Babies diagnosed with ALD through newborn screening are asymptomatic at birth. This means the individual has a mutation in the ABCD1 gene but does not have any symptoms. Boys with ALD often develop symptoms in childhood, including adrenal insufficiency and/or cerebral ALD. Or, they may be asymptomatic until adulthood, and develop symptoms associated with adrenomyeloneuropathy (AMN). Girls with ALD typically do not develop symptoms until later on in adulthood. Myeloneuropathy is common in women with ALD, while cerebral ALD and adrenal insufficiency are very rare in women.
There is currently no way to predict the way that an individual’s symptoms will change over time. ABCD1 pathogenic variants (i.e. the specific “spelling change” in the DNA sequence of the ABCD1 gene) have no predictive value with respect to the clinical outcome of an individual patient. Even brothers with the same genetic variant of the ABCD1 gene can have different symptoms. One brother may develop childhood cerebral ALD while the other remains asymptomatic until adulthood. Dr. Stephan Kemp, ALD Connect Board Member, manages the ALD Variant Database. His website, adrenoleukodystrophy.info provides excellent information about the ABCD1 gene and documented variants associated with ALD.
Sometimes, a baby diagnosed by newborn screening is identified to have an unique variant in the ABCD1 gene that has not been seen before in symptomatic ALD patients. When this happens, it is unclear whether the change identified in the ABCD1 gene is harmful (pathogenic) or not harmful (benign), and thus the variants are called “variants of uncertain significance” or VUS. In the case of VUSes, it is important to consider whether the patient has any symptoms or family history and whether their biochemical markers are elevated to establish an ALD diagnosis. Due to the serious consequences of ALD manifestations, particularly adrenal insufficiency and cerebral ALD in boys, it is important that children with a VUS in the ABCD1 gene still undergo routine monitoring for ALD. Ongoing research studies aim to understand which of these VUSs may truly be pathogenic or benign. ALD Connect is proud to support these studies as a part of The Grey Zone Project.
