c) Parametri clinici e storiografia terapeutica delle leucodistrofie


i) ADRENOLEUCODISTROFIA
(ADRENOLEUKODYSTROPHY)


DEFINITION:

A disorder of peroxisomes transmitted as a X-linked trait characterized by the accumulationof 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: 
      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