CASE STUDYZoe PortlasBIOC460

■A couple brought their 7 year old son to the doctor.

■The boy had been developing normally and had done well in 1st grade, but now in 2nd grade, he is having issues concentrating, temper tantrums, and hyperactivity. Recently, he has had trouble listening to teachers and doesn’t seem to hear his parents when they ask him things.

■A hearing test shows hearing loss.■The doctor does a blood test.■The results show higher than normal levels

of Very Long Chain Fatty Acids (VLCFA).■She suspects a diagnosis, but needs to

confirm by checking for genetic abnormalities.

■This confirms that the boy has a mutation in the ABCD1 gene on his X chromosome.

Diagnosis■Symptoms: Hyperactivity, tantrums, trouble

listening, loss of concentration■Test results: Hearing loss, elevated VLCFA in blood,

mutation at the ABCD1 gene on the X chromosome.

Childhood Adrenoleukodystrophy (ALD)

ALD■Affects 1 in 18,000 people (about 400,000

people worldwide)■X-linked, so mostly affects men and boys.

Heterozygous women may show mild symptoms late in life

■45% of cases are male patients with onset between the ages of 4 and 10. Childhood ALD is the most severe.

Impact■Very rare (less than 1%)■Childhood form has prognosis of only 2 to 5

years■Progressive neurological decline leads to coma

and death■No cure■Few treatment options

What causes ALD?■Defective β-oxidation from

ABCD1, an ATP-binding-cassette transporter that is located in the peroxisomal membrane.

■Accumulation of VLCFA in brain and adrenal glands causes demyelination and the loss of white matter, leading eventually to dementia. A healthy brain (left) and a brain of a boy

with ALD showing loss of white matter (right)(http://www.x-ald.nl/treatment-options/hsct/)

ABCD1 ■ β-oxidation in peroxisomes break down fatty acids, such

as Very Long Chain Fatty Acids

Normal oxidation of fatty acidsThe Cell: A Molecular Approach. 2nd edition.Cooper GM.Sunderland (MA): Sinauer Associates; 2000.

• In ALD, ABCD1 (ALDP) can’t bring VLCFA into peroxisomes

The Biomolecule: Very Long Chain Fatty Acids■ Very Long Chain Fatty Acids are naturally occurring fatty

acids that are elongated in the body and consumed in the diet.

■ VLCFAs are a normal part of the brain, including myelin sheaths, which insulate nerve axons.

Cerotic acid

■ Very hydrophobic because of the long fatty acid tail.

■ Toxic to cells at high levels.

■ The most common VLCFA in ALD cases is cerotic acid (26:0).

VLCFAs and Myelin

■ VLCFAs can disrupt membrane structure because of their hydrophobicity and can cause depolarization of mitochondria, oxidative damage to proteins, and apoptosis of oligodendrocytes in the CNS, which produce the myelin sheath.

Oligodendrocyte function Public Domain, https://commons.wikimedia.org/w/index.php?curid=10888009

Treatments: Lorenzo’s Oil■ VLCFAs are produced in the body

through fatty acid elongation■ Elongase is the enzyme that

elongates fatty acids and has a higher affinity for monounsaturated long-chain fatty acids

■ The introduction of oleic acid (C18:1) and erucic acid (C22:1) along with dietary restrictions of VLCFAs lower VLCFA levels by 60% by successfully competing for elongase activity.

■ Downsides: Lower efficacy in brain, may not prevent damage because of the blood-brain barrier

Oleic acid (top) has one double bond at C-9 and erucic acid (bottom) has one at C-13

Treatments: Bone Marrow Transplant■ Stem cells are infused

intravenously.■ Donor stem cells have

a functioning ABCD1 gene that produces the protein patients cannot produce. The donor cells can perform β-oxidation on VLCFAs in the patient’s body.

■ Most effective at stabilizing patients who show no or very few neurological symptoms.

Survival difference by year for patients with and without bone marrow transplants. (Mahmood, et al. 2007)

Treatments: Adrenal steroids■The adrenal cortex is also

damaged by ALD■In a study of boys without

neurological symptoms yet showed that 80% already had adrenal cortex damage

■Insufficiency requires lifelong management with glucocorticoids and mineralglucocorticoids

Location of the adrenal glandshttp://www.x-ald.nl/treatment-options/the-adrenal-gland/

Prevention■The only way to prevent ALD is through

genetic testing to determine if a woman who wants to have a child is a carrier of an ABCD1 mutation.

■Onset cannot be prevented or delayed in boys that have an ABCD1 mutation with Lorenzo’s oil

References■ http://www.ninds.nih.gov/disorders/adrenoleukodystrophy/adrenoleuko

dystrophy■ http://bmt.umn.edu/adrenoleukodystrophy-ald■ http://www.aldconnect.org/new_diagnosis.php■ http://www.stopald.org■ http://www.x-ald.nl/biochemistry-genetics/vlcfa/■ http://www.myelin.org■ http://onlinelibrary.wiley.com/doi/10.1016/0014-5793(86)80256-3/pdf