hypocholesterolemia

Microcephaly, Congenital Cataracts, and Psoriasiform Dermatitis

Clinical Characteristics
Ocular Features: 

Congenital cataracts are usually present.  No further description is available.  Some individuals have a chronic blepharitis.

Systemic Features: 

Small stature, microcephaly, and developmental delay are important features. The skin in early life, even in infancy, may have an psoriasiform dermatitis that waxes and wanes in some patients while others have only dry skin.  Chronic arthralgias are sometimes present leading to joint contractures especially in the lower extremities.  Skeletal maturation is delayed and there may be cognitive deficits.

Serum total cholesterol levels are generally low but triglycerides are in the normal range.  Serum levels of IgE and IgA may be elevated.  This condition results from defects in the cholesterol synthesis pathway.

Genetics

Compound heterozygosity or homozygosity of mutations in the SC4MOL gene (4q32.3) (also known as MSMO1) is responsible for this condition.  Parents with a single mutation may have mildly elevated plasma methylsterol levels.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cholesterol supplementation and the use of statins has been reported to improve symptoms.  The usual treatments for psoriasis may provide some temporary relief.  Physical therapy may prevent joint contractures.  Antibiotic drops or ointment may be helpful in the treatment of blepharitis.

References
Article Title: 

The role of sterol-C4-methyl oxidase

He M, Smith LD, Chang R, Li X, Vockley J. The role of sterol-C4-methyl oxidase
in epidermal biology. Biochim Biophys Acta. 2014 Mar;1841(3):331-5. Review.

PubMed ID: 
24144731

Peroxisome Biogenesis Disorder 3B (Infantile Refsum Disease)

Clinical Characteristics
Ocular Features: 

This peroxisomal disorder presents in the first year of life with both systemic and ocular features.  Night blindness is the major ocular feature and at least some have optic atrophy similar to the adult form.  Nystagmus may be present.  Reduction or absence of rod responses on ERG can be used in young children to document the retinopathy. Blindness and deafness commonly occur in childhood.

Systemic Features: 

This disorder is classified as a peroxisomal biogenesis disorder (PBD) associated with the breakdown of phytanic acid.  Ataxia and features of motor neuron disease are evident early.  Hepatomegaly and jaundice may also be an early diagnostic feature as bile acid metabolism is defective.  Infant hypotonia is often seen.  Nonspecific facial dysmorphism has been reported as a feature. The teeth are abnormally large and often have yellowish discoloration.  Postural unsteadiness is evident when patients begin walking.  Diagnosis can be suspected from elevated serum phytanic and pipecolic acid (in 20% of patients) or by demonstration of decreased phytanic acid oxidation in cultured fibroblasts.  Other biochemical abnormalities such as hypocholesterolemia and elevated very long chain fatty acids and trihydroxycholestanoic acid are usually present.  Anosmia and mental retardation are nearly universal features.  Early mortality in infancy or childhood is common although some survive into the 2nd and 3rd decades.

Genetics

This is an autosomal recessive peroxisomal biogenesis disorder (PBD) resulting from mutations in a number of PEX genes (PEX1, PEX2, PEX3, PEX12, PEX26).  It shares many features with other PBDs including those formerly called Zellweger syndrome (214100), rhizomelic chondrodysplasia punctata (215100), and neonatal adrenoleukodystrophy (601539).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Peroxisome Biogenesis Disorder 1B (neonatal adrenoleukodystrophy)

Clinical Characteristics
Ocular Features: 

This peroxisomal disorder presents in the first year of life with both systemic and ocular features.  Night blindness is the major ocular feature and at least some have optic atrophy similar to the adult form.  Central acuity is reduced secondary to macular degeneration.  A pigmentary retinopathy is frequently present and often follows the appearance of whitish retinal flecks in the midperipheray.  Nystagmus and cataracts are common features.  Reduction or absence of ERG responses can be used in young children to document the retinopathy.  Blindness and deafness commonly occur in childhood.

