Adrenoleukodystrophy (ALD)
ALD is inherited in an X-linked pattern, meaning that the ABCD1 gene is located on the X chromosome. Males have one X chromosome and one Y chromosome, whereas females have two X chromosomes (and thus two copies of the ABCD1 gene). Therefore, males with an ABCD1 mutation will be affected with the symptoms typically associated with ALD, while females with a mutation are carriers because they have a second, functional ABCD1 gene, and therefore usually don't experience symptoms in childhood. When a woman carries an ABCD1 mutation, the chance for her to pass this mutation on to a son is 50%. The chance for her to pass the ABCD1 mutation to a daughter is also 50%, and the daughter will be a carrier of ALD as well.
Approximately 20% of female carriers of an ABCD1 mutation develop mild to moderate spastic paraparesis in middle age or later. Their adrenal function is not affected.
There are three types of ALD, each with different symptoms and age of onset. Disease phenotype cannot be predicted based on VLCFAs, ABCD1 mutation, or family history.
- Childhood cerebral form - Age of onset is usually between 4 and 8 years. Presenting symptoms may mimic ADHD or hyperactivity, but progress to impaired cognition, behavior, vision, hearing and motor function. Rapid symptom progression usually leads to total disability within 2 years. Brain MRIs are always abnormal in neurologically symptomatic males.
- Adrenomyeloneuropathy (AMN) - Age of onset is approximately in the late 20’s. Most common symptoms are paraparesis, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function. Progression is slower, occurring over several decades.
- Addison disease only - Age of onset is between 2 and adulthood, but most often by 8 years. Presents with adrenal insufficiency without evidence of neurologic abnormality, but some degree of neurologic dysfunction (usually AMN) may develop later in life.
- Incidence: The overall incidence of ALD is approximately 1 in 17,000 births. It is panethnic.
- New York State Method of Screening (First Tier): Screening for ALD is accomplished by analysis of very long chain fatty acids (VLCFAs) by mass spectrometry, specifically the concentration of C26:0. If concentrations are normal, the sample is deemed within acceptable limits. If abnormal, second tier screening is performed.
- Second Tier Screening: Samples with VLCFA concentrations above a certain threshold will be tested a second time using a more specific assay. If concentrations are normal, the sample is deemed within acceptable limits. If abnormal, third tier screening is performed, however persistent elevations of VLCFAs still warrant referral and further work-up regardless of whether an ABCD1 mutation is present.
- Third Tier Screening: Sequencing of the ABCD1 gene.
- Testing can be affected by: Elevations in VLCFAs, including C26:0, may be caused by other Peroxisomal Biogenesis Disorders besides ALD. These include Zellweger Syndrome (ZS), Neonatal Adrenoleukodystrophy (NALD), and Infantile Refsum Disease (IRD). VLCFAs may also be elevated in healthy newborns, thus giving a false positive result. Interpretation/Reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral. Referrals are reported out as one mutation or no mutations.
- When an ABCD1 mutation is identified in a male, it is consistent with a diagnosis of ALD.
- When an ABCD1 mutation is identified in a female, it is consistent with her being a carrier of ALD.
- When no mutation is identified in ABCD1, the baby must be evaluated for other Peroxisomal Biogenesis Disorders.
- Referral to Specialty Care Center: Babies with an abnormal newborn screen for ALD are referred to an Inherited Metabolic Disease Specialty Care Center for a diagnostic evaluation. If diagnosed with ALD, patients will be referred to Pediatric Endocrinology and Pediatric Neurology for clinical assessments of adrenal and neurological function and need for treatment.
All babies who have a positive ALD newborn screen should be assessed by testing the plasma for VLCFAs, and females with an ABCD1 mutation or newborns without a mutation should have their plasmalogen levels measured as well. Babies with confirmed diagnoses must be assessed for adrenal insufficiency and neurological function at a Specialty Care Center with a Pediatric Endocrinologist and Pediatric Neurologist. Assessments of adrenal function include measurements of serum ACTH and cortisol. In addition to a clinical examination, neurological assessment includes regular brain MRIs beginning at 6 months of age.
Adrenal insufficiency – Adrenal replacement therapy can prevent a potentially life-threatening adrenal crisis, and improves general strength and well-being. It does not slow neurological progression.
Neurological – Hematopoietic stem cell transplant (HSCT) is considered in asymptomatic males with ALD in whom mild MRI abnormalities are present. In these individuals, HSCT has shown long-term benefit and increased survival. HSCT is not needed in individuals who do not have the cerebral form of ALD, and is of limited benefit to males already showing neurological symptoms. Use of Lorenzo’s Oil (a 4:1 mixture of glyceryl-trioleate and glyceryl-trierucate) normalizes plasma VLCFA levels and is under investigation as a preventative measure.
Prognosis is variable and dependent on multiple factors including the severity of disease and response to treatments. The childhood cerebral form of ALD is fatal, but at varying ages.
Online Brochures:
- Newborn Screening for X-linked Adrenoleukodystrophy: Information for Parents
X-linked adrenoleukodystrophy (ALD) is a genetic disorder caused by mutations in the ABCD1 gene. It is a progressive metabolic condition affecting the adrenal glands and nervous system in males. The ABCD1 gene codes for a peroxisomal membrane protein which is necessary for the degradation of very long chain fatty acids (VLCFAs). Mutations in ABCD1 result in an accumulation of saturated VLCFAs in the brain, adrenal glands, and plasma.