XALD

Question 1

Most frequently observed clinical manifestations are in line with three main ALD phenotypes

Answer 1

The most frequent and mildest form is an isolated adrenal insufficiency, or Addison disease, observed among around 50% of X-ALD patients, leading to hypotension, hypoglycemia, fatigue, or joint pain. The second main form of X-ALD is Adrenomyeloneuropathy (AMN), an adult-onset slowly progressive myelopathy and peripheral neuropathy, that begins between the ages of 20 and 40 with full penetrance beyond age 60 in men and may also affect heterozygous females. Finally, the most rapidly progressive and devastating form of ALD form of X-ALD is Childhood Cerebral ALD (CCALD), occurring within the first 10 years of life.

Question 2

Available treatment for CCALD

Answer 2

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment approved in France, which has been shown to have a beneficial effect on clinical indices of disease and long-term survival [8]. However, it must be performed at the earliest stage of cerebral demyelination process to be effective

Question 3

Treatment for severe CCALD

Answer 3

For more severe patients, allo-HSCT is not recommended, as allo-HSCT will need weeks to months to be effective and will not tackle the rapid disease evolution, leading to irreversible brain damage. Only a limited number of patients will actually present all required conditions to benefit from an allo-HSCT

Question 4

Possible triggers of CALD

Answer 4

What triggersCALDremainsunclear;among beenproposedascausativeagents.7Neuroinflammation inCALDischaracterizedbybreakdownof thebloodbrainbarrier (BBB), infiltrationofmonocytes/macrophages, and, toa lowerextent,Tcells.3,8Hypertrophic astrocytes and activatedmicroglial cells beyond the leadingedgeofbrainlesions indicatebothastrogliosis andmicrogliosis as early events, probably preceding demyelination and invasion of peripheral immune cells

Question 5

Newborn screening of XALD

Answer 5

WithX-ALDadded tonewbornscreening inmany states of theU.S.Aand inTheNetherlands,17,18more patientswithalife-longriskforCALDconversionwillbe identified.

Question 6

NFL in XALD

Answer 6

Blood NfL is now a well-established prognostic marker indicatingdiseaseseverityand/orprogression across variousneurodegenerativediseases including, for example,multiple sclerosis andAlzheimer’s disease.21,30,31 Recently, three independent studies demonstratedthatbloodNfLaccuratelyreflectsdisease activity inX-ALDpatients.5,32,33 Currently, measurementofbloodNfLhasnotyetbeenimplementedinthe clinical management of X-ALD.