Systemic Features: 

This disorder is classified as a leukodystrophy, or disease of white matter of the brain, associated with the breakdown of phytanic acid.  Ataxia and features of motor neuron disease are evident early.  Hepatomegaly and jaundice may also be early diagnostic features as bile acid metabolism is defective.  Infant hypotonia is often seen.  Nonspecific facial dysmorphism has been reported.  The ears are low-set and epicanthal folds are present.  The teeth are abnormally large and often have yellowish discoloration.  Postural unsteadiness is evident when patients begin walking.  Diagnosis can be suspected from elevated serum phytanic and pipecolic acid (in 20% of patients) or by demonstration of decreased phytanic acid oxidation in cultured fibroblasts.  Other biochemical abnormalities such as hypocholesterolemia, and elevated very long chain fatty acids and trihydroxycholestanoic acid are usually present.  Anosmia, developmental delays, and mental retardation are nearly universal features.  Early mortality in infancy or childhood is common.

Genetics

This is a genetically heterogeneous disorder of peroxisome biogenesis caused by mutations in at least three genes, PEX1 (7q21-q22), PEX2 (8q21.1), and PEX6 (22q11-21).  Each is inherited in an autosomal recessive pattern.  The mechanism of disease is different from the classic or adult Refsum disorder (266500) and some have debated whether the term ‘infantile Refsum disease’ is appropriate.

This disorder shares some clinical features with other peroxisomal disorders such as Zellweger syndrome (214100) and rhizomelic chondrodysplasia punctata (215100).  Zellweger syndrome (214100), neonatal adrenoleukodystrophy and infantile Refsum disease (601539) are now considered to be peroxisomal biogenesis or Zellweger spectrum disorders.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Tangier Disease

Clinical Characteristics
Ocular Features: 

This disorder of lipoprotein metabolism is associated in many cases with corneal infiltrates, cicatricial ectropion, poor lid closure, and exposure keratopathy.  The corneal clouding alone generally cause little reduction of acuity but those with poor lid function and exposure keratopathy may have severe vision loss.  There may be weakness in the periorbital and lid muscles.  The corneal infiltration occurs late in life but is progressive with older individuals having the greatest visual impairment.  The corneal infiltrates are described as a “dot-like haze”, more prominent centrally and located in the stroma.  On electron microscopy, deposits in the conjunctiva are described as birefringent lipid particles located in pericytes and fibrocytes.  Lipid deposition occurs throughout the body including the conjunctiva.  Corneal hypesthesia has been reported.

In a series of 13 patients, ectropion and corneal scarring were reported in 3 and corneal infiltrates in 9.  Four had orbicular muscle weakness.  The latter together with corneal hypesthesia may be the earliest ocular signs of Tangier disease and should suggest the diagnosis even before the corneal clouding occurs.

Systemic Features: 

Patients with Tangier disease have significant enlargement of the liver, spleen and lymph nodes.  The tonsils are also frequently enlarged and have a characteristic yellow-orange  coloration.  The enlargement of these organs is due to lipid infiltration.  Plasma levels of cholesterol and HDL are characteristically slightly low while triglycerides are mildly elevated.  Peripheral neuropathy and muscle atrophy can be debilitating.  Severe coronary artery disease is common with onset sometime in the 5th decade.

Genetics

Tangier disease is an autosomal recessive disorder resulting from mutations in the ATP-binding cassette-1 gene ABCA1 (9p31.1) located in exon 22.  Parental consanguinity is common.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder beyond local organ treatment as indicated.
 

References
Article Title: 

Ocular complications of Tangier disease

Pressly, T. A.; Scott, W. J.; Ide, C. H.; Winkler, A.; Reams, G. P. : Ocular complications of Tangier disease. Am. J. Med. 83: 991-994, 1987.

PubMed ID: 
3314502
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