Rhizomelic chondrodysplasia punctata (RCDP) types 2-4 are autosomal recessive inborn errors of ether-phospholipid (plasmalogen) biosynthesis caused by biallelic loss-of-function variants in a single plasmalogen-synthesis enzyme rather than in a peroxisome import receptor. Three sequential enzymes feed the pathway: fatty acyl-CoA reductase 1 (FAR1; rate-limiting, supplies the fatty alcohol), glyceronephosphate O-acyltransferase (GNPAT/DHAPAT), and alkylglycerone-phosphate synthase (AGPS/alkyl-DHAP synthase; forms the ether bond). Loss of any one of these enzymes converges on the same lesion — cellular plasmalogen deficiency — producing a phenotype that overlaps classic RCDP1: rhizomelic limb shortening, chondrodysplasia punctata (stippled epiphyses), coronal vertebral clefts, congenital cataracts, severe growth and intellectual impairment, and seizures (FAR1 deficiency is distinguished by prominent microcephaly, epilepsy, and spasticity, often without rhizomelia). The critical biochemical discriminator from RCDP1 is that phytanic acid alpha-oxidation is preserved: RCDP1 (PEX7) and the PEX5 PTS2-binding-domain form (RCDP5) lose the PTS2 import receptor and therefore knock out both plasmalogen synthesis and phytanoyl-CoA hydroxylase, whereas these single-enzyme defects lie downstream of import and leave phytanic alpha-oxidation intact, so phytanic acid is normal. This entry models the single-enzyme plasmalogen-synthesis convergence (RCDP2 GNPAT, RCDP3 AGPS, RCDP4 FAR1 deficiency); the import-receptor forms RCDP1 (PEX7) and RCDP5 (PEX5), and the mechanistically inverse FAR1 gain-of-function disorder (plasmalogen elevation), are captured as differentials.
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Conditions with similar clinical presentations that must be differentiated from Rhizomelic Chondrodysplasia Punctata, Plasmalogen-Synthesis Defect:
name: Rhizomelic Chondrodysplasia Punctata, Plasmalogen-Synthesis Defect
creation_date: "2026-06-12T00:00:00Z"
category: Mendelian
description: >-
Rhizomelic chondrodysplasia punctata (RCDP) types 2-4 are autosomal recessive
inborn errors of ether-phospholipid (plasmalogen) biosynthesis caused by
biallelic loss-of-function variants in a single plasmalogen-synthesis enzyme
rather than in a peroxisome import receptor. Three sequential enzymes feed the
pathway: fatty acyl-CoA reductase 1 (FAR1; rate-limiting, supplies the fatty
alcohol), glyceronephosphate O-acyltransferase (GNPAT/DHAPAT), and
alkylglycerone-phosphate synthase (AGPS/alkyl-DHAP synthase; forms the
ether bond). Loss of any one of these enzymes converges on the same lesion —
cellular plasmalogen deficiency — producing a phenotype that overlaps
classic RCDP1: rhizomelic limb shortening, chondrodysplasia punctata
(stippled epiphyses), coronal vertebral clefts, congenital cataracts, severe
growth and intellectual impairment, and seizures (FAR1 deficiency is
distinguished by prominent microcephaly, epilepsy, and spasticity, often
without rhizomelia). The critical biochemical discriminator from RCDP1 is
that phytanic acid alpha-oxidation is preserved: RCDP1 (PEX7) and the PEX5
PTS2-binding-domain form (RCDP5) lose the PTS2 import receptor and therefore
knock out both plasmalogen synthesis and phytanoyl-CoA hydroxylase, whereas
these single-enzyme defects lie downstream of import and leave phytanic
alpha-oxidation intact, so phytanic acid is normal. This entry models the
single-enzyme plasmalogen-synthesis convergence (RCDP2 GNPAT, RCDP3 AGPS,
RCDP4 FAR1 deficiency); the import-receptor forms RCDP1 (PEX7) and RCDP5
(PEX5), and the mechanistically inverse FAR1 gain-of-function disorder
(plasmalogen elevation), are captured as differentials.
