Refsum Disease

Clinical Diagnosis

Refsum disease [also referred to as "classic Refsum disease" (CRD) or "adult Refsum disease" (ARD)] is suspected in individuals with late childhood-onset retinitis pigmentosa and variable combinations (in decreasing order of frequency) of the following:

• Anosmia

• Sensory motor neuropathy

• Hearing loss

• Ataxia

• Ichthyosis

• Short metacarpals and metatarsals present from birth (about 35% of individuals)

• Cardiac arrhythmias

It should be noted that: (1) the full constellation of signs and symptoms is rarely seen in an affected individual; (2) most features develop with age.

Testing

For laboratories offering biochemical testing, see .

Deficiency of phytanoyl-CoA hydroxylase enzyme activity.  Greater than 90% of individuals with Refsum disease have a deficiency of phytanoyl-CoA hydroxylase, the enzyme encoded by PHYH that catalyses the conversion of phytanoyl-CoA into 2-hydroxyphytanoyl-CoA, a key step in the breakdown of phytanic acid via alpha-oxidation in peroxisomes. To assess activity of this enzyme, phytanic acid alpha-oxidation is first measured in cultured fibroblasts. If alpha-oxidation is deficient, the activity of the enzyme phytanoyl-CoA hydroxylase is measured.

Deficiency of the peroxisome-targeting signal type 2 (PTS2) receptor.  Fewer than 10% of individuals with Refsum disease have a deficiency of the PTS2 receptor encoded by the PEX7 gene. The PTS2 receptor plays a key role in peroxisome biogenesis by catalyzing the transport across the peroxisomal membrane of proteins equipped with a peroxisome-targeting signal type 2 (like phytanoyl-CoA hydroxylase). Abnormalities in fibroblasts of such individuals include the presence of an abnormal molecular form of peroxisomal thiolase (44 kd) and a partial deficiency of alkyldihydroxyacetonephosphate synthase [van den Brink et al 2003a].

CSF protein concentration.  The normal CSF protein concentration in adults ranges from 15 to 50 mg/dL. Values in individuals with Refsum disease are considerably higher. In one Arab family, CSF protein concentration was 101 mg/dL [Fertl et al 2001].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Genes.  Mutations in two different genes have been identified in Refsum disease.

• PHYH, the gene that encodes phytanoyl-CoA hydroxylase, is mutated in more than 90% of individuals with Refsum disease [Waterham & Wanders, unpublished observations].

• PEX7, the gene that encodes the PTS2 receptor, is mutated in fewer than 10% of individuals with Refsum disease.

Molecular genetic testing: Clinical uses

• Confirmatory diagnostic testing

• Carrier testing

• Prenatal diagnosis

Molecular genetic testing: Clinical method

• Full gene sequencing.  Sequencing of coding exons and flanking intron sequences from genomic DNA for PHYH and PEX7 detects mutations in more than 95% of individuals [Waterham & Wanders, unpublished observations].

Table 2 summarizes molecular genetic testing for this disorder.

Table 2. Molecular Genetic Testing Used in Refsum Disease

Test Method	Mutations Detected	Mutation Detection Rate	Test Availability
Full gene sequencing	Sequence alterations in PHYH	>95%	Clinical
	Sequence alterations in PEX7

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

Genetically Related (Allelic) Disorders

PHYH.  No other phenotypes are associated with mutations in PHYH.

PEX7.  Mutations in PEX7 account for rhizomelic chondrodysplasia punctata type I (RCDP type I), a severe and often lethal disorder characterized by mental retardation, rhizomelic shortening of the upper extremities, dwarfism, and cataract [Braverman et al 2002, Motley et al 2002].

Ntural History

Onset of symptoms in "classic Refsum disease" (CRD) or "adult Refsum disease" (ARD) ranges from seven months to greater than 50 years of age. However, because the onset is insidious, it is difficult for many individuals to know exactly when symptoms first started. A few individuals remain asymptomatic until adulthood [Skjeldal et al 1987]. Early-onset disease is not necessarily associated with a poor prognosis for life span.

