Diagnosis and Management of Patients With Adrenoleukodystrophy
Summary of Recommendations
- Presenting symptoms - when to consider ALD
- In boys and men with confluent white matter abnormalities on brain MRI in a pattern suggestive of ALD with or without cognitive and neurologic symptoms;
- In adult men and women with symptoms and signs of chronic myelopathy with a normal MRI;
- In boys and men with primary adrenal insufficiency with no detectable steroid-21-hydroxylase antibodies or other organ specific antibodies;
- In all at-risk patients with a relative diagnosed with ALD.
- Screen all boys and men for cerebral ALD with MRI, including in the absence of neurologic or cognitive symptoms. Screening frequency is discussed in Figure 4. Gadolinium is indicated when a new lesion or questionable lesion is identified, or sedation is used.
- To treat cerebral ALD, consult an ALD transplantation expert who can determine allogeneic or genetically transduced autologous stem cell transplantation eligibility.
- Use history and neurologic examination to diagnose myeloneuropathy.
- Solely screen apparently asymptomatic men for symptoms or physical signs of myeloneuropathy in parallel to any other testing.
- Schedule yearly follow-up for men and women with myeloneuropathy
- Treatment is supportive. Aim treatment at reducing pain and spasticity and maintaining functional ability and quality of life.
- Screen all boys and men for adrenal insufficiency with early morning cortisol, ACTH, plasma renin, and serum electrolytes. If symptoms suggestive of adrenal insufficiency manifest, evaluate adrenal insufficiency promptly to prevent an adrenal crisis.
- Consult a (pediatric) endocrinologist for glucocorticoid replacement therapy when adrenal insufficiency is present. Do not initiate mineralocorticoid replacement therapy based on symptoms alone but also take into account plasma renin and serum electrolyte abnormalities.
- Data to support the efficacy of Lorenzo's oil as a disease-modifying treatment in patients with ALD are insufficient.
Overview of the Management of Patients With ALD
Diagnosis Presenting Symptoms
- Cerebral ALD should be considered in boys and men with white matter abnormalities on brain MRI in a pattern suggestive of ALD with or without cognitive and neurologic symptoms.
- ALD-related myelopathy should be considered in adult men and women with signs or symptoms of chronic myelopathy (gait disorder, spastic paraparesis, sphincter disturbances) with a normal MRI.
- ALD-related adrenal insufficiency should be considered in boys and men with primary adrenal insufficiency with no detectable steroid-21-hydroxylase antibodies or other organ specific antibodies.
- In all at-risk patients with a relative diagnosed with ALD, ALD should be considered.
Treatment and Management - Multidisciplinary Team of Health Care Professionals
- A central coordinator should be assigned as the case manager.
- For male patients, a neurologist, endocrinologist, or metabolic specialist (adult or pediatric), a pediatrician, and a genetic counselor should be consulted. For female patients, this should be a neurologist, metabolic specialist, and genetic counselor.
Diagnosis With MRI and the Use of Gadolinium and Sedation
- For the diagnosis of cerebral ALD, the minimum set of MR sequences is T1 (±gadolinium), T2, and FLAIR. Sedation should be used if necessary.
- Gadolinium is indicated when a new lesion or questionable lesion is identified.
- The interval between gadolinium administration and postcontrast T1-weighted image acquisition can influence study interpretation where shorter intervals can yield a false-negative result. Although the optimal timing is not known, based on our experience, we recommend an interval of at least 5 minutes.
Screening for Cerebral ALD
- All boys and men with ALD should be screened for cerebral ALD, including in the absence of neurologic or cognitive symptoms.
- A baseline MRI scan should be obtained at age 2 years. Between 2 and 12 years, male patients should be screened every 6 months. From age 12 years, screening should be yearly.
- We do not recommend routine screening for cerebral ALD in girls and women.
Alternative Methods for Screening and Diagnosis of Cerebral Disease
- Nonimaging biomarkers for the diagnosis of cerebral ALD are not indicated outside of a research setting.
- No consensus was reached on the implementation of neuropsychological testing as a screening tool for cerebral ALD.
Cerebral ALD Treatment
- Transplantation eligibility should be determined by an ALD transplantation expert.
- Eligibility criteria are not exclusive. In general, boys are considered eligible for transplantation when they have demyelination with gadolinium enhancement (MR severity score [Loes score] ≤ 9) and a neurologic function score of 0 or 1 and adult men when they have demyelinating lesions with gadolinium enhancement and no or few neurocognitive impairment.
