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Rhizomelic Chondrodysplasia Punctata Type 1

Synonym: RCDP 1

, MS, MD, , BA, and , PhD.

Author Information
, MS, MD
Departments of Human Genetics and Pediatrics
McGill University - Montreal Children's Hospital Research Institute
Montreal, Quebec, Canada
, BA
Department of Neurogenetics
Kennedy Krieger Institute
Baltimore, Maryland
, PhD
Department of Neurogenetics
Kennedy Krieger Institute
Baltimore, Maryland

Initial Posting: ; Last Update: September 13, 2012.

Summary

Disease characteristics. Rhizomelic chondrodysplasia punctata type 1 (RCDP1) classic type, a peroxisome biogenesis disorder (PBD), is characterized by proximal shortening of the humerus and to a lesser degree the femur (rhizomelia), punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata, or CDP), coronal clefts of the vertebral bodies, and cataracts that are usually present at birth or appear in the first few months of life. Birth weight, length, and head circumference are often at the lower range of normal; postnatal growth deficiency is profound. Intellectual disability is severe, and the majority of children develop seizures. Most affected children do not survive the first decade of life; a proportion die in the neonatal period. A milder phenotype in which all affected individuals have congenital cataracts and chondrodysplasia is now recognized; some do not have rhizomelia, and some have less severe intellectual disability and growth deficiency.

Diagnosis/testing. The diagnosis of RCDP1 is based on clinical findings and confirmed by biochemical or molecular genetic testing. Biochemical tests of peroxisome function include: red blood cell concentration of plasmalogens (deficient), plasma concentration of phytanic acid (elevated), and plasma concentration of very long chain fatty acids (VLCFA) (normal), which has consistently predicted the PEX7 receptor defect in RCDP1. PEX7, which encodes the receptor for a subset of peroxisomal matrix enzymes, is the only gene in which mutations are known to cause RCDP1.

Management. Treatment of manifestations: Management is supportive and limited by the multiple handicaps present at birth and poor outcome. Cataract extraction may restore some vision. Physical therapy is recommended to improve contractures; orthopedic procedures may improve function in some individuals.

Prevention of primary manifestations: Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with milder forms of RCDP.

Prevention of secondary manifestations: Poor feeding and recurrent aspiration may necessitate placement of a gastrostomy tube; attention to respiratory function with administration of influenza vaccine and RSV monoclonal antibody; docosohexanoic acid (DHA) supplementation in those who are deficient.

Surveillance: Monitoring of growth and development and regular assessments for seizure control, vision, hearing, contractures, and orthopedic complications.

Genetic counseling. RCDP1 is inherited in an autosomal recessive manner. At conception, each sib of a proband has a 25% chance of inheriting both mutant alleles and being affected, a 50% chance of inheriting one mutant allele and being an unaffected carrier, and a 25% chance of inheriting both normal alleles. Once the mutations have been identified in an affected family member, molecular genetic testing for carrier testing of at-risk relatives and prenatal testing for pregnancies at increased risk are possible. Prenatal diagnosis by assay of plasmalogen biosynthesis is possible for pregnancies at 25% risk for RCDP1.

Diagnosis

Clinical Diagnosis

Classic rhizomelic chondrodysplasia punctata type 1 (RCDP1) is recognized in the neonatal period by the presence of:

  • Cataracts
  • Skeletal features. Classic findings include the following:
    • Rhizomelia (proximal shortening of the long bones)
    • Chondrodysplasia punctata (CDP): punctate calcifications observed in radiographs in the epiphyseal cartilage at the knee, hip, elbow, and shoulder that can be more extensive, involving the hyoid bone, larynx, costochondral junctions, and vertebrae. Metaphyseal abnormalities may be present.
    • Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage

Classic RCDP1 is recognized in childhood by the presence of:

  • Congenital cataracts
  • Severe intellectual disability
  • Profound growth retardation
  • Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after age one to three years
  • Possible calcification of the intervertebral discs

Milder RCDP1 phenotype is recognized by:

  • Congenital cataracts
  • Chondrodysplasia (manifesting as mild epiphyseal changes)
  • Variable rhizomelia
  • Milder intellectual disability and growth deficiency

Testing

Biochemical tests. Three biochemical tests of peroxisome function are routinely used to confirm the diagnosis of RCDP1:

  • Red blood cell concentration of plasmalogens (Table 1)
  • Plasma concentration of phytanic acid (Table 2)
  • Plasma concentration of very long chain fatty acids (VLCFA)

The finding of a deficiency of plasmalogens in red blood cells, increased plasma concentration of phytanic acid, and normal plasma concentration of very long chain fatty acids has consistently predicted the PEX7 receptor defect in RCDP1.

