Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.0
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: ABCD1
• Condition: Adrenoleukodystrophy
• Mode(s) of Inheritance: X-linked

Actionability Assertion

• ABCD1 ⇔ 0018544 (adrenoleukodystrophy): Strong Actionability

Actionability Rationale

The majority of the expert panel agreed with the suggested assertion of strong, but several panel members would have asserted moderate actionability, commenting on the relative importance of the CALD phenotype (for which the treatment is not as effective), and the fact that effectiveness for the adrenal insufficiency phenotype relied on extrapolation.

Final Consensus Scores

Gene Condition Pairs: ABCD1 ⇔ 0018544 (OMIM:300100)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity and mortality due to cerebral adrenoleukodystrophy (males only) / Evaluation and surveillance by specialist to guide initiation of hematopoietic cell transplantation or gene therapy	2	3C	2B	2	9CB
Morbidity and mortality due to adrenal insufficiency (males only) / Evaluation and management by specialist to guide hormone replacement	2	3C	3B	3	11CB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The birth prevalence of X-linked adrenoleukodystrophy (X-ALD) is estimated at 1:15,000 when including male hemizygotes and female heterozygotes. The estimated prevalence in males ranges from 1:14,000 to 20,000. [1, 2, 3, 4, 5, 6, 7, 8]

Clinical Features

X-ALD is a progressive metabolic disorder that independently affects the adrenal glands and central nervous system and is characterized by elevated serum very-long-chain fatty acids (VLCFA), which are a diagnostic marker of X-ALD. There are three core clinical forms of X-ALD, with the most severe form being childhood cerebral ALD (CCALD). CCALD is associated with cerebral demyelination with initial symptoms of emotional lability, hyperactive behavior, diminishing school performance, and visuo-spatial impairment followed by worsening cognitive and neurologic disability. In some males, seizures may be the first manifestation.
Adult males with or without CALD may develop another form of X-ALD called adrenomyeloneuropathy (AMN), which is characterized by gradually progressive spastic paraparesis, leg weakness, sensory ataxia with impaired vibration sense, spinal cord symptoms, sphincter dysfunction (mostly urinary), pain in the legs, and impotence. An increased risk of psychiatric morbidity has been reported with depression often observed in patients with severe motor disability. Of those with AMN approximately 20% will also develop cerebral disease. After an initial progression, demyelinating lesions can stabilize spontaneously leading to moderate cognitive defections. However, the prognosis may be as poor as in CALD.
The third form is primary adrenal insufficiency (AI), which can be the presenting symptoms of X-ALD in boys and men years or decades before neurological symptoms. AI is often latent, but may present as fatigue, nausea, unexplained vomiting and weakness or coma, leading of the diagnosis of primary AI. Hair of patients is often thin and sparse and patients often show baldness at an early age. AI generally presents without evidence of neurologic abnormality, however some decrease of neurologic disability (most commonly AMN) usually develops later.
Heterozygous females are symptom-free in childhood and not at increased risk to develop CALD but are at increased risk to develop AMN and occasionally AI with increasing age. In general, the symptoms of AMN are similar, though less severe, in women; however, sensory ataxia, fecal incontinence, and pain in the legs are often more prominent in women with AMN. [1, 2, 3, 4, 5, 6, 7, 8]

Natural History

X-ALD has a variable and unpredictable clinical course. Individuals are asymptomatic at birth but develop symptoms as the disease progresses. Currently, it is not possible to predict the individual disease course.
Onset of CALD ranges from childhood (typically ages 4 to 8 years) to adolescence (ages 11 to 21 years) and adulthood. Approximately 90% are diagnosed between 3 and 12 years old. CCALD is associated with rapid cognitive and neurologic decline. CALD can also present in adolescence and adulthood, though much less frequently. If not treated with hematopoietic cell transplantation (HCT) and lifelong hormone replacement therapy, most CCALD patients deteriorate, with severe disability within 2 to 5 years of symptom onset followed shortly by death. However, 10% to 21% of patients with CCALD will undergo spontaneous arrest of disease. But even after a 10–15 year period of stability, sudden onset of rapid neurologic deterioration may occur.
The typical age of onset of AMN is after age 28-30; however, neurological symptoms can begin to manifest in childhood or adolescence. Onset is typically in the 20s and 30s. The course of AMN is highly variable. Within a mean of 13 years from recognized onset in adults, the rate of death or severe disability is 12%. The phenotype in most cases is slowly progressive, causing severe motor disability of the lower limbs over one or two decades. Progression in a specific individual cannot be predicted. There is a marked variability ranging from men with that are wheelchair bound by age 35 and others who can walk with a cane into their seventies.
AI can present at any age, most commonly by age 7.5 years. For 10% of affected individuals AI is the only presentation. Although the treatment of AI is very effective, the identification is often delayed and may lead to significant morbidity or even death.
Affected heterozygous females generally have onset of symptoms in the 4th or 5th decade of life. Females can develop symptoms, usually of AMN, in mid- to late adulthood.
Newborn screening for X-ALD has been added to the recommended uniform screening panel in the United States. Newborn screening for X-ALD has increased the number of presymptomatic individuals under observation. As such, there is an evolving clinical experience by prospectively following these presymptomatic patients. [1, 2, 3, 4, 5, 6, 7, 8]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening. https://www.acmg.net/PDFLibrary/X-ALD-ACT-Sheet.pdf [9]

