Adrenoleukodystrophy

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: ABCD1 (HGNC:61)
• Mode(s) of Inheritance: X-linked
• Literature Search: 11/16/2016
• Curation Status: Released (1.2.2)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
ABCD1	adrenoleukodystrophy (0018544)	300100	Assertion Pending

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Neurological/Cognitive decline / Neurological surveillance to plan initiation of HCT	2	3C	3C	3	11CC
Adrenal insufficiency (males only) / Monitoring adrenal hormones with replacement as needed	1	2C	3C	3	9CC

Severity of Outcome

Prevalence of the Genetic Condition

The birth incidence of X-linked adrenoleukodystrophy (X-ALD) is estimated at 1:17,000 when including male hemizygotes and female heterozygotes. The estimated incidence in males ranges from 1:20,000 to 42,000. Based on US cases, female heterozygotes X-ALD cases are approximately 1.5 times more prevalent than male X-ALD.

Clinical Features (Signs / symptoms)

X-ALD is a metabolic disorder that affects the adrenal glands and central nervous system and is characterized by elevated serum very-long-chain fatty acids (VLCFA). The most severe form of X-ALD is childhood cerebral ALD (CCALD). CCALD is associated with adrenal insufficiency and cerebral demyelination with initial symptoms of emotional lability, hyperactive behavior, school failure, and visuo-spatial impairment followed by worsening cognitive and neurologic disability. Adult males with or without CCALD may develop adrenomyeloneuropathy (AMN) which is characterized by gradually progressive spastic paraparesis, sensory ataxia with impaired vibration sense, spinal cord symptoms, sphincter dysfunction (mostly urinary), pain in the legs, and impotence. An increased risk of psychiatric morbidity has been reported with depression often observed in patients with severe motor disability. Of those with AMN approximately 20% will also develop cerebral disease. After an initial progression, demyelinating lesions can stabilize spontaneously leading to moderate cognitive defections. However, the prognosis may be as poor as in CCALD. Adrenocortical insufficiency (AI, Addison’s disease) can be the presenting symptoms of X-ALD in boys and men years or decades before neurological symptoms. AI is often latent, but may present as fatigue, nausea, or even acute primary AI. Hair of patients is often thin and sparse and patients often show baldness at an early age. AI generally presents without evidence of neurologic abnormality, however some decrease of neurologic disability (most commonly AMN) usually develops later. An estimated 50-65% of heterozygous females can develop symptoms, usually of AMN, in mid- to late adulthood. In general the symptoms are similar, though less severe, in women; however, sensory ataxia, fecal incontinence, and pain in the legs are often more prominent in women with AMN. Addison disease and cerebral disease are rare, occurring in 1-2% in heterozygotes.

Natural History (Important subgroups & survival / recovery)

X-ALD phenotypes are not static. Presymptomatic males are nearly all at risk to develop neurologic (cerebral ALD, MMN) or endocrinologic (AI) symptoms.CCALD impacts between 31-57% of hemizygous males and typically presents between ages 2 and 12 and is associated with rapid cognitive and neurologic decline. ALD can also present in adolescence and adulthood, though much less frequently. If not treated with hematopoietic cell transplantation (HCT) and lifelong hormone replacement therapy, CCALD patients deteriorate, with severe disability within 2 to 5 years of symptom onset followed shortly by death.The typical age of onset of AMN is after age 28-30; however, neurological symptoms can begin to manifest in childhood or adolescence. The course of AMN is highly variable. Within a mean of 13 years from recognized onset in adults, the rate of death or severe disability is 12%. The phenotype in most cases is slowly progressive, causing severe motor disability of the lower limbs over one or two decades. Progression in a specific individual cannot be predicted. There is a marked variability ranging from men with that are wheelchair bound by age 35 and others who can walk with a cane into their seventies.AI presents between age two and adulthood, most commonly by age 7.5 years. For 10% of affected individuals AI is the only presentation. Although the treatment of AI is very effective, the identification is often delayed and may lead to significant morbidity or even death.Affected heterozygous females generally have onset of symptoms in the 4th or 5th decade of life.

Likelihood of Outcome

Mode of Inheritance

X-linked

Prevalence of Genetic Variants

1-2 in 50000

Given that the ABCD1 mutation is the only cause of X-ALD the prevalence of the genetic mutation is estimated to be the same as that of X-ALD among males. The birth incidence of X-linked adrenoleukodystrophy (X-ALD) is estimated at 1:17,000 when including male hemizygotes and female heterozygotes. The estimated incidence in males ranges from 1:20,000 to 42,000 and 1:28,000 in heterozygous females.

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

The biochemical phenotype of elevated plasma concentration of VLCFA has nearly 100% penetrance in males.

Tier 4

>= 40 %

Males with an ABCD1 mutation have a 31-57% risk of developing CCALD.

Tier 3

Virtually all males with an ABCD1 mutation who reach adulthood will develop AMN.

Tier 4

5-39 %

20% of adult males with the AMN phenotype will develop cerebral demyelination later in life.

