skin hyperpigmentation

Adrenoleukodystrophy, Autosomal

Clinical Characteristics
Ocular Features: 

This early onset and rapidly progressive form of adrenoleukodystrophy is rare.  The early onset and rapidly fatal course of the disease has limited full delineation of the ocular features.  The most striking is the presence of 'leopard-spots' pigmentary changes in the retina.  Polar cataracts, strabismus, and epicanthal folds have also been reported. 

Systemic Features: 

Onset of symptoms occurs shortly after birth often with seizures and evidence of psychomotor deficits.  Rapid neurologic deterioration begins at about 1 year of age with death usually by the age of 3 years.  Hyperpigmentation of the skin may be apparent a few months after birth.  Opisthotonus has been observed.  The ears may be low-set, the palate is highly arched, and the nostrils anteverted.  Frontal bossing may be present.  Serum pipecolic acid and very-long-chain fatty acids (VLCFAs) can be markedly elevated.  Cystic changes in the kidneys have been reported. 

Genetics

This is an autosomal recessive peroxismal disorder resulting from homozygous mutations in receptor gene mutations such as PEX1, PEX5, PEX13, and PEX26.

There is also an X-linked recessive adrenoleukodystrophy (300100) sometimes called ALD but it lacks some of the morphologic features and is somewhat less aggressive. 

Neonatal adrenoleukodystrophy along with infantile Refsum disease (266510, 601539) and Zellweger syndrome (214100) are now classified as Zellweger spectrum or perioxismal biogenesis disorders.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is mainly supportive for associated health problems. 

References
Article Title: 

Adrenoleukodystrophy, X-Linked

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

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 recessive, father affected
Treatment
Treatment Options: 

Treatment of adrenal insufficiency is important and can be lifesaving.  Low vision aids, physical therapy and special education may be helpful.  Some young patients with early disease have benefitted from bone marrow transplantation.  "Lorenzo's Oil" (a mixture of oleic acid and erucic acid) has been reported to reduce or delay symptoms in some boys. 

References
Article Title: 

X-linked adrenoleukodystrophy

Moser HW, Mahmood A, Raymond GV. X-linked adrenoleukodystrophy. Nat Clin Pract Neurol. 2007 Mar;3(3):140-51. Review.

PubMed ID: 
17342190
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