Clinical characteristics: X-linked adrenoleukodystrophy (X-ALD) involves the central or peripheral nervous system and the adrenal cortex. The nervous system and adrenal glands are involved independently; thus, an affected male may be diagnosed with cerebral adrenoleukodystrophy (CALD), adrenomyeloneuropathy (AMN), and/or primary adrenocortical insufficiency. CALD is characterized by progressive behavioral, cognitive, and neurologic deficits; onset of symptoms ranges from childhood (typically ages 4 to 8 years) to adolescence (ages 11 to 21 years) and adulthood. AMN is characterized by leg weakness, spasticity, clumsy gait, pain, and bladder and bowel dysfunction; onset is typically in the 20s and 30s. Onset of primary adrenocortical insufficiency ranges from age two years to adulthood (most commonly by age 7.5 years). Heterozygous females are not at increased risk to develop CALD, but are at increased risk to develop AMN and primary adrenocortical insufficiency with increasing age.
Diagnosis/testing: Three scenarios for suspecting the diagnosis are: (1) positive newborn screening result, which to date is performed in more than half of the United States; (2) a male or female proband with suggestive clinical and laboratory findings; (3) a male not known to have X-ALD ascertained and diagnosed via family screening. The diagnosis is established by identification of a hemizygous ABCD1 pathogenic variant in a male or a heterozygous ABCD1 pathogenic variant in a female on molecular genetic testing.
Management: Treatment of manifestations: For neurologic disease, treatment options in males are age dependent. Newborns and asymptomatic infant boys (most commonly diagnosed following a positive newborn screening result or family screening) require immediate referral to a neurologist or biochemical geneticist who will develop a plan for scheduled neurologic examinations and brain MRIs to identify promptly those boys at risk to develop childhood CALD (cCALD) who will benefit from targeted therapy (either hematopoietic stem cell transplantation or, in some, an ex vivo gene therapy recently approved in the US). Older males with CALD and males and females with AMN require supportive treatment by multidisciplinary specialists in relevant fields to improve quality of life, maximize function, and reduce complications. For primary adrenocortical insufficiency, newborn males and asymptomatic infant boys with confirmed X-ALD require immediate referral to a pediatric endocrinologist to screen for adrenocortical insufficiency in order to either promptly treat those with confirmed adrenal insufficiency according to published steroid replacement guidelines or institute a plan for scheduled screening throughout childhood for boys who do not yet have adrenal insufficiency. Older males require scheduled screening to detect later-onset adrenal insufficiency.
Surveillance: For boys receiving targeted therapy for neurologic disease, the treating neurologist / biochemical geneticist monitors existing manifestations, the individual's response to targeted therapy, and need for supportive care. Older males with CALD and males and females with AMN receiving supportive care require scheduled examinations by their multidisciplinary care providers to identify and address emerging issues. Boys at risk for cCALD who are possible candidates for targeted therapy require frequent assessments starting at age 12 months. For primary adrenocortical insufficiency, boys who do not yet have adrenal involvement require scheduled assessments by their treating pediatric endocrinologist throughout childhood. Males with AMN require scheduled assessment (at least yearly) by their treating endocrinologist.
Agents/circumstances to avoid: Triggers known or suspected to be associated with activation of cerebral disease, including significant head injury, coma associated with adrenal crisis, and neurosurgical procedures.
Evaluation of relatives at risk: It is appropriate to evaluate at-risk male relatives of an affected individual through measurement of plasma concentration of very long-chain fatty acids – or molecular genetic testing if the familial ABCD1 pathogenic variant is known – in order to identify as early as possible those who would benefit from screening for primary adrenocortical insufficiency and to facilitate timely identification of young males who might benefit from targeted treatment for cCALD.
Genetic counseling: X-ALD is inherited in an X-linked manner. Approximately 95% of probands inherit an ABCD1 pathogenic variant from one parent; at least 4% of individuals with X-ALD have a de novo pathogenic variant. If the mother of the proband has an ABCD1 pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%; if the father of the proband is affected (i.e., hemizygous for an ABCD1 pathogenic variant), he will transmit the pathogenic variant to all of his daughters and none of his sons. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will typically be symptom-free in childhood but may manifest findings in adulthood. A positive newborn screening result in a female infant should prompt identification and evaluation of at-risk male relatives, as identification of males with X-ALD before symptoms occur or early in the course of the disease can allow for diagnosis and management of adrenal insufficiency before life-threatening complications occur; such testing can also allow for correct diagnosis of early (and often nonspecific) neurologic, behavioral, and/or cognitive signs and symptoms. Once the ABCD1 pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives and prenatal and preimplantation genetic testing are possible.
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