Rhode Island Medical Home Portal - Adrenoleukodystrophy (ALD)

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Adrenomyeloneuropathy (AMN)

Cerebral ALD (cALD)

X-linked Adrenoleukodystrophy (X-ALD)

ICD-10 Coding

E71.52, X-linked adrenoleukodystrophy

Disorder Category

Genetic disorder

Screening

Abnormal Finding

Elevated lysophosphatidylcholines

Tested By

The first newborn screen tests by tandem mass spectrometry (MS/MS). If levels exceed the cutoff, it is repeated on the same blood spot sample by MS/MS. Then, the second newborn blood spot is tested by liquid chromatography-mass spectrometry (LC-MS).

Description

ALD is a disease affecting the brain, spinal cord, and endocrine (adrenal) system. In boys, ALD can cause adrenal insufficiency (Addison’s disease) and, potentially, sudden onset of brain demyelination leading to death. In men and women, ALD can also lead to a slowly progressive disease with chronic neuropathy. ALD is in several different disease category types, including a leukodystrophy, a peroxisomal disorder, an inborn error of metabolism, or an endocrine disease (due to the adrenal insufficiency that can develop).

ALD is characterized by accumulation of very long-chain fatty acids (VLCFAs) primarily affecting the adrenal cortex and white matter of the brain and spinal cord. Three variants of X-ALD are categorized by clinical presentation: a childhood cerebral form that occurs primarily in males, adrenomyeloneuropathy (AMN), and Addison-only disease. Females can develop AMN, but the onset is typically later and milder than in affected males. The most debilitating presentation (cALD; cerebral ALD) occurs in males about 4-10 years old with newly-noted attention deficit hyperactivity disorder, followed by progressive cognitive and behavioral decline, adrenal impairment, and characteristic changes on MRI that reflect a demyelinating process.

Prompt follow-up with a specialist after a positive newborn screen is critical because cALD is treatable, but only if therapy is started with the earliest signs of disease. Boys with ALD are typically seen and have brain MRIs twice per year.

Clinical Characteristics

There are 4 main ways ALD can manifest:

Asymptomatic: ALD without signs or symptoms
Adrenal insufficiency: ALD that results in adrenal symptoms such as fatigue, loss of appetite, hyperpigmentation (skin darkening), and belly pain. Most boys with ALD will eventually develop adrenal insufficiency. Although adrenal insufficiency is manageable, it can become life-threatening if it is not detected early.
Adrenomyeloneuropathy (AMN): ALD that commonly starts in adulthood and affects the spinal cord and nerves
Cerebral ALD: ALD that progresses to affect the brain. The condition can progress very quickly, so early diagnosis and continued monitoring are essential.

With treatment for ALD, hematopoietic stem cell therapy (HSCT) is the only treatment for males with cALD, but it has to be done in the earliest stages to be effective. Corticosteroid replacement is used for the adrenal insufficiency.

Without treatment, boys can develop adrenal insufficiency, which at its most severe can be life-threatening. Without monitoring using MRIs and, if positive, then immediate HSCT, boys who develop cALD will have progressive neurological degeneration leading to death.

Incidence

The incidence of ALD is approximately 1:15,000 live births. Nearly 100% of males have neurologic symptoms by adulthood. Females do not usually present with neurological symptoms until adulthood.

Inheritance

X-linked recessive

Primary Care Management

Next Steps After a Positive Screen

Contact the family to ensure that the baby is doing well and to help them understand the testing, condition, and confirmatory testing plan.
Inquire about a family history of ALD or individuals with signs/symptoms consistent with ALD.

Confirming the Diagnosis

To confirm the diagnosis of ALD, contact Newborn Screening Services (see RI providers [2]) to coordinate confirmatory testing.
Newborn screening for ALD is very sensitive (>95%) and specific. The false-positive rate is >0.01%.
Following confirmation of the elevated VLCFAs, the baby should be referred to a specialist for confirmatory testing, which may include repeating VLCFA levels, endocrine testing, and genetic testing for ABCD1 and its variants.

If the Diagnosis is Confirmed

For evaluation and ongoing collaborative management, consult the specialists recommended by your Newborn Screening Service, which may include Pediatric Neurology (see RI providers [17]) and Pediatric Endocrinology (see RI providers [13]).
After confirmation of ALD, close follow-up is important; it is not possible to predict what type (fast or slow disease progression) of ALD the infant will have.
Once a diagnosis is confirmed, endocrine testing is completed. Then, long-term care requires a specialist team and testing on a repeating basis (endocrine testing and brain MRIs for males).
Although scary, ALD is a treatable disease!
With close follow-up and care by specialists in ALD, infants, children, and adults can expect to live healthy, productive, and full lives.

Resources

Information & Support

Related Portal Content
After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Parents and Patients

ALD Connect
A nonprofit organization focused on improving the quality of life for those living with adrenoleukodystrophy. Initiatives include advocating for newborn screening, funding research, providing financial support to low-income families, and promoting education.

United Leukodystrophy Foundation (ULF)
A non-profit organization dedicated to funding cutting-edge research and providing patients and their families with disease information and medical referrals.

ALD Alliance
Helps families understand a new diagnosis of adrenoleukodystrophy (ALD) by giving them the resources they need to fight this rare and devastating disease.

Hunter’s Hope/Leukodystrophy Care Network
Established to address the acute need for information and research with respect to leukodystrophies and also support and encourage those afflicted and their families.

Navigating ALD
Information for those with ALD and their caregivers about about building a care team, managing adrenal insufficiency, monitoring for cerebral ALD, and exploring treatment.

Practice Guidelines

AAP Leukodystrophy Practice Guideline in Press.

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. PubMed abstract / Full Text

Regelmann MO, Kamboj MK, Miller BS, Nakamoto JM, Sarafoglou K, Shah S, Stanley TL, Marino R.
Adrenoleukodystrophy: Guidance for Adrenal Surveillance in Males Identified by Newborn Screen.
J Clin Endocrinol Metab. 2018;103(11):4324-4331. PubMed abstract / Full Text

Patient Education

A Parent’s Guide; A Guide to Living with ALD (Adrenoleukodystrophy) ( PDF Document 7.2 MB)
Provides support and guidance for parents of children with ALD to help manage the condition and give children the best quality of life possible.

Living with Leukodystrophy: A Guide for Caring for Leukodystrophy Patients
E-book produced by Cure MLD for caregivers, nurses, and doctors; free to download by using the code provided on webpage.

Tools

ACT Sheet for Elevated Lysophosphatidylcholines / X-ALD (ACMG) ( PDF Document 192 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Services for Patients & Families in Rhode Island (RI)

Service Categories	RI	NW		MT	NM	NV	OH
Newborn Screening Services	2	1	4	1	2	1	3
Pediatric Endocrinology	13	1	14	1	6	1	3
Pediatric Neurology	17		15		5		5

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Studies

University of Utah/Primary Children’s Leukodystrophy Studies
Established in 2004, the pediatric leukodystrophy center has cared for and treated hundreds of children and adults with leukodystrophies from all over the country and internationally.

Global Leukodystrophy Initiative
A shared research infrastructure supports collection and analysis of robust clinical data and biological specimen to pave the way for transformative therapeutic trials across the leukodystrophies.

Authors & Reviewers

Initial publication: January 2021

Current Authors and Reviewers:

Authors:	Emily Hardy, BSN, RN
	Joshua L Bonkowsky, MD, PhD