Retinitis pigmentosa is, in most cases, an early clinical feature. Other findings that may occur in the following 10 to 15 years in decreasing order of frequency are neuropathy, deafness, ataxia, and ichthyosis [Skjeldal et al 1987]. Wierzbicki et al (2002) documented in 15 individuals the cumulative incidence of the following features over many decades: retinitis pigmentosa (15/15), anosmia (14/15), neuropathy (11/15), deafness (10/15), ataxia (8/15), and ichthyosis (4/15). In a few instances, psychiatric disturbances have also been observed.

The four cardinal features, originally described by Refsum (1946) (retinitis pigmentosa, a chronic polyneuropathy, ataxia, and raised CSF protein concentration) are rarely seen in a single individual.

Some investigators distinguish between acute ARD and chronic ARD. In acute ARD, polyneuropathy, weakness, ataxia, sudden visual deterioration, and often auditory deterioration are often accompanied by ichthyosis, possibly cardiac arrhythmias, and elevated liver transaminases and bilirubin. Triggers for acute presentations include weight loss, stress, trauma, and infections. In contrast, in chronic ARD, RP is present, but the other features of ARD are subtle.

Ophthalmologic findings.  Retinitis pigmentosa (pigmentary retinal degeneration, tapeto-retinal degeneration) is present in all individuals with biochemical findings of Refsum disease and therefore appears to be an obligatory finding; in a series of 17 individuals, retinitis pigmentosa was present in all [Skjeldal et al 1987].

Virtually every individual ultimately diagnosed to have Refsum disease experiences visual symptoms first. If a detailed past medical history is obtained, many individuals confirm the onset of night blindness in childhood. The delay between first ophthalmologic evaluation and diagnosis ranged between one and 28 years (mean=11 years) in one study of 23 individuals [Claridge et al 1992].

Typically, individuals with Refsum disease experience night blindness years before the progressive changes of constricted visual fields and decreased central visual acuity appear. Because night blindness can be difficult to ascertain, particularly in children, electroretinography, which shows either a reduction or a complete absence of rod and cone responses, can help support the diagnosis in early stages. (See GeneReview: Retinitis Pigmentosa Overview.)

Anosmia.  This is the absence of smell. Although the sense of smell and the sense of taste have their own specific receptors, they are intimately related. Both may be normal, reduced, or absent in individuals with Refsum disease. Studies by Wierzbicki et al (2002) have shown that anosmia is present in most, if not all, individuals with ARD/CRD. If smell is tested experimentally, all individuals with ARD/CRD have an abnormal smell test [Gibberd et al 2004].

Polyneuropathy.  The polyneuropathy is a mixed motor and sensory neuropathy that is asymmetric, chronic, and progressive in untreated individuals. It may not be clinically apparent at the start of the illness. Initially, symptoms often wax and wane. Later, the distal lower limbs are affected with resulting muscular atrophy and weakness. Over the course of years, muscular weakness can become widespread and disabling, involving not only the limbs, but also the trunk.

Almost without exception, individuals with Refsum disease have peripheral sensory disturbances, most often impairment of deep sensation, particularly perception of vibration and position-motion in the distal legs.

Hearing loss.  Bilaterally symmetric mild-to-profound sensorineural hearing loss affects the high frequencies or middle-to-high frequencies [Oysu et al 2001, Bamiou et al 2003]. Auditory nerve involvement (auditory neuropathy) may be evident on testing of auditory brainstem evoked responses (ABER) [Oysu et al 2001, Bamiou et al 2003]. Individuals with auditory nerve involvement may experience hearing difficulty even in the presence of a normal audiogram. (See GeneReview: Hereditary Hearing Loss and Deafness.)

Ataxia.  Although cerebellar dysfunction is considered to be a main clinical sign of Refsum disease, onset is nevertheless relatively late, particularly when compared with the onset of retinopathy and neuropathy. Unsteadiness of gait is the main symptom related to cerebellar dysfunction. Ataxia is thus characteristically more marked than the degree of muscular weakness and sensory loss would indicate. (See GeneReview: Hereditary Ataxia Overview.)

Ichthyosis.  Mild generalized scaling may occur in childhood, but usually begins in adolescence. This finding is present in a minority of affected individuals.

Cardiac arrhythmias.  Cardiac arrhythmia and heart failure resulting from cardiomyopathy are frequent causes of death in Refsum disease.

