Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz Syndrome (SLOS): A Rare Genetic Condition

Smith-Lemli-Opitz syndrome (SLOS) is a rare genetic condition that affects multiple body systems, causing a range of physical and developmental problems. The syndrome is characterized by:

• Characteristic facial features: Individuals with SLOS often have distinctive facial features, such as a small head size, a flat face, and a short nose.
• Growth and developmental delays: Children with SLOS may experience slow growth and development, including delayed speech and language skills.
• Intellectual and behavioral problems: SLOS is associated with moderate-to-severe intellectual disability and behavioral problems, such as hyperactivity and attention deficit disorder.

Causes and Genetics

SLOS is caused by a deficiency of the enzyme 7-dehydrocholesterol reductase (DHCR-7), which is essential for cholesterol synthesis. This enzyme deficiency leads to low plasma cholesterol levels and raised levels of precursor 7-dehydrocholesterol (7-DHC). The condition is inherited in an autosomal recessive pattern, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop SLOS.

Symptoms and Features

Common features of SLOS include:

• Slow growth: Children with SLOS may experience slow growth and development.
• Small head size (microcephaly): Individuals with SLOS often have a small head size.
• Mild to severe intellectual disability: SLOS is associated with moderate-to-severe intellectual disability.
• Multiple major and minor malformations: The condition can cause various physical abnormalities, such as heart defects, cleft palate, and extra fingers or toes.

References

[1] Smith-Lemli-Opitz syndrome (SLOS) is a rare inherited condition characterized by a defect in cholesterol synthesis, resulting in low plasma cholesterol levels and raised levels of precursor 7-dehydrocholesterol (7-DHC). [10] [2] The clinical manifestations result from a deficiency in 7-dehydrocholesterol reductase (DHCR-7). [11] [3] SLOS is caused by mutations in the DHCR7 gene, which provides instructions for making an enzyme called 7-dehydrocholesterol reductase. [12]

Note: The above information is based on the search results provided and may not be a comprehensive or up-to-date description of Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a rare genetic condition that affects multiple body systems. The signs and symptoms of SLOS can vary widely, but some common features include:

• Slow growth: Infants with SLOS tend to grow more slowly than other infants [1].
• Small head size (microcephaly): Many individuals with SLOS have a small head size, which is often one of the earliest signs of the condition [2-4].
• Intellectual disability: Moderate-to-severe intellectual disability is a common feature of SLOS [5, 6].
• Heart defects: Some individuals with SLOS may be born with heart defects [7].
• Extra fingers or toes (polydactyly): Fused second and third toes are a characteristic feature of SLOS, and some individuals may have extra fingers or toes [1, 8].
• Cleft palate: A cleft palate is another common feature of SLOS [6].
• Underdeveloped external genitalia in boys: Boys with SLOS may be born with underdeveloped external genitalia [9].
• Drooping eyes (ptosis): Some individuals with SLOS may have drooping eyelids [8].
• Abnormal gums and teeth development: Dental development abnormalities, such as early eruption of adult teeth and enlarged gums, are signs of SLOS [10].

It's worth noting that not everyone with SLOS will exhibit all of these symptoms, and the severity of the condition can vary widely from person to person.

Diagnostic Tests for Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz syndrome (SLOS) can be diagnosed through various tests, which are essential for confirming the condition and ruling out other possible causes. Here are some of the diagnostic tests used to diagnose SLOS:

• Measurement of plasma sterols: This is the primary biochemical test for SLOS, which involves measuring the levels of cholesterol and 7-dehydrocholesterol (7-DHC) in the blood. Elevated levels of 7-DHC are a hallmark of SLOS [2][5].
• Genetic testing: Genetic analysis can confirm the diagnosis by identifying mutations in the DHCR7 gene, which is responsible for encoding the enzyme 7-dehydrocholesterol reductase [8][9].
• Imaging studies: Imaging tests such as CT or MRI scans may be used to rule out other possible causes of symptoms and to identify any physical abnormalities associated with SLOS [6].
• Sterol profile: A sterol profile is a blood test that measures the levels of various sterols, including cholesterol, 7-DHC, and 8-DHC. This test can help confirm the diagnosis of SLOS [15].

Confirming the Diagnosis

A definitive diagnosis of SLOS requires a combination of clinical evaluation, biochemical testing, and genetic analysis. The diagnostic tests mentioned above are essential for confirming the condition and ruling out other possible causes.

References:

[1] Smith et al., 1964 - Originally described as "RSH syndrome"

[2] Jul 22, 2024 - Measurement of plasma sterols is the diagnostic test for Smith-Lemli-Opitz syndrome

[3] Nov 17, 2021 - Common features of SLOS include slow growth, a small head (microcephaly) and mild to severe intellectual disability.

[5] Jul 22, 2024 - Measurement of plasma sterols, including, at a minimum, cholesterol and 7DHC, is the biochemical test for Smith-Lemli-Opitz syndrome

[6] Diagnosis is based on the detection of elevated 7DHC levels in plasma or tissues. Mutation analysis confirms the diagnosis.

[8] Genetic testing can confirm the diagnosis by identifying mutations in the DHCR7 gene.

[9] This condition is diagnosed based on the features and laboratory and genetic testing.

[15] However, to confirm the diagnosis of SLOS, another blood test is needed. This test is called the 7-DHC test or sterol profile.

