Newborn Screening for X-Linked Adrenoleukodystrophy (X-ALD): Biochemical, Molecular, and Clinical Characteristics of Other Genetic Conditions
Abstract
1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Matteson, J.; Sciortino, S.; Feuchtbaum, L.; Bishop, T.; Olney, R.S.; Tang, H. Adrenoleukodystrophy Newborn Screening in California Since 2016: Programmatic Outcomes and Follow-Up. Int. J. Neonatal Screen. 2021, 7, 22. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Barendsen, R.W.; Dijkstra, I.M.E.; Visser, W.F.; Alders, M.; Bliek, J.; Boelen, A.; Bouva, M.J.; van der Crabben, S.N.; Elsinghorst, E.; van Gorp, A.G.M.; et al. Corrigendum: Adrenoleukodystrophy Newborn Screening in the Netherlands (SCAN Study): The X-Factor. Front. Cell Dev. Biol. 2021, 9, 631655, Erratum in Front. Cell Dev. Biol. 2020, 8, 499. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Armangue, T.; Orsini, J.J.; Takanohashi, A.; Gavazzi, F.; Conant, A.; Ulrick, N.; Morrissey, M.A.; Nahhas, N.; Helman, G.; Gordish-Dressman, H.; et al. Neonatal detection of Aicardi Goutières Syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots. Mol. Genet. Metab. 2017, 122, 134–139, Erratum in Mol. Genet. Metab. 2022, 136, 80. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Tise, C.G.; Morales, J.A.; Lee, A.S.; Velez-Bartolomei, F.; Floyd, B.J.; Levy, R.J.; Cusmano-Ozog, K.P.; Feigenbaum, A.S.; Ruzhnikov, M.R.Z.; Lee, C.U.; et al. Aicardi-Goutières syndrome may present with positive newborn screen for X-linked adrenoleukodystrophy. Am. J. Med. Genet. A 2021, 185, 1848–1853. [Google Scholar] [CrossRef] [PubMed]
- Niehaus, A.D.; Mendelsohn, B.A.; Zimmerman, B.; Lee, C.U.; Manning, M.A.; Cusmano-Ozog, K.P.; Tise, C.G. Neonatal lupus is a novel cause of positive newborn screening for X-linked adrenoleukodystrophy. Am. J. Med. Genet. A 2023, 191, 1412–1417. [Google Scholar] [CrossRef] [PubMed]
- Klouwer, F.C.; Berendse, K.; Ferdinandusse, S.; Wanders, R.J.; Engelen, M.; Poll-The, B.T. Zellweger spectrum disorders: Clinical overview and management approach. Orphanet. J. Rare Dis. 2015, 10, 151. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Jansen, R.L.M.; Santana-Molina, C.; van den Noort, M.; Devos, D.P.; van der Klei, I.J. Comparative Genomics of Peroxisome Biogenesis Proteins: Making Sense of the PEX Proteins. Front. Cell Dev. Biol. 2021, 9, 654163. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Steinberg, S.J.; Raymond, G.V.; Braverman, N.E.; Moser, A.B. Zellweger Spectrum Disorder. In GeneReviews®; Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., Amemiya, A., Eds.; University of Washington: Seattle, WA, USA, 1993–2024. Available online: https://www.ncbi.nlm.nih.gov/books/NBK1448/ (accessed on 10 April 2024).
- Braverman, N.E.; Raymond, G.V.; Rizzo, W.B.; Moser, A.B.; Wilkinson, M.E.; Stone, E.M.; Steinberg, S.J.; Wangler, M.F.; Rush, E.T.; Hacia, J.G.; et al. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol. Genet. Metab. 2016, 117, 313–321. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Heubi, J.E.; Setchell, K.D.R.; Bove, K.E. Long-Term Cholic Acid Therapy in Zellweger Spectrum Disorders. Case Rep. Gastroenterol. 2018, 12, 360–372. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Klouwer, F.C.C.; Koot, B.G.P.; Berendse, K.; Kemper, E.M.; Ferdinandusse, S.; Koelfat, K.V.K.; Lenicek, M.; Vaz, F.M.; Engelen, M.; Jansen, P.L.M.; et al. The cholic acid extension study in Zellweger spectrum disorders: Results and implications for therapy. J. Inherit. Metab. Dis. 2019, 42, 303–312. [Google Scholar] [CrossRef] [PubMed]