Elevated plasma concentration of pipecolic acid.  A few individuals with elevated plasma concentrations of both phytanic acid and pipecolic acid have been described [Tranchant et al 1993, Baumgartner et al 2000]. Subsequently, sequencing of the gene encoding human L-pipecolic acid oxidase [IJlst et al 2000] in these individuals did not reveal mutations [Waterham & Wanders, unpublished results], supporting the view that the accumulation of pipecolic acid in these patients is a secondary event.

Baumgartner et al (2000) described an individual with psychomotor retardation and abnormally short metatarsals and metacarpals, but no other signs of classic Refsum disease. Phytanoyl-CoA hydroxylase enzyme activity was deficient; a homozygous deletion of PHYH causing a frameshift was identified. L-pipecolic acid concentration was elevated in plasma. Microscopy of the liver showed the presence of peroxisomes, although they were reduced in number and increased in size. These abnormal liver peroxisomes lacked catalase. Moreover, in fibroblasts, a mosaic pattern of cells with and without peroxisomes was found, in contrast to the peroxisomes in fibroblasts from individuals with classic Refsum disease that cannot be distinguished from controls by catalase immunofluorescence. Most likely, this individual is affected by two distinct genetic disorders with mutations in different genes of which one is PHYH, whereas the other gene remains to be identified. The latter gene may well be one of the PEX genes.

Tranchant et al (1993) described three members of a family diagnosed with Refsum disease. Two had a significant increase of pipecolic acid concentration in plasma and a fourth individual, a brother, died at 17 years of age from a progressive neurological disorder with unusual clinical and neuropathological abnormalities. Homozygosity mapping [Nadal et al 1995] localized the gene to chromosome 10p. Subsequently these sibs were confirmed to have phytanoyl-CoA hydroxylase deficiency in fibroblasts and disease-causing mutations in PHYH [Waterham & Wanders, unpublished observations]. Most likely, the mild accumulation of pipecolic acid in these individuals is the secondary result of the accumulation of phytanic acid. This hypothesis is supported by data of Wierzbicki et al (2002) showing elevated plasma pipecolic acid levels in 20% of individuals with Refsum disease.

Genotype-Phenotype Correlations

More studies are needed to determine if the phenotype differs between those with Refsum disease caused by mutations in PHYH and those with Refsum disease caused by mutations in PEX7. Preliminary data suggest that the Refsum disease phenotype caused by mutations in PEX7 may be milder [van den Brink et al 2003b].

Manifestations of Refsum disease may vary considerably among affected individuals in a family, i.e., among individuals with identical PHYH mutations. These phenotypic differences are comparable to those among affected individuals from different families. Consequently, no clear phenotype-genotype correlations have been identified as yet. This may be related to the dietary intake of phytanic acid, which is thought to be the toxic compound.

Nomenclature

Adult Refsum disease was first described in 1946 by the Norwegian neurologist Sigwald Refsum as a distinct autosomal recessive neurological entity, which he called heredopathia atactica polyneuritiformis.

In the literature, Refsum disease is also referred to as "classic Refsum disease" (CRD) or "adult Refsum disease" (ARD) to distinguish it from infantile Refsum disease (IRD), which belongs to the group of peroxisome biogenesis disorders, Zellweger syndrome spectrum. Distinction between so-called infantile Refsum disease and classic Refsum disease is readily apparent on clinical grounds. IRD has a much earlier onset with cerebral and hepatic dysfunction, craniofacial dysmorphia, developmental delay, and death usually in infancy or early childhood. The only finding shared by IRD and CRD/ARD is the accumulation of phytanic acid in plasma and tissues. In CRD/ARD, phytanic acid metabolism is the only abnormality, whereas in IRD, a number of biochemical abnormalities result from the defect in peroxisome biogenesis. Thus, infantile Refsum disease is a poor designation, given the lack of resemblance to classic Refsum disease.

Prevalence

The prevalence of Refsum disease is probably very low. In the literature, no estimates of its prevalence have been reported. The fact that most individuals described in the literature have been identified in the United Kingdom and Norway, where awareness of Refsum disease is high, suggests that the true prevalence of Refsum disease may be much higher than currently reported. According to Wierzbicki (personal communication), the incidence is around one in 10⁶ in the United Kingdom.