It is recommended that a multidisciplinary team of providers be involved in the care of individuals with X-ALD. For males, a neurologist, endocrinologist or metabolic specialist, a pediatrician and a genetic counselor should be consulted. For females, a neurologist, metabolic specialist and genetics provider should be consulted. Additionally, a care coordinator should be involved to manage ongoing care. (Tier 2) [2, 8]

To assess for CALD, MRI is recommended for males, beginning with a baseline at age of 1-2 years, depending on the guideline. Clinicians may choose to obtain an MRI at earlier time points based on clinical presentation and experience. MRI should be performed as soon as possible in all patients who develop potential signs or symptoms of CALD during follow-up. Guidelines differ in their recommendation of use of gadolinium, with one guideline recommending it for boys age 3-12 years because the risk of developing CALD is deemed highest at this point, and another guideline recommending using it only when a new or questionable lesion is identified (unless sedation is required or real-time review of MRI is unavailable and additional visit for gadolinium administration would be challenging). (Tier 2) [2, 3]

Behavioral, developmental, and speech assessments are recommended for symptomatic males with CCALD. (Tier 4) [5]

The standard treatment for cerebral X-ALD is allogenic hematopoietic cell therapy (HCT). Due to the risk of mortality related to the procedure, HCT is recommended only for males with evidence of brain involvement. Transplantation eligibility should be determined by a X-ALD transplantation specialist. HCT is unlikely to affect AMN or AI, but data are limited. Several studies have shown that HCT can halt progression. (Tier 2) [2, 3, 8]

•One study conducted a large multicenter retrospective chart review to describe outcomes of HCT in boys with CALD (72 with CALD who did not undergo HCT and 65 who underwent HCT at 5 clinical sites in the US and France). Of note, the untreated and HCT cohorts were chronologically distinct (prior to 2001, HCT had not been widely adopted as a treatment for CALD, while after 2001, nearly all eligible boys with CALD underwent HCT). Estimates of 5-year overall survival from the time of CALD diagnosis were 55% (95% CI,42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HCT cohort overall (P = .01). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HCT. Mortality rates post-HCT were 8% (5 of 65) at 100 days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Early disease treatment was predictive of major functional disability-free survival. (Tier 2) [2, 3, 8]

•Another study performed baseline and long-term follow-up neurocognitive testing in 33 males with CALD who received HSCT. Data were obtained from the patients’ most recent evaluation at a median of 4.2 years (range, 1.8-25.4 years) after transplant. When considering frequency of neurocognitive impairment, 22 of the boys (67%) had a severe impairment in at least 1 domain. Nine patients (27%) demonstrated only mild impairment in 1 or more domains. Only 2 patients (6%) performed within or above the average range on all tasks at long-term follow-up. Patients with higher pretransplant MRI severity scores had a higher frequency of severe neurocognitive impairments. (Tier 2) [2, 3, 8]

•Results for HCT in adults is sparse, however, one study evaluated 14 adult males with CALD treated with allogenic HCT on a compassionate basis in four European centers. Median age of diagnosis of CALD was 33 years (range 21-48 years). In addition to cerebral inflammation, five patients had established severe motor disability from AMN. Eight patients survived (estimated survival 57 +/- 13%) with a median follow-up of 65 months (minimum 38 months). Arrest of progressive cerebral demyelination and prevention of severe loss of neurocognition was achieved in all 8 survivors, but deterioration of motor function occurred in the majority (n=5). Death was directly transplant/infection-related (n=3), due to primary progression in advanced CALD (n=1) or secondary disease progression (n=2) after transient multi-organ failure or non-engraftment. (Tier 2) [2, 3, 8]