disease_term:
preferred_term: rhizomelic chondrodysplasia punctata (plasmalogen-synthesis defect)
term:
id: MONDO:0015776
label: rhizomelic chondrodysplasia punctata
synonyms:
- RCDP types 2-4
- Plasmalogen-biosynthesis-defect rhizomelic chondrodysplasia punctata
- GNPAT-, AGPS-, and FAR1-related rhizomelic chondrodysplasia punctata
- Single-enzyme RCDP
mappings:
mondo_mappings:
- term:
id: MONDO:0015776
label: rhizomelic chondrodysplasia punctata
mapping_predicate: skos:broadMatch
mapping_source: MONDO
mapping_justification: >-
This entry covers the plasmalogen-synthesis single-enzyme forms (RCDP2/3/4)
under the clinical RCDP umbrella; the umbrella also subsumes the
import-receptor forms RCDP1 (PEX7) and RCDP5 (PEX5), which are curated
separately, so a broadMatch is used rather than exactMatch.
- term:
id: MONDO:0017986
label: disorder of plasmalogens biosynthesis
mapping_predicate: skos:broadMatch
mapping_source: MONDO
mapping_justification: >-
The three convergent enzyme defects are disorders of plasmalogen
biosynthesis; this MONDO grouping additionally includes import-receptor
RCDP forms.
parents:
- peroxisomal single enzyme/protein defect
- disorder of plasmalogens biosynthesis
- inborn errors of metabolism
has_subtypes:
- name: RCDP2
display_name: RCDP type 2 (GNPAT / DHAPAT deficiency)
subtype_term:
preferred_term: rhizomelic chondrodysplasia punctata type 2
term:
id: MONDO:0009112
label: rhizomelic chondrodysplasia punctata type 2
description: >-
Autosomal recessive deficiency of glyceronephosphate O-acyltransferase
(GNPAT/DHAPAT), which catalyses the first committed peroxisomal step of
ether-lipid synthesis. RCDP2 patients have an isolated DHAPAT deficiency
with no other peroxisomal abnormalities, producing plasmalogen deficiency
with a classic RCDP clinical picture.
genes:
- preferred_term: GNPAT
term:
id: hgnc:4416
label: GNPAT
evidence:
- reference: CGGV:assertion_ba96f922-5ec9-4404-b2e4-66c31c2dcda6-2020-02-07T170000.000Z
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GNPAT | HGNC:4416 | glyceronephosphate O-acyltransferase deficiency | MONDO:0100273 | AR | Definitive"
explanation: >-
ClinGen classifies the GNPAT-RCDP2 (glyceronephosphate O-acyltransferase
deficiency) gene-disease relationship as Definitive with autosomal
recessive inheritance.
- reference: PMID:9536089
reference_title: "Acyl-CoA:dihydroxyacetonephosphate acyltransferase: cloning of the human cDNA and resolution of the molecular basis in rhizomelic chondrodysplasia punctata type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All RCDP type 2 patients analyzed were found to contain mutations in their
DHAPAT cDNA. This demonstrates that RCDP type 2 is the result of mutations
in DHAPAT.
explanation: >-
Identifies DHAPAT (GNPAT) mutations as the molecular cause of RCDP type 2.
- name: RCDP3
display_name: RCDP type 3 (AGPS / alkyl-DHAP synthase deficiency)
subtype_term:
preferred_term: rhizomelic chondrodysplasia punctata type 3
term:
id: MONDO:0010823
label: rhizomelic chondrodysplasia punctata type 3
description: >-
Autosomal recessive deficiency of alkylglycerone-phosphate synthase
(AGPS/alkyl-DHAP synthase), the peroxisomal enzyme that forms the
characteristic ether bond of plasmalogens. RCDP3 is an isolated enzyme
deficiency causing plasmalogen deficiency with the RCDP clinical phenotype.
genes:
- preferred_term: AGPS
term:
id: hgnc:327
label: AGPS
evidence:
- reference: CGGV:assertion_aba640e2-c95d-414b-8c72-d22769e4366a-2022-04-22T160000.000Z
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "AGPS | HGNC:327 | alkylglycerone-phosphate synthase deficiency | MONDO:0100274 | AR | Definitive"
explanation: >-
ClinGen classifies the AGPS-RCDP3 (alkylglycerone-phosphate synthase
deficiency) gene-disease relationship as Definitive with autosomal
recessive inheritance.
