Rhizomelic chondrodysplasia punctata type 5 is caused by biallelic PEX5 variants that remove the long isoform of the protein while sparing the short one. It exists as a distinct entity because of an isoform accident with unusually clean mechanistic consequences. PEX5 is the cytosolic receptor for peroxisomal matrix proteins carrying targeting signal 1, and it is transcribed as two isoforms: PEX5S, which does PTS1 import only, and PEX5L, which does PTS1 import and additionally acts as the co-receptor through which PEX7 delivers PTS2-tagged cargo. Every previously reported PEX5 patient had a Zellweger spectrum disorder, because their variants knocked out PTS1 import. The RCDP5 variant sits in exon 9, which is specific to the long isoform, so PTS1 import survives intact and only the PTS2 arm fails - reproducing exactly the lesion that PEX7 loss produces in RCDP1, from the other side of the same receptor complex. One gene therefore gives two unrelated diseases depending on which isoform an allele hits, and the practical consequence is stated in the founding paper: a patient with a selective PTS2 import defect needs PEX7 sequenced and PEX5 exon 9 sequenced, because the biochemistry alone will not tell them apart. Clinically the four reported patients had congenital cataracts, postnatal growth delay, microcephaly, and severe intellectual disability, but only mild humeral shortening in three and chondrodysplasia punctata in two - a milder and less consistently rhizomelic skeletal picture than classic RCDP1, which matters when deciding whether to look for the disorder at all.
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Conditions with similar clinical presentations that must be differentiated from Rhizomelic Chondrodysplasia Punctata Type 5:
name: Rhizomelic Chondrodysplasia Punctata Type 5
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
Rhizomelic chondrodysplasia punctata type 5 is caused by biallelic PEX5 variants that
remove the long isoform of the protein while sparing the short one. It exists as a
distinct entity because of an isoform accident with unusually clean mechanistic
consequences. PEX5 is the cytosolic receptor for peroxisomal matrix proteins carrying
targeting signal 1, and it is transcribed as two isoforms: PEX5S, which does PTS1
import only, and PEX5L, which does PTS1 import and additionally acts as the co-receptor
through which PEX7 delivers PTS2-tagged cargo. Every previously reported PEX5 patient
had a Zellweger spectrum disorder, because their variants knocked out PTS1 import.
The RCDP5 variant sits in exon 9, which is specific to the long isoform, so PTS1 import
survives intact and only the PTS2 arm fails - reproducing exactly the lesion that PEX7
loss produces in RCDP1, from the other side of the same receptor complex. One gene
therefore gives two unrelated diseases depending on which isoform an allele hits, and
the practical consequence is stated in the founding paper: a patient with a selective
PTS2 import defect needs PEX7 sequenced and PEX5 exon 9 sequenced, because the
biochemistry alone will not tell them apart. Clinically the four reported patients had
congenital cataracts, postnatal growth delay, microcephaly, and severe intellectual
disability, but only mild humeral shortening in three and chondrodysplasia punctata in
two - a milder and less consistently rhizomelic skeletal picture than classic RCDP1,
which matters when deciding whether to look for the disorder at all.
synonyms:
- RCDP5
- PEX5 rhizomelic chondrodysplasia punctata
- Rhizomelic chondrodysplasia punctata, type 5
- PEX5L deficiency
disease_term:
preferred_term: rhizomelic chondrodysplasia punctata type 5
term:
id: MONDO:0014743
label: rhizomelic chondrodysplasia punctata type 5
parents:
- Rhizomelic Chondrodysplasia Punctata
- Peroxisome Biogenesis Disorder
classifications:
harrisons_chapter:
- classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
An autosomal recessive Mendelian skeletal dysplasia diagnosed by molecular testing.