Tier 3

5-39 %

Adrenal insufficiency has been reported in up to 35% of in males with an ABCD1 mutation.

Tier 3

>= 40 %

Symptoms similar to AMN develop in about 50-65% of women with a heterozygous ABCD1 mutation.

Tier 3

1-4 %

Adrenal insufficiency and cerebral disease are rare in women with a heterozygous ABCD1 mutation (1%).

Tier 4

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

No information on relative risk was identified.

Expressivity

Widely varying phenotypes often co-occur in a single kindred or sibship.

Tier 3

Intervention Effectiveness

Patient Management

To establish the extent of disease and needs in an individual diagnosed with X-ALD the following evaluations are recommended:

- Neurologic examination

- Brain MRI

- Adrenal function tests

- Medical genetics consultation

Tier 4

If ACTH or cortisol abnormalities develop (indicative of AI), adrenal hormone therapy should be instituted. In addition, patients should be educated on the need for lifelong therapy and the management of physiologic stresses such as fever, vomiting, and surgery.

Tier 2

No data regarding the specific benefit of presymptomatic detection of AI were identified. Cortisol for adrenal hormone insufficiency has been studied in many other conditions and is recognized as efficacious. However, little is known about adrenal insufficiency specifically associated with X-ALD, including long-term prognosis, adherence to cortisol treatment, or the clinical consequences of incomplete treatment.

Tier 4

The only effective treatment for cerebral X-ALD is hematopoietic cell therapy (HCT).Due to the risk of mortality related to the procedure, HCT is recommended only for males with evidence of brain involvement.

Tier 2

HCT remains the only therapeutic intervention that can arrest or slow the progression of cerebral demyelination in X-ALD, provided the procedure is performed very early (e.g., when affected boys or men have no or minor symptoms due to cerebral demyelinating disease).

Tier 3

It seems likely that HCT is effective in adults with early stage cerebral ALD, but there are no published studies or cases describing this treatment. No published study directly compares treatment outcomes for individuals detected presymptomatically with those diagnosed symptomatically. Indirect evidence suggests that earlier age of treatment with HCT is associated with better outcomes. However, HCT does not modify the course of AI or other types of myelopathy and neuropathy.

Tier 4

Physical therapy, management of urologic complications, and family and vocational counseling are of value for men with AMN.

Tier 3

Surveillance

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. These screens allow for timely administration of symptomatic treatment and specialist referral.

Tier 4

In asymptomatic men, serum ACTH, cortisol, and a brain MRI without contrast should be done annually starting at age 18. These recommendations are based on evidence that cerebral demyelination visible on brain MRI is the first evidence of the disease.

Tier 2

Circumstances to Avoid

No recommendations on circumstances to avoid were identified.

Nature of Intervention

Nature of Intervention

Interventions include MRI, screening of hormone levels, physical therapy, and potentially adrenal hormone therapy and hematopoietic cell therapy. \nHSCT is associated with a 20% risk for morbidity and mortality.

Context: Adult

Chance to Escape Clinical Detection

The differences in symptom onset across the full lifespan, clinical area affected (e.g., adrenal cortex, cerebral or peripheral nervous system), and severity of symptoms in the affected area have complicated and delayed diagnosis of X-ALD by a mean of 9.9 years (range 1-33 years).

Context: Adult

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			ABCD1			300100	0018544	0010247

References List

Adrenomyeloneuropathy. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=139399

Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, Aubourg P, Poll-The BT. (2012) X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet journal of rare diseases. 7(1750-1172):51.

Kemper AR, Brosco J, Comeau AM, Green NS, Grosse SD, Jones E, Kwon JM, Lam WK, Ojodu J, Prosser LA, Tanksley S. (2017) Newborn screening for X-linked adrenoleukodystrophy: evidence summary and advisory committee recommendation. Genetics in medicine : official journal of the American College of Medical Genetics. 19(1):121-126.

Kemper AR, Brosco J, Green NS, Kwon J, Prosser LA, Jones E, Comeau AM, Grosse S, Ojodu J, Tanksley S, Lam KK. Newborn Screening for X-Linked Adrenoleukodystrophy (X-ALD): A Systematic Review of Evidence. (2015) Accessed: 2017-02-15. URL: https://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/nominatecondition/reviews/alddecisionletter.pdf

Krasemann E, Kemp S, Gal A. (2012) Clinical utility gene card for: adrenoleukodystrophy. European journal of human genetics : EJHG. 20(3).

SJ Steinberg, AB Moser, GV Raymond. X-Linked Adrenoleukodystrophy. (1999) [Updated Apr 09 2015]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1315/

Vogel BH, Bradley SE, Adams DJ, D'Aco K, Erbe RW, Fong C, Iglesias A, Kronn D, Levy P, Morrissey M, Orsini J, Parton P, Pellegrino J, Saavedra-Matiz CA, Shur N, Wasserstein M, Raymond GV, Caggana M. (2015) Newborn screening for X-linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines. Molecular genetics and metabolism. 114(4):599-603.

X-linked cerebral adrenoleukodystrophy. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=139396