Desmosterolosis

Other names:deficiency of 3beta-hydroxysterol delta24-reductase

Desmosterolosis is a defect in cholesterol biosynthesis.

Desmosterolosis is a condition that is characterized by neurological problems, such as brain abnormalities and developmental delay, and can also include other signs and symptoms.

Epidemiology

The prevalence of desmosterolosis is unknown; at least 10 affected individuals have been described in the scientific literature.

Cause

Desmosterolosis is caused by mutations in the DHCR24 gene. This gene provides instructions for making an enzyme called 24-dehydrocholesterol reductase, which is involved in the production (synthesis) of cholesterol. Cholesterol is a waxy, fat-like substance that can be obtained from foods that come from animals (particularly egg yolks, meat, poultry, fish, and dairy products). It can also be produced in various tissues in the body. For example, the brain cannot access the cholesterol that comes from food, so brain cells must produce their own. Cholesterol is necessary for normal embryonic development and has important functions both before and after birth.

DHCR24 gene mutations lead to the production of 24-dehydrocholesterol reductase with reduced activity. As a result, there is a decrease in cholesterol production. Because the brain relies solely on cellular production for cholesterol, it is most severely affected. Without adequate cholesterol, cell membranes are not formed properly and nerve cells are not protected by myelin, leading to the death of these cells. In addition, a decrease in cholesterol production has more severe effects before birth than during other periods of development because of the rapid increase in cell number that takes place. Disruption of normal cell formation before birth likely accounts for the additional developmental abnormalities of desmosterolosis.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Children with desmosterolosis have delayed speech and motor skills (such as sitting and walking). Later in childhood, some affected individuals are able to walk with support; verbal communication is often limited to a few words or phrases. Common brain abnormalities in desmosterolosis include malformation of the tissue that connects the left and right halves of the brain (the corpus callosum) and loss of white matter, which consists of nerve fibers covered by a fatty substance called myelin.

People with desmosterolosis commonly have muscle stiffness (spasticity) and stiff, rigid joints (arthrogryposis) affecting their hands and feet. Other features seen in some affected individuals include short stature, abnormal head size (either larger or smaller than normal), a small lower jaw (micrognathia), an opening in the roof of the mouth (cleft palate), involuntary eye movements (nystagmus) or eyes that do not look in the same direction (strabismus), heart defects, and seizures.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Absent septum pellucidum
• Agenesis of corpus callosum
• Bifid uvula
• Failure to thrive(Faltering weight)
• Feeding difficulties(Feeding problems)
• Intellectual disability(Mental deficiency)
• Intrauterine growth retardation(Prenatal growth deficiency)
• Microcephaly(Abnormally small skull)
• Micrognathia(Little lower jaw)
• Muscle stiffness
• Retrognathia(Receding chin)
• Rigidity(Muscle rigidity)
• Severe short stature(Dwarfism)
• Spasticity(Involuntary muscle stiffness, contraction, or spasm)
• Submucous cleft hard palate

30%-79% of people have these symptoms

• Depressed nasal bridge(Depressed bridge of nose)
• Large earlobe(Fleshy earlobe)
• Low-set, posteriorly rotated ears
• Narrow mouth(Small mouth)
• Nystagmus(Involuntary, rapid, rhythmic eye movements)
• Short nose(Decreased length of nose)
• Status epilepticus(Repeated seizures without recovery between them)
• Strabismus(Cross-eyed)
• Ventriculomegaly

5%-29% of people have these symptoms

• Ambiguous genitalia(Ambiguous external genitalia)
• Anomalous pulmonary venous return
• Dermal atrophy(Skin degeneration)
• Downslanted palpebral fissures(Downward slanting of the opening between the eyelids)
• Epicanthus(Eye folds)
• Frontal bossing
• Hydrocephalus(Too much cerebrospinal fluid in the brain)
• Intestinal malrotation
• Macrocephaly(Increased size of skull)
• Macrogyria
• Metatarsus adductus(Front half of foot turns inward)
• Micromelia(Smaller or shorter than typical limbs)
• Osteopetrosis(Harder, denser, fracture-prone bones)
• Pachygyria(Fewer and broader ridges in brain)
• Patent ductus arteriosus
• Polymicrogyria(More grooves in brain)
• Prominent forehead(Pronounced forehead)
• Renal agenesis(Absent kidney)
• Splenomegaly(Increased spleen size)
• Talipes

Diagnosis

The diagnosis of desmosterolosis was established by detection of significant elevation of plasma desmosterol levels and reduced enzyme activity of DHCR24 upon expression of the patient’s DHCR24 cDNA in yeast.

NIH genetic and rare disease info

• NIH info on Desmosterolosis

Desmosterolosis is a rare disease.

Desmosterolosis Resources
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