- classification_value: ENDOCRINOLOGY_METABOLISM
notes: >-
Also an inborn error of metabolism: the entity is defined by a selective peroxisomal
protein-import defect with a measurable metabolite signature - reduced plasmalogens
with elevated phytanic acid.
icimd_category:
- classification_value: peroxisomal_biogenesis
notes: >-
ICIMD (Ferreira et al. 2021, PMID:33340416): group "Peroxisomal biogenesis disorders
(peroxin-related)" under category "Disorders of organelle biogenesis, dynamics and
interactions". PEX5 is a peroxin and the lesion is at the matrix-protein import step,
which is the same reasoning that places RCDP1 (PEX7) here and distinguishes both from
the single-enzyme forms RCDP2/3/4, which take "Disorders of glycerophospholipid
metabolism".
isds_skeletal_category:
- classification_value: chondrodysplasia_punctata
notes: >-
ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
PMID:36779427), group 23 "Chondrodysplasia punctata (CDP) group", row
NOS 23-0100 "Rhizomelic CDP, PEX5-related" (MIM 616716). This row is new relative to
the 2019 revision, which predated wide recognition of the entity; the group itself
was numbered 21 there. The nosology lists the five rhizomelic-CDP entities as five
separate rows by gene, and dismech follows that split here rather than folding this
entity into the PEX7 entry.
mappings:
mondo_mappings:
- term:
id: MONDO:0014743
label: rhizomelic chondrodysplasia punctata type 5
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
The dismech entry and the MONDO class denote the same entity: PEX5-related rhizomelic
chondrodysplasia punctata arising from loss of the PEX5 long isoform. The other PEX5
phenotype, Zellweger spectrum disorder from loss of PTS1 import, is a separate concept
and is handled here as a differential.
references:
- reference: PMID:26220973
title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
- reference: PMID:20301447
title: "PEX7-Related Rhizomelic Chondrodysplasia Punctata."
tags:
- GeneReviews
prevalence:
- population: Reported patients
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
The entity was defined on four patients from two independent families, all homozygous
for the same frameshift allele. No prevalence estimate exists, and the founding paper
argues the entity is likely under-ascertained because its biochemistry is
indistinguishable from RCDP1.
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In four patients with RCDP from two independent families, we identified a homozygous
frame shift mutation
explanation: Gives the size and structure of the founding cohort.
progression:
- phase: Infancy - congenital cataracts
notes: >-
All four reported patients had congenital cataracts requiring surgery in the first
months. As in RCDP1, the cataract is the earliest and most consistent feature and
typically precedes recognition of the metabolic disorder.
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the phenotype in our patients, including congenital cataracts,
explanation: Records congenital cataracts as a feature of the reported cohort.
- phase: Early childhood - growth delay, microcephaly, developmental impairment
notes: >-
Growth delay and microcephaly emerge after the first one to two years, with severe
intellectual disability in all four patients. Seizures with epileptiform EEG developed
in several.
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
postnatal growth delay, microcephaly and severe intellectual
disability in all four patients, mild shortening of humeri in
three patients, and chondrodysplasia punctata in two patients,
explanation: >-
Gives the phenotype with the per-feature counts, including the important observation
that the skeletal features were present in only some patients.
- phase: Survival beyond the first decade
notes: >-
Unlike classic RCDP1, where death within the first decade is typical, the reported
RCDP5 patients survived into the second decade, with clinical assessments recorded at
9.5, 10.5, and 13 years.
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
while some individuals lack rhizomelia, show less profound
growth and developmental delays, and have longer survival
explanation: >-
Support is partial: the quoted sentence describes the nonclassic RCDP phenotype in
general, which is the pattern the reported RCDP5 patients fit, rather than making a
survival claim about RCDP5 specifically.
pathophysiology:
- name: Loss of the PEX5 Long Isoform
biological_scale: MOLECULAR
description: >-
PEX5 is transcribed as two isoforms. Both PEX5L and PEX5S recognize PTS1-tagged cargo,
but only PEX5L serves as the co-receptor for PEX7-mediated import of PTS2-tagged cargo.
The RCDP5 frameshift lies in exon 9, which is present only in the long transcript, so
it removes PEX5L and leaves PEX5S intact. This is the whole mechanism of the disorder
and the reason it is not a Zellweger spectrum disorder.
genetic_context:
functional_impact_category: LOSS_OF_FUNCTION
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
gene:
preferred_term: PEX5
term:
id: hgnc:9719
label: PEX5
description: >-
Homozygous frameshift in the PEX5L-specific exon 9 in all four reported patients from
two independent families. The functional impact is isoform-selective rather than
whole-gene: PEX5S is unaffected, which is why PTS1 import is preserved.
biological_processes:
- preferred_term: protein import into peroxisome matrix
modifier: DECREASED
term:
id: GO:0016558
label: protein import into peroxisome matrix
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
PEX5 encodes two isoforms, PEX5L and PEX5S, and we show that the c.722dupA mutation,
located in the PEX5L-specific exon 9, results in loss of PEX5L only.
explanation: Establishes the isoform-selective consequence of the variant.
