Picture of the Month—Diagnosis | Endocrinology | JAMA Pediatrics | JAMA Network
[Skip to Navigation]
Sign In
Citations 0
Special Feature
January 4, 2010

Picture of the Month—Diagnosis

Arch Pediatr Adolesc Med. 2010;164(1):98. doi:10.1001/archpediatrics.2009.245-b

Denouement and Discussion: Adrenoleukodystrophy and Adrenomyeloneuropathy

Laboratory evaluation revealed a fasting cortisol level of 3 μg/dL, a 60-minute cosyntropin-stimulated cortisol level of 3.5 μg/dL, an 8 AMcorticotropin level of 7240 pg/mL, plasma renin activity of 955 ng/ dL/h, a serum aldosterone of 3 ng/dL, a testosterone level of 562 ng/dL, follicle-stimulating hormone of 3.3 mIU/mL, luteinizing hormone 14 mIU/mL, and elevated very-long-chain fatty acid (VLCFA) levels. Magnetic resonance imaging of the brain revealed an enhancing lesion in the left limb of the internal capsule extending into the corticospinal tract and a focus of abnormal signal in the left globus pallidus. Magnetic resonance imaging of the spine revealed diffuse atrophy of the cervical and thoracic cord without any enhancement.

Adrenoleukodystrophy is an X-linked disorder of VLCFA metabolism with an estimated incidence of 1 in 21 000 males.1The defective gene (ABCD1), located on chromosome Xq28, codes for a peroxisomal membrane protein responsible for forming the channel through which VLCFA moves into peroxisomes. Mutations in this gene impair channel formation, leading to VLCFA accumulation. The adrenal cortex, Leydig cells in the testes, and the central nervous system are the most severely affected. The overabundance of cholesterol-esterified VLCFA is resistant to corticotropin stimulation and can only be weakly converted into steroids, resulting in adrenal insufficiency.

Three types of adrenoleukodystrophy (ALD) can be seen in childhood: childhood cerebral form, adolescent ALD, and adrenomyeloneuropathy (AMN). The childhood cerebral form usually presents between 4 and 8 years of age with hyperactivity, often leading to the misdiagnosis of attention-deficit/hyperactivity disorder. Other neurological findings include difficulty hearing, vision problems, ataxia, poor handwriting, and seizures.2Adolescent ALD manifests with neurologic symptoms between the ages of 10 and 21 years. The phenotype is similar to the childhood cerebral form but progresses slower. Adrenomyeloneuropathy typically presents in young adulthood but can present in adolescence3with progressive paraparesis secondary to degeneration of the long tracts in the spinal cord. Approximately half of girls who are carriers will develop a mild syndrome similar to AMN but later in life.4

The central nervous system can be affected in 2 different ways. In the severe childhood cerebral form and the rapidly progressive adult forms of ALD, there is perivascular lymphocytic infiltration of the parieto-occipital white matter. In AMN—the slow, progressive adult form—there is loss of myelinated axons in the corticospinal tracts, nucleus gracilis, and dorsal spinocerebellar tracts. Sural and peroneal nerves reveal a loss of myelinated fibers.5

Diagnosis is made by identifying abnormally high levels of VLCFA in the plasma, red blood cells, or skin fibroblasts and mutation analysis for the defective gene. Elevated baseline corticotropin and abnormal rise in cortisol after corticotropin stimulation are also found in most cases, especially in the childhood form. Any male who presents with Addison disease should have his VLCFA levels tested to rule out ALD as the underlying etiology.6,7

Corticosteroid (hydrocortisone) replacement prevents life-threatening complications of adrenal insufficiency; affected children may require stress-dose steroids when ill. Aldosterone deficiency is treated with fludrocortisone acetate, a salt-retaining hormone.

Bone marrow transplant has been used in young boys and adolescents in the early stage of the cerebral form. Lorenzo's oil (a 4:1 mixture of glyceryl trioleate and glyceryl trierucate) received fame in 1992 through a film of the same name, which featured the journey of an affected boy's parents, who discovered their own treatment for the disease. When Hugo Moser, MD, the world expert on ALD, published data in 2005, it became clear that while the oil may not help already sick boys,8it is beneficial in delaying or preventing the onset of symptoms in neurologically asymptomatic boys younger than 8 years with normal magnetic resonance imaging results.9

It is important to identify all at-risk male family members and possible female carriers and to test them for VLCFA levels and/or with mutational DNA analysis. We counseled the family regarding the X-linked inheritance pattern and 50% risk to future males, prenatal diagnostic options, and at-risk relatives, and tested the at-risk males in our patient's immediate family (males 4 and 5 in Figure 2). They had normal VLCFA levels.

Figure 2. 
Patient's family pedigree.

Patient's family pedigree.

Return to Quiz Case.

Correspondence:April O. Buchanan, MD, Department of Pediatrics, Children's Hospital, Greenville Hospital System University Medical Center, University of South Carolina School of Medicine, 701 Grove Rd, 4th Floor Balcony Suites, Greenville, SC 29605 (abuchanan@ghs.org).

Accepted for Publication:July 27, 2009.

Author Contributions:Study concept and design: Buchanan and Quintos. Acquisition of data: Burke, Buchanan, Gambosova, Harappanahally, and Quintos. Analysis and interpretation of data: Buchanan, Shur, Harappanahally, and Quintos. Drafting of the manuscript: Burke, Buchanan, Shur, and Quintos. Critical revision of the manuscript for important intellectual content: Buchanan, Shur, Gambosova, Harappanahally, and Quintos. Administrative, technical, and material support: Buchanan, Shur, and Quintos. Study supervision: Buchanan, Harappanahally, and Quintos.

Financial Disclosure:None reported.

Bezman  LMoser  ABRaymond  GV  et al.  Adrenoleukodystrophy.  Ann Neurol 2001;49 (4) 512- 517PubMedGoogle ScholarCrossref
Kliegman  RBehrman  REHenson  HBStanton  B Nelson Textbook of Pediatrics.  Philadelphia, PA W.B. Saunders Co2007;577- 578
Moser  HWMoser  ABSmith  KD  et al.  Adrenoleukodystrophy: phenotypic variability and implications for therapy.  J Inherit Metab Dis 1992;15 (4) 645- 664PubMedGoogle ScholarCrossref
Moser  HW Adrenoleukodystrophy.  Brain 1997;120 (pt 8) 1485- 1508PubMedGoogle ScholarCrossref
Swaiman  KFAshwal  SFerriero  D Pediatric Neurology: Principles and Practice.  Philadelphia, PA Mosby2006;29746
Laureti  SCasucci  GSanteusanio  FAngeletti  GAubourg  PBrunetti  P 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- 474PubMedGoogle Scholar
Sadeghi-Nejad  ASenior  B Adrenomyeloneuropathy presenting as Addison's disease in childhood.  N Engl J Med 1990;322 (1) 13- 16PubMedGoogle ScholarCrossref
Lerner  BH Complicated lessons.  Lancet 2009;373 (9667) 888- 889PubMedGoogle ScholarCrossref
Moser  HWRaymond  GVLu  SE  et al.  Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo's oil.  Arch Neurol 2005;62 (7) 1073- 1080PubMedGoogle ScholarCrossref