Genetically transduced autologous hematopoietic stem cell transplantation (gene therapy) should be considered (if available) in boys if allogeneic donor options are poor. (Tier 2) [2]

Elivaldogene autotemcel (SKYSONA) is a Lenti-D lentiviral vector-based gene therapy. Elivaldogene has been FDA approved for males, aged 4 to 17 years old, with evidence of early and active CALD. The STARBEAM trial enrolled males (n=17, ages 4 to 13 years) with early active CALD treated with elivaldogene. After a median follow-up of 29 months, 15 of 17 (88%) patients remained alive and free of major functional disabilities. Lesion progression had stabilized in 12 of the 17 patients (71%). Safety and efficacy of elivaldogene was assessed by two open-label clinical trials with total enrollment of 67 males with early active ALD, demonstrating 90% overall survival 2 years post therapy. Slower progression to major functional disability or death from time of symptom onset was seen for patients treated with elivaldogene compared with the known natural history rates of lesion progression among untreated boys. (Tier 5) [10]

To assess for AMN, medical history and neurologic examination is recommended for males and females over 18 years old. Asymptomatic individuals should only be screened for symptoms or physical signs of AMN in parallel with other testing. (Tier 2) [2]

Treatment for AMN is supportive and should be aimed at reducing pain (with pharmaceuticals such as pregabalin or gabapentin) and spasticity (with spasmolytics like baclofen) and maintaining functional ability and quality of life. In addition to routine neurologic care, referral to a rehabilitation specialist, continence care specialist, or pain management specialist/team may be considered. (Tier 2) [2]

All patients in whom symptoms suggestive of AI manifest should undergo prompt evaluation to identify and prevent an adrenal crisis. If the patient is in crisis, a random cortisol and adrenocorticotropic hormone (ACTH) level measurement is sufficient (provided that serum specimens are drawn before glucocorticoid administration); if mildly symptomatic, early morning fasted cortisol and ACTH measurement is preferred. (Tier 2) [2]

If AI is present (ACTH or cortisol abnormalities) glucocorticoid replacement therapy should be instituted by an endocrinologist. Mineralocorticoid replacement therapy should not be initiated based on symptoms alone but should also take into account plasma renin and serum electrolyte abnormalities. In addition, patients should be educated on the need for lifelong therapy and the management of physiologic stresses such as fever, vomiting, and surgery. (Tier 2) [2, 8]

If symptoms manifest, gonadal insufficiency should be evaluated with biochemical testing (early morning testosterone, LH, FSH). In males, delayed progression to puberty could indicate gonadal insufficiency. Treatment of gonadal insufficiency should be restricted to endocrinologists. (Tier 2) [2]

Surveillance

All males with X-ALD should be screened for CALD, including in the absence of neurologic or cognitive symptoms. One guideline recommends brain MRI annually from 6 months- 30 months of age, then every 6 months from ages 36 months -10 years, then annually after age 10. Another guideline recommends that between the ages of 2-12 years, screening should occur every 6 months, and after age 12 years, screening should be yearly. A third guideline recommends annual brain MRI beginning at age 12-18 months of age. Between the ages of 3 and 12 years contrast-enhanced brain MRI is recommended every 6 months, then annual brain MRI after age 12 years (w/out contrast). This same guideline also recommended general anesthesia for the duration of the scan in young children unable to lie still, with the use of child life specialists and behavioral psychology services to decrease the need for anesthesia. MRI surveillance should continue as long as HCT is a therapeutic option, although extended surveillance may be requested by individual patients for prognostic purposes. (Tier 2) [2, 3, 8]

For males and females with AMN, yearly follow-up is recommended. (Tier 2) [2]

Annual neurology evaluation is recommended for asymptomatic boys in childhood. (Tier 2) [8]

All males should be routinely screened for AI with early morning cortisol and ACTH measurements. Screening for AI should be initiated in the first 6 months of life. Then, patients should be screened every 3–6 months before the age of 10 years and yearly thereafter. Screening in adult patients should continue irrespective of age. Guidelines recommend that adrenal function assessment should be performed before the first sedated MRI. (Tier 2) [2, 3, 4, 8]

A recent integrative review concluded that there is overwhelming consensus that serial adrenal evaluation prevents adrenal crisis and death. (Tier 1) [11]

One guideline states that all patients screened for AI or diagnosed with AI should also be screened for mineralocorticoid deficiency with plasma renin and serum electrolytes. Another guideline suggests further evaluation of aldosterone production if the patient has symptoms such as salt craving and polyuria. However, because symptoms are difficult to assess in infancy, this guideline also recommends serum plasma renin activity and electrolytes should be drawn every 6 months. All patients in whom symptoms suggestive of mineralocorticoid deficiency manifest should undergo prompt evaluation with plasma renin and serum electrolytes. (Tier 2) [2, 4]

