He Smith-Lemli-Opitz syndrome (SLO) is a metabolic disorder that encompasses several different symptoms, such as significantly slow growth, characteristic easy traits, Microcephaly (Measurement of the head smaller than normal), Mental retardation Which can be mild or moderate, learning difficulties And behavior problems.
It is also accompanied by malformations in the lungs, heart, kidneys, intestines and even in the genitals. In addition, they may file Syndactyly Or fusion of some of the fingers, or Polydactyly ; Which means they have more than 5 fingers on one foot or hand.
It seems to be due to the lack of an enzyme that is important to metabolize the cholesterol that is acquired by genetic inheritance of pattern Autosomal recessive .
However, such presentations appear to vary greatly depending on the severity of the disease even in the same family.
This syndrome may appear in the literature with names such as: 7-dehydrocholesterol reductase deficiency, RSH syndrome or SLO syndrome.
A little history…
In 1964, pediatricians David Smith, Luc Lemli and John Opitz described 3 male patients with microcephaly and hypogenitalism, and defined this condition as RSH by the initials of the original surnames of such patients.
Subsequently, the name of the syndrome was changed by the names of the discoverers (SLO).
About 30 years later, Tint et al. (1994) found in 5 patients with this condition, significantly lower blood cholesterol concentrations, but an increase of more than 1000 fold 7-dehydrocholesterol . They saw that increase was due to the lack of an enzyme that should convert 7-dehydrocholesterol to cholesterol.
The DHCR7 gene associated with this disease was later identified and cloned in 1998 (Witsch-Baumgartner & Lanthaler, 2015).
About us
Smith-Lemli-Opitz syndrome affects approximately 1 in 20,000 to 60,000 live births worldwide. It can actually be inherited in 1 in 1590 to 13,500 individuals, but this figure is not used because many fetuses with this condition die before birth (National Organization for Rare Disorders, 2016).
As for sex, it affects both men and women alike, although it is more easily diagnosed in men since the genital malformations are more visible than in women. In addition, it seems to have more frequency in people of European descent; Especially in countries belonging to central Europe such as the Czech Republic or Slovakia. However, it is very rare in the population of Africa or Asia.
Causes of Smith-Lemli-Opitz syndrome
SLO syndrome appears due to mutations in the DHCR7 gene, present on chromosome 11, which is in charge of sending orders to manufacture the enzyme 7-dehydrocholesterol reductase. This is the enzyme that modulates cholesterol production and would be absent or very little in this syndrome, which leads to an insufficient production of cholesterol that would impede normal growth.
This has a great impact since the cholesterol Is important in the body. It consists of a fat-like lipid that is mainly obtained from foods of animal origin, such as egg yolks, dairy products, meat, poultry and fish.
It is essential for the embryo to develop without difficulties, having important functions such as the contribution to the structure of the cells membranes and the Myelin (Substance that covers brain cells). It also serves to produce hormones and digestive acids.
The lack of the enzyme 7-dehydrocholesterol reductase causes components that may be toxic to cholesterol to accumulate in the body. So we have, on the one hand, low cholesterol levels, and at the same time accumulation of substances that can be toxic to the body; Causing lack of growth, mental retardation, physical malformations and problems in internal organs.
However, it is not known with complete certainty how these problems associated with cholesterol give rise to the symptoms of Smith-Lemli-Opitz syndrome.
More than 130 mutations related to the syndrome have been found in the DHCR7 gene. In fact, there is a database containing all the described cases of SLO with their variants, their Phenotypes Y Genotypes .
Although there are as many mutations as possible, most cases belong to the 5 most frequent and the rest are very rare (Witsch-Baumgartner & Lanthaler, 2015).
These mutations in the DHCR7 gene are inherited with an autosomal recessive pattern, meaning that a person presenting the syndrome must have inherited the mutated gene from both parents. If you only get it from a parent, you will not have the disease; But it could be a carrier and transmit it in the future.
There is a 25% risk that the two parents have an affected child, while the risk of the child being a carrier would also be 50% in each pregnancy. On the other hand, in 25% of cases can be born without these genetic mutations or be a carrier; All being data independent of the sex of the baby (National Organization for Rare Disorders, 2016).
It should be noted that there is a higher probability of having children with any recessive genetic disorder if the parents are close relatives (or blood relatives) than the parents who do not have these links.
What are the symptoms?
The symptoms vary depending on the affected, depending on the amount of cholesterol they can produce.
According to Jiménez Ramírez et al. (2001), the clinical features cover several aspects and can be very diverse. Generally, they are found on the face, limbs and genitals; Although they may involve other body systems.
Many of those affected have typical autism , Affecting social interaction. If the condition is mild, there may be only some problems in learning and behavior; But in more severe cases, the person may have a high intellectual disability and physical abnormalities that can lead to death.
There are symptoms that may already be present since the birth of the individual, although we will include those that occur in all stages of life:
In more than 50% of patients:
- Lack of physical development observed after birth.
- Mental retardation (100%).
- Microcephaly (90%).
- Syndactyly or fusion of 2 or 3 toes ( - Eyelid ptosis, ie, one of the upper eyelids has fallen (70%).
- Urinary meatus located in a place different from normal in men, such as in the lower part of the glans, trunk or union between scrotum and penis. It is present in 70% of cases.
- Cleft palate, which manifests as a kind of elongated hole in the palate (50%).
- Very reduced jaw or micrognathia.
- Very small tongue (microglosia).
- Ears of low implantation.
- Small nose.
- Incomplete descent of one or both testicles.
- Hypotonia or low muscle tone.
- Eating disorders.