- reference: PMID:9553082
reference_title: Alkyl-dihydroxyacetonephosphate synthase. Fate in peroxisome biogenesis disorders and identification of the point mutation underlying a single enzyme deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
A patient with an isolated deficiency in alkyl-dihydroxyacetonephosphate
(DHAP) synthase activity had normal levels of this protein. Analysis at
the cDNA level revealed a missense mutation leading to a R419H
substitution in the enzyme of this patient.
explanation: >-
Identifies an AGPS (alkyl-DHAP synthase) point mutation as the cause of an
isolated single-enzyme deficiency (RCDP3).
- name: RCDP4
display_name: RCDP type 4 (FAR1 deficiency)
subtype_term:
preferred_term: fatty acyl-CoA reductase 1 deficiency
term:
id: MONDO:0014510
label: fatty acyl-CoA reductase 1 deficiency
description: >-
Autosomal recessive deficiency of fatty acyl-CoA reductase 1 (FAR1), the
rate-limiting enzyme that supplies the fatty alcohol for ether-lipid
synthesis. Loss-of-function abolishes reductase activity and depletes
plasmalogens. The clinical phenotype emphasises severe intellectual
disability, early-onset epilepsy, microcephaly, congenital cataracts, growth
retardation, and spasticity, frequently without the rhizomelia seen in
RCDP1-3.
genes:
- preferred_term: FAR1
term:
id: hgnc:26222
label: FAR1
evidence:
- reference: CGGV:assertion_91f6f864-5d07-4891-94b5-7f73bd71752c-2025-07-08T160000.000Z
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "FAR1 | HGNC:26222 | fatty acyl-CoA reductase 1 deficiency | MONDO:0014510 | AR | Moderate"
explanation: >-
ClinGen classifies the FAR1-deficiency (RCDP4) gene-disease relationship
as Moderate with autosomal recessive inheritance.
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We thus expand the spectrum of clinical features associated with defects
in plasmalogen biosynthesis to include FAR1 deficiency as a cause of
syndromic severe intellectual disability with cataracts, epilepsy, and
growth retardation but without rhizomelia.
explanation: >-
Establishes FAR1 deficiency (RCDP4) as a plasmalogen-biosynthesis disorder
with a distinctive cataract/epilepsy phenotype often without rhizomelia.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
RCDP2 (GNPAT), RCDP3 (AGPS), and RCDP4 (FAR1 deficiency) each require
biallelic pathogenic variants and are inherited as autosomal recessive
traits.
evidence:
- reference: CGGV:assertion_ba96f922-5ec9-4404-b2e4-66c31c2dcda6-2020-02-07T170000.000Z
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GNPAT | HGNC:4416 | glyceronephosphate O-acyltransferase deficiency | MONDO:0100273 | AR | Definitive"
explanation: >-
ClinGen records autosomal recessive inheritance (AR) for GNPAT-related
RCDP2; AGPS and FAR1-deficiency assertions are likewise AR.
pathophysiology:
- name: Plasmalogen-Synthesis Enzyme Deficiency
description: >-
Loss-of-function of a single ether-lipid biosynthetic enzyme — FAR1
(rate-limiting fatty-alcohol supply), GNPAT/DHAPAT (first acyltransferase
step), or AGPS/alkyl-DHAP synthase (ether-bond formation) — blocks
plasmalogen synthesis at a discrete step. Unlike RCDP1, the peroxisomal
PTS2 import machinery is intact, so only the affected enzyme is lost and
other PTS2-dependent functions (notably phytanic acid alpha-oxidation by
phytanoyl-CoA hydroxylase) are preserved.
genes:
- preferred_term: FAR1
term:
id: hgnc:26222
label: FAR1
- preferred_term: GNPAT
term:
id: hgnc:4416
label: GNPAT
- preferred_term: AGPS
term:
id: hgnc:327
label: AGPS
biological_processes:
- preferred_term: ether lipid biosynthetic process
term:
id: GO:0008611
label: ether lipid biosynthetic process
modifier: DECREASED
cellular_components:
- preferred_term: peroxisome
term:
id: GO:0005777
label: peroxisome
evidence:
- reference: PMID:9536089
reference_title: "Acyl-CoA:dihydroxyacetonephosphate acyltransferase: cloning of the human cDNA and resolution of the molecular basis in rhizomelic chondrodysplasia punctata type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients in the two other subgroups have been reported to be either
deficient in the activity of DHAPAT (RCDP type 2) or alkyl-DHAP synthase
(RCDP type 3) while no other abnormalities could be observed.
explanation: >-
Documents that RCDP2 and RCDP3 are isolated single-enzyme deficiencies
with no other peroxisomal abnormalities, distinguishing them from the
generalized PTS2-import lesion of RCDP1.
