International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy

In the paper

“The risk of developing cerebral disease is highest in childhood but remains present throughout life.1,29,33-39”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016; 12(10): 606- 615. 27312864 source
• Partly supported

  The Results (Surveillance guidelines; page unavailable) say the risk peaks at ages 3–12 and declines during the teenage years. The Methods exclude studies focused solely on adults, so this paper does not establish that the risk remains present throughout life. (LLM, conf=0.87)

  cites [29] Mallack EJ, Turk BR, Yan H, et al. MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines. J Inherit Metab Dis. 2021; 44(3): 728- 739. 33373467 PMC8113077 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [33] Huffnagel IC, Laheji FK, Aziz-Bose R, et al. The natural history of adrenal insufficiency in X-linked adrenoleukodystrophy: an international collaboration. J Clin Endocrinol Metab. 2019; 104(1): 118- 126. 30252065 source
• ?Not checked — no full text of the sourcecites [34] Baumann M, Korenke GC, Weddige-Diedrichs A, et al. Haematopoietic stem cell transplantation in 12 patients with cerebral X-linked adrenoleukodystrophy. Eur J Pediatr. 2003; 162(1): 6- 14. 12486501 source
• Supported

  The Introduction (page unavailable) says cerebral X-linked adrenoleukodystrophy affects about a third of males in childhood, while primary cerebral disease in adolescence or adulthood is uncommon. It also reports secondary cerebral demyelination in adult males with adrenomyeloneuropathy, supporting the point that cerebral disease can develop beyond childhood. (LLM, conf=0.85)

  cites [35] Kuhl JS, Suarez F, Gillett GT, et al. Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy. Brain. 2017; 140(4): 953- 966. 28375456 source
• ?Not checked — no full text of the sourcecites [36] Mahmood A, Raymond GV, Dubey P, Peters C, Moser HW. Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol. 2007; 6(8): 687- 692. 17618834 source
• Partly supported

  The Introduction (page unavailable) says childhood X-ALD usually develops symptoms at ages four to eight, including demyelination and leukodystrophy. The Results and Discussion table (page unavailable) reports leukodystrophy in 10 of 11 childhood X-ALD patients and 2 of 4 adult-onset AMN patients. This supports cerebral involvement in childhood and adulthood, but the small case series does not establish that the risk is highest in childhood or persists throughout life. (LLM, conf=0.82)

  cites [37] Vargas CR, Coelho DD, Barschak AG, et al. X-linked adrenoleukodystrophy: clinical and laboratory findings in 15 Brazilian patients. Genet Mol Biol. 2000; 23(2): 261- 264. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [38] Raymond GV, Aubourg P, Paker A, et al. Survival and functional outcomes in boys with cerebral adrenoleukodystrophy with and without hematopoietic stem cell transplantation. Biol Blood Marrow Transpl. 2019; 25(3): 538- 548. 30292747 source
• ?Not checked — no full text of the sourcecites [39] Liberato AP, Mallack EJ, Aziz-Bose R, et al. MRI brain lesions in asymptomatic boys with X-linked adrenoleukodystrophy. Neurology. 2019; 92(15): e1698- e708. 30902905 PMC6511088 source

In the paper

“Women develop myeloneuropathy; men can develop all 3 syndromes.7-9”

What the sources say

• ?Not checked — no full text of the sourcecites [7] Engelen M, Barbier M, Dijkstra IM, et al. X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. Brain. 2014; 137(Pt 3): 693- 706. 24480483 source
• Supported

  The Background states that more than 80% of women with ALD eventually develop progressive spinal cord disease. It also lists spinal cord disease, primary adrenal insufficiency, and cerebral inflammatory disease in the clinical spectrum for men. The paper notes that adrenal insufficiency and cerebral disease can occur in women too, but the citing sentence does not say they cannot. (LLM, conf=0.93)

  cites [8] Huffnagel IC, Dijkgraaf MGW, Janssens GE, et al. Disease progression in women with X-linked adrenoleukodystrophy is slow. Orphanet J Rare Dis. 2019; 14(1): 30. 30732635 PMC6367840 source
• Partly supported

  The Background reports that some women with X-ALD develop myeloneuropathy resembling adrenomyeloneuropathy. It also names cerebral ALD and adrenomyeloneuropathy as male phenotypes, but does not identify three core syndromes or state that men can develop all three. The indexed copy provides no page numbers for these passages. (LLM, conf=0.86)

  cites [9] Habekost CT, Schestatsky P, Torres VF, et al. Neurological impairment among heterozygote women for X-linked Adrenoleukodystrophy: a case control study on a clinical, neurophysiological and biochemical characteristics. Orphanet J Rare Dis. 2014; 9: 6. 24410807 PMC3896743 sourceExperimental — accuracy not yet measured

In the paper

“In women, the sensitivity of VLCFAs analysis is 85%, whereas C26:0-lysoPC has a sensitivity of >99%.18,19,22”

