X-Linked Adrenoleukodystrophy (XLA)

A disorder characterized by progressive demyelinization of the central nervous system and peripheral adrenal insufficiency resulting from adrenal gland atrophy.

Adrenomyeloneuropathy; Addison Disease and Cerebral Sclerosis; Siemerling-Creutzfeldt Disease; Bronze Schilder Disease; Melanodermic Leukodystrophy.

Genetic disorder, mainly affecting males but 50% of female heterozygotes have symptoms.

1:15,000 to 1:100,000 in general population.

X-linked with six phenotypes, classified according to age of onset, organ involvement, and neurological progression rate. Most common form: X-adrenoleukodystrophy childhood form: (most severe); second most common form: adrenomyeloneuropathy. Gene locus is the long arm of X chromosome at position 28 (Xq28), which codes for an 80-kDa transmembrane transporter protein. Mutation can be missense, frameshift, nonsense, or deletion. This is distinct from neonatal adrenoleukodystrophy (autosomal recessive).

Very-long-chain fatty acids (VLCFA) are metabolized by VLC acyl-CoA synthetases in peroxisomes or mitochondrion. Adrenoleukodystrophy gene mutation may impair the peroxisomal import of this synthetase, leading to VLCFAs (>C22) accumulation. It is uncertain whether these long, rigid, acyl fatty acids reduce membrane fluidity, causing an inflammatory response in the nervous system (demyelination), and reduce steroid synthesis in the adrenal glands.

Clinical course with demyelinization signs and association of peripheral adrenal insufficiency in 80% of children forms and 65% of adult forms. Diagnosis is confirmed by abnormally high saturated VLCFAs and C26:C22 ratio in blood or accessible tissues. Radiologic imaging reveals symmetrical hypodense corpus callosum and periventricular white matter. Prenatal (chorion villus biopsy) and female heterozygotes (VLCFA profiles) diagnosis available.

X-adrenoleukodystrophy childhood form: normal childhood development until a mean age of 7 years, followed by parietal-occipital demyelination with rapidly progressive dementia, behavioral changes, visual/auditory defect, and seizures; 90% of patients have an adrenal insufficiency. Average life span is 9.4 years. Adrenomyeloneuropathy: milder form with adult onset. Spinal cord involvement (paraparesis/sphincter problems) is more common than cerebral (50% of cases) or adrenal (30% of cases) dysfunction. Female heterozygotes: similar clinical picture as adrenomyeloneuropathy; however, presenting normal adrenal glands (99% of cases). Often misdiagnosed as multiple sclerosis.

Evaluate the neurological status for evidence of cerebral and spinal demyelination (clinical, EEG, CT/MRI, nerves velocity). Determine if adrenal dysfunction is present and adequately treated. Blood examination: electrolytes, cell blood count, glucose, cortisol levels.

N.B: Thrombocytopenia is often observed in patients treated with Lorenzo's oil (40% of cases). As well, the use of this oil may cause significant cardiac dysfunction.

Rapid sequence induction is indicated if airway reflexes are impaired. The presence of dementia as a result of neuronal demyelination may make the patient sensitive to opioids. Regional anesthesia can be difficult (scoliosis) or contraindicated (thrombocytopenia). Osteoporosis (hypogonadism) calls for careful intraoperative positioning.

Succinylcholine should be avoided in the presence of spinal cord compression or acute demyelination. Hypnomidate should also be omitted (depresses adrenal function). Meperidine, ketamine, sevoflurane and enflurane are relative contraindications if seizures are present. Doses and/or concentrations must be carefully selected. Additional steroid stress doses are essential. Consider interaction between anesthetic drugs and antiepileptic treatment.

Neonatal Adrenoleukodystrophy: Inherited as an autosomal recessive pattern and rapidly progressive. Both males and females are affected. The abnormalities of the brain and adrenal glands seem different from those caused by other types of adrenoleukodystrophies. Characteristically, the first symptoms begin at birth or shortly after. Mental retardation; facial abnormalities; seizures; polymicrogyria; retinal degeneration; hypotonia; hepatomegaly; and/or adrenal insufficiency. In this form of adrenoleukodystrophy, the demyelinization can affect the gray matter within the spinal cord. Hepatic peroxisomes may be absent or decreased in number in the liver. The concentration of pipecolic acid may be increased in the plasma. Patients with only one of the pair of genes for this disorder typically have no neurological or adrenal symptoms.

Alexander Syndrome: A degenerative and progressive disorder of the nervous system caused by leukodystrophy. Affects mainly males and usually begins at about 6 months of age. Symptoms include mental and physical retardation, enlargement of the brain and head, spasticity (arms and legs), and seizures.

Addisonian Syndrome: Rare disorder associated with chronic and progressive hypofunction of the cortex of the adrenal gland resulting in hypocortisolemia and hypoaldosteronemia. Electrolyte imbalance is the most important consequence of this disease. Hypotension and severe intravascular dehydration can be present if not detected early. The main characteristics are fatigue, weakness, anorexia, frequent diuresis, gastrointestinal discomfort, and changes in skin pigmentation.

Canavan Syndrome: Another type of leukodystrophy that affects the central nervous system. Progressive degeneration of nerves within the brain and spinal cord is characteristic of this disorder. The symptoms begin in infancy and are characterized initially by apathy, hypotonia and the loss of previously acquired mental and motor skills and subsequently by hypertonia, spasticity of the arms and legs, poor head control because of lack of muscle atrophy in the neck, megalocephaly, and blindness. Megalocephaly might be present resulting in the development of craniosynostosis and hydrocephaly. The infant may be more susceptible to respiratory tract infections because of the progressive loss of muscle strength in the chest.

Metachromatic Leukodystrophy: Rare, inherited form of leukodystrophy described as the accumulation of fat-like substances (sulfatides) in the nervous system and other organs. It is characterized by severe nerve demyelinization. Blindness, seizures, hypertonia, spasticity, paralysis, and dementia are reported. There is an infantile, juvenile, and adult form. The infantile form is generally detected in the 2nd year of life, typically before 30 months of age. The juvenile form has an onset between the ages of 4 and 10 years. The adult usually begins after 16 years of age.

Pelizaeus-Merzbacher Syndrome: A very rare slowly progressive demyelinating disease affecting in a diffuse pattern the cerebrum, cerebellum, brainstem, and spinal cord. Two types are described: X-linked (Infantile form) and the autosomal dominant (preadulthood form). Clinical features also include: stridor, muscle spasticity, nystagmus. Often fatal in the first year of life from respiratory complications.

Zellweger Syndrome: Rare, hereditary disorder characterized by decreased or missing peroxisomes in the liver, kidney, and brain. It is characterized by facial abnormalities, central nervous system dysfunctions, ocular problems, and hepatomegaly. Most symptoms present in development before birth. Newborns have a typical flat face with a high forehead, hypertelorism, and epicanthal folds. Other symptoms may include hypotonia, dysphagia, seizures, congenital heart defects, hepatomegaly, and/or vision abnormalities such as cataracts.