- Tang, H.; Matteson, J.; Rinaldo, P.; Tortorelli, S.; Currier, R.; Sciortino, S. The Clinical Impact of CLIR Tools toward Rapid Resolution of Post-Newborn Screening Confirmatory Testing for X-Linked Adrenoleukodystrophy in California. Int. J. Neonatal Screen. 2020, 6, 62. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Bose, M.; Yergeau, C.; D’Souza, Y.; Cuthbertson, D.D.; Lopez, M.J.; Smolen, A.K.; Braverman, N.E. Characterization of Severity in Zellweger Spectrum Disorder by Clinical Findings: A Scoping Review, Meta-Analysis and Medical Chart Review. Cells 2022, 11, 1891. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Slaton, D.; Chang, A.; Ahluwalia, T.; Alfaro, S.; Javed, B.; Greer, R. Zellweger’s Syndrome with PEX6 Gene Mutation in Mixteco Neonates Due to Possible Founder Effect. Cureus 2023, 15, e45162. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Galarreta, C.I.; Wong, K.; Carmichael, J.; Woods, J.; Tise, C.G.; Niehaus, A.D.; Schildt, A.J.; Verscaj, C.P.; Cusmano-Ozog, K.P. A homozygous Gly470Ala variant in PEX6 causes severe Zellweger spectrum disorder. Am. J. Med. Genet. A 2023, 191, 2057–2063. [Google Scholar] [CrossRef] [PubMed]
- Chen, H.A.; Hsu, R.H.; Chen, P.W.; Lee, N.C.; Chiu, P.C.; Hwu, W.L.; Chien, Y.H. High incidence of null variants identified from newborn screening of X-linked adrenoleukodystrophy in Taiwan. Mol. Genet. Metab. Rep. 2022, 32, 100902. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Shimozawa, N.; Takashima, S.; Kawai, H.; Kubota, K.; Sasai, H.; Orii, K.; Ogawa, M.; Ohnishi, H. Advanced Diagnostic System and Introduction of Newborn Screening of Adrenoleukodystrophy and Peroxisomal Disorders in Japan. Int. J. Neonatal Screen. 2021, 7, 58. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Bonaventura, E.; Alberti, L.; Lucchi, S.; Cappelletti, L.; Fazzone, S.; Cattaneo, E.; Bellini, M.; Izzo, G.; Parazzini, C.; Bosetti, A.; et al. Newborn screening for X-linked adrenoleukodystrophy in Italy: Diagnostic algorithm and disease monitoring. Front. Neurol. 2023, 13, 1072256, Erratum in Front. Neurol. 2024, 15, 1376447. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
Newborn Screening (NBS) Results | Case #1 | Case #2 | Case #3 | Case #4 | Case #5 | Case #6 | Case #7 | Case #8 | Case #9 |
---|---|---|---|---|---|---|---|---|---|
NBS 1st-tier C26 μmL/L (Cutoff ≤ 0.42) | 2.29 | 2.20 | 3.01 | 1.79 | 1.05 | 0.44 | 0.54 | 1.95 | 1.85 |
NBS 2nd-tier C26 μmL/L (Cutoff ≤ 0.22) | 1.28 | 1.178 | 1.239 | 1.475 | 0.903 | 0.224 | 0.33 | 1.041 | 1.34 |
NBS 3rd-tier ABCD1 sequencing | Negative | Negative | Negative | Negative | Negative | None | Heterozygous VUS in ABCD1 (see below) | None | VUS in ABCD1, c.1489-6delC |
Molecular testing | |||||||||
Variant 1 | PEX1, c.2972delC (p.Pro991Leufs*9) PV | PEX6, c.1233 + 3G > C VUS | PEX1, c.2368C > T (p.Arg790*) PV | PEX12, c.625C > T (pGln209*) PV | PEX6, 1409G > C (p.Gly470Ala) PV | 84 kb contiguous deletion of Xq28 including the ABCD1, BCAP31, SLC6A8 and PLXNB3 genes | ABCD1 (c.576 C > A (p.Asn192Lys) hemizygous VUS | PEX6 (c.2095-21_2095-10del) PV | PEX1 (c.2391_2392del, p.Arg798Serfs*35) LPV |
Variant 2 | PEX1, c.2528G > A (p.Gly843Asp) PV | PEX6, c.1233 + 3G > C VUS | PEX1, c.3152_3156del (p.Leu1051Glnfx*24) PV | PEX12, c.268_271delAAGA (p.Lys90Glufs*3) LPV | PEX6, c.2735C > T (p.Ala912Val) PV | None | None | PEX6 c.1313T > C (p.L438P) VUS | PEX1 (c.2966T > C, p.Ile989Thr) PV |
Clinical Status | Case #1 | Case #2 | Case #3 | Case #4 | Case #5 | Case #6 | Case #7 | Case #8 | Case #9 |
Alive | Yes | No | No | No | Yes | Yes | Yes | Yes | Yes |
IUGR | No | Yes | No | No | No | Yes | No | No | No |
Age at last f/up | 11 m | 2 m | 2 m | 5 m | 4 m | 33 m | 34 m | 10 m | 10 m |
Current age or age at death | 12 m | 4 m | 2 m | 7 m | 5 m | 37 m | 38 m | 14 m | 68 m |
Height (percentile) | <1st | <1st | 38th | <1st | 43rd | 45th | 89th | 5th | 25th |
Weight (percentile) | <1st | <1st | <1st | <1st | 83rd | 60th | 48th | <1st | 10th |
Head circumference (percentile) | 3rd | NA | <1st | 3rd | 46th | 51st | 38th | 76th | NA |