Circumstances to Avoid

Male patients should be counseled on the possible association between head injury and onset of CALD so that they can make an informed lifestyle choice. Severe head trauma has been reported as possible trigger for CALD. Definitive proof on causality is not available. (Tier 2) [2]

Additional triggers anecdotally reported have included coma associated with adrenal crisis and neurosurgical procedures. (Tier 4) [5]

3. What is the chance that this threat will materialize?

Mode of Inheritance

X-linked [5, 6, 7]

Prevalence of Genetic Variants

The population prevalence of pathogenic variants associated with X-ALD was not found. Given that ABCD1 pathogenic variants are the only cause of X-ALD, the prevalence of pathogenic variants is estimated to be the same as that of X-ALD among males.

Detection rates for pathogenic variants in ABCD1 related to X-ALD approaches 100%. (Tier 3) [5]

Approximately 4% of individuals with X-ALD have a de novo pathogenic variant. (Tier 3) [1, 5]

Penetrance

Although the variation in X-ALD clinical phenotypes is great, neurologic manifestations are present in nearly all males by adulthood. (Tier 3) [5]

Males with an ABCD1 pathogenic variant have a 35-40% risk of developing CALD manifestations between the ages of 5-12 years. Males with an ABCD1 pathogenic variant have a ~5% chance of developing CALD between the ages of 11-21 years, and a ~20% chance of developing CALD after age 21 years. (Tier 3) [3, 5, 8]

CALD is rare in women with a heterozygous ABCD1 pathogenic variants (1%), and likely due to skewed X-inactivation. (Tier 4) [8]

Virtually all males and most females with X-ALD eventually develop symptoms and signs of AMN. (Tier 3) [2]

Symptoms similar to AMN develop in about 50-80% of women with a heterozygous ABCD1 pathogenic variant. (Tier 3) [8]

Approximately 40%-45% of individuals with AMN show some degree of involvement on brain MRI or clinical examination. In 20%-63% of individuals with AMN, progressive brain involvement leads to serious cognitive and behavioral disturbances that may progress to total disability and death. (Tier 3) [1, 5]

The prevalence of AI is reported to be 86% in males with X-ALD. Approximately 10% of males have primary AI with no apparent neurological involvement. Primary AI is rare in females. (Tier 3) [2, 4, 5]

Overall, adrenocortical function is abnormal in 90% of neurologically symptomatic boys and 70% of men with AMN. (Tier 4) [5]

Relative Risk

No information on relative risk was identified.

Expressivity

Different neurologic presentations (CCALD and AMN) can occur within the same family and there is no correlation between genotypes, phenotypes, or age at onset of the disease. (Tier 3) [3, 8]

The same phenotype can be observed both with large deletions that result in absence of the gene product and with missense pathogenic variants associated with abundant immunoreactive protein product. (Tier 3) [5]

X-ALD phenotype cannot be predicted by VLCFA plasma concentration, family history, or by the nature of the ABCD1 pathogenic variant, as the same pathogenic variant can be associated with each of the known phenotypes. (Tier 4) [5]

4. What is the Nature of the Intervention?

Nature of Intervention

MRI with sedation has been recommended by some guidelines. Recent evidence offers some reassurance against major neurocognitive deficits among children with single and multiple exposures to general anesthesia in early childhood. Repeated exposure to gadolinium-based contrast agents can cause them to be retained in the body for months to years after exposure but have not been linked to disease in patients with normal kidney function. [3]

In a pediatric cohort, adverse events post-HCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (31%; 18 of 58), and chronic graft-versus-host-disease (7%; 4 of 58). Risks of HCT are increased with the use of HLA-mismatched and unrelated donors. In a study of HCT on a compassionate basis in adults (n=14), specific complications included deterioration of motor and bladder functions (n = 12) as well as behavioral changes (n = 8). [2]

Hematological malignancy developed in 3 study participants who received elivaldogene (SKYSONA) and is a boxed warning on the package insert. The most common adverse reactions include mucositis, nausea, vomiting, diarrhea, decreased appetite, febrile neutropenia, alopecia, and seizures. Laboratory abnormalities include leukopenia, lymphopenia, neutropenia, anemia, and hypokalemia. [10]