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We demonstrate that PEX5L expression restores the import of PTS2-tagged proteins in
patient fibroblasts.
explanation: >-
Complementation of patient fibroblasts with PEX5L restores the defective function,
establishing causation rather than association.
downstream:
- target: Selective PTS2 Import Failure
description: >-
With PEX5L gone, PEX7 has no co-receptor, so PTS2-tagged cargo is not delivered into
the peroxisomal matrix, while PTS1 import proceeds through the surviving short
isoform.
causal_link_type: DIRECT
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Both PEX5 isoforms recognize PTS1-tagged proteins, but PEX5L is also a co-receptor
for PTS2-tagged proteins.
explanation: >-
The division of labour between the isoforms is what makes the import failure
selective.
- name: Selective PTS2 Import Failure
conforms_to: "peroxisomal_metabolic_failure#Peroxisomal Biogenesis or Enzyme Defect"
biological_scale: CELLULAR
description: >-
An isolated failure to import the three known PTS2-tagged peroxisomal matrix proteins:
alkyl-DHAP synthase (AGPS), which makes the ether bond in plasmalogens; phytanoyl-CoA
2-hydroxylase (PHYH), which performs phytanic-acid alpha-oxidation; and acetyl-CoA
acyltransferase 1 (ACAA1). Peroxisomes are otherwise assembled and PTS1 import is
normal, so this is a targeted functional lesion rather than a general peroxisome
biogenesis failure - which is why the disorder is an RCDP and not a Zellweger spectrum
disorder. The node is deliberately named to match the corresponding node in the RCDP1
entry, since the two disorders converge on it from opposite sides of the same receptor
pair.
cellular_components:
- preferred_term: peroxisome
term:
id: GO:0005777
label: peroxisome
biological_processes:
- preferred_term: protein targeting to peroxisome
modifier: DECREASED
term:
id: GO:0006625
label: protein targeting to peroxisome
- preferred_term: protein import into peroxisome matrix
modifier: DECREASED
term:
id: GO:0016558
label: protein import into peroxisome matrix
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Similarly to mutations in PEX7, loss of PEX5L results in deficient import of
PTS2-tagged proteins only, thus causing RCDP instead of ZSD.
explanation: >-
States both the selectivity of the import defect and the nosological consequence that
follows from it.
downstream:
- target: Plasmalogen (Ether Lipid) Deficiency
description: >-
Failure to import AGPS impairs ether-phospholipid synthesis. Notably the reduction is
described as mild in these patients, and the surrogate marker GNPAT activity was also
reduced - the pattern expected when the PTS2-targeted AGPS fails to reach the matrix.
causal_link_type: DIRECT
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
All RCDP types
are characterized by low levels of plasmalogens
explanation: >-
Establishes plasmalogen deficiency as the shared biochemical endpoint of every RCDP
type, this one included.
- target: Phytanic Acid Accumulation
description: >-
Failure to import PHYH blocks phytanic-acid alpha-oxidation. This is the feature that
the import-receptor forms share and that the single-enzyme plasmalogen-synthesis forms
RCDP2/3/4 do not have, and it is therefore the biochemical discriminator between the
two mechanistic classes.
causal_link_type: DIRECT
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Three PTS2-tagged peroxisomal matrix proteins are known:
AGPS, involved in plasmalogen biosynthesis
explanation: >-
Identifies the PTS2 cargo set, whose members' failure to be imported produces both
the plasmalogen and the phytanic-acid abnormalities.