What the sources say

• Partly supported

  The Discussion (page not available) reports that plasma VLCFA analysis gives false negatives in approximately 15–20% of women with ALD, consistent with roughly 80–85% sensitivity. The Results report elevated C26:0-LPC in all 19 women with ALD studied, but that small cohort does not establish a general sensitivity greater than 99% in women. (LLM, conf=0.84)

  cites [18] Jaspers YRJ, Ferdinandusse S, Dijkstra IME, et al. Comparison of the diagnostic performance of C26:0-lysophosphatidylcholine and very long-chain fatty acids analysis for peroxisomal disorders. Front Cell Dev Biol. 2020; 8: 690. 32903870 PMC7438929 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [19] Huffnagel IC, van de Beek MC, Showers AL, et al. Comparison of C26:0-carnitine and C26:0-lysophosphatidylcholine as diagnostic markers in dried blood spots from newborns and patients with adrenoleukodystrophy. Mol Genet Metab. 2017; 122(4): 209- 215. 29089175 source
• ?Not checked — no full text of the sourcecites [22] Moser AB, Kreiter N, Bezman L, et al. Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol. 1999; 45(1): 100- 110. 9894883 source

In the paper

“ALD has a birth prevalence of 1:15,000 (male patients and female patients).10”

What the sources say

• Partly supported

  The Introduction reports an estimated minimum birth incidence of about 1 in 17,000 for males and females combined in the United States. The Discussion reports approximately 1 in 14,700 positive newborn screens in New York, close to the claimed 1 in 15,000, but does not present that figure as the overall birth prevalence for males and females. (LLM, conf=0.87)

  cites [10] Moser A, Jones RO, Hubbard WC, et al. Newborn screening for X-linked adrenoleukodystrophy. Int J Neonatal Screen. 2016; 2(4): 1- 5. PMC6715319 31467997 sourceExperimental — accuracy not yet measured

In the paper

“Peripheral neuropathy is a common feature of ALD but is rarely the presenting symptom.7,14-16”

What the sources say

• ?Not checked — no full text of the sourcecites [7] Engelen M, Barbier M, Dijkstra IM, et al. X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. Brain. 2014; 137(Pt 3): 693- 706. 24480483 source
• ?Not checked — no full text of the sourcecites [14] Horn MA, Nilsen KB, Jorum E, Mellgren SI, Tallaksen CM. Small nerve fiber involvement is frequent in X-linked adrenoleukodystrophy. Neurology. 2014; 82(19): 1678- 1683. 24719486 source
• Partly supported

  The Results (page unavailable) say clinical signs of potential peripheral neuropathy were common in the studied AMN patients, supporting that part of the claim for this ALD phenotype. The Background describes AMN in adults with ALD, but neither it nor the retrieved passages say that neuropathy is rarely the presenting symptom of ALD. (LLM, conf=0.85)

  cites [15] Rattay TW, Just J, Roben B, et al. Nerve ultrasound characterizes AMN polyneuropathy as inhomogeneous and focal hypertrophic. Orphanet J Rare Dis. 2018; 13(1): 194. 30390710 PMC6215661 sourceExperimental — accuracy not yet measured
• Partly supported

  The ELECTRONEUROGRAPHY section (page not specified) reports nerve-conduction abnormalities in 12 of 16 neurologically symptomatic patients, most often compatible with sensorimotor polyneuropathy. This supports peripheral neuropathy as a common feature in the studied symptomatic patients, but the paper does not establish that it is rarely the presenting symptom. (LLM, conf=0.85)

  cites [16] van Geel BM, Assies J, Haverkort EB, et al. Progression of abnormalities in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy despite treatment with "Lorenzo's oil". J Neurol Neurosurg Psychiatry. 1999; 67(3): 290- 299. 10449548 PMC1736534 sourceExperimental — accuracy not yet measured

In the paper

“The interval between gadolinium administration and postcontrast T1-weighted image acquisition can influence study interpretation where shorter intervals can yield a false-negative result.”

In the paper

“Twenty-eight of the 30 invited experts participated in the first questionnaire round, 26 in the second questionnaire round, and 20 in the consensus meeting.”

In the paper

“Female patients with ALD remain asymptomatic in childhood and adolescence, while in adulthood, myeloneuropathy symptoms can arise.7,14”

What the sources say

• ?Not checked — no full text of the sourcecites [7] Engelen M, Barbier M, Dijkstra IM, et al. X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. Brain. 2014; 137(Pt 3): 693- 706. 24480483 source
• ?Not checked — no full text of the sourcecites [14] Horn MA, Nilsen KB, Jorum E, Mellgren SI, Tallaksen CM. Small nerve fiber involvement is frequent in X-linked adrenoleukodystrophy. Neurology. 2014; 82(19): 1678- 1683. 24719486 source

In the paper

“Cerebral ALD and primary adrenal insufficiency are extremely rare in women.”

In the paper

“First, a literature review (Figure 1) identified 132 relevant articles, which were mostly (small) retrospective and observational studies and thus insufficient for an isolated evidence-based approach.”

In the paper

“The age for the baseline MRI was set at 2 years because cerebral ALD before the age of 3 years is rare, and MRI scans obtained before the age of 2 years are difficult to interpret because of incomplete myelination.”