These assays are extremely specialized and are reliably performed in only a few laboratories worldwide.

Table 1. Values for Red Blood Cell Plasmalogens (Dimethylacetals) in RCDP1

C16 Saturated Dimethylacetals (DMA) to C16 Saturated Fatty Acid
MeanRange
Normal 0.077±0.0090.051-0.090
Abnormal (RCDP1) 0.001-0.025 1

Values are expressed as a ratio of C16 or C18 dimethylacetyls to fatty acid molecules.

1. Values are for the classic RCDP1 phenotype; individuals with a mild RCDP1 phenotype may fall outside this range.

Table 2. Plasma Concentration of Phytanic Acid in RCDP1

MeanRange
Normal 0.80 µg/mL ± 0.400-2.5 µg/mL 1
Abnormal (RCDP1) ≤300 µg/mL

1. Plasma concentration of phytanic acid varies with dietary intake of animal fat. It can be normal in infants with RCDP1 because breast milk is low in phytanic acid and most formulas use vegetable fat.

Assays in cultured skin fibroblasts

  • Defective plasmalogen biosynthesis, defective phytanic acid (PA) oxidation, and normal VLCFA oxidation are confirmed in cultured fibroblasts.
  • The absence of processed thiolase is determined in some laboratories.
  • The fibroblast assays allow more complete characterization of peroxisomal functions and are critical in establishing the diagnosis in individuals with milder forms of RCDP1, whose plasmalogen levels may not be markedly abnormal.

Molecular Genetic Testing

Gene. PEX7, which encodes the receptor for a subset of peroxisomal matrix enzymes, is the only gene in which mutations are known to cause RCDP1.

Clinical testing

Table 3. Summary of Molecular Genetic Testing Used in Rhizomelic Chondrodysplasia Punctata Type 1

Gene Symbol Test MethodMutations DetectedMutation Detection Rate 1
Two mutationsOne mutation
PEX7Sequence analysisSequence variants 2, 394% 46% 4
Targeted mutation analysis 5p.Leu292X, p.Gly217Arg, p.Ala218Val 651%-68% of mutant alleles

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. Some laboratories may offer sequence analysis of select exons; exons tested may vary by laboratory.

4. Sequence analysis of PEX7 coding and flanking intronic regions in 133 individuals with RCDP1 from the United States and the Netherlands identified 97% of mutant alleles [Braverman et al 2002, Motley et al 2002]. Note: In all individuals with biochemically confirmed RCDP1, at least one mutant PEX7 allele was identified.

5. Targeted mutation analysis refers to testing for specific common mutation(s). Mutations detected may vary among laboratories.

6. p.Leu292X was the most common, accounting for 51% of alleles. c.903+1G>C, p.Gly217Arg, and p.Ala218Val together account for 17% of alleles.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband

1.

When the diagnosis of RCDP is considered, blood should be sent first for measurement of red blood cell plasmalogen, plasma phytanic acid, and plasma very long chain fatty acid concentrations.

2.

When abnormalities are identified (see 1), the diagnosis is confirmed by enzymatic assays in cultured fibroblasts.

3.

Molecular genetic testing is used to identify the two disease-causing alleles in the proband, establish genotype-phenotype correlations, and enable prenatal diagnosis and carrier testing of at-risk relatives.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Prenatal diagnosis by biochemical testing is also possible; however, ideally the biochemical defects in cultured fibroblasts from an affected family member should be confirmed first.

