Adrenomyeloneuropathy

Adrenomyeloneuropathy is the adult form of X-linked adrenoleukodystrophy (ABCD1), with slowly progressive spastic paraparesis, sensory neuropathy, sphincter dysfunction and adrenal insufficiency.

Onset is usually in the second to fourth decade in men. About 50 to 65% of heterozygous women develop a milder myelopathy after age 40 years. About 20 to 30% of men later develop cerebral inflammatory demyelination.

Pathophysiology

ABCD1 variants impair peroxisomal transport of very long chain fatty acids, which accumulate in the adrenal cortex, spinal cord and white matter.

Progressive stiffness and weakness of the legs, sensory loss (vibration and proprioception), urinary urgency, erectile dysfunction, bowel dysfunction, and adrenal insufficiency (fatigue, weight loss, skin pigmentation, hypotension, hyponatraemia).

Hypogonadism occurs. Cerebral disease shows behavioural change, cognitive decline, visual and hearing loss.

Red flags.

• Adrenal crisis with vomiting, hypotension or collapse.

• Rapid cognitive, visual or behavioural change (cerebral demyelination).

Plasma very long chain fatty acids (raised C26:0 and ratios) is the screening test. ABCD1 sequencing confirms the diagnosis. Check morning cortisol and corticotropin, with short corticotropin stimulation test, renin and electrolytes.

MRI of brain (white matter lesions, Loes score, gadolinium enhancement at the edge of lesions) and spine (cord atrophy). Nerve conduction studies show axonal neuropathy.

Differential diagnosis.

• Hereditary spastic paraplegia, multiple sclerosis and primary progressive myelopathy.

• Vitamin B12 deficiency, HTLV-1 myelopathy and Addison disease from other causes.

• Other leukodystrophies and spinal cord compression.

Adrenal insufficiency. Hydrocortisone 15 to 25 mg daily in two or three divided doses, with fludrocortisone 0.05 to 0.2 mg daily if mineralocorticoid deficiency. Provide stress dosing and an emergency card and injection kit. Adrenal crisis: hydrocortisone 100 mg IV, then 200 mg over 24 hours with saline resuscitation.

Cerebral disease. Allogeneic haematopoietic stem cell transplantation, or gene therapy where available, in early cerebral disease with enhancement and minimal deficit. Monitor with MRI every 6 months in men from age 3 years until age 40 years, and then yearly.

Spasticity. Baclofen 5 mg three times daily, increased to 30 to 80 mg daily in divided doses (do not stop suddenly), tizanidine 2 to 8 mg three times daily, and botulinum toxin.

Bladder and bowel. Oxybutynin 2.5 to 5 mg two or three times daily, or mirabegron 25 to 50 mg daily, and bowel regimen.

Hypogonadism. Testosterone replacement as indicated.

Dietary therapy. Dietary erucic acid therapy does not prevent progression in symptomatic patients.

Rehabilitation. Physiotherapy, orthoses and falls prevention.

Monitoring. Cortisol every 6 to 12 months, MRI, bladder function and mobility.

Referral and escalation. Refer to neurology, endocrinology and genetics. Refer urgently for new cerebral signs.

Special groups. Genetic counselling and cascade testing for family, including female carriers, and newborn screening where available.