ClinGen Actionability ABCD1
- X-linked adrenoleukodystrophy (X-ALD) has a highly variable phenotype even within families that ranges in age of onset, presenting symptoms, and severity from childhood through adulthood. Most mutations are unique and there is no recognized genotype-phenotype correlation within or across families, even with identical gene mutations.
- As an X-linked condition, males are in general affected more severely than females. However, females carrying one ABCD1 mutation can develop symptoms.
- The most severe form of X-ALD is childhood cerebral ALD (CCALD), impacting between 31-57% of hemizygous males and typically presenting between ages 2 - 12.
- Adult males with or without CCALD may develop adrenomyeloneuropathy (AMN), often with onset after age 28-30.
- An estimated 50-65% of heterozygous females can develop symptoms, usually of AMN, in mid- to late adulthood.
- Adrenocortical insufficiency (AI, Addison’s disease) can be the presenting symptoms of X-ALD in boys and men years or decades before neurological symptoms.
- Women and men with X-ALD, with or without signs of AMN, should be evaluated yearly or bi-annual by a neurologist to screen for symptoms of AMN. In asymptomatic men, serum ACTH, cortisol, and a brain MRI without contrast should be done annually starting at age 18.
- Interventions include MRI, screening of hormone levels, physical therapy, and potentially adrenal hormone therapy and hematopoietic cell therapy.
- A diagnosis of X-ALD must be followed by extended family screening to detect 1) heterozygous women who can be offered prenatal/preimplantation diagnosis for future pregnancies and 2) boys or adult males who are asymptomatic but at risk to develop cerebral demyelination or adrenocortical insufficiency.
The full ClinGen Actionability report on X-linked adrenoleukodystrophy can be found here.
Genetic counseling may be available to you through your health-care network. In the US, genetic counselors may be found via this webpage of the National Society of Genetic Counselors.