Pearls &amp; Oy-sters: Adolescent-onset adrenomyeloneuropathy and arrested cerebral adrenoleukodystrophy

Lin, Jieru E.; Armour, Eric A; Heshmati, Arezou; Umandap, Christine; Couto, Julia J.; Iglesias, Alejandro; Mallack, Eric J.; Bain, Jennifer

doi:10.1212/wnl.0000000000007755

Cited by 10 publications

(7 citation statements)

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“…Hematopoietic stem cell transplantation (HSCT) is a therapeutic option for boys with active CCALD 9,10 . Conversely, 10% to 21% of CCALD patients will undergo spontaneous arrest of disease, without evidence of blood brain barrier breakdown, and the lesion does not contrast‐enhance 3,11‐15 . These individuals should not receive HSCT due to the morbidity and mortality associated with HSCT, and its failure to modify the disease course 14,16 …”

Section: Introductionmentioning

confidence: 99%

“…9,10 Conversely, 10% to 21% of CCALD patients will undergo spontaneous arrest of disease, without evidence of blood brain barrier breakdown, and the lesion does not contrast-enhance. 3,[11][12][13][14][15] These individuals should not receive HSCT due to the morbidity and mortality associated with HSCT, and its failure to modify the disease course. 14,16 Historically, it may have taken years for patients with CCALD to be correctly diagnosed.…”

Section: Introductionmentioning

confidence: 99%

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MRI surveillance of boys with X‐linked adrenoleukodystrophy identified by newborn screening: Meta‐analysis and consensus guidelines

Mallack

Turk

Yan

et al. 2021

J of Inher Metab Disea

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Background Among boys with X‐Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence‐based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy. Methods To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta‐analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus. Results One hundred twenty‐three studies met inclusion criteria yielding 1285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0‐9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2‐weighted and contrast‐enhanced T1‐weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (a) Obtain an MRI between 12 and 18 months old. (b) Obtain a second MRI 1 year after baseline. (c) Between 3 and 12 years old, obtain a contrast‐enhanced MRI every 6 months. (d) After 12 years, obtain an annual MRI. Conclusion Boys with adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MRI surveillance of boys with X‐linked adrenoleukodystrophy identified by newborn screening: Meta‐analysis and consensus guidelines

Mallack

Turk

Yan

et al. 2021

J of Inher Metab Disea

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“…3 Patients diagnosed with arrested CALD were excluded given the difference in natural history, and patients with self-halted disease do not qualify for HSCT or gene therapy. 23-25 Excluded patients in this age range had radiographically stable lesions, with no change in LS for ≥6 months, no evidence of enhancement at any time point, no change in NFS, and remained untreated (although continuously monitored by MRI) at the time of this study. Participation in the Lorenzo's Oil trial did not preclude participation in this study.…”

