The range of phenotypic expression in X-ALD is wide and cannot be predicted by very long-chain fatty acid (VLCFA) levels, the ABCD1 pathogenic variant, or family history. Varying phenotypes often co-occur in a single kindred or sibship. Some individuals with X-ALD remain asymptomatic until their adult years.
Affected Males
Childhood cerebral adrenoleukodystrophy (cCALD). Inflammatory cerebral demyelination may occur at almost any age in X-ALD, but it is characteristically seen as a childhood presentation. It most commonly occurs between ages four and eight years, with a peak at age seven years. It rarely occurs before age three years.
It is important to identify as early as possible males with neuroimaging findings of cCALD in order to refer them promptly to determine if they are candidates for targeted therapy that can slow the disease course (see Management, Targeted Therapy).
Affected males present with behavioral or learning deficits, often diagnosed as attention-deficit/hyperactivity disorder, which may respond to stimulant medication. These behaviors may persist for months or longer, and are followed by symptoms suggestive of a more serious underlying disorder, including "spacing out" in school (inattention, deterioration in handwriting skills, and diminishing school performance); difficulty in understanding speech (though sound perception is normal); difficulty in reading, spatial orientation, and comprehension of written material; clumsiness; visual disturbances and occasionally diplopia; and aggressive or disinhibited behavior.
Brain MRI examination performed at this time can be strikingly abnormal even when symptoms are relatively mild. The presence of advanced disease on MRI even with seemingly mild neurologic findings may preclude an attempt at targeted therapy.
In some males, seizures may be the first manifestation.
While variable, the rate of disease progression may be rapid, with total disability occurring within six months to two years, followed by death at varying ages.
Most individuals have impaired adrenocortical function at the time that neurologic disturbances are first noted.
Adrenomyeloneuropathy (AMN). The typical presentation is a man in his adult years who develops progressive stiffness and weakness in the legs (due to spastic paraparesis), abnormalities of bladder and bowel control, abnormal sensory perception (especially of vibratory sense), and sexual dysfunction. All manifestations progress over decades.
Approximately 40%-45% of individuals with AMN show some degree of involvement on brain MRI or clinical examination. In 20%-63% of individuals with AMN, progressive brain involvement leads to serious cognitive and behavioral disturbances that may progress to total disability and death [de Beer et al 2014].
Approximately 70% of men with AMN have impaired adrenocortical function at the time that neurologic manifestations are first noted.
Primary adrenocortical insufficiency. Males can present with signs of adrenal insufficiency at any age, although commonly by age 7.5 years. Presenting signs include unexplained vomiting and weakness or coma, leading to the diagnosis of primary adrenocortical insufficiency. A variable finding is increased skin pigmentation resulting from excessive adrenocorticotropic hormone secretion.
Overall, adrenocortical function is abnormal in 90% of neurologically symptomatic boys and 70% of men with AMN. Most males who are initially diagnosed as having only primary adrenocortical insufficiency will develop some neurologic manifestations; however, it may be decades later.
Heterozygous Females
Heterozygous females are symptom-free in childhood. In adulthood, an AMN-like phenotype in females is reported as mild-to-moderate spastic paraparesis with bladder and bowel issues. The onset of these issues is often subtle and – if not specifically examined for – easily overlooked. The findings do correlate with age, and may not become evident until later in life. Progression is also slower than that seen in males with AMN [Huffnagel et al 2019]. For these reasons, the reported incidence of an AMN-like phenotype in heterozygous females varies between 65% and 80% [Huffnagel et al 2019, Schirinzi et al 2019].
It may be stated that adrenal insufficiency in heterozygous females is rare, and the present recommendation is not to routinely screen females for this feature. There are also rare reports of cerebral myelin involvement caused, in some females, by genetic mechanisms such as chromosomal rearrangement or skewed X-inactivation [Hershkovitz et al 2002].