CADDS
August 24th, 2010 |“contiguous ABCD1 DXS1357E deletion syndrome” (CADDS)
In May 2002, a paper by Corzo et al., was published in the American Journal of Human Genetics. The authors described three newborn boys who had clinical symptoms and initial biochemical results consistent with a peroxisomal biogenesis disorder (PBD) or a peroxisomal single-enzyme defect (SED).
| Contiguous Deletion of the X-Linked Adrenoleukodystrophy Gene (ABCD1) and DXS1357E: A Novel Neonatal Phenotype Similar to Peroxisomal Biogenesis Disorders. Corzo D, Gibson W, Johnson K, Mitchell G, LePage G, Cox GF, Casey R, Zeiss C, Tyson H, Cutting GR, Raymond GV, Smith KD, Watkins PA, Moser AB, Moser HW, Steinberg SJ Abstract: X-linked adrenoleukodystrophy (X-ALD) results from mutations in ABCD1. ABCD1 resides on Xq28 and encodes an integral peroxisomal membrane protein (ALD protein [ALDP]) that is of unknown function and that belongs to the ATP-binding cassette-transporter superfamily. Individuals with ABCD1 mutations accumulate very-long-chain fatty acids (VLCFA) (carbon length >22). Childhood cerebral X-ALD is the most devastating form of the disease. These children have the earliest onset (age 7.2 ± 1.7 years) among the clinical phenotypes for ABCD1 mutations, but onset does not occur at <3 years of age. Individuals with either peroxisomal biogenesis disorders (PBD) or single-enzyme deficiencies (SED) in the peroxisomal beta-oxidation pathway-disorders such as acyl CoA oxidase deficiency and bifunctional protein deficiency-also accumulate VLCFA, but they present during the neonatal period. Until now, it has been possible to distinguish unequivocally between individuals with these autosomal recessively inherited syndromes and individuals with ABCD1 mutations, on the basis of the clinical presentation and measurement of other biochemical markers. We have identified three newborn boys who had clinical symptoms and initial biochemical results consistent with PBD or SED. In further study, however, we showed that they lacked ALDP, and we identified deletions that extended into the promoter region of ABCD1 and the neighboring gene, DXS1357E. Mutations in DXS1357E and the ABCD1 promoter region have not been described previously. We propose that the term “contiguous ABCD1 DXS1357E deletion syndrome” (CADDS) be used to identify this new contiguous-gene syndrome. The three patients with CADDS who are described here have important implications for genetic counseling, because individuals with CADDS may previously have been misdiagnosed as having an autosomal recessive PBD or SED. |
The paper describes three boys with clinical symptoms pointing either towards a peroxisomal biogenesis disorder (PBD) or a defect in one of the peroxisomal beta-oxidation enzymes (SED). Careful analysis of patient material (blood, DNA and cell lines), however, revealed that the genes responsible for PBD and SED were not involved. Surprisingly, the defect was located in the X-linked adrenoleukodystrophy gene (ABCD1).
The clinical findings are summarized in the following table.
| CADDS patients | bifunctional protein deficiency | Acyl-CoA oxidase deficiency | Zellweger syndrome | X-linked adrenoleukodystrophy | |
| age of death | 4, 4 and 11 months | < 1 year | 4 years | < 1 year | 9.4 years |
| neonatal hypotonia | + | + | + | + | - |
| neonatal seizures | +/- | + | + | + | - |
| craniofacial dysmorphism | - | + | - | + | - |
| intrauterine growth retardation | +/- | - | - | - | - |
| liver disease | + | +/- | - | + | - |
| neonatal cholestasis | + | - | - | +/- | - |
| cataracts | +/- | - | - | + | - |
| sensorineural deafness | +/- | +/- | +/- | +/- | - |
The boys were born to healthy women with no known family history of peroxisomal disorders and none of the relationships were consanguineous. The patients had profound neonatal hypotonia, failure to thrive, cholastatic liver disease with intracanalicular & ductal cholestasis, 2 boys had seizures at the age of 2 months and 1 patient had episodes of opisthotonos and bruxism. All three patients died during the first year of life (4, 4 and 11 months). The cause of death was liver or respiratory failure and gastrointestinal bleeding. An autopsy was performed on one patient (4 months of age). The findings were: total body weight was 2.2 kilogram, the adrenal glands were small and fibrotic and their combined weight was only 0.5 grams, the liver was small, fibrotic and jaundiced and brain abnormalities were present. MRI showed that myelination was delayed significantly, there was, however, no demyelination.
Biochemical findings in plasma demonstrated that VLCFA levels (C26:0 and C26:1) and ratios (C24:0/C22:0 and C26:0/C22:0) were elevated. The levels were intermediate values between those found in X-ALD and Zellweger syndrome patients. In contrast to patients with Zellweger syndrome, plasmalogens and L-pipecolic acid levels were normal. Additional biochemical studies in patient fibroblasts confirmed these results. These also demonstrated that peroxisomal VLCFA beta-oxidation was decreased, while peroxisomal alpha-oxidation and plasmalogen synthesis were normal. In addition, catalase solubility was unaffected, thus indicating that peroxisomes were intact.
Immunofluorescence with anti-catalase and anti-PMP70 antibodies showed that peroxisomes were present and that their size and number were unaffected. In contrast, there was no signal when an antibody against ALDP was used. Complementation studies with known X-ALD patient fibroblasts showed that the genetic defect was in the X-ALD (ABCD1) gene. Using PCR, it was not possible to amplify exons 1 through 10 in 2 patients and exons 1 through 5 in the third patient. Southern blot analysis and additional PCR studies demonstrated that the ABCD1 gene and the upstream DXS1357E gene (a.k.a. CDM or BAP31) were disrupted. The DXS1357E gene and the ABCD1 gene are orientated head-to-head and are transcribed in opposite directions. The minimal region that was deleted included exons 1 to 4 from the DXS1357E gene and exons 1 to 5 from the ABCD1 gene.
The severe clinical presentation of the three patients is most likely due to the additional missing of the DXS1357E gene. The earliest age at which X-ALD presents is 2.75 years. In addition, many patients with relatively mild X-ALD phenotypes have been identified and described who have no detectable ALDP caused by both frameshifts and nonsense mutations introduced early in the coding region of the protein.
