic acid is normal. Rhizomelic_Chondrodysplasia_Punctata_Type_1 (PEX7) does conform at the central effector, because losing PTS2 import blocks phytanic acid alpha-oxidation as well as plasmalogen synthesis, so both halves hold.
RELATIONSHIP TO cns_myelin_failure. Plasmalogen deficiency causes generalized CNS hypomyelination progressing to demyelination, and oligodendrocytes require plasmalogens to ensheath and initiate membrane wrapping; VLCFA accumulation in X-ALD produces loss of myelin and oligodendrocytes. The peroxisomal leukodystrophies are therefore genuine conformers of BOTH modules, at different nodes: this module explains how the toxic substrate arises and the ether lipid is lost, and cns_myelin_failure explains what that does to the oligodendrocyte lineage and the sheath. This module deliberately stops at the neural-membrane and redox lesion and does not re-derive the myelin chain.
RELATIONSHIP TO lysosomal_substrate_accumulation. The two are structurally parallel - an organelle-localized degradative failure producing substrate accumulation - but they are different organelles with different substrates and are not interchangeable. Do not route a peroxisomal disorder through the lysosomal module.
NEURONAL MIGRATION IS A BIOGENESIS-ARM FEATURE ONLY. The severe biogenesis disorders carry congenital neuronal migration defects, which are a developmental malformation established in utero, not a consequence of postnatal substrate accumulation. Milder ZSD phenotypes do not have congenital malformations at all. A conformer should curate migration defects on its own node and may cross-reference microtubule_dependent_neuronal_migration_failure; this module records the association without claiming the postnatal metabolic chain produces it.
Peroxisomal Biogenesis or Enzyme Defect
trigger
A heritable lesion disables peroxisomal function, by one of two routes. In the peroxisome biogenesis disorders, mutation of a PEX gene impairs membrane assembly, import of peroxisomal matrix proteins, or division of the organelle, so that peroxisomal enzymes are not delivered to a functional compartment. In the single-enzyme and single-transporter defects the organelle is assembled normally but one pathway within it - a transporter such as ABCD1, an alpha-oxidation enzyme such as PHYH, or an ether-lipid synthase such as GNPAT or AGPS - is lost. Which route the lesion takes determines how much of the downstream biochemistry is affected, and conforming entries must specialize this node accordingly.
Downstream
-
Failure of Peroxisomal Fatty-Acid Oxidation and Ether-Lipid Synthesis
Loss of the organelle or of one of its enzymes disables the metabolic pathways it uniquely carries.
Failure of Peroxisomal Fatty-Acid Oxidation and Ether-Lipid Synthesis
amplifier
The two metabolic functions peroxisomes uniquely perform fail. On the catabolic side, beta-oxidation of very-long-chain and branched-chain fatty acids and alpha-oxidation of phytanic acid can no longer proceed; on the anabolic side, the first committed steps of ether-linked glycerophospholipid synthesis, which are peroxisomal, can no longer produce plasmalogens. In the biogenesis disorders both sides fail together. In the selective disorders only one does, and which one is the biochemical signature that distinguishes them.
Downstream
-
Toxic Fatty-Acid Accumulation with Ether-Lipid Deficiency
Undegraded substrate accumulates while the unmade product falls.
Toxic Fatty-Acid Accumulation with Ether-Lipid Deficiency
central effector
The rate-limiting, disorder-agnostic convergence point of the module and its key conformance target. The metabolic block produces a characteristic two-sided lesion: substrates that cannot be degraded accumulate in plasma and tissue (very-long-chain fatty acids in the biogenesis disorders and in X-linked adrenoleukodystrophy, phytanic acid in Refsum disease and in the PTS2-import disorders), while plasmalogens that cannot be synthesized fall. In cerebral adrenoleukodystrophy both sides are measurable in the same brain white matter, and the plasmalogen loss there tracks with oxidative stress rather than being independent of it. Conforming entries must specialize this node to the analytes their own disorder actually perturbs, and must not assert accumulation of a substrate their disorder leaves in the normal range.
Downstream
-
Neural Membrane and Redox Dysfunction
Loss of the most abundant ether phospholipid of myelin, plus accumulation of membrane-disruptive pro-oxidant fatty acids, damages membrane-rich neural tissue.
Neural Membrane and Redox Dysfunction
effector
The biochemical lesion becomes a cellular one in the tissues whose function depends most on membrane lipid composition. Plasmalogens are the most abundant form of ether phospholipids in myelin, and oligodendrocytes require them intrinsically in order to ensheath an axon and initiate membrane wrapping; their loss produces generalized CNS hypomyelination that evolves into progressive demyelination with astrocytosis and white-matter-selective microgliosis. In parallel, accumulated very-long-chain fatty acids drive reactive oxygen species production and lipid peroxidation, with reactive lipid aldehydes and oxidized proteins detectable throughout the affected brain rather than only within plaques. Retina, peripheral nerve, adrenal cortex, liver, and kidney are affected alongside white matter.
Downstream
-
Multisystem Peroxisomal Disease
Injury to membrane-rich and myelinating tissues manifests as the characteristic multisystem clinical spectrum.
Multisystem Peroxisomal Disease
consequence
The clinical endpoint of the module: a phenotypic continuum, not a single syndrome. At the severe end, affected newborns are hypotonic, feed poorly, and carry congenital malformations - neuronal migration defects with neonatal-onset seizures, renal cysts, and chondrodysplasia punctata - with severe liver disease and death usually within the first year. At the milder end there are no congenital malformations at all, and the disease is instead a progressive peroxisomal dysfunction expressed as retinal dystrophy and sensorineural hearing loss, ataxia, polyneuropathy and leukodystrophy, liver dysfunction, adrenal insufficiency, and renal oxalate stones, with intellect that can be normal. The single-enzyme disorders occupy their own narrower slices of this range. Conforming entries specialize this node to their own position on the spectrum; the module deliberately asserts no uniform severity or age of onset.