Evaluations at Initial Diagnosis to Establish the Extent of Disease

• Ophthalmology: examination for retinitis pigmentosa / miosis, cataract and visual fields [Claridge et al 1992]

• Anosmia testing using the procedure described by Gibberd et al (2004)

• Neurology: ataxia, neuropathy, myography, and electrophysiological assessment

• Audiology: pure tone audiometry and possibly otoacoustic emission testing and auditory brainstem evoked response (ABER) testing if hearing difficulties are suspected but not identified on pure tone audiometry [Bamiou et al 2003]

• Radiology: physical examination of hands, feet, and knees [Plant et al 1990]; radiological assessment of hands and feet

• Cardiology: cardiac evaluation including electrocardiography (ECG) and cardiac ultrasound examination

Treatment of Manifestations

Chronic treatment

• Dietary restriction of phytanic acid intake

• Avoidance of sudden weight loss

• Lifelong treatment with hydrating creams

• Regular care by a cardiologist for cardiac arrhythmias and cardiomyopathy in order to treat signs and symptoms properly with anti-arrhythmic and cardiogenic supportive drugs

Treatment of acute presentation

• Many acute features such as polyneuropathy, ataxia, ichthyosis, and cardiac arrhytmias resolve with reduction in plasma phytanic acid concentration. (See Prevention of Primary Manifestations.)

• Plasmapheresis [Gibberd et al 1979] or lipapheresis can be used in the event of acute arrhythmias or extreme weakness because phytanic acid is transported on lipoproteins [Gutsche et al 1996, Wierzbicki et al 1999]. During plasmapheresis, cardiac monitoring should be continuous and plasma glucose concentration should be kept high to prevent onset or exacerbation of arrhythmias.

• A low phytanic acid diet can be given orally or by nasogastric tube. If oral intake is restricted, appropriate parenteral nutrition and fluid therapies are needed to maintain plasma glucose concentrations and prevent ketosis.

Prevention of Primary Manifestations

• No curative therapy currently exists for Refsum disease.

• By restricting dietary intake of phytanic acid or eliminating phytanic acid by plasmapheresis or lipid apheresis [Gibberd et al 1979, Moser et al 1980, Gutsche et al 1996], plasma phytanic acid concentrations can be reduced by 50% to 70%, typically to about 100 to 300 µmol/L. This reduction in plasma phytanic acid concentration successfully resolves symptoms of ichthyosis, sensory neuropathy, and ataxia in approximately that order. However, it is uncertain whether treatment affects the progression of the retinitis pigmentosa, anosmia, and deafness [Gibberd & Wierzbicki 2000].

• A high-calorie diet is necessary to avoid mobilization of stored lipids, including phytanic acid, into the plasma.

• Postoperative care requires parenteral nutrition.

Agents/Circumstances to Avoid

• All food products containing phytanic acid such as ruminant (cow, sheep, goat) products and certain fish (cod) products. Also some nuts should be avoided (see Brown et al 1993).

• Fasting because stored lipids, including phytanic acid, are mobilized into the plasma

• Ibuprofen because it is metabolized by AMACR and might interfere with the metabolism of phytanic acid

Testing of Relatives at Risk

• It is appropriate to evaluate the sibs of a proband by measuring plasma phytanic acid concentration before symptoms of Refsum disease occur in order to institute early treatment to reduce plasma phytanic acid concentration.

Therapies Under Investigation

• At present, the potential of enzyme replacement therapy (ERT) similar to that for lysosomal storage diseases (e.g., Hurler syndrome (MPS I), Fabry disease, and Gaucher disease) is under investigation. This may eventually replace dietary restrictions and plasma- or lipapheresis.

• In the long run, gene therapy may be the treatment of choice, but many issues need to be resolved before it can be applied.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Refsum disease is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

Offspring of a proband.  The offspring of an individual with Refsum disease are obligate heterozygotes (carriers) for a disease-causing mutation.

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

Carrier Detection

• Carrier testing using molecular genetic testing is available on a clinical basis once the PEX7 or PHYH mutations have been identified in the proband.

• Biochemical testing is not accurate for carrier testing, as the biochemical findings (i.e., plasma phytanic acid concentration) in obligate heterozygotes (carriers) are near normal [Wierzbicki et al 2003].