Clinical Description

Natural History

Classic RCDP1

The characteristic clinical features observed in RCDP1 are skeletal abnormalities, cataracts, growth retardation, and intellectual disability. The majority of children do not survive beyond the first decade of life and a proportion die in the neonatal period. In a review of 69 children with RCDP diagnosed by the Peroxisomal Diseases Laboratory at the Kennedy Krieger Institute, 60% of children survived the first year and 39% the second; a few survived beyond age ten years. In a review of 35 affected children older than age one month, White et al [2003] reported 90% survival at age one year, 50% survival to age six years, and approximately 20% survival at age 12 years. Most deaths were secondary to respiratory complications. Clinical experience suggests that neonatal deaths have been associated with congenital heart disease or pulmonary hypoplasia [Oswald et al 2011].

Skeletal findings. Infants with RCDP1 have bilateral shortening of the humerus and to a lesser degree the femur. They typically have contractures and stiff, painful joints, causing irritability in infancy. Cartilaginous structures of the face are affected, resulting in frontal bossing and a short, concave nasal ridge.

Cataracts. Bilateral cortical cataracts develop in virtually all affected individuals. They are usually present at birth or appear in the first few months of life and are progressive.

Growth retardation. Whereas birth weight, length, and head circumference are often at the lower range of normal, postnatal growth deficiency is profound.

Intellectual disability. Developmental quotients are below 30. Early developmental skills such as smiling and recognizing voices are achieved by most children with RCDP, but at delayed ages. Skills usually achieved in normal children beyond age six months are never seen [White et al 2003].

The majority of children develop seizures.

Routine brain imaging is normal or has shown cerebral and cerebellar atrophy with enlargement of the ventricles and CSF spaces [Powers et al 1999]. MR imaging and MR spectroscopy have shown delayed myelinization, signal abnormalities in supratentorial white matter, decreased choline-to-creatine ratios, and increased levels of mobile lipids, thought to reflect the deficiency of plasmalogens, which are substantial components of myelin [Alkan et al 2003, Bams-Mengerink et al 2006].

Other. Most children with RCDP1 have recurrent respiratory tract infections caused by neurologic compromise, aspiration, immobility, and a small chest with restricted expansion.

Radiologic and MRI evidence of multilevel cervical stenosis with or without compression of the spinal cord has been observed. Spinal cord compression may complicate the neurologic picture, which often includes spastic quadriplegia [Khanna et al 2001].

Ichthyotic skin changes are noted in fewer than one third of individuals.

Approximately 5%-10% of individuals have a cleft of the soft palate.

Other malformations observed in individuals with RCDP1 include congenital heart disease and ureteropelvic junction (UPJ) obstruction.

Mild RCDP1

Only a few individuals with milder forms of RCDP1 have been described. All have had chondrodysplasia and cataracts but variable expression of punctate calcifications, rhizomelia, growth retardation, and intellectual disability [Braverman et al 2002, Bams-Mengerink et al 2006]. One child, presenting with developmental delay and poor growth, subsequently developed retinitis pigmentosa and peripheral neuropathy, features overlapping those of adult Refsum disease [Braverman et al 2002]. Thus, it is likely that a continuum of phenotypes will emerge within the RCDP group. Molecular analysis of PEX7 may identify individuals with unusual phenotypes.

Genotype-Phenotype Correlations

The degree of plasmalogen deficiency correlates directly with phenotypic severity:

  • Individuals in the milder RCDP group exhibit intermediate defects in fibroblast plasmalogen synthesis and RBC plasmalogen concentrations that are approximately 30% of the mean in controls and more than two standard deviations above the mean in children with classic RCDP.
  • Individuals with more variant phenotypes have near-normal plasmalogen biochemistry.
  • Defects in phytanic acid oxidation in fibroblast assays are severe in all PEX7 defects.

Some correlations between the predicted severity of PEX7 mutations and phenotype have emerged:

Penetrance

Penetrance is complete and the same for either sex.

Nomenclature

RCDP1 is one of two groups of peroxisome biogenesis disorders (PBD). The other PBD group is the Zellweger syndrome spectrum.

Although individuals with RCDP1 have a perturbation in matrix protein import consistent with a peroxisomal assembly defect, they have a biochemical, cellular, and clinical phenotype distinct from PBD of the Zellweger syndrome spectrum.