- Genetically transduced autologous stem cell transplantation (gene therapy) should be considered (if available) in boys if allogeneic donor options are poor.
- Male patients should be counseled on the possible association between head injury and onset of cerebral disease so that they can make an informed lifestyle choice.
Screening of Myeloneuropathy
- Screening for and follow-up of myeloneuropathy:
- History and neurologic examination should be used to diagnose myeloneuropathy.
- Asymptomatic men and women should only be screened for symptoms or physical signs of myeloneuropathy in parallel with other testing.
- For men and women with myeloneuropathy, we recommend yearly follow-up. For men, coordinating annual visit with annual brain MRI may improve convenience and compliance.
Treatment of Myeloneuropathy
- Treatment 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.
Screening for Adrenal Insufficiency
- All boys and men, but not girls and women, should be routinely screened for adrenal insufficiency with early morning cortisol and adrenocorticotropin hormone (ACTH) measurements.
- Screening for adrenal insufficiency 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 should be performed parallel to MRI where possible.
- All patients in whom symptoms suggestive of adrenal insufficiency manifest should undergo prompt evaluation for adrenal insufficiency to identify and prevent an adrenal crisis. If the patient is in crisis, a random cortisol and 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.
- All patients who are screened for adrenal insufficiency, or after diagnosis of adrenal insufficiency, should also be screened for mineralocorticoid deficiency with plasma renin and serum electrolytes.
- All patients in whom symptoms suggestive of mineralocorticoid deficiency manifest should undergo prompt evaluation with plasma renin and serum electrolytes.
Treatment of Adrenal Insufficiency
- If adrenal insufficiency is present, we recommend glucocorticoid replacement therapy 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.
- Routine evaluation of bone health with dual energy x-ray absorptiometry measurements in boys with adrenal insufficiency and glucocorticoid replacement therapy is not recommended.
- No consensus was reached on the evaluation of bone health in men.
Screening for Gonadal Insufficiency
- Boys and men should not be screened for gonadal insufficiency.
- If symptoms manifest, gonadal insufficiency should be evaluated with biochemical testing (early morning testosterone, LH, FSH). In boys, delayed progression to puberty could indicate gonadal insufficiency (testicular volume <4 mL and/or no signs of puberty by the age of 14 years).
Treatment of Gonadal Insufficiency
- Treatment of gonadal insufficiency is restricted to endocrinologists.
Additional Management Recommendations
- Data to support the efficacy of Lorenzo's oil as a disease-modifying treatment in patients with ALD is insufficient.
- All patients who are diagnosed with ALD should be informed about the option of family screening.
- Patients who wish to conceive must be informed regarding the potential benefits of preimplantation (preimplantation genetic diagnosis; oocyte donation) and prenatal (noninvasive fetal sex determination in maternal plasma; invasive prenatal testing) diagnostic options.
- We recommend classifying female patients with an ABCD1 pathogenic variant as “asymptomatic/presymptomatic” or “symptomatic women with ALD” and to refrain from using terms as heterozygotes or carriers.
- ACTH: Adrenocorticotropic Hormone
- ALD: Adrenoleukodystrophy
- VUS: Variants Of Unknown Significance
Diagnosis and Management of Patients With Adrenoleukodystrophy
November 22, 2022
Supplemental Implementation Tools
Country of Publication
Male, Female, Adolescent, Adult, Child, Infant
Health Care Settings
Nurse, nurse practitioner, physician, physician assistant
Counseling, Diagnosis, Assessment and screening, Management
D000326 - Adrenoleukodystrophy
adrenal insufficiency, Addison's disease, Adrenoleukodystrophy, Addison's, acth, adrenocorticotropin hormone, ald, X-ALD, X-Linked Adrenoleukodystrophy, adrenomyeloneuropathy
Marc Engelen, Wouter J.C. van Ballegoij, Eric James Mallack, Keith P. Van Haren, Wolfgang Köhler, Ettore Salsano, A.S.P. van Trotsenburg, Fanny Mochel, Caroline Sevin, Molly O. Regelmann, Nicholas A. Tritos, Alyssa Halper, Robin H. Lachmann, James Davison, Gerald V. Raymond, Troy C. Lund, Paul J. Orchard, Joern-Sven Kuehl, Caroline A. Lindemans, Paul Caruso, Bela Rui Turk, Ann B. Moser, Frédéric M. Vaz, Sacha Ferdinandusse, Stephan Kemp, Ali Fatemi, Florian S. Eichler, Irene C. Huffnagel
Neurology Nov 2022, 99 (21) 940-951; DOI: 10.1212/WNL.0000000000201374