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Adrenoleukodystrophy

X-linked adrenoleukodystrophy (ALD) is a disease that can affect the adrenal glands (glands on top of the kidneys that secrete hormones), the brain and/or the spinal cord1. ALD is caused by genetic variants in the ABCD1 gene on the X chromosome. ABCD1 is important in allowing for the breakdown of very long chain fatty acids (VLCFA), a type of metabolite. Because this gene is dysfunctional, patients with ALD will have a build-up of VLCFA. These elevated VLCFA levels are used to detect ALD at birth, before symptoms have developed, in individuals born in places that utilize the ALD newborn screen1.

Males with ALD can be affected by the disease in several different ways. Seventy to eighty percent of males with ALD will have adrenal insufficiency, or a low level of hormone secretion from the adrenal glands2,3. This results primarily in low levels of cortisol, the stress hormone. Adrenal insufficiency causes inability to mount an appropriate bodily response to stress (including illness, surgery and procedures, and sometimes psychosocial stress). Adrenal insufficiency can cause vomiting/diarrhea, poor growth, fatigue, tan skin (hyperpigmentation), and in extremes it can lead to shock and death if not treated with steroids. Adrenal insufficiency can be present in infancy in patients with ALD or it can develop later in life.

Neurologically, all males with ALD are born asymptomatic (without any features of disease). Some rare males with ALD will remain asymptomatic throughout life, while some (~35%) will develop disease of the brain (cerebral disease), and many will develop disease of the spinal cord, a disease manifestation termed adrenomyeloneuropathy (AMN) (AMN is a subtype of ALD)1. Both neurologic manifestations are caused by demyelination, or breakdown of the myelin sheath, a coding around neurons. Without myelin, messages cannot be passed between neurons, and there is disconnection between parts of the brain, the spinal cord, and the rest of the body with subsequent breakdown. While specific neurologic signs and symptoms vary individually based on the part of the brain/spinal cord affected, cerebral ALD typically develops in childhood (between ages 4-10) with progressive attention challenges, language and vision difficulties, and motor deficits1. AMN usually develops later in life (age 20-40) with slowly progressive spastic motor difficulties and bladder/bowel troubles4. Adult-onset cerebral ALD can also occur, mostly among men with existing AMN. Cerebral disease is rapidly progressive in 80% of cases and results in death within 2-4 years in most patients if untreated4. In the remaining 20%, there is spontaneous stoppage of the disease at variable stages and with variable outcomes.

Importantly, ALD has weak phenotype-genotype correlation, meaning that the severity and features of disease experienced by a patient does not correlate well with the specific mutation that they have in their ABCD1 gene5. This means that different members of the same family who have the same genetic variant might end up with different disease effects, and the severity of disease that an individual will experience cannot be predicted well based on their gene variant. For example, if two brothers have the same ABCD1 mutation, one might end up with cerebral disease and the other with AMN. Efforts are being made to expand our understanding of various ALD gene variants and improve prognostication6.

 

Females with ALD

Most females with ALD will develop signs and symptoms of disease. Females with ALD, i.e. females with a pathogenic ABCD1 variant on one of their X chromosomes, can range from being asymptomatic carriers to having severe disease.

While studies into females with ALD are limited, new evidence suggests that more than 80% of women with ALD will develop progressive spinal cord disease resembling AMN. The prevalence of symptoms increases dramatically with age, with 18% of females under 40 and 88% of women over 60 experiencing symptoms of disease in one study7.

In 2025, a relatively large study looked at 127 females with ALD and found that neurologic symptoms were present in 91% of them, with the most common being urinary symptoms (inability to control bladder) in 74% of the women, walking difficulty in 66%, spasticity in 65% and mental health symptoms (most commonly depression and anxiety) in 64%8. A 2014 study that looked at 46 females with ALD found similarly that 63% of females had symptoms of myelopathy (spinal cord disease) including difficulty walking, peeing and pooping. Fecal incontinence (having uncontrollable bowel movements) was reported in 28% of females with ALD8. Numbness, pain in feet, restless leg syndrome (feeling the urge to move legs, particularly at night), cerebellar ataxia (balance difficulty) and dystonia (recurrent muscle contractions) are all commonly seen among women with ALD. Falls and resulting injuries are also commonly reported. Treatment for females with ALD is limited at this time to symptom management, with many patients taking analgesics and antispasmotic medications.