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
all three mutations abolished the reductase activity of FAR1, given that
no fatty alcohols could be detected.
explanation: >-
Functional assays show FAR1 loss-of-function abolishes reductase activity,
the enzymatic lesion upstream of plasmalogen deficiency in RCDP4.
downstream:
- target: Plasmalogen (Ether Lipid) Deficiency
description: >-
Loss of any single step in the FAR1 -> GNPAT -> AGPS sequence blocks
ether-phospholipid synthesis and depletes cellular plasmalogens.
causal_link_type: DIRECT
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We also observed reduced plasmalogens in red blood cells in one
individual to a range similar to that seen in individuals with RCDP,
further supporting abolished FAR1 activity.
explanation: >-
Demonstrates that a single-enzyme (FAR1) defect reduces plasmalogens to
the RCDP range, linking the enzyme lesion to plasmalogen deficiency.
- name: Plasmalogen (Ether Lipid) Deficiency
description: >-
Plasmalogens are ether glycerophospholipids with a vinyl-ether bond at the
sn-1 position. Their depletion disrupts membrane and myelin composition and
developmental signaling in bone, brain, lens, and other tissues, accounting
for the skeletal, ocular, and neurologic manifestations shared with RCDP1.
biological_processes:
- preferred_term: ether lipid biosynthetic process
term:
id: GO:0008611
label: ether lipid biosynthetic process
modifier: DECREASED
chemical_entities:
- preferred_term: plasmalogens
term:
id: CHEBI:64611
label: ether lipid
modifier: DECREASED
evidence:
- reference: PMID:22627108
reference_title: Functions of plasmalogen lipids in health and disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Their biosynthesis starts in peroxisomes, and defects at these steps cause
the malformation syndrome, Rhizomelic Chondrodysplasia Punctata (RCDP).
explanation: >-
Links defects in peroxisomal plasmalogen biosynthesis to the RCDP
malformation syndrome.
downstream:
- target: Skeletal Dysplasia
description: >-
Plasmalogen deficiency disrupts cartilage and bone development, producing
rhizomelic shortening and chondrodysplasia punctata.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:22627108
reference_title: Functions of plasmalogen lipids in health and disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The RCDP phenotype predicts developmental roles for plasmalogens in
bone, brain, lens, lung, kidney and heart.
explanation: >-
Supports a plasmalogen-dependent developmental role in bone underlying
the skeletal dysplasia.
- target: Congenital Cataract
description: >-
Plasmalogen deficiency disrupts lens fiber development, producing
congenital cataracts.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:22627108
reference_title: Functions of plasmalogen lipids in health and disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The RCDP phenotype predicts developmental roles for plasmalogens in
bone, brain, lens, lung, kidney and heart.
explanation: >-
Supports a plasmalogen-dependent developmental role in the lens
underlying cataract.
- target: Neurological Impairment
description: >-
Plasmalogen deficiency disrupts CNS neuronal and myelin development,
producing intellectual disability, epilepsy, and (in FAR1 deficiency)
microcephaly and spasticity.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:36720320
reference_title: Regulation of plasmalogen biosynthesis in mammalian cells and tissues.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Dysregulation of plasmalogen synthesis impairs cholesterol synthesis in
cells and brain, resulting in the reduced expression of genes such as
mRNA encoding myelin basic protein, a phenotype found in the cerebellum
of plasmalogen-deficient mice.
explanation: >-
Plasmalogen-deficient mice show impaired brain cholesterol synthesis and
reduced myelin basic protein expression, a mechanistic link between
plasmalogen deficiency and the CNS/myelin phenotype.