Prevalence

The prevalence of RCDP1 is estimated to be lower than 1:100,000. The disorder is pan ethnic. The high frequency of the p.Leu292X allele is secondary to a founder effect in individuals of Northern European descent [Braverman et al 2000].

Differential Diagnosis

The classic RCDP1 phenotype can be mimicked by isolated deficiencies of either of two peroxisomal enzymes involved in plasmalogen biosynthesis, as well as by severe Conradi-Hünermann syndrome. In addition, several different disorders, described below, have similar punctate cartilaginous changes and various combinations of limb asymmetry, short stature, intellectual disability, cataracts, and skin changes. The radiologic finding of chondrodysplasia punctata (CDP) has been observed in various metabolic disorders, skeletal dysplasias, chromosome abnormalities, and teratogen exposures. Exhaustive classifications of CDP have been published [Irving et al 2008].

  • Rhizomelic chondrodysplasia punctata, type 2 (RCDP2) and type 3 (RCDP3). RCDP2 is caused by deficiency of the peroxisomal enzyme dihydroxyacetone phosphate acyltransferase, encoded by GNPAT (OMIM 602744). RCDP3 is caused by deficiency of the peroxisomal enzyme alkyl-dihydroxyacetone phosphate synthase, encoded by AGPS (OMIM 600121). The clinical phenotypes resemble that seen in RCDP1, emphasizing the role of plasmalogen deficiency in determining the RCDP phenotype. RCDP2 and RCDP3 are inherited in an autosomal recessive manner and are rarer than RCDP1. The specific enzyme defect is confirmed by measurement of the enzyme activity in cultured skin fibroblasts and/or identification of two disease causing mutations by sequence analysis of AGPS or GNPAT.
  • X-linked recessive chondrodysplasia punctata, or brachytelephalangic type (CDPX1) is caused by defects in arylsulfatase E (ARSE), a vitamin K-dependent enzyme. Affected males have hypoplasia of the distal phalanges without limb shortening or cataracts. The diagnosis is confirmed by molecular genetic testing. Contiguous gene deletions involving ARSE result in more complex phenotypes, including ichthyosis and corneal opacities resulting from steroid sulfatase deficiency.
  • Warfarin embryopathy and other fetal vitamin K deficiencies (including vitamin K epoxide reductase deficiency (OMIM 277450]) are phenotypically similar to CDPX1.
  • Maternal systemic lupus erythematosis (SLE) (OMIM 152700) and other maternal autoimmune diseases can cause CDP in the offspring that is phenotypically similar to CDPX1.
  • X-linked dominant chondrodysplasia punctata, or Conradi-Hünermann syndrome (CDPX2) is usually lethal in males. It is caused by defects in sterol- Δ8-isomerase which catalyzes an intermediate step in the conversion of lanosterol to cholesterol. Lyonization in females results in phenotypic variability and asymmetric findings. Cataracts are sectorial and limb shortening is rhizomesomelic and usually asymmetric. Severely affected infants have bilateral findings resembling those of RCDP1. The diagnosis is confirmed by measuring the plasma concentration of sterols, which show accumulation of the precursors 8(9)-cholestenol and 8-dehydrocholesterol and/or identification of two disease-causing mutations by molecular genetic testing of EBP.
  • Chondrodysplasia punctata, tibia-metacarpal type (OMIM 118651) and humero-metacarpal type [Fryburg & Kelly 1996] are inherited in an autosomal dominant manner. The gene(s) in which mutation is causative are unknown. Affected individuals have short metacarpals with shortening of various long bones. No cataracts or skin changes are present.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with rhizomelic chondrodysplasia punctata type I (RCDP1), the following evaluations are recommended:

  • Full skeletal survey (with flexion and extension views of the neck)
  • Ophthalmologic examination
  • Growth parameters
  • Developmental assessment
  • MR imaging of brain (with MR spectroscopy)
  • Cardiac ultrasound examination
  • Renal ultrasound examination
  • Medical genetics consultation

Treatment of Manifestations

Management is supportive and limited because of the multiple handicaps present at birth and the poor outcome.

Cataract extraction may preserve some vision.

