Ailments & Illness > Adrenoleukodystrophy (ALD)

Adrenoleukodystrophy (ALD) To Read:

ADRENOLEUKODYSTROPHY

DEFINITION:

A disorder of peroxisomes transmitted as a X-linked trait characterized by the accumulation of saturated very long chain fatty acids (VLCFA) resulting in the progressive dysfunction of CNS white matter and the adrenal cortex.

If diagnosed early enough, disease can be prevented and cured with Lorenzo's Oil:

• 4 parts GTO: 1 part GTE
• VLCFA-restricted diet with Lorenzo's Oil may normalize C26:0 levels within 4 weeks
• normalizes RBC membrane microviscosity

 

EPIDEMIOLOGY:

• incidence: 1/100,000
• age of onset:
  • 4 to 8 years of age
• risk factors:
  • familial - x-linked recessive
    • chrom. #: Xq28 (terminal segment)
    • gene: ? lignoceroyl-CoA ligase (peroxisomal enzyme)

MANAGEMENT:

1. Neurologic Manifestations

1. Behavioural

• comprehensive management programme, special education

2. Medical

• soft diet -> pureed foods -> gastrostomy for loss of bulbar muscular control

3. Diet

1. Goals

• to decrease the exogenous source of VLCFA - food sources of fats, cholesterol, grains, nuts, fruits and vegetable skins, milk -> very restrictive diet
• to decrease the endogenous production of VLCFA with the ingestion of monounsaturated VLCFA's

2. Glyceryl Trierucate Oil (GTO)

• 90% oleic acid (C18:1) found naturally in olive oil, corn oil, sunflower seed oil
• ingestion results in a decrease in VLCFA's by 50% in 4 months

3. Glyceryl Trioleate Oil (GTE)

• erucic acid (C22:1) - found naturally in rapseed oil

4. Lorenzo's Oil

• 4 parts GTO: 1 part GTE
• VLCFA-restricted diet with Lorenzo's Oil may normalize C26:0 levels within 4 weeks
• normalizes RBC membrane microviscosity

PATHOGENESIS/PATHOLOGY:

1. Peroxisomes

1. Structure

• intracellular organelles
• present in all cells except mature erythrocytes, especially in those that specialize in lipid metabolism
• abundant in:
  • neurons during the first two postnatal weeks
  • oligodendroglial processes forming myelin shealths during active myelination

2. Function

• contain enzymes (40) necessary for cellular metabolism
  • enzymes catalyzing the beta-oxidation of VLCFA
  • enzymes catalyzing the synthesis of plasmalogen
  • decomposition of hydrogen peroxide (catalase)

2. X-linked Adrenoleudodystrophy

• considered to be a disorder of lipid metabolism and particularly the peroxisomes; also considered a storage disorder
• deficiency in the peroxisomal enzyme that catalyzes the formation of Co-A derivatives of VLCFA (lignoceroyl-CoA ligase) results in the accumulation of saturated, unbranched VLCFA in the rER of tissues throughout the body, particularly hexacosanoic (C26:0), pentacosanoic (C25:0), tetracosanoic (C24:0)
• the genetic defect may not be due to a mutant ligase gene but instead due to a deficiency in a peroxisomal membrane protein needed to import the ligase into the peroxisome (ATP-binding transporter protein)
• particularly affected is the:

  1. Adrenal Cortex

  • zona fasciculata distended with abnormal lipids accumulation of VLCFA results in:
    • limited capacity to convert cholesterol -> active steroids
    • increased viscosity of the plasma membrane -> receptor dysfunction

  2. CNS White Matter

  • acute and symmetric demyelinating lesions
  • perivascular infiltration of lymphocytes
  • at least 1/3 of patients with ALD are free of neurol. manifestations and thus CNS involvement may depend upon some factor other than VLCFA accumulation
  • considered one of the degenerative diseases of white matter of the cerebral cortex

CLINICAL FEATURES:

1. Male Phenotypes (6)

• 48% - Childhood ALD
• 26% - Adrenomyeloneuropathy
• 10% - Addison Disease Only
• 8% - Presymptomatic/Asymptomatic
• 5% - Adolescent Cerebral ALD
• 3% - Adult Cerebral ALD

2. Female Phenotypes (2)

• 85-95% - Asymptomatic
• 10-15% - Adrenomyeloneuropathy - late onset, less severe

3. Childhood ALD

• age of onset: 4-8 years (mean = 7.2 years, as early as 2 years)
• affected children develop normally up until 3-4 years of age

1. Neurologic Manifestations

1. Presenting Symptoms

• hyperactivity (most common)
• impaired auditory discrimination - difficulties with speech in a noisy room or over the telephone (retain pure tone perception)
• parietal lobe dysfunction - construction & dressing apraxia, astereognosis, graphesthesia, impaired spatial orientation
• visual disturbances - field cuts, strabismus, visual acuity
• focal or generalized seizures (33%)
• others: ataxia, poor handwriting, subtle changes in affect, behaviour, & attention span, increased ICP, dementia

2. Later Symptoms

• tends to progress rapidly with increased spasticity and paralysis, visual and hearing loss, and bulbar musculature dysfunction (loss of ability to speak +/- swallow), cognitive loss -> vegetative state
• mean interval between onset of neurologic symptoms and the vegetative state is 1.9 +/- 2 years
• may continue in vegetative state for >10 years

2. Endocrine Manifestations

• primary adrenal insufficiency
  • FTT, nausea & vomiting, postural hypotension, weakness, weight loss, salt craving
  • mild hyperpigmentation (over joints, scar tissue, lips, nipples, buccal mucosa)
  • usually present after the neurologic manifestations

4. Adolescent Cerebral ALD

• age of onset: 10-21 years
• the neurologic and endocrine manifestations are the same as in the childhood cerebral ALD form except with a slower progression

5. Adrenomyeloneuropathy

• age of onset: late adolescence or adulthood

1. Neurologic Manifestations

• progressive spastic paraparesis and sphincter disturbance due to long-tract degeneration in the spinal cord and peripheral nervous system
• 33% have CNS white matter involvement
• 10-15% of female heterozygotes (carriers) develop neurologic disturbances resembling adrenomyeloneuropathy
• progressive loss over 5-15 years without cognitive loss

2. Endocrine Manifestations

• 90% have varying degrees of adrenal insufficiency

INVESTIGATIONS:

1. Serum

1. VLCFA

• very high levels of VLCFA in the plasma, RBC, and cultured skin fibroblasts is diagnositic:
• positive in 100% of affected males
• positive in 85% of carrier females
• high levels of C26
• abnormal ratio of C26:C22 and C24:C22 fatty acids
• 15% of obligate carriers will test within the normal range

2. Adrenal Insufficiency

• hyponatremia, hyperkalemia, mild metabolic acidosis
• low serum cortisol level with elevated ACTH levels
• impaired cortisol response to ACTH stimulation in 85%

2. Imaging Studies - CT/MRI

1. Cerebral White Matter Lesions (80%)

• even in the early stages, striking changes may be found
• characteristic with two types of features:
• low-attenuation lesions
  • represent symmetrical areas of degeneration or demyelination
  • involve the periventricular white matter in the posterior parietal and occipital lobes (peritrigonal)
  • also involved are the corticospinal tracts, corpus callosum, medial/lateral geniculate bodies, thalamus
  • in 12% the initial lesions are in the frontal lobes
  • affected white matter may also be calcified
• high-attenuation lesions
  • zones of intense perivascular lymphocytic infiltration where the blood-brain barrier breaks down

3. Perinatal Diagnosis

• elevated VLCFA in cultured amniocytes or chorionic villus cells
• carrier identification
• VLCFA assay identifies 85% of carrier females
• DXS-52 polymorphic DNA probe

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