OVERVIEW: What every practitioner needs to know

Are you sure your patient has X-linked adrenoleukodystrophy? What are the typical findings for this disease?

The most common symptoms in X-linked adrenoleukodystrophy (X-ALD) are both neurologic and endocrine in nature. The most common first neurologic symptoms in boys with cerebral ALD are inattention and hyperactivity. The most common first endocrine symptoms are related to adrenal insufficiency.

Because of the rapidly evolving brain demyelination, the neurologic symptoms proceed within months to gait difficulties and ataxia. The devastating brain disease is at times preceded by latent or manifested adrenal insufficiency. These symptoms are often recognized only in hindsight and may include fatigue, increased skin pigmentation, and prolonged need for antibiotics after an infection. In rare cases, fulminant addisonian crisis can be a first manifestation of X-ALD.

What other disease/condition shares some of these symptoms?

Symptoms of inattention and hyperactivity are most often seen in attention deficit hyperactivity disorder, and it is not unusual for a boy with cerebral ALD to be misdiagnosed initially and treated with stimulants. The constellation of both cognitive and motor decline in a child within the first decade of life has a broad differential and includes infectious, autoimmune, toxic, vascular, neoplastic, and genetic conditions.

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Children with acute disseminated encephalomyelitis and multiple sclerosis can demonstrate similar symptoms. Vascular insults, whether ischemic or hemorrhagic, as well as masses, such as brain tumors, can cause a similar constellation of symptoms. Magnetic resonance imaging (MRI) can differentiate these conditions. Among the genetic conditions that can manifest in this age group, metachromatic leukodystrophy should come to mind.

What caused this disease to develop at this time?

The gene defect in X-ALD localizes to Xq28 and encodes the peroxisomal half-transporter
ABCD1. Mutations in this gene invariably lead to elevations of saturated very long chain fatty acids, which are lipids with a chain length of greater than 20 carbons. This can easily and reliably be detected in plasma and is the method of choice to establish the diagnosis of X-ALD. Although both the gene and biochemical defect are present at birth, adrenal insufficiency has not been reported during infancy, and brain disease usually manifests after the fourth year of life.

A mutation in this gene is necessary but is not sufficient for the development of cerebral ALD. Monozygotic twins with divergent phenotypes have been described. Therefore, there must be other factors (environmental, nutritional, toxic exposures, injuries) that contribute to the progressive inflammatory brain disease.

The vulnerable period for inflammatory brain disease to develop is between 4 and 10 years of age. Although brain demyelination can develop in boys during puberty, it is a rare occurrence.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

In boys, elevations in plasma very long chain fatty acids are diagnostic for X-ALD. In girls with carrier status, plasma very long chain fatty acid determinations can be normal and results should be interpreted with caution. Mutation testing should therefore be performed in all girls suspected of being carriers and is necessary to rule out carrier status. After the diagnosis, boys should be tested for adrenal insufficiency. This can often be latent and detected only by elevations in adrenocorticotropic hormone. Furthermore, boys within the high-risk period (4-10 years of age) should be monitored by brain MRI on a yearly basis.

Would imaging studies be helpful? If so, which ones?

Changes on conventional brain MRI precede symptom development. Therefore, asymptomatic boys in early childhood should receive yearly MRI. If a lesion is found, it is important to administer contrast , as the presence of a gadolinium-enhancing lesion edge is associated with more fulminant and rapid disease progression. Beyond conventional imaging, MR spectroscopy has proved useful in showing early metabolic changes in the brain. A rise in choline levels precedes lesion development within normal-appearing white matter. Computed tomography is less sensitive than MRI in depicting white matter changes and exposes the patient to unnecessary radiation.

Confirming the diagnosis

Beyond a careful clinical examination to detect spasticity in a young boy with attention problems or personality changes, one should always take a careful family history. The occurrence of adrenal insufficiency or neurologic disease in male relatives on the mother’s side of the family raises the suspicion for X-ALD. Further, abnormal skin pigmentation or a “tanned” appearance in a young boy with the aforementioned behavioral changes should raise suspicion for the disorder. At times, a thorough history will reveal the need for prolonged antibiotics during infection.

Early detection of ALD and the occurrence of brain disease is crucial, as the only treatment able to arrest disease progression is bone marrow transplantation. Bone marrow transplantation works best in the early stages of brain disease, but is contraindicated once the disease has progressed too far.