In the paper

“Allogeneic hematopoietic cell transplantation (HCT) is the standard treatment for cerebral ALD and can halt progression.34-36,38,e8-e13”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites 34-36,38,e8-e13

In the paper

“No consensus was reached on the implementation of neuropsychological testing as a screening tool for cerebral ALD.”

In the paper

“Virtually all men and most women with ALD eventually develop symptoms and signs of myeloneuropathy.8,33,e23-e25”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites 8,33,e23-e25

In the paper

“HCT is unlikely to affect myeloneuropathy or adrenal insufficiency, but data are limited.e18,e19”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites e18,e19

In the paper

“For the very new ex vivo gene-corrected autologous transplantation approach, there are no data.”

In the paper

“We identified 39 discrete areas of consensus.”

In the paper

“The extent of brain involvement on MRI can be quantified with the MR severity scoring system (Loes score), ranging from 0 (no abnormalities) to 34 (severely abnormal).28”

What the sources say

• ?Not checked — no full text of the sourcecites [28] Loes DJ, Hite S, Moser H, et al. Adrenoleukodystrophy: a scoring method for brain MR observations. AJNR Am J Neuroradiol. 1994; 15(9): 1761- 1766. 7847225 PMC8333737

In the paper

“All 28 experts agreed to the final version of the recommendations.”

In the paper

“Cerebral ALD causes severe disability and death.1”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016; 12(10): 606- 615. 27312864 source

In the paper

“There are 3 core clinical syndromes: a slowly progressive myeloneuropathy (adrenomyeloneuropathy), a rapidly progressive leukodystrophy (cerebral ALD), and primary adrenal insufficiency.”

In the paper

“De novo pathogenic variants and variants of uncertain significance (VUS) are common.”

In the paper

“Two reviewers of Adelphi Values (A.V.) independently screened all abstracts and where applicable concomitant full text for their eligibility.”

In the paper

“The screening protocol for cerebral ALD and lifestyle management are examples of topics that remain subject of discussion.”

In the paper

“No medical librarian was involved.”

In the paper

“No consensus was reached on the evaluation of bone health in men.”

In the paper

“In addition, we conducted a gray literature search of internet-based sources and extended the search with snowballing.”

In the paper

“We aimed to include all relevant specialists with experience in the field of ALD, but this group is small, and the clinical experience of panelists varied from smaller regional to larger international cohorts with more than 100 patients.”

In the paper

“All articles on ALD involving human participants were included, and nonhuman (animal) studies were excluded.”

In the paper

“The gray literature search included GeneReviews, UpToDate, ClinicalKey, The International Leukodystrophy Association (or Global Leukodystrophy Initiative), ALD.info, and the Society for the Study of Inborn Errors of Metabolism.”

In the paper

“The search terms used were “adrenoleukodystrophy” or “x-linked adrenoleukodystrophy” or “X-ALD.””

In the paper

“Nonetheless, this guideline addresses a need in the ALD community because of the worldwide increase in diagnoses and the number of presymptomatic individuals because of newborn screening and improved diagnostic procedures.”

In the paper

“Adrenal insufficiency is characterized by low or normal early morning cortisol levels with high levels of ACTH.1,33”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016; 12(10): 606- 615. 27312864 source
• ?Not checked — no full text of the sourcecites [33] Huffnagel IC, Laheji FK, Aziz-Bose R, et al. The natural history of adrenal insufficiency in X-linked adrenoleukodystrophy: an international collaboration. J Clin Endocrinol Metab. 2019; 104(1): 118- 126. 30252065 source

In the paper

“The search was limited to full-text availability in English and a publication date between 1990 to the year 2019.”

In the paper

“The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge.”

In the paper

“The study quality was assessed using the Newcastle-Ottawa Scale for Assessing the Quality of Nonrandomized Studies in Meta-analysis, and the results are available as eTable 1 (links.lww.com/WNL/C366).”

In the paper

“Furthermore, this approach is at risk for bias because of panelist selection and repeat review.”

In the paper

“For instance, erectile dysfunction may reflect primary gonadal insufficiency or can be caused by spinal cord disease.1”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016; 12(10): 606- 615. 27312864 source

In the paper

“Therefore, some panelists did not agree with specific recommendations although consensus was reached.”

In the paper

“Experts were instructed to withhold from voting on recommendations outside their field of expertise, but no additional correction was applied for differences in clinical experience.”

In the paper

“After completion, the results were reviewed and compared by a third senior reviewer (A.V.), to resolve discrepancies and reach consensus on inclusion in the literature review.”

In the paper

“No consensus was reached on recommendations for invasive spasticity treatments (i.e., intrathecal baclofen therapy, selective dorsal rhizotomy) or urinary incontinence.”

In the paper

“Still, on some topics, consensus could not be reached (for instance, the exact timing of adrenal testing in the first year of life).”

In the paper

“Experts were instructed to withhold from voting on recommendations outside their field of expertise, but no additional correction was applied for differences in clinical experience.”

In the paper

“Our consensus-based approach among ALD experts across the world allowed us to formulate recommendations despite limited scientific evidence.”