- name: Plasmalogen (Ether Lipid) Deficiency
conforms_to: "peroxisomal_metabolic_failure#Toxic Fatty-Acid Accumulation with Ether-Lipid Deficiency"
biological_scale: MOLECULAR
description: >-
Reduced cellular plasmalogens, the shared endpoint of every RCDP type. In the reported
RCDP5 patients the reduction was mild rather than profound, which fits their milder and
less consistently rhizomelic skeletal phenotype but also means the disorder can be
missed on a plasmalogen screen alone.
biological_processes:
- preferred_term: ether lipid biosynthesis
modifier: DECREASED
term:
id: GO:0008611
label: ether lipid biosynthetic process
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Three additional RCDP types, RCDP2-3-4, are caused, respectively, by mutations in
GNPAT, AGPS and FAR1, encoding enzymes involved in plasmalogen biosynthesis.
explanation: >-
Places the plasmalogen pathway as the common convergence point across RCDP types,
reached here through import failure rather than through enzyme loss.
downstream:
- target: Skeletal Dysplasia
description: >-
Plasmalogen deficiency is the lesion shared by all RCDP types and the presumed route
to the skeletal phenotype, though the intervening steps are not established in any of
them.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Congenital Cataract
description: >-
Congenital cataract is the most consistent non-skeletal feature across the RCDP types
and was present in all four RCDP5 patients; the route from plasmalogen deficiency to
lens opacity is not established.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Phytanic Acid Accumulation
biological_scale: MOLECULAR
description: >-
Loss of peroxisomal phytanic-acid alpha-oxidation, following failure to import PHYH.
In the reported patients plasma phytanic acid was highly elevated and fibroblast
alpha-oxidation markedly reduced - a more striking abnormality than their mild
plasmalogen reduction, and the finding that most clearly marks the disorder as an
import-receptor rather than a single-enzyme RCDP.
biological_processes:
- preferred_term: fatty acid alpha-oxidation
modifier: DECREASED
term:
id: GO:0001561
label: fatty acid alpha-oxidation
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
phytanoyl-CoA
2-hydroxylase (PHYH) (28), involved in phytanic acid
explanation: >-
Identifies phytanoyl-CoA 2-hydroxylase, the enzyme of phytanic-acid alpha-oxidation, as
PTS2-tagged cargo - so a selective PTS2 import failure necessarily blocks that pathway.
downstream:
- target: Neurological Impairment
description: >-
Phytanic acid accumulation is neurotoxic in the peroxisomal disorders generally; the
specific contribution it makes to the developmental and peripheral-nerve findings in
this disorder is not separable from that of plasmalogen deficiency on the available
evidence.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Skeletal Dysplasia
biological_scale: TISSUE
description: >-
Disordered endochondral ossification with punctate epiphyseal calcification and
proximal limb shortening. In RCDP5 this arm of the phenotype is attenuated relative to
classic RCDP1: humeral shortening was mild and present in three of four patients, and
chondrodysplasia punctata in only two.
cell_types:
- preferred_term: chondrocyte
term:
id: CL:0000138
label: chondrocyte
- preferred_term: growth plate cartilage chondrocyte
term:
id: CL:1000217
label: growth plate cartilage chondrocyte
biological_processes:
- preferred_term: endochondral ossification
modifier: ABNORMAL
term:
id: GO:0001958
label: endochondral ossification
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
mild shortening of humeri in
three patients, and chondrodysplasia punctata in two patients,
explanation: >-
Gives the frequency and severity of the two skeletal features in the founding cohort.
downstream:
- target: Epiphyseal Stippling
causal_link_type: DIRECT
description: Punctate epiphyseal calcification, present in two of the four reported patients.
- target: Short Humerus
causal_link_type: DIRECT
description: Mild proximal (rhizomelic) shortening of the upper limb.
- name: Neurological Impairment
biological_scale: ORGANISM
description: >-
Severe intellectual disability in all four patients, with microcephaly, seizures with
epileptiform EEG, and in at least one patient findings compatible with a chronic
demyelinating peripheral neuropathy - the last being a feature more usually associated
with the Zellweger spectrum than with classic RCDP.
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
postnatal growth delay, microcephaly and severe intellectual
disability in all four patients
explanation: States the neurological findings and that they were present in all four patients.
downstream:
- target: Severe Intellectual Disability
causal_link_type: DIRECT
description: Severe intellectual disability was present in all four reported patients.
- target: Microcephaly
causal_link_type: DIRECT
description: Microcephaly developed postnatally.