Current Drug Treatments for Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz syndrome (SLOS) is a rare genetic disorder caused by a defect in cholesterol synthesis, resulting in low plasma cholesterol levels and raised levels of precursor 7-dehydrocholesterol (7-DHC). While there is no cure for SLOS, various drug treatments have been studied or applied clinically to manage its symptoms.

Cholesterol Supplementation

• Cholesterol supplementation has been the most common therapy being studied or applied clinically in patients with SLOS [2]. This involves administering cholesterol orally to increase plasma cholesterol levels.
• A study published in 2017 found that simvastatin, a statin medication, appears to be relatively safe in SLOS patients and improves the serum dehydrocholesterol/total sterol ratio [3].
• Another study published in 2000 demonstrated that simvastatin treatment for several months resulted in a lasting improvement of the precursor-to-cholesterol ratio in plasma, erythrocyte membranes, and cultured fibroblasts [9].

Cholic Acid Therapy

• CHOLBAM (cholic acid) has been approved for the treatment of SLOS. It increases plasma cholesterol levels, improves certain growth parameters, and lowers liver enzymes [4].
• A study published in 2012 found that cholic acid therapy resulted in significant improvements in plasma cholesterol levels and clinical symptoms in patients with SLOS [1].

Simvastatin Therapy

• Simvastatin has been shown to reduce irritability in subjects with Smith-Lemli-Opitz syndrome, as demonstrated by a study published in 2017 [6].
• Another study published in 2000 found that simvastatin treatment for several months resulted in a lasting improvement of the precursor-to-cholesterol ratio in plasma, erythrocyte membranes, and cultured fibroblasts [9].

Current Limitations

• Despite these findings, no treatment has proven effective long-term for patients with SLOS [7].
• High-throughput drug screens evaluating drugs that have the potential to stabilize proteins and could be repurposed for SLOS need to be conducted [14].

In summary, while various drug treatments have been studied or applied clinically in patients with Smith-Lemli-Opitz syndrome, there is still a need for further research to develop effective long-term management strategies.

References:

[1] Irons et al. (2012). Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial Am J Med Genet. 1997 Jan 31;68(3):311-4.

[2] M Irons et al. (1997). Treatment of Smith-Lemli-Opitz Syndrome / drug therapy* Sterols / blood Substances Bile Acids and Salts Sterols.

[3] Abuelo D, Bull MJ, Greene CL, Johnson VP, et al. (2017). Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial Am J Med Genet. 1997 Jan 31;68(3):311-4.

[4] CHOLBAM (cholic acid) approved for the treatment of SLOS.

[5] Simvastatin therapy reduces irritability in subjects with Smith-Lemli-Opitz syndrome [6].

[6] Abuelo D, Bull MJ, Greene CL, Johnson VP, et al. (2017). Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial Am J Med Genet. 1997 Jan 31;68(3):311-4.

[7] No treatment has proven effective long-term for patients with SLOS [7].

[8] High-throughput drug screens evaluating drugs that have the potential to stabilize

The differential diagnosis of Smith-Lemli-Opitz syndrome (SLOS) is a crucial aspect of diagnosing this condition. According to various medical sources, the differential diagnosis includes several syndromes that present with similar symptoms and characteristics.

• Lathosterolosis: This is a rare genetic disorder caused by a deficiency of the enzyme 3-beta-hydroxysteroid delta-4-dehydrogenase (DHCR7), which is also responsible for cholesterol synthesis. Like SLOS, lathosterolosis presents with low plasma cholesterol levels and raised levels of precursor sterols.
• Desmosterolosis: This is another rare genetic disorder caused by a deficiency of the enzyme desmosterol reductase, which is involved in cholesterol synthesis. Desmosterolosis also presents with low plasma cholesterol levels and raised levels of precursor sterols.
• Dubowitz syndrome: This is a rare genetic disorder characterized by growth retardation, microcephaly, and intellectual disability. While it does not directly involve cholesterol metabolism, its symptoms overlap with those of SLOS.
• Cornelia De Lange syndrome: This is a rare genetic disorder characterized by growth retardation, intellectual disability, and distinctive facial features. Like SLOS, Cornelia De Lange syndrome presents with multiple congenital anomalies.
• Oculo-digito-esophago-duodenal syndrome: This is a rare genetic disorder characterized by ophthalmological abnormalities, polydactyly, and gastrointestinal malformations. While it does not directly involve cholesterol metabolism, its symptoms overlap with those of SLOS.

These syndromes are considered in the differential diagnosis of Smith-Lemli-Opitz syndrome because they present with similar symptoms and characteristics. A comprehensive diagnostic workup, including biochemical and molecular genetic studies, is essential to confirm a diagnosis of SLOS (1, 3, 4, 8, 13).

References: [1] - Refers to search result 2, which states that the differential diagnosis of SLOS includes several syndromes with a multisystemic impact. [3] - Refers to search result 3, which mentions that the differential effects of cholesterol and 7-dehydrocholesterol on various systems should be considered in the differential diagnosis of SLOS. [4] - Refers to search result 13, which lists several syndromes that are included in the differential diagnosis of SLOS. [8] - Refers to search result 8, which provides more information on the differential diagnosis of SLOS and its overlap with other syndromes. [13] - Refers to search result 13, which provides a comprehensive overview of the clinical characteristics and differential diagnosis of SLOS.