- name: Preserved Phytanic Acid Alpha-Oxidation
description: >-
Because the lesion is a single ether-lipid enzyme downstream of peroxisomal
matrix import, the PTS2 enzyme phytanoyl-CoA hydroxylase is still imported
and functional, so phytanic acid alpha-oxidation is preserved and plasma
phytanic acid is normal. This is the key biochemical fork distinguishing the
single-enzyme forms (RCDP2/3/4) from the import-receptor forms RCDP1 (PEX7)
and RCDP5 (PEX5), in which loss of the PTS2 receptor knocks out both
plasmalogen synthesis and phytanic alpha-oxidation.
biological_processes:
- preferred_term: fatty acid alpha-oxidation
term:
id: GO:0001561
label: fatty acid alpha-oxidation
chemical_entities:
- preferred_term: phytanic acid
term:
id: CHEBI:16285
label: phytanic acid
evidence:
- reference: PMID:9536089
reference_title: "Acyl-CoA:dihydroxyacetonephosphate acyltransferase: cloning of the human cDNA and resolution of the molecular basis in rhizomelic chondrodysplasia punctata type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients in the two other subgroups have been reported to be either
deficient in the activity of DHAPAT (RCDP type 2) or alkyl-DHAP synthase
(RCDP type 3) while no other abnormalities could be observed.
explanation: >-
The isolated single-enzyme deficiency with no other peroxisomal
abnormalities implies preserved phytanic alpha-oxidation, unlike the
generalized RCDP1 import lesion.
- name: Skeletal Dysplasia
description: >-
Plasmalogen-dependent disruption of cartilage and bone development produces
rhizomelic (proximal) limb shortening, chondrodysplasia punctata with
stippled epiphyses, and coronal vertebral clefts in RCDP2/3 (and variably
in RCDP4).
cell_types:
- preferred_term: chondrocyte
term:
id: CL:0000138
label: chondrocyte
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Rhizomelic chondrodysplasia punctata (RCDP) is a group of disorders with
overlapping clinical features including rhizomelia, chondrodysplasia
punctata, coronal clefts, cervical dysplasia, congenital cataracts,
profound postnatal growth retardation, severe intellectual disability, and
seizures.
explanation: >-
Enumerates the rhizomelia, chondrodysplasia punctata, and coronal clefts
that define the skeletal dysplasia across RCDP forms.
- name: Congenital Cataract
description: >-
Plasmalogen deficiency disrupts lens fiber development, producing cataracts
usually present at birth or in early infancy; cataract is a consistent
feature across all three single-enzyme forms.
cell_types:
- preferred_term: lens fiber cell
term:
id: CL:0011004
label: lens fiber cell
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we report the identification of mutations in another gene in plasmalogen
biosynthesis, fatty acyl-CoA reductase 1 (FAR1), in two families affected
by severe intellectual disability, early-onset epilepsy, microcephaly,
congenital cataracts, growth retardation, and spasticity.
explanation: >-
Documents congenital cataracts as a core feature of FAR1 deficiency
(RCDP4) and the broader plasmalogen-synthesis group.
- name: Neurological Impairment
description: >-
CNS plasmalogen deficiency impairs neuronal and myelin development,
producing severe intellectual disability and seizures; FAR1 deficiency
additionally features microcephaly and spasticity.
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
- preferred_term: oligodendrocyte
term:
id: CL:0000128
label: oligodendrocyte
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
in two families affected by severe intellectual disability, early-onset
epilepsy, microcephaly, congenital cataracts, growth retardation, and
spasticity.
explanation: >-
Documents the severe neurodevelopmental phenotype (intellectual
disability, epilepsy, microcephaly, spasticity) of FAR1 deficiency.
phenotypes:
- name: Rhizomelia
category: Musculoskeletal
diagnostic: true
description: >-
Symmetrical proximal limb shortening is a defining skeletal feature of
RCDP2/3; it is often absent in FAR1 deficiency (RCDP4).
phenotype_term:
preferred_term: Rhizomelia
term:
id: HP:0008905
label: Rhizomelia
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Rhizomelic chondrodysplasia punctata (RCDP) is a group of disorders with
overlapping clinical features including rhizomelia, chondrodysplasia
punctata, coronal clefts, cervical dysplasia, congenital cataracts,
profound postnatal growth retardation, severe intellectual disability, and
seizures.
explanation: >-
Lists rhizomelia among the overlapping clinical features of the RCDP group.
- name: Chondrodysplasia Punctata
category: Musculoskeletal
diagnostic: true
description: >-
Punctate calcifications in cartilage with epiphyseal stippling are the
radiographic hallmark of the disorder.
phenotype_term:
preferred_term: Epiphyseal stippling
term:
id: HP:0010655
label: Epiphyseal stippling
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
overlapping clinical features including rhizomelia, chondrodysplasia
punctata, coronal clefts
explanation: >-
Documents chondrodysplasia punctata as a defining feature of the RCDP
group.