- target: Seizure
causal_link_type: DIRECT
description: Seizures with epileptiform EEG activity developed in several patients.
phenotypes:
- name: Congenital Cataract
category: Visual
diagnostic: true
description: >-
Bilateral cataracts present at birth and operated in the first months of life in all
four reported patients - the earliest and most consistent feature, as in the other RCDP
types.
phenotype_term:
preferred_term: Cataract
term:
id: HP:0000518
label: Cataract
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In contrast, some of their
key features such as congenital cataracts and chondrodysplasia
punctata are usually associated with RCDP
explanation: >-
Records congenital cataract in the cohort and identifies it as an RCDP-typical rather
than ZSD-typical feature.
- name: Epiphyseal Stippling
category: Skeletal
description: >-
Punctate epiphyseal calcification, present in two of the four reported patients - less
consistent than in classic RCDP1.
phenotype_term:
preferred_term: Epiphyseal stippling
term:
id: HP:0010655
label: Epiphyseal stippling
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "and chondrodysplasia punctata in two patients,"
explanation: Gives the frequency of the punctate calcification in the founding cohort.
- name: Short Humerus
category: Skeletal
description: >-
Mild rhizomelic shortening of the humerus in three of four patients. The mildness is
diagnostically important: an RCDP without striking rhizomelia is easy to miss.
phenotype_term:
preferred_term: Short humerus
term:
id: HP:0005792
label: Short humerus
severity: MILD
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
mild shortening of humeri in
three patients
explanation: States the severity and frequency of the humeral shortening.
- name: Severe Intellectual Disability
category: Neurologic
description: Severe intellectual disability in all four reported patients.
phenotype_term:
preferred_term: Severe intellectual disability
term:
id: HP:0010864
label: Severe intellectual disability
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
microcephaly and severe intellectual
disability in all four patients
explanation: States the finding and its frequency.
- name: Microcephaly
category: Neurologic
description: Postnatally acquired microcephaly, emerging after the first one to two years.
phenotype_term:
preferred_term: Microcephaly
term:
id: HP:0000252
label: Microcephaly
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
postnatal growth delay, microcephaly and severe intellectual
disability in all four patients
explanation: States microcephaly in all four patients.
- name: Postnatal Growth Retardation
category: Growth
description: Growth delay emerging after infancy in all four reported patients.
phenotype_term:
preferred_term: Postnatal growth retardation
term:
id: HP:0008897
label: Postnatal growth retardation
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "postnatal growth delay, microcephaly and severe intellectual"
explanation: States postnatal growth delay in the cohort.
- name: Seizure
category: Neurologic
description: Seizures with epileptiform activity on EEG developed in several of the reported patients.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "developed seizures, and an EEG"
explanation: Documents seizures with EEG confirmation in a reported patient.
genetic:
- name: PEX5
relationship_type: CAUSATIVE
presence: Present
gene_term:
preferred_term: PEX5
term:
id: hgnc:9719
label: PEX5
notes: >-
PEX5 is the striking case of one gene giving two unrelated diseases according to which
isoform an allele affects. Variants hitting both isoforms remove PTS1 import and cause
a Zellweger spectrum disorder; the exon 9 variant hits only PEX5L, leaves PTS1 import
intact, and causes RCDP5. Any diagnostic strategy that does not cover exon 9
specifically will miss this entity in a patient whose biochemistry looks like RCDP1.
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Previous patients with PEX5 mutations had ZSD, mainly due to deficient import of
PTS1-tagged proteins.
explanation: >-
Establishes the contrasting PEX5 phenotype and the import defect that produces it.
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutations in PEX5 or 12 other PEX genes cause peroxisome biogenesis disorders,
collectively named the Zellweger spectrum disorders (ZSDs), whereas mutations in PEX7
cause rhizomelic chondrodysplasia punctata type 1 (RCDP1).
explanation: >-
States the pre-existing gene-disease assignments that RCDP5 complicates, since it
places PEX5 on both sides of that division.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
All four reported patients were homozygous for the same frameshift allele, in two
independent families.