Development | GDD | GDD | NA | GDD | Normal | Normal | Normal | Normal | Normal |
Newborn hearing screening | Failed NB hearing screen and repeat hearing test. Wearing hearing aids | Failed NB hearing screen | NA | Failed NB hearing screen | Failed NB hearing screen and repeat hearing test | Failed NB hearing screen unilaterally. Normal hearing exam at 4 m | Failed NB hearing screen but later passed at his outpatient hearing test | Failed NB hearing screen unilaterally, which he later passed | Passed |
Renal | US: normal | US: Mild right side hydronephrosis | US: bilateral mild hydronephrosis and echogenic kidneys | Initial US: Multiple tiny cysts throughout R kidney. On f/up US: small bilateral renal cysts | Renal US not performed | Renal US not performed | Renal US not performed | US: normal | US: normal |
Liver | Cholestasis, elevated transaminases | Cholestasis, elevated transaminases. Liver failure | Cholestasis, elevated transaminases. Liver failure | Cholestasis, elevated transaminases | Cholestasis, elevated transaminases | ND | Normal | Elevated transaminases | Elevated transaminases |
Ophthalmologic | Progressive opacity in lenses and cornea, pigmentary retinopathy | ND | ND | ND | No lenses, corneal or retinal lesions | ND | No lenses, corneal or retinal lesions | No lenses, corneal or retinal lesions | No lenses, corneal or retinal lesions |
Hypotonia | Profound | Profound | Profound | Profound | Mild | No | No | No | No |
Seizures | No | No | Yes | Yes | No | No | No | No | No |
Brain MRI | |||||||||
Age performed | 1 m | 2 wk | ND | 2 wk | ND | ND | 14 m. Subsequent at 20, 26, 34 m | ND | ND |
Findings | Brachycephaly and bilateral subependymal cyst | Mild prominence of the lateral ventricles | ND | Colpocephaly, left greater than right; thinning of the corpus callosum; mild to moderate white matter volume loss | ND | ND | Chronic microhemorrhages in the cerebellar hemispheres. Nonspecific signal abnormality in the left periatrial white matter | ND | ND |
Case #1 | Case #2 | Case #3 | Case #4 | Case #5 | Case #6 | Case #7 | Case #8 | Case #9 | |
---|---|---|---|---|---|---|---|---|---|
Cholic acid | Yes | No | Yes | No | Yes | No | No | Yes | No |
Age when started | 3 m | NA | 2 m | NA | 5 m | NA | NA | 8 m | N/A |
Dose | 100 mg/d | NA | 100 mg/d | NA | 100 mg/d | NA | NA | 100 mg/d | N/A |
G-tube fed | No | No | No | Yes | No | No | No | No | No |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Mares Beltran, C.F.; Tise, C.G.; Barrick, R.; Niehaus, A.D.; Sponberg, R.; Chang, R.; Enns, G.M.; Abdenur, J.E. Newborn Screening for X-Linked Adrenoleukodystrophy (X-ALD): Biochemical, Molecular, and Clinical Characteristics of Other Genetic Conditions. Genes 2024, 15, 838. https://doi.org/10.3390/genes15070838
Mares Beltran CF, Tise CG, Barrick R, Niehaus AD, Sponberg R, Chang R, Enns GM, Abdenur JE. Newborn Screening for X-Linked Adrenoleukodystrophy (X-ALD): Biochemical, Molecular, and Clinical Characteristics of Other Genetic Conditions. Genes. 2024; 15(7):838. https://doi.org/10.3390/genes15070838
Chicago/Turabian StyleMares Beltran, Carlos F., Christina G. Tise, Rebekah Barrick, Annie D. Niehaus, Rebecca Sponberg, Richard Chang, Gregory M. Enns, and Jose E. Abdenur. 2024. "Newborn Screening for X-Linked Adrenoleukodystrophy (X-ALD): Biochemical, Molecular, and Clinical Characteristics of Other Genetic Conditions" Genes 15, no. 7: 838. https://doi.org/10.3390/genes15070838
APA StyleMares Beltran, C. F., Tise, C. G., Barrick, R., Niehaus, A. D., Sponberg, R., Chang, R., Enns, G. M., & Abdenur, J. E. (2024). Newborn Screening for X-Linked Adrenoleukodystrophy (X-ALD): Biochemical, Molecular, and Clinical Characteristics of Other Genetic Conditions. Genes, 15(7), 838. https://doi.org/10.3390/genes15070838