Section: Methodsmentioning

confidence: 99%

Presymptomatic Lesion in Childhood Cerebral Adrenoleukodystrophy

et al. 2022

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Background and ObjectivesWe sought to characterize the natural history and standard-of-care practices between the radiologic appearance of brain lesions, the appearance of lesional enhancement, and treatment with hematopoietic stem-cell transplant or gene therapy among boys diagnosed with presymptomatic childhood-onset cerebral adrenoleukodystrophy (CCALD).MethodsWe analyzed a multicenter, mixed retrospective/prospective cohort of patients diagnosed with presymptomatic CCALD (Neurologic Function Score = 0, Loes Score [LS] = 0.5–9.0, and age <13 years). Two time-to-event survival analyses were conducted: (1) time from CCALD lesion onset-to-lesional enhancement and (2) time from enhancement-to-treatment. The analysis was repeated in the subset of patients with (1) the earliest evidence of CCALD, defined as an MRI LS ≤ 1, and (2) patients diagnosed between 2016 and 2021.ResultsSeventy-one boys were diagnosed with presymptomatic cerebral lesions at a median age of 6.4 years [2.4–12.1] with a LS of 1.5 [0.5–9.0]. Fifty percent of patients had lesional enhancement at diagnosis. In the remaining 50%, the median Kaplan-Meier (KM)-estimate of time from diagnosis-to-lesional enhancement was 6.0 months (95% CI 3.6–17.8). The median KM-estimate of time from enhancement-to-treatment is 3.8 months (95% CI 2.8–5.9); 2 patients (4.2%) developed symptoms before treatment. Patients with a diagnostic LS ≤ 1 were younger (5.8 years [2.4–11.5]), had a time-to-enhancement of 4.7 months (95% CI 2.7–9.30), and were treated in 3.8 months (95% CI 3.1–7.1); no patients developed symptoms before treatment. Time from CCALD diagnosis-to-treatment decreased over the course of the study (ρ = −0.401, p = 0.003).DiscussionOur findings offer a more refined understanding of the timing of lesion formation, enhancement, and treatment among boys with presymptomatic CCALD. These data offer benchmarks for standardizing clinical care and designing future clinical trials.

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“…Lorenzo's oil was suggested as a treatment to normalize VLCFAs in the brain and potentially decelerate ALD progression. [7] A neurological follow-up was scheduled within 3-6 months, with corticosteroid replacement therapy to be considered if serum corticosteroid levels are found to be low.…”

Section: Case Presentationmentioning

confidence: 99%

A novel ABCD1 gene mutation causes adrenomyeloneuropathy presenting with spastic paraplegia: A case report

Liu,

Wang,

Huang

et al. 2024

Medicine

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Rationale: X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene leading to very long chain fatty acid (VLCFA) accumulation. The disease demonstrates a spectrum of phenotypes including adrenomyeloneuropathy (AMN). We aimed to identify the genetic basis of disease in a patient presenting with AMN features in order to confirm the diagnosis, expand genetic knowledge of ABCD1 mutations, and elucidate potential genotype-phenotype associations to inform management. Patient concerns: A 29-year-old male presented with a 4-year history of progressive spastic paraplegia, weakness of lower limbs, fecal incontinence, sexual dysfunction, hyperreflexia, and positive Babinski and Chaddock signs. Diagnoses: Neuroimaging revealed brain white matter changes and spinal cord thinning. Significantly elevated levels of hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) suggested very long chain fatty acids (VLCFA) metabolism disruption. Genetic testing identified a novel hemizygous ABCD1 mutation c.249dupC (p.F83fs). These findings confirmed a diagnosis of X-linked ALD with an AMN phenotype. Interventions: The patient received dietary counseling to limit VLCFA intake. Monitoring for adrenal insufficiency and consideration of Lorenzo’s oil were advised. Genetic counseling and testing were offered to at-risk relatives. Outcomes: At present, the patient continues to experience progressive paraplegia. Adrenal function remains normal thus far without steroid replacement. Family members have undergone predictive testing. Lessons: This case expands the known mutation spectrum of ABCD1-linked X-ALD, providing insight into potential genotype-phenotype correlations. A thoughtful diagnostic approach integrating clinical, biochemical and genetic data facilitated diagnosis. Findings enabled genetic counseling for at-risk relatives regarding this X-linked disorder.

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Pearls & Oy-sters: Adolescent-onset adrenomyeloneuropathy and arrested cerebral adrenoleukodystrophy

Cited by 10 publications

References 10 publications

MRI surveillance of boys with X‐linked adrenoleukodystrophy identified by newborn screening: Meta‐analysis and consensus guidelines

MRI surveillance of boys with X‐linked adrenoleukodystrophy identified by newborn screening: Meta‐analysis and consensus guidelines

Presymptomatic Lesion in Childhood Cerebral Adrenoleukodystrophy

A novel ABCD1 gene mutation causes adrenomyeloneuropathy presenting with spastic paraplegia: A case report

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