X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a rare genetic neurometabolic disorder caused by impaired peroxisomal metabolism of very-long-chain fatty acids, resulting in progressive disease affecting the nervous system and adrenal cortex. It typically occurs as an inherited X-linked genetic condition; de novo pathogenic variants account for a minority of cases, so absence of a relevant family history does not exclude the diagnosis. It affects both males and females, but clinically significant disease is more common and generally more severe in males. The major neurologic phenotypes include cerebral X-ALD, characterized by progressive cerebral demyelination, and adrenomyeloneuropathy (AMN), characterized predominantly by progressive spinal cord and peripheral nerve dysfunction in adulthood.

It can present with psychiatric features such as mania or manic-like symptoms, irritability, behavioural change, depression, anxiety, cognitive impairment, and psychosis. Psychiatric manifestations may become apparent or clinically significant during adolescence or adulthood and may precede the characteristic neurologic manifestations. Psychiatric and behavioural manifestations can occur in both cerebral X-ALD and AMN, although psychosis is particularly associated with cerebral involvement, including adult-onset cerebral X-ALD. Psychiatric symptoms may occasionally be the initial or predominant presentation.

Other characteristic features include cerebral demyelination with progressive cognitive and neurologic decline, seizures, spasticity, gait disturbance, weakness, impaired coordination, and visual or speech impairment. AMN may present in adulthood with progressive leg stiffness and weakness, spastic paraparesis, sensory abnormalities, bladder and bowel dysfunction, and sexual dysfunction. Primary adrenocortical insufficiency may occur independently of neurologic disease and can precede neurologic manifestations.

From a multisystemic lens perspective, clinical features in other body systems include (but are not limited to):

• Renal/electrolytes: hyponatremia, hyperkalemia, and other electrolyte abnormalities may occur as a consequence of primary adrenocortical insufficiency.

• Endocrine: primary adrenocortical insufficiency (Addison disease) is a characteristic manifestation, particularly in males, and may present with weakness, vomiting, hypotension, hyperpigmentation, or adrenal crisis.

• Dermatologic: hyperpigmentation may occur as a manifestation of primary adrenocortical insufficiency.

Early diagnosis is important to recognize potentially treatable psychiatric manifestations, particularly when they precede neurologic findings, identify cerebral disease at a stage when disease-modifying treatment may be beneficial, detect and treat primary adrenocortical insufficiency before potentially life-threatening adrenal crisis, distinguish X-ALD from primary psychiatric or other neurologic disorders, and enable appropriate genetic counselling and screening of at-risk relatives.