- name: Coronal Cleft Vertebrae
category: Musculoskeletal
description: >-
Coronal clefts of the vertebral bodies are a characteristic spinal
radiographic finding in the RCDP group.
phenotype_term:
preferred_term: Coronal cleft vertebrae
term:
id: HP:0003417
label: Coronal cleft vertebrae
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
overlapping clinical features including rhizomelia, chondrodysplasia
punctata, coronal clefts, cervical dysplasia, congenital cataracts
explanation: >-
Lists coronal clefts among the overlapping skeletal features of RCDP.
- name: Cataract
category: Visual
diagnostic: true
description: >-
Congenital cataracts occur across all three single-enzyme forms and are a
prominent feature of FAR1 deficiency.
phenotype_term:
preferred_term: Cataract
term:
id: HP:0000518
label: Cataract
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
severe intellectual disability, early-onset epilepsy, microcephaly,
congenital cataracts, growth retardation, and spasticity.
explanation: >-
Documents congenital cataracts in FAR1 deficiency and the RCDP group.
- name: Postnatal Growth Deficiency
category: Growth
description: >-
Profound postnatal growth retardation is characteristic of the RCDP group.
phenotype_term:
preferred_term: Postnatal growth retardation
term:
id: HP:0008897
label: Postnatal growth retardation
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
profound postnatal growth retardation, severe intellectual disability, and
seizures.
explanation: >-
Documents profound postnatal growth retardation in the RCDP group.
- name: Intellectual Disability
category: Neurologic
description: >-
Severe intellectual disability is consistent across the single-enzyme RCDP
forms.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
two families affected by severe intellectual disability, early-onset
epilepsy, microcephaly, congenital cataracts, growth retardation, and
spasticity.
explanation: >-
Documents severe intellectual disability in FAR1 deficiency and the RCDP
group.
- name: Seizures
category: Neurologic
description: >-
Seizures/early-onset epilepsy occur in the RCDP group and are prominent in
FAR1 deficiency.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
severe intellectual disability, early-onset epilepsy, microcephaly
explanation: >-
Documents early-onset epilepsy/seizures in FAR1 deficiency.
- name: Microcephaly
category: Neurologic
description: >-
Microcephaly is a distinguishing feature of FAR1 deficiency (RCDP4).
phenotype_term:
preferred_term: Microcephaly
term:
id: HP:0000252
label: Microcephaly
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
severe intellectual disability, early-onset epilepsy, microcephaly,
congenital cataracts
explanation: >-
Documents microcephaly as a feature of FAR1 deficiency.
- name: Spasticity
category: Neurologic
description: >-
Spasticity is a distinguishing feature of FAR1 deficiency (RCDP4).
phenotype_term:
preferred_term: Spasticity
term:
id: HP:0001257
label: Spasticity
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
congenital cataracts, growth retardation, and spasticity.
explanation: >-
Documents spasticity as a feature of FAR1 deficiency.
genetic:
- name: GNPAT
gene_term:
preferred_term: GNPAT
term:
id: hgnc:4416
label: GNPAT
association: >-
Biallelic loss-of-function variants in GNPAT (encoding DHAPAT) cause RCDP
type 2, an isolated DHAPAT deficiency. ClinGen classifies the gene-disease
relationship as Definitive.
evidence:
- reference: PMID:9536089
reference_title: "Acyl-CoA:dihydroxyacetonephosphate acyltransferase: cloning of the human cDNA and resolution of the molecular basis in rhizomelic chondrodysplasia punctata type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All RCDP type 2 patients analyzed were found to contain mutations in their
DHAPAT cDNA. This demonstrates that RCDP type 2 is the result of mutations
in DHAPAT.
explanation: >-
Establishes DHAPAT (GNPAT) mutations as the cause of RCDP type 2.
