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Diagnosis and Discussion: Case 1155

Final Diagnosis

X-linked Adrenoleukodystrophy (X-ALD)

Discussion

X-linked adrenoleukodystrophy (X-ALD, OMIM 300100) is a peroxisomal disorder caused by mutations in the ABCD1 gene, leading to impaired peroxisomal beta-oxidation of very long chain fatty acids (VLCFAs) [1,2]. The resultant accumulation of VLCFAs in the brain, adrenal cortex, and testes causes progressive demyelination, adrenal insufficiency, and neurological dysfunction. The childhood cerebral form, as illustrated in this case, typically presents with progressive gait abnormalities, behavioral changes, and cognitive decline [1,2].

This case is unusual in several respects. It is atypical to first encounter a peroxisomal deficiency at age 12, and even more unusual that the diagnosis emerged in the context of trauma follow-up rather than through developmental concerns or newborn screening. Traditionally, X-ALD cases were identified clinically; however, more recently prospective newborn screening is the primary means whereby cases are identified.

The patient’s clinical presentation of toe walking, early-life clumsiness, and MRI findings of symmetrical white matter changes with corpus callosum gliosis are consistent with X-ALD. However, the absence of cognitive decline, behavioral symptoms, or adrenal dysfunction at this stage is highly atypical. The biochemical hallmark remains elevated plasma VLCFAs, particularly C26:0, and increased C24:0/C22:0 and C26:0/C22:0 ratios [2,3]. Normal adrenal function early in disease is not uncommon but requires ongoing monitoring. The normal serum neurofilament light chain level suggests a diagnosis was established before widespread neuroaxonal injury. Additional peroxisomal function testing revealed RBC plasmalogens within near-normal limits and pipecolic acid normal, helping to rule out broader peroxisomal biogenesis disorders.

Early diagnosis is critical, as hematopoietic stem cell transplantation (HSCT) can slow or halt progression if performed before significant neurological decline [4]. The expanding implementation of newborn screening for X-ALD highlights the potential for presymptomatic detection and timely intervention. Genetic counseling is essential due to the X-linked inheritance pattern. The family history of hereditary neuropathy further underscores the complexity of overlapping neurological conditions and the value of comprehensive genetic workup [5].

This case underscores the importance of integrating clinical, radiologic, biochemical, and molecular data for timely diagnosis and treatment of inherited leukodystrophies, while also emphasizing that even well-characterized disorders like X-ALD can present in unexpected contexts.

References

  1. Kemp S, Berger J, Aubourg P. X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochim Biophys Acta. 2012 Sep;1822(9):1465-74. doi: 10.1016/j.bbadis.2012.03.012. Epub 2012 Mar 28. PMID: 22483867.
  2. Moser HW, Mahmood A, Raymond GV. X-linked adrenoleukodystrophy. Nat Clin Pract Neurol. 2007 Mar;3(3):140-51. doi: 10.1038/ncpneuro0421. PMID: 17342190.
  3. Turk BR, Theda C, Fatemi A, Moser AB. X-linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies. Int J Dev Neurosci. 2020 Feb;80(1):52-72. doi: 10.1002/jdn.10003. Epub 2020 Jan 26. PMID: 31909500; PMCID: PMC7041623.
  4. Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S, Thrasher AJ, Armant M, Dansereau C, Lund TC, Miller WP, Raymond GV, Sankar R, Shah AJ, Sevin C, Gaspar HB, Gissen P, Amartino H, Bratkovic D, Smith NJC, Paker AM, Shamir E, O'Meara T, Davidson D, Aubourg P, Williams DA. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2017 Oct 26;377(17):1630-1638. doi: 10.1056/NEJMoa1700554. Epub 2017 Oct 4. PMID: 28976817; PMCID: PMC5708849.
  5. Wiesinger C, Eichler FS, Berger J. The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis. Appl Clin Genet. 2015 May 2;8:109-21. doi: 10.2147/TACG.S49590. PMID: 25999754; PMCID: PMC4427263.