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.
EPIDEMIOLOGY:
- incidence: 1/100,000
- age of onset:
- risk factors:
- familial - x-linked recessive
- chrom. #: Xq28 (terminal segment)
- gene: ? lignoceroyl-CoA ligase (peroxisomal enzyme)
PATHOGENESIS/PATHOLOGY:
- 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:
- 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:
- 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
- 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
- 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:
- 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
- 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
MANAGEMENT:
- oral glucocorticoid (cortisone acetate)
- oral mineralocorticoid (fludrocortisone)
- increase at times of illness, trauma, surgery
- does not tend to influence the course of the disease
- test adrenal function regularly i.e., yearly
2. Neurologic Manifestations
- comprehensive management programme, special education
2. Medical
- beclofen for acute episodes of painful muscle spasms
- anticonvulsants for seizure activity
- chloral hydrate for changes in sleep-wake cycle
- soft diet -> pureed foods -> gastrostomy for loss of
bulbar muscular control
3. Diet
- 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
4. Bone Marrow Transplant
- experimental
- poor results in severe cases and mild results in those
less severely affected
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