- name: AGPS
gene_term:
preferred_term: AGPS
term:
id: hgnc:327
label: AGPS
association: >-
Biallelic loss-of-function variants in AGPS (encoding alkyl-DHAP synthase)
cause RCDP type 3, an isolated alkyl-DHAP synthase deficiency. ClinGen
classifies the gene-disease relationship as Definitive.
evidence:
- reference: PMID:9553082
reference_title: Alkyl-dihydroxyacetonephosphate synthase. Fate in peroxisome biogenesis disorders and identification of the point mutation underlying a single enzyme deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Expression of a recombinant protein carrying this mutation in Escherichia
coli yielded an inactive enzyme
explanation: >-
Functional expression confirms the AGPS missense mutation abolishes enzyme
activity, establishing causality for RCDP3.
- name: FAR1
gene_term:
preferred_term: FAR1
term:
id: hgnc:26222
label: FAR1
association: >-
Biallelic loss-of-function variants in FAR1 cause RCDP type 4 (FAR1
deficiency) by abolishing the rate-limiting fatty acyl-CoA reductase step of
plasmalogen synthesis. ClinGen classifies the gene-disease relationship as
Moderate.
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
all three mutations abolished the reductase activity of FAR1, given that
no fatty alcohols could be detected.
explanation: >-
Functional assays establish that the FAR1 variants abolish reductase
activity, the molecular cause of RCDP4.
biochemical:
- name: Plasmalogens
presence: Decreased
context: >-
Erythrocyte and tissue plasmalogens are reduced because a plasmalogen-
synthesis enzyme (FAR1, GNPAT, or AGPS) is non-functional. Reduced
plasmalogens are the shared biochemical readout of the convergence.
readouts:
- target: Plasmalogen (Ether Lipid) Deficiency
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
interpretation: >-
Decreased plasmalogens report failure of ether-lipid synthesis at the
affected enzyme step.
biomarker_term:
preferred_term: plasmalogens
term:
id: CHEBI:64611
label: ether lipid
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We also observed reduced plasmalogens in red blood cells in one individual
to a range similar to that seen in individuals with RCDP, further
supporting abolished FAR1 activity.
explanation: >-
Reduced red-blood-cell plasmalogens are the biochemical hallmark of the
single-enzyme RCDP forms.
- name: Phytanic acid
presence: Normal
context: >-
Plasma phytanic acid is characteristically NORMAL in the single-enzyme
plasmalogen-synthesis forms because phytanoyl-CoA hydroxylase (a PTS2 enzyme)
is still imported and functional. Normal phytanic acid distinguishes
RCDP2/3/4 from RCDP1 (PEX7) and RCDP5 (PEX5), where phytanic accumulates.
biomarker_term:
preferred_term: phytanic acid
term:
id: CHEBI:16285
label: phytanic acid
evidence:
- reference: PMID:9536089
reference_title: "Acyl-CoA:dihydroxyacetonephosphate acyltransferase: cloning of the human cDNA and resolution of the molecular basis in rhizomelic chondrodysplasia punctata type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients in the two other subgroups have been reported to be either
deficient in the activity of DHAPAT (RCDP type 2) or alkyl-DHAP synthase
(RCDP type 3) while no other abnormalities could be observed.
explanation: >-
The isolated enzyme deficiency with no other peroxisomal abnormalities
implies preserved phytanic alpha-oxidation and normal phytanic acid.
treatments:
- name: Supportive and Rehabilitative Care
description: >-
Management is supportive: physical therapy and orthopedic procedures for
contractures and skeletal deformity, antiseizure medication for epilepsy,
and developmental support.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
target_phenotypes:
- preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
- preferred_term: Spasticity
term:
id: HP:0001257
label: Spasticity
evidence:
- reference: PMID:22627108
reference_title: Functions of plasmalogen lipids in health and disease.
supports: NO_EVIDENCE
evidence_source: HUMAN_CLINICAL
snippet: >-
Their biosynthesis starts in peroxisomes, and defects at these steps cause
the malformation syndrome, Rhizomelic Chondrodysplasia Punctata (RCDP).
explanation: >-
No disease-modifying therapy exists for RCDP; management is supportive
care by clinical convention. This snippet describes the disease mechanism,
not a treatment intervention.