Compared to males with ALD, females are typically affected by the disease later in life (with males developing AMN symptoms at median age of 28 years and females at 37 years) and females typically experience slower progression of disease8. Notably, unlike in males, females with ALD almost never develop cerebral disease or adrenal insufficiency. Less than 1% of females with ALD develop cerebral disease, with fewer than 10 cases reported to date, many of which were proven to involve dramatically skewed X-inactivation9. Adrenal insufficiency is thought to develop in only 5% of females with ALD3. Thus, the more life-threatening aspects of ALD do not commonly impact females.

Of note, most females with ABCD1 variants have increased VLCFA (like males), and thus the newborn screening test also works for detecting females. Like in males, the phenotype-genotype correlation seen in females with ALD is poor. In fact, several studies have noted that (with the exception of extremes), X-inactivation patterns do not seem to correlate with disease severity among women with ALD9. One study looking at X-inactivation in ALD found that there was a general phenomenon where the affected X chromosome was unevenly favored in most females with ALD, regardless of symptoms (in other words, there is usually some degree of skewed X-inactivation, but it can not be used to predict symptoms)10. Thus, as is the case in males with ALD, the disease severity that an individual female will experience is variable and cannot be well predicted.

Importantly, females with ALD often struggle to be diagnosed in the absence of an affected male family member, and female signs and symptoms of disease are often overlooked. In the large 2025 study, 90% of interviewed women reported having difficulty accessing health care for their symptoms, and 22 out of 46 females who sought clinical care before diagnosis were initially misdiagnosed. Overall quality of life was reduced in 86% of interviewed women9.

This page was last updated in July, 2026. Please note that research into females with this condition is limited. As a result, percentages and prevalence rates may not be accurate or widely applicable. Decisions regarding your own health should be made in consultation with your medical provider.

  1. Engelen M, van Ballegoij WJC, Mallack EJ, et al. International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy. Neurology. 2022;99(21):940-951. doi:10.1212/WNL.0000000000201374 
  2. Zhu J, Eichler F, Biffi A, Duncan CN, Williams DA, Majzoub JA. The Changing Face of Adrenoleukodystrophy. Endocr Rev. 2020;41(4):577-593. doi:10.1210/endrev/bnaa013 
  3. Cappa M, Todisco T, Bizzarri C. X-linked adrenoleukodystrophy and primary adrenal insufficiency. Front Endocrinol. 2023;14:1309053. doi:10.3389/fendo.2023.1309053 
  4. Engelen M, Kemp S, de Visser M, et al. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012;7:51. doi:10.1186/1750-1172-7-51 
  5. Zemanova M, Chrastina P, Dvorakova L, et al. X-linked adrenoleukodystrophy: phenotype-genotype correlation in hemizygous males and heterozygous females with ABCD1 mutations. Neuro Endocrinol Lett. 2021;42(5):359-367. 
  6. The Grey Zone. ALD Connect. Accessed July 20, 2026. https://aldconnect.org/clinical-trials-and-research/the-grey-zone/ 
  7. Engelen M, Barbier M, Dijkstra IME, et al. X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. Brain. 2014;137(3):693-706. doi:10.1093/brain/awt361 
  8. Grant NR, Li Y, De La Rosa Abreu L, et al. Disease Burden in Female Patients With X-Linked Adrenoleukodystrophy. Neurology. 2025;104(5):e213370. doi:10.1212/WNL.0000000000213370 
  9. Grant NR, Li Y, De La Rosa Abreu L, et al. Disease Burden in Female Patients With X-Linked Adrenoleukodystrophy. Neurology. 2025;104(5):e213370. doi:10.1212/WNL.0000000000213370 
  10. Salsano E, Tabano S, Sirchia SM, et al. Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms. Orphanet J Rare Dis. 2012;7:10. doi:10.1186/1750-1172-7-10