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In four patients with RCDP from two independent families, we identified a homozygous
frame shift mutation
explanation: Documents homozygosity in two independent families.
biochemical:
- name: Erythrocyte or fibroblast plasmalogens
notes: >-
Reduced, but only mildly so in the reported patients - a softer signal than in classic
RCDP1. GNPAT activity in fibroblasts was also reduced, which is the expected surrogate
when the PTS2-targeted AGPS fails to reach the peroxisomal matrix.
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
All RCDP types
are characterized by low levels of plasmalogens
explanation: Establishes reduced plasmalogens as the expected finding in every RCDP type.
- name: Plasma phytanic acid
notes: >-
Highly elevated, with markedly reduced fibroblast phytanic-acid alpha-oxidation. This
is the discriminator from RCDP2/3/4, where alpha-oxidation is preserved, and it is
shared with RCDP1 - so it separates the mechanistic class but not the two entities
within it.
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
phytanoyl-CoA
2-hydroxylase (PHYH) (28), involved in phytanic acid
explanation: >-
Identifies phytanoyl-CoA 2-hydroxylase as PTS2-tagged cargo, which is why an import
defect raises phytanic acid while a defect in a plasmalogen-synthesis enzyme does not.
diagnosis:
- name: Sequencing PEX7 and PEX5 exon 9 in a selective PTS2 import defect
description: >-
Because RCDP1 and RCDP5 are biochemically indistinguishable, a patient shown to have a
selective PTS2 import defect needs both genes tested. The founding paper makes this an
explicit recommendation, and it is the disorder's main practical consequence for
laboratory workflow.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Due to the biochemical overlap between RCDP1 and RCDP5, sequencing of PEX7 and exon 9
in PEX5 should be performed in patients with a selective defect in the import of
PTS2-tagged proteins.
explanation: States the testing recommendation and the reason for it.
treatments:
- name: Supportive and rehabilitative care
description: >-
No disease-modifying therapy exists. Management follows the RCDP pattern: cataract
surgery, developmental and orthopedic support, and seizure management.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:20301447
reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Physical therapy to improve contractures; orthopedic procedures may improve function
in some individuals; consider need for positioning and mobility devices
explanation: >-
Support is partial: the source describes management of PEX7-related RCDP, and is cited
here on the basis that RCDP5 shares its lesion and clinical problems. No
RCDP5-specific management literature exists.
- name: Cataract extraction
description: Surgical removal of the congenital cataracts, performed in the first months of life in all four reported patients.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: surgical procedure
term:
id: NCIT:C15329
label: Surgical Procedure
target_phenotypes:
- preferred_term: cataract
term:
id: HP:0000518
label: Cataract
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Congenital cataracts were operated
at 4 months
explanation: Documents cataract surgery in the reported cohort.
differential_diagnoses:
- name: Rhizomelic chondrodysplasia punctata type 1 (PEX7)
disease_term:
preferred_term: rhizomelic chondrodysplasia punctata type 1
term:
id: MONDO:0008972
label: rhizomelic chondrodysplasia punctata type 1
description: >-
The differential that cannot be resolved biochemically. RCDP1 and RCDP5 are the two
import-receptor forms and produce the identical selective PTS2 import defect, from the
two partners of the same receptor complex. Only sequencing separates them.
distinguishing_features:
- RCDP1 is caused by PEX7 variants; RCDP5 by variants in the PEX5L-specific exon 9
- The biochemical profiles are indistinguishable, which is why both genes must be tested
- The reported RCDP5 patients had milder and less consistent skeletal features than classic RCDP1 and survived into the second decade
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Due to the biochemical overlap between RCDP1 and RCDP5,"
explanation: States the biochemical overlap that makes molecular testing necessary.
- name: Rhizomelic chondrodysplasia punctata, plasmalogen-synthesis defect (RCDP2/3/4)
disease_term:
preferred_term: rhizomelic chondrodysplasia punctata
term:
id: MONDO:0015776
label: rhizomelic chondrodysplasia punctata
description: >-
The single-enzyme forms, caused by loss of GNPAT, AGPS, or FAR1 rather than by an
import defect. They converge on plasmalogen deficiency but lie downstream of import, so
phytanic-acid alpha-oxidation is preserved.
distinguishing_features:
- Phytanic acid is normal in RCDP2/3/4 and elevated in RCDP5
- The lesion is in a biosynthetic enzyme rather than in peroxisomal protein import
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Three additional RCDP types, RCDP2-3-4, are caused, respectively, by mutations in
GNPAT, AGPS and FAR1, encoding enzymes involved in plasmalogen biosynthesis.
explanation: Identifies the single-enzyme forms and their genes.
