X-linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder due to variants in ABCD1 (Xq28), with accumulation of very long chain fatty acids and a range of phenotypes: childhood cerebral disease, adrenomyeloneuropathy, and Addison disease. Early detection by newborn screening and MRI surveillance has made curative treatment possible.

Pathophysiology. ABCD1 encodes a peroxisomal membrane transporter for very long chain fatty acyl-CoA. Failure of transport leads to accumulation of saturated very long chain fatty acids (C26:0) in the brain white matter, adrenal cortex and testes.

Inflammatory demyelination in cerebral disease follows a loss of the blood brain barrier.

The same variant can give different phenotypes within a family.

• Childhood cerebral X-ALD (about 35%): onset at 4 to 10 years with behavioural change, school decline, visual and hearing problems, then rapid loss of function.
• Adrenomyeloneuropathy: onset in the twenties to forties, with progressive spastic paraparesis, sphincter disturbance and sexual dysfunction.
• Adrenal insufficiency: the sole manifestation in some, often appearing from early childhood.
• Adult cerebral disease in some men with adrenomyeloneuropathy.
• Female carriers: a myeloneuropathy resembling adrenomyeloneuropathy in most by 60 years, rarely cerebral disease.
• Hypogonadism and testicular dysfunction in men.

• Plasma very long chain fatty acids: raised C26:0, and raised C26:0/C22:0 and C24:0/C22:0 ratios, in males; sensitivity is lower in females.
• ABCD1 sequencing with deletion and duplication analysis, which confirms the diagnosis and permits carrier testing.
• Brain MRI: parieto occipital white matter lesions with gadolinium enhancement at the edge of the lesion. Loes score quantifies severity.
• Adrenal assessment: morning cortisol, ACTH and short synacthen test.
• Newborn screening using C26:0 lysophosphatidylcholine on dried blood spots, with confirmation by very long chain fatty acids and ABCD1.
• Family testing of all at risk relatives, including cascade testing of maternal relatives.

Differential diagnosis.

• Other peroxisomal disorders (Zellweger spectrum, D-bifunctional protein deficiency)
• Metachromatic leukodystrophy and Krabbe disease
• Multiple sclerosis and hereditary spastic paraplegia in adults
• Other causes of primary adrenal insufficiency (autoimmune, congenital adrenal hyperplasia)

• Adrenal insufficiency: hydrocortisone 8 to 10 mg/m2 daily in three divided doses (adults 15 to 25 mg daily), and fludrocortisone 0.05 to 0.2 mg daily if mineralocorticoid deficiency is shown. Double or triple the dose during illness, and in crisis give hydrocortisone 50 to 100 mg/m2 (maximum 100 mg) intravenously with fluids and glucose.
• Early cerebral disease: allogeneic haematopoietic stem cell transplantation when MRI lesions are present with a Loes score of 9 or less and neurological examination is normal or nearly so. Elivaldogene autotemcel gene therapy is an alternative where available. Both halt progression only if given before advanced disease, and patients treated by gene therapy need long term follow up for haematological malignancy.
• Spasticity in adrenomyeloneuropathy: baclofen 5 mg three times daily increasing every 3 days to 20 mg three times daily (maximum 100 mg daily), physiotherapy, and botulinum toxin for focal spasticity.
• Bladder and bowel care: oxybutynin 5 mg two or three times daily (maximum 5 mg four times daily) for urgency, and macrogol 1 to 3 sachets daily.
• Hypogonadism: testosterone replacement when the testosterone level is low with symptoms.
• Dietary therapy: glyceryl trioleate and glyceryl trierucate (Lorenzo's oil) lowers C26:0 but has not been shown to prevent cerebral disease in symptomatic patients; it may be offered to asymptomatic boys with a normal MRI.
• Supportive care for advanced disease: gastrostomy, seizure treatment with levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, and palliative care.
• Genetic counselling: a carrier mother has a 50% chance of transmitting the variant to each child; sons are affected and daughters are carriers. Prenatal diagnosis is available.

Special groups.

• Asymptomatic boys with a positive newborn screen: begin adrenal testing and the MRI schedule immediately.
• Female carriers: examine for myelopathy from the age of 40 years.

Monitoring. Boys under 3 years: MRI of the brain at diagnosis and as symptoms indicate. Boys aged 3 to 12 years: MRI every 6 months, then yearly. Adrenal function (ACTH and cortisol) every 6 months in childhood and yearly in adults. Neurological examination yearly in adults.

Referral and escalation. Refer to clinical genetics, paediatric or adult neurology, endocrinology and a transplant centre. Urgent for any new MRI lesion, behavioural change or adrenal crisis.