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.

DNA banking.  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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

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 about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. Both disease-causing PEX7 or PHYH alleles of an affected family member must be identified before prenatal testing can be performed.

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

Biochemical genetic testing.  Prenatal diagnosis for pregnancies at 25% risk is possible by measurement of phytanic acid oxidation in fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation* or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. For laboratories offering biochemical testing, see .

Requests for prenatal testing for typically adult-onset diseases such as Refsum disease are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

Mutations in PHYH and PEX7 are known to cause Refsum disease by interfering with the alpha-oxidation of phytanic acid.

Alpha-oxidation of phytanic acid.  Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is derived from dietary sources only, mainly from dairy and ruminant fats. Phytanic acid is a 3-methyl branched chain fatty acid, which cannot undergo straightforward beta-oxidation like other fatty acids since the presence of the methyl group at the 3-position blocks beta-oxidation. Nature has resolved this problem by creating an alpha-oxidation mechanism in which the terminal carboxyl group is released as CO₂. Accordingly, phytanic acid first undergoes alpha-oxidative chain shortening to produce pristanic acid (2,4,6,10-tetramethylpentadecanoic acid) and CO₂. All steps from phytanoyl-CoA to pristanic acid occur in peroxisomes [Wanders et al 2001]:

• Activation of phytanic acid to phytanoyl-CoA

• Hydroxylation of phytanoyl-CoA to 2-hydroxyphytanoyl-CoA by the enzyme phytanoyl-CoA hydroxylase, encoded by PHYH. Phytanoyl-CoA hydroxylase is equipped with a PTS2 signal, and is targeted to the peroxisome by means of the PTS2 receptor, encoded by the PEX7 gene.*

• Conversion of 2-hydroxyphytanoyl-CoA into pristanal and formyl-CoA via the enzyme 2-hydroxyphytanoyl-CoA lyase** encoded by 2-HPCL.

• Conversion of pristanal into pristanic acid via an ill-defined aldehyde dehydrogenase [Jansen et al 2001].

• Conversion of pristanic acid into pristanoyl-CoA via the peroxisomal very-long-chain acyl-CoA synthetase**, which has its catalytic site facing the lumen of the peroxisome [Smith et al 2000].

*In case of a deficiency at the level of the PTS2 receptor, phytanoyl-CoA hydroxylase cannot be properly imported into the peroxisome, leading to its functional deficiency.

**The other enzymes from the phytanic acid alpha-oxidation route, including 2-hydroxyphytanoyl-CoA lyase and very-long-chain acyl-CoA synthetase, are PTS1 proteins, which are targeted to the peroxisome by means of the PTS1 receptor, encoded by the PEX5 gene.

Beta-oxidation.  Once pristanic acid has been activated to pristanoyl-CoA, it undergoes three cycles of beta-oxidation in the peroxisomes to generate 4,8-dimethylnonanoyl-CoA, which then is transported to mitochondria for final oxidation to CO₂ and H₂O in the form of its carnitine ester.

Note that unimpaired breakdown of phytanic acid is only possible if pristanic acid, the product generated from phytanic acid by alpha-oxidation, also undergoes unimpaired degradation. If pristanic acid oxidation is blocked, as in 2-methylacylCoA racemase deficiency caused by mutations in the AMACR gene, phytanic acid degradation is partially blocked, leading to elevated plasma phytanic acid concentration.

PHYH

Normal allelic variants: Jansen et al (2004) have described one sequence variant (c.636A>G) with an incidence of around 10% in 93 control individuals that causes no amino acid change.

Pathologic allelic variants: Sequence analysis of the PHYH gene has now been performed in 31 unrelated families and has revealed 29 different variants of which 18 (62.1%) are unique to one patient or family. Of these 29 variants,

• Sixteen (55.2%) are missense mutations.

• Four (13.8%) are deletions. All deletions are found in the first half of the coding sequence and all cause a frame-shift.

• Two are insertions (6.8%). One causes a frame-shift; the other, a three nucleotide insertion, causes the insertion of a single amino acid into the PhyH protein.