- name: Zellweger spectrum disorders
disease_term:
preferred_term: Zellweger spectrum disorders
term:
id: MONDO:0019609
label: Zellweger spectrum disorders
description: >-
The other, and far more common, PEX5 phenotype. Variants affecting both isoforms remove
PTS1 import and cause a generalized peroxisome biogenesis disorder. The reported RCDP5
patients lacked the ZSD-typical hepatic dysfunction and sensorineural hearing loss.
distinguishing_features:
- ZSD involves failure of PTS1 import and hence generalized peroxisomal dysfunction; RCDP5 spares PTS1 import entirely
- Hepatic dysfunction and sensorineural hearing loss are typical of ZSD and were absent in the RCDP5 patients
- Congenital cataract with chondrodysplasia punctata points towards RCDP rather than ZSD
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
lacked several features
typically associated with ZSD, such as hepatic dysfunction and
sensorineural hearing loss
explanation: >-
Names the ZSD features absent in these patients, which is what separated the two
phenotypes clinically before the isoform mechanism was established.
discussions:
- discussion_id: rcdp5_phenotypic_boundary
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Skeletal Dysplasia
- disease#Rhizomelic Chondrodysplasia Punctata Type 5
prompt: >-
Is the milder, less consistently rhizomelic skeletal phenotype of RCDP5 a real property
of the disorder, or an artefact of the single allele on which the entity was defined?
rationale: >-
All four described patients are homozygous for one frameshift in two families, so the
entity's clinical description and its genotype are entirely confounded. The reported
phenotype - chondrodysplasia punctata in only two of four, mild humeral shortening in
three, survival into the second decade - is milder than classic RCDP1 and would fit the
nonclassic RCDP pattern. Whether that reflects the isoform lesion, this particular
allele, or the two families is untestable on the published cohort. It matters for
ascertainment: if RCDP5 is genuinely milder, patients are being missed, since a
plasmalogen screen showing only mild reduction in a child without striking rhizomelia is
unlikely to prompt PEX5 exon 9 sequencing.
proposed_experiments:
- experiment_id: rcdp5_allelic_series
name: Broader ascertainment of PEX5L-selective alleles
description: >-
Targeted analysis of PEX5 exon 9 in cohorts with a selective PTS2 import defect and no
PEX7 variant, to determine whether other PEX5L-selective alleles exist and whether
they reproduce the attenuated skeletal phenotype.
evidence:
- reference: PMID:26220973
reference_title: "A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
mild shortening of humeri in
three patients, and chondrodysplasia punctata in two patients,
explanation: >-
The per-feature counts show that the defining skeletal features were not present in
every patient, which is the observation the question turns on.
notes: >-
Curated as its own dismech entry rather than merged into the PEX7 entry, even though the
two share a mechanism node. Three reasons. The ISDS 2023 nosology lists the five
rhizomelic-CDP entities as five separate rows by gene, and NOS 23-0100 is this one.
MONDO carries a distinct class, MONDO:0014743. And the interesting content here is
gene-specific rather than mechanism-specific: it is the isoform-selective allele that
makes one gene give two unrelated diseases, which has no counterpart in the PEX7 entry.
This is a different judgement from the one made for RCDP2/3/4, which dismech lumps into a
single entry - there the three genes are consecutive steps of one biosynthetic pathway
with nothing gene-specific to say, whereas here the gene is the story. A member of the
Chondrodysplasia_Punctata grouping.
The two pathophysiology nodes shared with RCDP1 carry the same conforms_to links to the
peroxisomal_metabolic_failure module that the RCDP1 entry uses, since the lesion is the
same at both nodes - that is the whole point of naming them identically.
The GeneReviews-tagged reference (PMID:20301447) is the PEX7/RCDP1 chapter, not an RCDP5
chapter: none exists. It is cited once, for supportive management, and graded PARTIAL for
that reason. Deep-mining a PEX7 chapter for a PEX5 disease would be an entity-confusion
error, so the restraint is deliberate.