OMIM ID:
Adrenoleukodystrophy, X-Linked
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
Virtually all patients have visual symptoms. Loss of acuity, hemianopia, visual agnosia, optic atrophy, and strabismus are the most common features. Neuropathy may cause a decrease in corneal sensation. Gaze abnormalities due to ocular apraxia are sometimes seen. Ocular symptoms often occur after the systemic abnormalities are noted. However, there is considerable heterogeneity in age of onset and progression of symptoms.
Histopathology of ocular structures reveals characteristic inclusions in retinal neurons, optic nerve macrophages, and the loss of ganglion cells with thinning of the nerve fiber layer of the retina.
Systemic Features
This is a peroxisomal disorder of very-long-chain fatty acid (VLCF) metabolism that leads to progressive neurological and adrenal dysfunction from accumulation of VLCFAs in the nervous system, adrenal glands, and testes. The age of onset and clinical course are highly variable and there may be several forms. The childhood form begins between the ages of 4 and 8 years but in other patients with the adult form, symptoms may not appear until the third decade of life. A viral illness may precipitate the onset. Symptoms of both central and peripheral neurologic disease are often present with cognitive problems, ataxia, spasticity, aphasia, and loss of fine motor control. Hearing loss is seen in some patients. Younger patients tend to have more behavioral problems while older individuals may develop dementia.
Adrenal insufficiency leads to skin hyperpigmentation, weakness, loss of muscle mass and eventually coma. Impotence in males is common.
Genetics
Inheritance
This is an X-linked disorder secondary to mutations in the ABCD1 gene (Xp28). The result is a deficiency in the cellular transporter known as adrenoleukodystrophy protein that is active in perioxosomes.
Although this X-linked disorder is primarily manifest in males, between 20 and 50% of female carriers have at least some symptoms, usually with a later onset than seen in males.
There are also rare cases with an apparent autosomal recessive pattern of inheritance (NALD) (202370) having an earlier onset and more aggressive course.
Pedigree
X-linked recessive, carrier mother
X-linked disorders are caused by a mutation on the X chromosome and both sexes can pass this to their children. If the mutation is in a recessive gene and carried by the mother, she usually does not have the disease since the normal X chromosome without the mutation neutralizes the mutation in the abnormal X chromosome. However, half her sons will inherit the mutation-containing X chromosome and therefore have the X-linked disease. Half the daughters will inherit the mutation-bearing X chromosome and are usuallly healthy 'carriers'.
X-linked disorders are caused by a mutation on the X chromosome and both sexes can pass this to their children. If the mutation is in a recessive gene and carried by the mother, she usually does not have the disease since the normal X chromosome without the mutation neutralizes the mutation in the abnormal X chromosome. However, half her sons will inherit the mutation-containing X chromosome and therefore have the X-linked disease. Half the daughters will inherit the mutation-bearing X chromosome and are usuallly healthy 'carriers'.
X-linked recessive, father affected
X-linked disorders are caused by a mutation on the X chromosome and both sexes can pass this to their children. If the mutation is in a recessive gene and carried by the father, he has the disease since his only X chromosome is mutant and he has no normal X to blunt the effects of the abnormal gene. His sons only receive his Y chromosome and thus are all normal. However, all his daughters receive his one and only X chromosome and will be healthy 'carriers'. Thus such males will have no affected children but half their grandsons from those daughters will have the same disease as he does.
X-linked disorders are caused by a mutation on the X chromosome and both sexes can pass this to their children. If the mutation is in a recessive gene and carried by the father, he has the disease since his only X chromosome is mutant and he has no normal X to blunt the effects of the abnormal gene. His sons only receive his Y chromosome and thus are all normal. However, all his daughters receive his one and only X chromosome and will be healthy 'carriers'. Thus such males will have no affected children but half their grandsons from those daughters will have the same disease as he does.