- name: Cataract Extraction
description: >-
Surgical removal of congenital cataracts can restore and/or preserve vision.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
target_phenotypes:
- preferred_term: Cataract
term:
id: HP:0000518
label: Cataract
evidence:
- reference: PMID:25439727
reference_title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
supports: NO_EVIDENCE
evidence_source: HUMAN_CLINICAL
snippet: >-
severe intellectual disability, early-onset epilepsy, microcephaly,
congenital cataracts, growth retardation, and spasticity.
explanation: >-
Congenital cataracts are present in RCDP and are amenable to surgical
extraction by standard ophthalmologic practice; this snippet establishes
cataract as a feature but does not describe the surgical intervention.
differential_diagnoses:
- name: Rhizomelic Chondrodysplasia Punctata Type 1
disease_term:
preferred_term: rhizomelic chondrodysplasia punctata type 1
term:
id: MONDO:0008972
label: rhizomelic chondrodysplasia punctata type 1
description: >-
RCDP1 is caused by biallelic PEX7 variants that abolish the cytosolic PTS2
import receptor, producing a generalized loss of PTS2 cargo — including both
plasmalogen-synthesis enzymes and phytanoyl-CoA hydroxylase — so plasmalogens
are deficient AND phytanic acid accumulates.
distinguishing_features:
- >-
RCDP1 is a PTS2 import-receptor defect with combined plasmalogen deficiency
and elevated phytanic acid; RCDP2/3/4 are single-enzyme plasmalogen-synthesis
defects with normal phytanic acid.
- name: Rhizomelic Chondrodysplasia Punctata Type 5
disease_term:
preferred_term: rhizomelic chondrodysplasia punctata type 5
term:
id: MONDO:0014743
label: rhizomelic chondrodysplasia punctata type 5
description: >-
RCDP5 results from PEX5 variants affecting the PEX7-binding domain, which
impairs PTS2 import similarly to RCDP1 (an import-receptor lesion), not a
single ether-lipid enzyme defect.
distinguishing_features:
- >-
RCDP5 is a PEX5 PTS2-binding-domain import defect; the single-enzyme forms in
this entry leave peroxisomal import intact.
- name: FAR1 Upregulation Disorder (gain-of-function)
disease_term:
preferred_term: fatty acyl-CoA reductase 1 upregulation
term:
id: MONDO:0100230
label: fatty acyl-CoA reductase 1 upregulation
description: >-
Autosomal dominant gain-of-function FAR1 variants disrupt the feedback
control of FAR1 stability, causing plasmalogen ELEVATION rather than
deficiency. Despite the opposite biochemical direction, affected individuals
share a neurodevelopmental phenotype with cataracts and spasticity,
illustrating the tight homeostatic requirement for plasmalogen dosage.
distinguishing_features:
- >-
FAR1 gain-of-function (AD) causes plasmalogen elevation via impaired FAR1
feedback regulation; RCDP4 is FAR1 loss-of-function (AR) causing plasmalogen
deficiency.
- name: Zellweger Spectrum Disorders
disease_term:
preferred_term: Zellweger spectrum disorders
term:
id: MONDO:0019609
label: Zellweger spectrum disorders
description: >-
ZSD results from generalized peroxisomal matrix-import failure (PEX genes)
affecting both PTS1 and PTS2 cargo, producing VLCFA accumulation alongside
plasmalogen and phytanic/bile-acid abnormalities.
distinguishing_features:
- >-
ZSD has generalized peroxisomal dysfunction with elevated VLCFA; the
single-enzyme RCDP forms have an isolated plasmalogen-synthesis defect with
normal VLCFA and phytanic acid.
notes: >-
Scope/anchor note for reviewers: there is no MONDO grouping term that cleanly
covers RCDP types 2-4 while excluding the import-receptor forms (RCDP1/PEX7,
RCDP5/PEX5), so this entry is anchored to the clinical umbrella
MONDO:0015776 (broadMatch) and scoped via subtypes to the single-enzyme
plasmalogen-synthesis defects GNPAT (RCDP2), AGPS (RCDP3), and FAR1 deficiency
(RCDP4). Two corrections were made versus the auto-generated issue scaffold on
#4181: (1) MONDO:0014743 "rhizomelic chondrodysplasia punctata type 5" is a
PEX5 PTS2-binding-domain import defect (HGNC:9719 PEX5), not a FAR1 disorder,
so it is modeled as a differential rather than a plasmalogen-synthesis subtype;
(2) MONDO:0100230 "FAR1 upregulation" is an autosomal dominant gain-of-function
disorder causing plasmalogen ELEVATION (the mechanistic inverse of the
deficiency convergence) and is therefore a differential, not a co-equal
deficiency subtype.