If you are able to confirm that the patient has X-linked adrenoleukodystrophy, what treatment should be initiated?

After the diagnosis of X-ALD, the possibility of associated adrenal insufficiency should be investigated. This is a treatable condition and appropriate adrenal replacement can be lifesaving. Particularly during infections and other illnesses, stress-dose steroids are necessary.

Next, brain MRI should be performed; results of imaging dictate the next steps of treatment. If the brain is normal in appearance, the patient would qualify for Lorenzo’s oil treatment. Lorenzo’s oil is a combination of oleic and erucic acid that with oral intake is able to lower plasma saturated very long chain fatty acids. In the presymptomatic stage, this has been shown to reduce the risk of cerebral ALD from 30% to 15%.

If the brain MRI result is not normal and shows signs of brain demyelination, the patient should be rapidly evaluated for bone marrow transplantation. It has been determined that patients with early lesions on brain MRI (Loes imaging score ≥9) and a performance IQ greater than 80 do well after bone marrow transplantation and there is a good chance of the brain disease being arrested. For more patients with more advanced disease (Loes imaging score >9 and a performance IQ <80), the transplant procedure brings additional risks and enhances morbidity and mortality.

What are the adverse effects associated with each treatment option?

Adrenal replacement should be performed under the expert care of an endocrinologist. In this setting, there are minimal risks associated with adrenal replacement. Together with Lorenzo’s oil, a strict dietary regimen is instituted. This can be difficult for patients and families, but under the guidance of a nutritionist can be instituted over time. It is important to monitor the platelet count and plasma saturated very long chain fatty acids while the child is taking Lorenzo’s oil.

Bone marrow transplantation carries multiple significant risks. First, immune suppression is instituted with cyclophosphamide and busulfan. Both these agents carry predictable risks and warrant monitoring. After engraftment of donor bone marrow cells, the patient remains at risk for graft versus host disease. These and other complications can be compounded by the rapidly progressing neurologic disorder.

What are the possible outcomes of X-linked adrenoleukodystrophy?

Boys with X-ALD can have a normal life expectancy and pursue a career and family life. However, careful monitoring during high-risk periods (4-10 years of age) must be in place. During this period, a fraction of the boys (approximately 35%) will be diagnosed with brain disease and neurologic dysfunction (personality changes, gait difficulties). If untreated, brain disease can rapidly lead to loss of language and ambulation. Patients with severe disease are vegetative or dead within years.

Girls who have X-ALD do not have disease manifestations during childhood, and diagnostic testing has no consequences and is therefore not warranted. However, once a girl reaches reproductive age, family planning may warrant knowledge of carrier status. Female carriers can also have signs and symptoms later in life. These include signs such as hyperreflexia and symptoms of spasticity and pain.

The most important risk/benefit consideration concerns bone marrow transplantation. Benefits of bone marrow transplantation outweigh risks only in the early stages of brain disease. In the more advanced stages of brain disease, the risks outweigh benefits, and immune suppression can aggravate the underlying neurologic condition.

What causes this disease and how frequent is it?

It is an X-linked genetic disorder that is usually passed on from a carrier mother to male offspring who manifest the disease in childhood. Although girls can also receive the mutant allele from the mother, they do not manifest the disease. If the father has X-ALD, all his daughters are obligate carriers, and none of the boys are affected. The incidence of male persons with X-ALD is 1/45,000. The incidence of male hemizygotes and female heterozygotes combined is 1/17,000. The disease manifests in all ethnic groups.

How do these pathogens/genes/exposures cause the disease?

It is currently not known how mutations in ABCD1 lead to brain demyelination.
ABCD1 encodes a peroxisomal half-transporter, known as adenosine triphosphate (ATP)-binding casette binding domain 1. The exact function of this protein is not known, although it likely has implications for the degradation of very long chain fatty acids occurring in the peroxisome.

As mentioned before, mutations in ABCD1 invariably lead to elevations in plasma saturated very long chain fatty acids. These abnormally long fatty acids have been described as having toxic properties. However, no correlation between levels of very long chain fatty acids and manifestation of brain disease has been established. It appears that in addition to the genetic and biochemical defects, additional factors are necessary for brain disease to become manifested.

Recently, a series of boys in whom brain demyelination developed after head trauma has been described. Other factors such as fever, infections, and toxic exposure, may play a role but have not been well explored or characterized.

What complications might you expect from the disease or treatment of the disease?

