RECOGNISE. MEASURE. CONSULT.

Could it be adrenoleukodystrophy (ALD)?

When we identify a child with adrenal insufficiency, if that child is a boy, one of the first things that we should think about is ALD

BRADLEY MILLER, MD, PhD Paediatric endocrinologist

ALD, adrenoleukodystrophy

Developed, sponsored and funded by bluebird bio. (Switzerland) GmbH

Patients are actor portrayalsPhysician is a paediatric endocrinologist

• Although ALD primarily affects males, it is possible for females to develop symptoms of the disease in adulthood6

• ALD has been reported in all ethnic backgrounds6

• ALD consists of a spectrum of phenotypes, which may overlap throughout the lifetime of a patient 1

As part of the initial evaluation of preadolescent boys with primary adrenal insufficiency, the Endocrine Society Clinical Practice Guidelines recommend screening for elevated very long–chain fatty acid (VLCFA) levels in plasma in order to detect the possibility of ALD2

ALD is caused by mutations in the ABCD1 gene that result in deficiency of the peroxisomal protein called the adrenoleukodystrophy protein (ALDP).6 This leads to accumulation of VLCFAs in plasma and tissue – primarily of the nervous system and adrenal glands.6 Genetic testing can help confirm the diagnosis of ALD6

Preliminary results suggest an approximate incidence rate in males of 1:30,000, with no major differences between countries worldwide5

Know how to recognise and manage patients who may have ALD

ABOUT ALD

The underlying cause of ALD is a genetic mutation6

ALD is a rare genetic disease that can progress to cerebral ALD; both are serious and life-threatening conditions3,4

An early diagnosis of ALD can save lives1

Xp22.32

Xp22.2

Xp22.12Xp21.3

Xp21.1

Xp11.3

Xp11.22

Xq12

Xq13.2

Xq21.1

Xq21.31

Xq21.33

Xq22.2

Xq23

Xq25

Xq26.2

Xq27.1

Xq27.3

Xq28(ABCD1 gene)7

ALD, adrenoleukodystrophy; ALDP, adrenoleukodystrophy protein; VLCFA, very long-chain fatty acid

2

Even among members of the same family, it is currently not possible to predict the future phenotype of a boy with ALD without monitoring3,6

3

In order to diagnose and address ALD in your patients with adrenal insufficiency, remember these 3 steps:

Identifying and managing ALD

1RECOGNISE

2MEASURE

3CONSULT

ALD, adrenoleukodystrophy

4

86%Up to

• Fatigue

• Loss of appetite

80% to 86% of boys diagnosed with ALD also have adrenal insufficiency9,a

While adrenal insufficiency can initially present as early as 5 months of age, on average, patients

are 4 to 5 years of age at presentation9,a

Some of the symptoms of ALD are associated with other conditions, such as Addison’s disease, creating difficulty in diagnosis8

Adrenal insufficiency is often the first symptom of ALD2

1 RECOGNISE THE LINK

SYMPTOMS ASSOCIATED WITH ADRENAL INSUFFICIENCY INCLUDE:2

• Hyperpigmentation of skin or gums

• Abdominal pain

aThese data are from a study conducted in the USA and may not be fully representative of the local populationALD, adrenoleukodystrophy

5

%40

The Endocrine Society Clinical Practice Guidelines recommend measuring VLCFA levels in plasma in order to diagnose ALD as part of the evaluation of preadolescent boys with primary adrenal insufficiency2

Endocrinologists may have the opportunity to identify the first signs of ALD. An early diagnosis of ALD could save a life1

In most patients, cerebral ALD is a rapidly progressing disease that causes progressive behavioural, cognitive and neurological deficits, and total disability followed by death, often within 5 years after onset of symptoms11,12

Approximately 40% of boys with ALD develop a severe, progressive and life-threatening neurodegenerative form of the disease known as cerebral ALD10,a

2 MEASURE VLCFA LEVELS IN PLASMA

3 CONSULT WITH AN ALD SPECIALIST

Early detection is possible, as increased levels of plasma VLCFAs are indicative of ALD10

If you confirm ALD, consult with and refer the patient to an ALD specialist for the best possible outcomes1

aThese data are from a study conducted in the USA and may not be fully representative of the local populationALD, adrenoleukodystrophy; VLCFA, very long-chain fatty acid

A neurologist with expertise in ALD, or another ALD specialist partner, can identify changes in the brain that are indicative of progression to cerebral ALD1

6

ALD, adrenoleukodystrophy; MRI, magnetic resonance imaging

• White matter changes on magnetic resonance imaging (MRI) precede the onset of symptoms, so MRI monitoring is critical, as it can detect progression to cerebral ALD before any symptoms arise1,6

• Symptoms of progression to cerebral ALD may mimic conditions like attention deficit hyperactivity disorder (ADHD) or autism, which can delay diagnosis1,6

• Patients should be assessed by an integrated team, including an endocrinologist and a neurologist1,6,11,12

An endocrinologist will provide:

• Regular adrenal assessments11 and referral to a neurologist or metabolic specialist

• Ongoing management of treatment for adrenal symptoms11

A neurologist will provide:

• Regular MRIs to monitor for changes in the brain indicative of cerebral progression1,12

• Consultations on management if progression to cerebral ALD is detected

• Broader access to specialised resources that can help boys and families manage ALD

If left undiagnosed and unmanaged, progression of cerebral ALD is rapid, causing severe loss of neurological functions and death10

Roles of the ALD care team

Cerebral ALD causes progressive loss of:10

Progression from ALD to cerebral ALD involves severe inflammatory demyelination of nerve cells in the brain12

MONITORING FOR CEREBRAL ALD

Cognition Vision Hearing Motor function

Progression of cerebral ALD causes severe neurological dysfunction; therefore, referral and monitoring by an integrated ALD care team is important for early identification and subsequent management1,11,12

ALD, adrenoleukodystrophy; VLCFA, very long-chain fatty acid

Once we have a positive VLCFA test, then we need to make the referral to determine ALD and start monitoringBRADLEY MILLER, MD, PhD Paediatric endocrinologist

7

8

ALD, adrenoleukodystrophy; MRI, magnetic resonance imaging

Studies support MRI evaluation at the earliest possible opportunity – ideally before symptoms of cerebral involvement appear in boys with ALD1,12

A neurologist or other ALD specialist will conduct vigilant MRI monitoring to help in timely identification of life-threatening cerebral ALD1

CURRENT GUIDANCE RECOMMENDS AN MRI ANNUALLY UNTIL AGE 3, EVERY 6 MONTHS BETWEEN

AGES 3 AND 12, AND ANNUALLY THEREAFTER12

Once a child has been diagnosed with ALD, it’s important that they see a neurologist for screening for brain changes that are part of the disease

BRADLEY MILLER, MD, PhD Paediatric endocrinologist

Early diagnosis of ALD, along with regular monitoring, can help ALD specialists manage the condition in cases where cerebral involvement is identified, before it leads to severe and irreversible brain damage1

9

10

Clinicians can help families of children diagnosed with ALD or cerebral ALD find additional support by connecting them to patient organisations, including advocacy groups

aldconnect.org

leukodystrophyalliance.org

These organisations provide education and support to those whose lives are affected by ALD – their work is crucial and commendable

Advocacy organisations support clinicians and provide resources for patients and caregivers

There are organisations that are here to help.For more information, visit www.ItMightBeALD.eu

theglia.org

ALD, adrenoleukodystrophy

PATIENT SUPPORT

11

References: 1. Moser HW, Mahmood A, Raymond GV. X-linked adrenoleukodystrophy. Nat Clin Pract Neurol. 2007;3(3):140-151. 2. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364-389. 3. Bezman L, Moser AB, Raymond GV, et al. Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. Ann Neurol. 2001;49(4):512-517. 4. Miller WP, Rothman SM, Nascene D, et al. Outcomes after allogenic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood. 2011;118(7):1171-1178. 5. Wiesinger C, Eichler FS, Berger J. The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis. Appl Clin Genet. 2015;8:109-121. 6. Kemp S, Huffnagel I, Linthorst GE, et al. Adrenoleukodystrophy – neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016;12(10):606-615. 7. NIH U.S. National Library of Medicine. ABCD1 gene: chromosomal location. https://ghr.nlm.nih.gov/gene/ABCD1#location. Accessed 16 August 2019. 8. Laureti S, Casucci G, Santeusanio F, et al. X-linked adrenoleukodystrophy is a frequent cause of idiopathic Addison’s disease in young adult male patients. J Clin Endocrinol Metab. 1996;81(2):470-474. 9. Dubey P, Raymond GV, Moser AB, et al. Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long-chain fatty acid screening. J Pediatr. 2005;146(4):528-532. 10. Engelen M, Kemp S, Poll-The B-T. X-linked adrenoleukodystrophy: pathogenesis and treatment. Curr Neurol Neurosci Rep. 2014;14(486):1-8. 11. Mahmood A, Dubey P, Moser HW, Moser A. X-linked adrenoleukodystrophy: therapeutic approaches to distinct phenotypes. Pediatr Transplant. 2005;9(Suppl 7):55-62. 12. 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.

VISIT www.ItMightBeALD.eu TO LEARN MORE

In boys with adrenal insufficiency, it might be ALD

1RECOGNISE

THE LINKFatigue, loss of appetite,

hyperpigmentation of skin or gums, or abdominal pain might point to adrenal insufficiency, which may be caused by ALD2

2MEASURE VLCFA LEVELS IN PLASMA

Measurement of VLCFAs is critical in aiding the early detection of ALD, which is

necessary for the prevention of irreversible brain damage10

3CONSULT WITH

AN ALD SPECIALISTAn ALD specialist, like

a neurologist, can monitor for cerebral involvement

of the disease and provide appropriate care1,12

ALD, adrenoleukodystrophy; VLCFA, very long-chain fatty acid

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