c) Parametri clinici e storiografia terapeutica delle leucodistrofie
i) ADRENOLEUCODISTROFIA
(ADRENOLEUKODYSTROPHY)
DEFINITION:
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)
PATHOGENESIS/PATHOLOGY:
1. Peroxisomes
1. Structure
intracellular organelles present in all cells except
mature erythrocytes, especially in those that specializein
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; alsoconsidered 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 adeficiency 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
MANAGEMENT:
1. Adrenal Insufficiency
1. Steroid Replacement
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
1. Behavioural
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
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 4weeks
normalizes RBC membrane microviscosity
4. Bone Marrow Transplant
experimental
poor results in severe cases and mild results in those
less severely affected