developmental regression

Cerebral Atrophy, Autosomal Recessive

Clinical Characteristics
Ocular Features: 

Severe visual impairment is noted before one year of age when infants cease following objects in their environment.  Cortical visual impairment has been diagnosed although 'atrophic optic fundi' and hypotrophic optic nerves and fovea have also been described.  Nystagmus has been observed as well.

Systemic Features: 

Microcephaly relative to age norms is evident usually by 2 months of age and there is little subsequent growth of the skull.  Regression of developmental milestones is noted by 4 months of age with signs of irritability, akathisia, spasticity, visual impairment, seizures, and increased startle responses.  Sucking responses and eye-to-eye contact are usually lost by 6 months of age.  Repetitive body stiffening and extension of arms in older individuals consistent with seizure activity has been confirmed by EEG in at least one infant.  Imaging consistently reveals cerebral atrophy with ventriculomegaly and general loss of brain volume. Progressive muscle weakness is evident after about 1 year of age and oral feeding is impaired. There is complete lack of responsive interaction beyond irritability and agitation while motor function is limited to involuntary responses.  Two individuals have lived into the second decade of life.

Genetics

This condition has been described in 4 individuals who were products of consanquineous Amish couples.  Homozygous mutations in the TMPRSS4 gene (11q23.3), whose product is a serine transmembrane protease, seems to be responsible.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

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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