- Behavior disorders: antisocial, self-destructive and violent behaviors. Autistic self-stimulation behaviors also appear as repetitive rocking movements.
- Autism.
From 10 to 50% of the cases:
- Early waterfalls.
- Polydactyly or one more finger after the little finger.
- Delayed growth in the fetal stage.
- Ambiguous genitalia.
- Heart defects.
- Multicystic kidney.
- Absence of a kidney or both at birth.
- Liver diseases.
- Adrenal hyperplasia
- Pulmonary anomalies.
- Excessive sweating.
- Cerebral anomalies in structures located in the midline, such as incomplete development of the hard body , Septum and cerebellar vermis.
- Acrocyanosis: skin vasoconstriction that causes a bluish color in hands and feet.
- Equinoxous feet.
- Pyloric stenosis (fifteen %)
- Hirschsprung's disease, which causes lack of intestinal motility (15%)
- Photosensitivity .
Other symptoms:
- Obnubilation or coma.
- Accumulation of fluid in the body of the fetus.
- Alterations in neurological development.
- Neuropsychiatric problems, which appear more frequently when they reach adulthood.
- Respiratory insufficiency due to problems in the lungs.
- Hearing loss.
- Alterations in vision, which may be accompanied by strabismus.
- Vomiting.
- Constipation.
- Convulsions.
How can you diagnose?
This syndrome appears from conception even though when the baby is born, the symptoms are not very clear and are more subtle than in late childhood or adulthood; Especially if they are milder forms of the disease. For this reason, on several occasions it is detected late.
However, the most common is that this condition is suspected shortly after being born due to the malformations that usually present (Steiner, 2015).
According to the National Organization for Rare Disorders (2016) the diagnosis is based on physical exams and a blood test that detects cholesterol levels. It is essential that the child is evaluated in all possible aspects associated with the disease such as eyes, ears, heart, skeletal muscles, genitals and gastrointestinal disorders.
As for blood tests, a subject with SLO will have a high concentration of 7-dehydrocholesterol (7-DHC) in the blood (precursor that must be transformed by the enzyme 7-dehydrocholesterol reductase to get cholesterol), and very high levels Low cholesterol.
It can also be detected before birth through an ultrasound or ultrasound technique, a device that uses sound waves to examine the inside of the uterus of the pregnant woman. With this technique can be observed the physical deformities typical of this syndrome.
Another test is the amniocentesis , Which consists of an extraction of a small sample of amniotic fluid (where the fetus develops) to detect defects of a genetic type. The same information can be obtained through a sampling of Chorionic villi (MVC) by extracting a tissue sample from the placenta.
On the other hand, molecular genetics tests can be used for prenatal diagnosis with the aim of observing if there are mutations in the DHCR7 gene, and if it is going to present the disease or will only be a carrier.
What is the course of the disease?
Unfortunately, most of the more severe cases of SLO die soon after birth. If there is severe intellectual disability, it is difficult for these people to develop independent living.
However, if you receive the right medical care and a good diet, these patients can lead a normal life.
What treatments are there?
There is currently no specific treatment for Smith-Lemli-Opitz syndrome. This is because it is not known today with absolute certainty the biochemical origin of the disease since cholesterol has several complex functions in the metabolism.
The medical treatment for SOLO is based on the specific problems that are found in the affected child and it is best to intervene early.
It can be helpful to receive cholesterol supplements or increase dietary intake, to improve the level of development and decrease photosensitivity. It is sometimes combined with bile acids.
For sun intolerance, it is advisable for these patients to use sunscreen, sunglasses and appropriate clothing when they go outside.
The supply of drugs such as simvastatin has been shown to decrease the severity of the disease. Although, as the clinical phenotype occurs during a lack of cholesterol in embryogenesis, it should be administered at that time (Witsch-Baumgartner & Lanthaler, 2015).
On the other hand, an antagonist drug of the cholesterol precursor that is in excess (7-dehydrocholesterol) may be used to prevent it from increasing. Vitamin E supplements may help.
Other specific medications may be helpful for symptoms such as vomiting, gastroesophageal reflux, or constipation.
Surgery or orthopedic appliances may be necessary if there are physical deformities or muscle problems associated with this syndrome such as cleft palate, heart defects, muscle hypotonia or genital alterations.
In conclusion, it is necessary to continue research on this syndrome to develop more effective and specific treatments.
References
- Jiménez Ramírez, A.; Valdivia Alfaro, R.; Hernández González, L.; León Corrales, L.; Machín Valero, Y. and Torrecilla, L. (2001). Smith Lemli Opitz Syndrome. Presentation of a case with biochemical diagnosis. Gaceta Médica Espirituana, 3 (3).
- Smith Lemli Opitz Syndrome. (S.f.). Retrieved on July 6, 2016, from the National Organization for Rare Disorders (NORD).
- Smith-Lemli-Opitz Syndrome. (S.f.). Retrieved July 6, 2016, from University of Utah, Health Sciences.
- Smith-Lemli-Opitz Syndrome. (S.f.). Retrieved on July 6, 2016, from Counsyl.
- Smith-Lemli-Opitz syndrome. (July 5, 2016). Retrieved from the Genetics Home Reference.
- Steiner, R. (April 1, 2015). Smith-Lemli-Opitz Syndrome. Obtained from Medscape.
- Tint, G.S., Irons, M., Elias, E. R., et al. (1994). Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med, 330: 107-113
- Witsch-Baumgartner, M., & Lanthaler, B. (2015). Smith-Lemli-Opitz Syndrome. European Journal of Human Genetics, 23 (3), 277-278.