Adrenal insufficiency, in its worst form, can bring about an addisonian crisis and be life-threatening. Patients with adrenal insufficiency therefore require high-dose steroids during infection or illness. Although long-term adrenal replacement carries few side effects, monitoring of blood pressure and blood glucose is warranted.

The brain disease in boys with X-ALD can result in a vegetative state and death. If boys do not acquire cerebral disease, in adulthood they may manifest a spastic paraparesis known as adrenomyeloneuropathy. This is seen only in adulthood and does not manifest in childhood.

How can this disease be prevented?

Careful family screening can detect patients in the asymptomatic or presymptomatic stages. It can also lead to prenatal diagnostics (chorionic villi sampling) and prevention of unwanted children who carry the genetic and biochemical defect. To perform prenatal diagnosis, the exact mutation must be known in female carriers. It is therefore helpful to establish the mutation in the index case, often the first male patient diagnosed in the family. Thereafter, targeted DNA testing in carriers can be performed.

What is the evidence?

Aubourg, P, Blanch, S, Jambaque, I. “Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation”. N Engl J Med. vol. 322. 1990. pp. 1860-6. (This is the first description of the ability of bone marrow transplantation to arrest diesease progression.)

Cartier, N, Hacein-Bey-Abina, S, Bartholomae, CC. “Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy”. Science. vol. 6. 2009. pp. 818-23. (This is the first report of gene therapy in X-ALD using autologous cells that received a lentiviral transfection of the corrected gene. Outcome at 24 and 30 months is reported in 2 boys with cerebral ALD.)

Dubey, P, Raymond, GV, Moser, AB. “Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long chain fatty acid screening”. J Pediatr. vol. 46. 15005. pp. 528-32. (This article describes the high prevalence of unrecognized adrenocortical insufficiency in asymptomatic boys with X-ALD.)

Loes, DJ, Fatemi, A, Melhem, ER. “Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy”. Neurology. vol. 61. 2003. pp. 369-74. (The Loes score is a 34-point MRI scoring system for cerebral ALD that has become an important parameter for treatment decisions in X-linked adrenoleukodystrophy.)

Mahmood, A, Raymond, GV, Dubey, P. “Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study”. Lancet Neurol. vol. 6. 2007. pp. 687-92. (The study supports the use of bone marrow transplantation in the early stages of cerebral ALD and provides evidence that boys who undergo transplantation at this stage do better than if left untreated.)

Martin, PL, Carter, SL, Kernan, NA. “Results of the cord blood transplantation study (COBLT): outcomes of unrelated donor umbilical cord blood transplantation in pediatric paients with lysosomal and peroxisomal storage diseases”. Biol Blood Marrow Transplant. vol. 12. 2006. pp. 184-94.

Moer, HW, Mahmood, A, Raymond, GV. “X-linked adrenoleukodystrophy”. Nat Clin Pract Neurol. vol. 3. 2007. pp. 140-51.

Moser, HW, Raymond, GV, Dubey, P. “Adrenoleukodystrophy: new approaches to a neurodegenerative disease”. JAMA. vol. 294. 2005. pp. 3131-4.

Moser, HW, Raymond, GV, Lu, SE. “Followup of 89 asymptomatic patients with adrenokeukodystrophy treated with Lorenzo's oil”. Arch Neurol. vol. 62. 2005. pp. 1073-80. (The paper presents a single-arm study that demonstrates the efficacy of Lorenzo's oil in reducing the risk for the development of brain lesions in asymptomatic boys with ALD who have normal brain MRI scans.)

Peters, C, Charnas, LR, Tan, Y. “Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999”. Blood. vol. 104. 2004. pp. 881-4. (This comprehensive study summarizes the international experience and describes the ability of hematopoietic stem cell transplantation to arrest disease progression. The study delineates morbidity and risks associated with transplantation and shows that patients who receive matched sibling donor bone marrow do better than those who receive unrelated donor bone marrow. Overall, boys with a Loes score of 9 or less before transplantation have a much higher survival rate than those with a Loes score of greater than 9.

Are there ongoing controversies regarding etiology, diagnosis, treatment?

Controversy exists over the exact mechanism by which bone marrow transplantation exerts its beneficial effect. Similarly, other cell-based therapies, such as gene therapy, remain to be explored. Future trials are awaited to demonstrate the utility of gene therapy. Other treatment modalities, such as Lorenzo’s oil, are effective only in the presymptomatic stages.