• Six (20.7%) are splice-site mutations. Two splice-site variants are located in IVS2 (c.135-2A>G and c.135-1G>C), which leads to skipping of exon 3, consisting of 111 nucleotides. This causes an in-frame deletion of 37 internal amino acids, and an altered protein (p.Y46-R82del), which, when heterozygously expressed in S. cerevisiae, is clearly detectable by Western blot analysis, but completely lacks enzymatic activity [Jansen et al 2000]. Four splice-site variants, one in IVS5 (c.497-2A>G) and three in IVS6 (c.678+2T.G, c.678+5G>T, and c679-1G>T), cause skipping of exon 6, which results in a frameshift and a premature stop codon (p.A166fsX3).

• One (3.4%) is a non-disease-causing variant that is also present in about 10% of a control population.

Normal gene product: See Molecular Genetic Pathogenesis.

Abnormal gene product: The impact of any mutation in the phytanoyl-CoA hydroxylase gene can be assessed by evaluating the consequences of certain mutations on the stability and the catalytic activity of the hydroxylase upon expression. Interestingly, 15 of the 17 missense mutations identified in the phytanoyl-CoA hydroxylase are located in exon 6 and 7. Structure-function analysis has demonstrated that these exons code in part for the conserved beta-barrel core, which suggests that this structurally important element in the protein is susceptible to changes that directly cause loss of enzymatic activity. The effect of only very few of the missense mutations has been tested by expressing the mutant proteins and testing protein stability and enzyme activity. Mukherji et al (2001) have studied a few mutants including the p.H175R, p.Q176K, and p.D177G mutants. The amino acid triad 175-177 (HQD) forms the iron-binding motif and mutations in any of these amino acids have been shown to cause a fully dysfunctional enzyme since the hydroxylase is completely dependent upon Fe²⁺ for the conversion of phytanoyl-CoA to 2-hydroxyphytanoyl-CoA. Two missense mutations, including p.G204S and p.N269H, cause the peculiar effect of uncoupling the hydroxylation of phytanoyl-CoA from the conversion of 2-oxoglutarate into succinate and CO₂. As demonstrated in expression studies, Mukherji et al (2001) found that no phytanoyl-CoA was hydroxylated while decarboxylation of 2-oxoglutarate to succinate and CO₂ still took place, although at a much-reduced rate. This uncoupling is also observed in the case of the p.Q176K substitution, which is also associated with a change in the iron-binding motif.

PEX7

Normal allelic variants: The PEX7 gene contains ten exons that span 91 kb of genomic DNA.

Pathologic allelic variants: So far, three individuals have been identified with mild mutations in the PEX7 gene. The two individuals described by van den Brink et al(2003a) who were both compound heterozygous for mutations in PEX7 had an Y40X nonsense mutation that introduces a premature stop codon in the N-terminal region of the protein. This mutation has also been found in classic RCDP type 1 with a severe clinical presentation [Motley et al 2002]. In patient 1, the second allele was a 7-nucleotide duplicate mutation, predicted to cause a frame-shift leading to a premature stop codon at amino acid position 57. However, the duplication occurs between two in-frame initiation codons, which would suggest that use of the second ATG may produce a protein that lacks the first ten amino acids but retains partial peroxin 7 transport functions. In patient 2, the second allele was a T14P-amino acid substitution, which is thought either to interfere with folding of the protein or to reduce the affinity for its binding partners [Braverman et al 2002].

Normal gene product: The normal product is a 323-amino acid protein with serial WD40 repeats. These domains fold into blades of a propeller-like structure, which provides several surfaces for protein interactions [Braverman et al 2002]. Peroxisomal targeting signal 2 receptor, the protein encoded by PEX7, is a receptor for a subclass of peroxisomal matrix enzymes and targets these enzymes to the peroxisomal membrane.

Abnormal gene product: Defects in peroxisomal targeting signal 2 receptor result in deficient activity of all PTS2 enzymes, but other peroxisomal functions remain intact. Fibroblast assays show that PTS2 proteins remain cytosolic in individuals with RCDP1 and are likely degraded, but PTS1 proteins are imported into peroxisomes normally. Peroxisome morphology is normal in fibroblasts, but abnormal in liver, according to several case reports (see Braverman et al 2002, van den Brink et al 2003b).

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Revision History

• 20 March 2006 (me) Review posted to live Web site

• 30 March 2004 (rw) Original submission