Physical therapy is recommended to assist in the improvement of contractures; orthopedic procedures have improved function in some individuals.

Prevention of Primary Manifestations

Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with milder forms of RCDP.

Prevention of Secondary Complications

Poor feeding and recurrent aspiration necessitate the placement of a gastrostomy tube. Note: Improved nutrition does not enhance linear growth.

Individuals with RCDP1 require good pulmonary toilet and careful attention to respiratory function. Influenza vaccine and RSV monoclonal antibody should be provided.

Low plasmalogen levels can be associated with low levels of docosohexanoic acid (DHA). DHA can be measured in plasma; oral supplementation should be provided if levels are low.

Surveillance

Based on a retrospective review of the natural history of 35 individuals with RCDP, White et al [2003] provide health supervision guidelines for primary caretakers of children with RCDP, including the following:

  • Growth curves that allow weight comparisons to help determine the need for gastrostomy
  • The ages at which developmental milestones are achieved to provide realistic expectations
  • Recommendations for medical assessments including seizure control, vision, hearing, orthopedic care, and prevention of respiratory infections and contractures

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Data suggest that oral plasmalogen supplementation using alkylglycerol sources can increase tissue plasmalogen concentrations in rodents and red blood cell (RBC) plasmalogen concentrations in individuals with Zellweger syndrome spectrum disorders. Anecdotal reports of alkylglycerol supplementation in a few individuals with classic RCDP1 have not indicated dramatic clinical benefit; however, alkylglycerol supplementation has not yet been studied in a systematic fashion. Studies in Pex7-deficient mouse models have shown that plasmalogen precursors can partially recover plasmalogen levels in body tissues, but not in brain [Brites et al 2004, Wood et al 2011]

Nonsense suppressor drugs were unable to recover protein production in individuals with the common p.Leu292X allele [Dranchak et al 2011].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

RCDP1 is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of a proband are obligate heterozygotes (carriers) and therefore carry one mutant allele.
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib of a proband has a 25% chance of inheriting both mutant alleles and being affected, a 50% chance of inheriting one mutant allele and being an unaffected carrier, and a 25% chance of inheriting both normal alleles.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Affected individuals do not reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carriers cannot be identified by biochemical methods.

Carrier testing of at-risk relatives using molecular genetic techniques is possible if the mutations have been identified in an affected family member.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation). Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Biochemical testing. Prenatal diagnosis for pregnancies at 25% risk for RCDP1 is also available by assay of plasmalogen biosynthesis in cultured chorionic villi obtained by CVS (usually performed at ~10-12 weeks' gestation) or in cultured amniocytes obtained by amniocentesis (usually performed at ~15-18 weeks' gestation).

The determination of enzyme activity of alkyl-dihydroxyacetone phosphate synthase (AGPS) and the subcellular localization of peroxisomal thiolase have also been performed successfully on uncultured chorionic villi.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination. Rhizomelia and punctate calcifications have been noted on ultrasound examination as early as 18 to 19 weeks [Krakow et al 2003, Zwijnenburg et al 2010]. Others have reported these findings along with bilateral cataracts at 32 weeks, and epiphyseal stippling shown four weeks later [Basbug et al 2005]. Homozygosity of the p.Leu292X mutation in PEX7 was verified in the case reported by Zwijnenburg et al [2010].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • RCDP Family Support Group
    137 - 25th Avenue
    Monroe WI 53566
    Phone: 608-325-2717
  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
    Email: info@lpaonline.org
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Rhizomelic Chondrodysplasia Punctata Type 1: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Rhizomelic Chondrodysplasia Punctata Type 1 (View All in OMIM)

215100RHIZOMELIC CHONDRODYSPLASIA PUNCTATA, TYPE 1; RCDP1
601757PEROXISOME BIOGENESIS FACTOR 7; PEX7

Molecular Genetic Pathogenesis

Role of the peroxisome targeting signal 2 receptor, PEX7, in peroxisome assembly. Peroxisomal matrix enzymes are synthesized on free polyribosomes and directed to the peroxisome by cytosolic receptors. The peroxisome targeting signal 1 receptor (encoded by PEX5) binds a C-terminal peroxisome targeting signal, PTS1, present on most matrix proteins. PEX7 binds an N-terminal PTS2, present on three. The two receptors themselves interact and carry their protein cargo to the peroxisome membrane; the matrix proteins are then translocated inside, the import complex is disassembled, and the receptors are recycled for another round of import. This import process, along with the formation of new peroxisomes and division of existing ones, is termed peroxisome biogenesis. Fourteen human proteins are required for peroxisome biogenesis; collectively they are called peroxins and they are encoded by PEX genes.

