Search for a rare disease
Other search option(s)
An adult form of the peroxisomal disease X-linked adrenoleukodystrophy (X-ALD), characterized by spastic paraparesia and often associated with peripheral adrenal insufficiency in males.
ORPHA:139399Classification level: Subtype of disorder
X-ALD estimated birth incidence is 1/20,000. Adrenomyeloneuropathy (AMN) manifests in more than 60% of female patients in adulthood and nearly all male patients who reach adulthood.
Initial neurologic symptoms reflecting involvement of spinal cord present most often in young men (20-30 years) with lower limb weakness, difficulties to run, gait imbalance due to sensory ataxia, sphincter disturbances and impotence and are slowly progressive. Clinical symptoms of peripheral neuropathy are rare. Sparse scalp hair may develop in teens and adrenocortical insufﬁciency (AI) may be present prior to neurological symptoms. AI is often latent, lacking melanoderma, but may present as fatigue, nausea, or even acute primary adrenal insufficiency (see this term). Hypogonadism may also manifest in adult males and impairment in spermatogenesis has been reported in some cases. Onset in women is later (40-50 years), AI is rare (1%) and disease progression is generally less severe. Increased risk of psychiatric morbidity has been reported. Depression is often observed in patients with severe motor disability.
AMN is due to mutations of ABCD1 (Xq28) encoding ALDP, a peroxisomal transmembrane protein involved in the transport of very long-chain fatty acid-CoA esters (VLCFA) into the peroxisome. Oxidative stress and damage to proteins and lipids due to VLCFA accumulation in glial cells (oligodendrocytes, Schwann cells) may impair their capacity to sustain axonal integrity in spinal cord and peripheral nerves.
Genetic testing must be preceded in men by testing for high plasma concentrations of VLCFA. Spinal cord MRI shows non-speciﬁc atrophy lacking gadolinium enhancement; magnetization transfer or diffusion tensor-based imaging may reveal more abnormalities. Electromyography and nerve conduction velocities may demonstrate polyneuropathy. Brain MRI may reveal abnormalities in the pyramidal tracts in brainstem and internal capsules. Heterozygous women may have normal plasmatic levels of VLCFAs; genetic testing is therefore mandatory.
Differential diagnoses include hereditary spastic paraplegias, primary lateral sclerosis, cerebrotendinous xanthomatosis, metachromatic leukodystrophy and Krabbe disease (see these terms) as well as difficiencies in vitamin B12, folic acid or copper. AI symptoms may ressemble Addison Disease (see this term).
Gestational chorionic villus sampling (10-13 weeks), amniocentesis (15-18 weeks) and pre-implantation genetic testing are feasible.
Transmission is via the X chromosome, counseling and genetic testing must be offered to the parents and extended family of those affected both to detect carriers and to follow the presymptomatic. All daughters of AMN males will be heterozygous.
Management and treatment
Treatment for myelopathy is symptomatic. An annual or bi-annual evaluation by a neurologist for treatment of spasticity and neuropathic pain and referral to a urologist are recommended. Plasma testosterone, cortisol, mineralocorticoids, ACTH levels and ACTH stimulation reponses must be tested regularly and replacement therapy may be required. In adult males with AMN, a yearly brain MRI must be performed to detect early signs of cerebral demyelination and propose allogeneic hematopoietic stem cell transplantation if a donor is available.
A marked progression of myelopathy within the ﬁrst 3-5 years of onset is observed in 35% of patients, others progress more slowly. Within 10-15 years, motor disability may become severe requiring aid for locomotion. Some patients (35% of men, 2% of women) develop additional cerebral demyelination entering into an active phase of neuroinflammation in the brain (X-CALD, see this term).