Long-term glucocorticoid replacement therapy has been associated with impaired bone health. [2]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Newborn screening for X-ALD was added to the recommended uniform screening panel in the United States in 2016. To date, more than half the states have begun screening. The reported sensitivity for newborn screening detecting X-ALD in boys is high, though the detection rate of female heterozygotes may be low. (Tier 3) [4, 5]

In the absence of presymptomatic neuroimaging surveillance, CCALD lesions grow silently for months or even years before they are large enough to cause overt clinical symptoms. Historically, it may have taken years for patients with CCALD to be correctly diagnosed. (Tier 3) [3]

Early clinical symptoms in boys and adolescents, such as decline of school performance, are often misdiagnosed as attention deficit hyperactivity disorder and can delay the diagnosis of CCALD. (Tier 3) [1]

In adults the diagnosis of X-ALD is often delayed, especially in the presence of psychiatric disturbances; particularly when no family history of X-ALD is present and when clinical symptoms of AI are absent. (Tier 4) [1]

The identification of AI is often delayed and may lead to significant morbidity or even death. (Tier 3) [8]

For women with X-ALD, 15% will have normal plasma VLCFA levels. (Tier 3) [1, 2]

Date of Search: 12.01.2023

Reference List

1. Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, Aubourg P, Poll-The BT. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. (2012) 7:51.

2. Engelen M, van Ballegoij WJC, Mallack EJ, Van Haren KP, Köhler W, Salsano E, van Trotsenburg ASP, Mochel F, Sevin C, Regelmann MO, Tritos NA, Halper A, Lachmann RH, Davison J, Raymond GV, Lund TC, Orchard PJ, Kuehl JS, Lindemans CA, Caruso P, Turk BR, Moser AB, Vaz FM, Ferdinandusse S, Kemp S, Fatemi A, Eichler FS, Huffnagel IC. International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach. Neurology. (2022) 99(1526-632X):940-951.

3. Mallack EJ, Turk BR, Yan H, Price C, Demetres M, Moser AB, Becker C, Hollandsworth K, Adang L, Vanderver A, Van Haren K, Ruzhnikov M, Kurtzberg J, Maegawa G, Orchard PJ, Lund TC, Raymond GV, Regelmann M, Orsini JJ, Seeger E, Kemp S, Eichler F, Fatemi A. MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines. J Inherit Metab Dis. (2021) 44(1573-2665):728-739.

4. Regelmann MO, Kamboj MK, Miller BS, Nakamoto JM, Sarafoglou K, Shah S, Stanley TL, Marino R, Pediatric Endocrine Society Drug and Therapeutics/Rare Diseases Committee. Adrenoleukodystrophy: Guidance for Adrenal Surveillance in Males Identified by Newborn Screen. J Clin Endocrinol Metab. (2018) 103(1945-7197):4324-4331.

5. SJ Steinberg, AB Moser, GV Raymond. X-Linked Adrenoleukodystrophy. 1999 Mar 26 [Updated 2015 Apr 09]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1315

6. Tiller G. ADRENOLEUKODYSTROPHY; ALD.. OMIM [Internet]. (2013) Website: https://www.omim.org/entry/300100?search=ADRENOLEUKODYSTROPHY%3B%20ALD.&highlight=adrenoleukodystrophy%2Cald

7. Aubourg P. X-linked cerebral adrenoleukodystrophy. Orphanet [Internet]. (2013) Website: https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-7-51

8. Vogel BH, Bradley SE, Adams DJ, D'Aco K, Erbe RW, Fong C, Iglesias A, Kronn D, Levy P, Morrissey M, Orsini J, Parton P, Pellegrino J, Saavedra-Matiz CA, Shur N, Wasserstein M, Raymond GV, Caggana M. Newborn screening for X-linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines. Mol Genet Metab. (2015) 114(4):599-603.

9. Newborn Screening ACT Sheet [Elevated Lysophosphatidylcholine] X-Linked Adrenoleukodystrophy (X-ALD). ACMG. (2023) Website: https://www.acmg.net/PDFLibrary/X-ALD-ACT-Sheet.pdf

10. Scott A. Elivaldogene autotemcel approved for treatment of cerebral adrenoleukodystrophy (CALD) in males: A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG). Genetics In Medicine Open. (2023) Website: https://www.gimopen.org/article/S2949-7744(23)00844-0/fulltext

11. Pitts L, White JM, Ladores S, Wilson CM. The impacts of adrenoleukodystrophy newborn screening on the evaluation of adrenal dysfunction in male children: An integrative literature review. J Pediatr Nurs. (2023) 72(1532-8449):e53-e70.