Metabolic pathways dependent on PEX7. The three PTS2 proteins transported to the peroxisome by PEX7 are alkyl-dihydroxyacetone phosphate synthase (AGPS), phytanoyl-CoA hydroxylase (PhyH), and peroxisomal 3-ketoacyl-CoA thiolase (ACAA1).

  • AGPS catalyzes the initial steps of plasmalogen biosynthesis in a complex with the PTS1 protein, dihydroxyacetone phosphate acyltransferase (GNPAT). Plasmalogens are a class of membrane phospholipids, in which the fatty acid at the C1 position of the glycerophospholipid is replaced by a fatty alcohol. Plasmalogens are present in significant proportions in plasma membranes and myelin, and their specific functions are now being investigated [Braverman & Moser 2012]. These compounds may protect against oxidative damage, be required for membrane fusion and fission processes, and function as lipid messengers. Since isolated defects in GNPAT or AGPS also result in RCDP (RCDP types 2 and 3), plasmalogen deficiency must play a major role in the pathogenesis of this disorder.
  • PhYH catalyzes the initial step in the catabolism of phytanic acid, a 16-carbon methyl-branched fatty acid of dietary origin. Isolated defects in PhYH cause adult Refsum disease.
  • Peroxisomal thiolase (ACAA1) catalyzes the last step in beta oxidation of very long straight-chain fatty acids. Beta oxidation is normal in RCDP1, presumably because the thiolase activity of sterol carrier protein-X, a PTS1 protein, compensates for this deficiency.
  • Other proteins with PTS2 targeting signals have been recently identified by bioinformatics and proteomics experiments [Wiese et al 2007, Kunze et al 2011] Their role in human disease caused by PEX7 mutation is not known.

Normal allelic variants. PEX7 contains ten exons that span 91 kb of genomic DNA. No normal allelic variants have been identified yet in the coding sequence.

Pathologic allelic variants. Approximately 39 unique PEX7 mutations have been identified thus far (see www.dbpex.org). The majority are nonsense, missense, or splice site mutations, small insertions, or deletions. The mutant allele p.Leu292X accounts for 51% of alleles; less common alleles are c.903+1G>C, p.Gly217Arg, p.Ala218Val, and p.Tyr40X.

Alleles associated with milder RCDP phenotypes, variant phenotypes, or adult Refsum disease are either missense alleles located on the surfaces of the PEX7 protein and thus unlikely to disrupt its structural integrity (p.Ser25Phe, p.His285Arg, p.Thr14Pro), or 'leaky' alleles, potentially able to generate residual amounts of normal PEX7 protein (c.-45C>T,c.442-10A>G) and re-initiate translation in-frame (p.His18Argfs*35) or at a downstream methionine residue (p.Gly7Valfs*51) [Braverman et al 2002, Motley et al 2002, van den Brink et al 2003].

Table 4. Selected PEX7 Pathologic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.-45C>T--NM_000288​.3
NP_000279​.1
c.340-10A>G
(IVS3-10A>G)
--
c.45_52dupGGGACGCC
(52insGGGACGCC)
p.His18Argfs*35
c.12_18dupGTGCGGTp.Gly7Valfs*51
c.74C>Tp.Ser25Phe
c.854A>Gp.His285Arg
c.40A>Cp.Thr14Pro
c.903+1G>C
(IVS9+1G>C)
--
c.649G>Ap.Gly217Arg
c.653C>Tp.Ala218Val
c.875T>Ap.Leu292X

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. PEX7, the peroxisome-targeting signal 2 receptor, is a 323-amino acid protein with serial WD40 repeats (short structural motif of approximately 40 amino acids, often terminating in a tryptophan-aspartic acid (W-D) dipeptide). These repeat domains fold into blades of a propeller-like structure, which resembles a torus on its side and provides several surfaces for protein interactions [Braverman et al 2002]. PEX7 is a receptor for a subclass of peroxisomal matrix enzymes and binds the PTS2 signal at the N-terminus of these proteins. PEX7 carries its cargo to the peroxisome membrane by virtue of its interaction with PEX5.

Abnormal gene product. Defects in PEX7 result in deficient activity of PTS2 enzymes, but other peroxisomal functions remain intact. Fibroblast assays show that PTS2 proteins remain cytosolic in individuals with RCDP1 and are degraded, but PTS1 proteins are imported into peroxisomes normally. Peroxisome morphology is normal in fibroblasts but abnormal in liver, according to several case reports.

References

Literature Cited

  1. Alkan A, Kutlu R, Yakinci C, Sigirci A, Aslan M, Sarac K. Delayed myelination in a rhizomelic chondrodysplasia punctata case: MR spectroscopy findings. Magn Reson Imaging. 2003;21:77–80. [PubMed: 12620550]
  2. Bams-Mengerink AM, Majoie CBLM, Duran M, Wanders RJA, Van Hove J, Scheurer CD, Barth PG, Poll-The BT. MRI of the brain and certical spinal cord in rhizomelic chondrodysplasia punctata. Neurology. 2006;66:798–803. [PubMed: 16567694]
  3. Basbug M, Serin IS, Ozcelik B, Gunes T, Akcakus M, Tayyar M. Prenatal ultrasonographic diagnosis of rhizomelic chondrodysplasia punctata by detection of rhizomelic shortening and bilateral cataracts. Fetal Diagn Ther. 2005;20:171–4. [PubMed: 15824492]
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  16. Powers JM, Kenjarski TP, Moser AB, Moser HW. Cerebellar atrophy in chronic rhizomelic chondrodysplasia punctata: a potential role for phytanic acid and calcium in the death of its Purkinje cells. Acta Neuropathol (Berl). 1999;98:129–34. [PubMed: 10442551]
  17. van den Brink DM, Brites P, Haasjes J, Wierzbicki AS, Mitchell J, Lambert-Hamill M, de Belleroche J, Jansen GA, Waterham HR, Wanders RJ. Identification of PEX7 as the second gene involved in Refsum disease. Am J Hum Genet. 2003;72:471–7. [PMC free article: PMC379239] [PubMed: 12522768]
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  19. Wiese S, Gronemeyer T, Ofman R, Kunze M, Grou CP, Almeida JA, Eisenacher M, Stephan C, Hayen H, Schollenberger L, Korosec T, Waterham HR, Schliebs W, Erdmann R, Berger J, Meyer HE, Just W, Azevedo JE, Wanders RJ, Warscheid B. Proteomics characterization of mouse kidney peroxisomes by tandem mass spectrometry and protein correlation profiling. Mol Cell Proteomics. 2007;6:2045–57. [PubMed: 17768142]
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Suggested Reading

  1. Gould SJ, Raymond GV, Valle D. The peroxisome biogenesis disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 129. Available online. Accessed 9-4-12.
  2. Steinberg SJ, Dodt G, Raymond GV, Braverman NE, Moser AB, Moser HW. Peroxisome biogenesis disorders. Biochim Biophys Acta. 2006;1763:1733–48. [PubMed: 17055079]
  3. Wanders RJ, Waterham HR. Peroxisomal disorders: the single peroxisomal enzyme deficiencies. Biochim Biophys Acta. 2006;1763:1707–20. [PubMed: 17055078]

Chapter Notes

Revision History

  • 13 September 2012 (me) Comprehensive update posted live
  • 2 March 2010 (me) Comprehensive update posted live
  • 18 July 2006 (me) Comprehensive update posted to live Web site
  • 7 February 2005 (cd) Revision: test availability
  • 26 February 2004 (cd) Revision: test availability
  • 13 February 2004 (me) Comprehensive update posted to live Web site
  • 16 November 2001 (me) Review posted to live Web site
  • 10 June 2001 (nb) Original submission
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