Lowe's syndrome: what is it, causes, symptoms, treatment, prognosis

What is Lowe's Syndrome?

Lowe's syndrome (or oculo–cerebro–renal syndrome) Is a rare recessive X-linked human disease belonging to the group of ciliopathies. Lowe's syndrome is characterized by vision problems, including clouding of the lens of the eyes (cataracts), which are present at birth, kidney problems, which usually develop in the first year of life, and brain abnormalities associated with intellectual disabilities.

Signs and symptoms

Patients with Lowe's syndrome have cataractwhich is present at birth in each eye (and is detected prenatally by high-resolution ultrasound in suspicious cases). With very few exceptions, cataracts require surgery early in life as soon as health conditions permit anesthesia. But even under optimal conditions, corrected visual acuities during recording are rarely better than 20/100. About half of the eyes develop high pressure in the eye (

glaucoma), which can damage the optic nerve and lead to blindness if left unchecked.

Infants with Lowe's syndrome have low muscle tone (hypotension) at birth and experience delayed motor development. Nearly all boys with Lowe's syndrome have developmental disabilities and mental retardation, which can range from mild (~ 10% -25%) to severe (~ 50% -65%). About half of them have seizures by the age of six, and some boys with Lowe's syndrome have behavioral problems. In some affected men, growths called keloids develop on the corneas of one or both eyes in early childhood and adolescence. These build-ups are progressive and can lead to blindness.

The kidney problem associated with Lowe's syndrome is called Fanconi-type proximal tubular dysfunction. This disorder results in the loss of certain substances (amino acids, bicarbonates and phosphates) in the urine, which are usually filtered before being excreted in the urine or reabsorbed by the body. However, as mentioned, an amino acid spill or leak into urine rarely begins before the end of the first year of life, sometimes delaying and confusing the diagnosis. Filters in the kidneys (glomeruli) usually begin to fail in boys with Lowe's syndrome after age 10. Renal failure is slow and progressive and leads to a decrease in life expectancy of about 30-40 years.

Other signs common in boys with Lowe's syndrome include short stature, dental cysts and abnormal dentin formation in the teeth, cutaneous cysts, and vitamin D deficiencywhich can lead to soft bones, skeletal changes (rickets), bone fractures, scoliosis and inflammatory degenerative joint diseases. In some patients after surgery, delayed hemorrhagic diathesis was noted, characterized by normal hemostasis and clot formation, and after a few hours - sudden recurrence bleeding. This can be an important factor in any surgery, but especially in cataract surgery and glaucoma, where bleeding inside the eye can have significant consequences.

Causes

Lowe's syndrome is an X-linked genetic disorder caused by a mutation in a gene OCRL, which leads to a decrease in the activity of the OCRL enzyme phosphatidylinositol-polyphosphate-5-phosphatase. About a third of affected men have a new mutation in the gene; in most other cases, the disorder is inherited from the mother who is the genetic carrier of the disease.

X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome that occurs primarily in males. Women who have the disease gene on one of their X chromosomes are carriers of the disorder. As with other X-linked disorders, female carriers have two X chromosomes and one is inactivated so that the genes on that chromosome do not function. Although in many X-linked disorders, female carriers usually show no symptoms because the activity of the product of the normal gene is sufficient to prevent abnormalities, this is not the case in the syndrome Lowe. Almost every woman with Lowe's syndrome over the age of 10 will show characteristic changes in the lenses of her eyes that are different from any other metabolic cataract. Some carriers, even at the age of 30, develop a visually significant cataract, sufficient for an operation to remove it, so the operating surgeon may miss it. However, these highly informative and distinctive changes in the lens of the female wearer should result in an ophthalmologist who suspects this diagnosis in a man should dilate his pupils and reflexively examine the mother of the person in question child.

A man has only one X chromosome, which he inherits from his mother; if a man inherits the X chromosome containing the disease gene, he will develop the disease. Women who are carriers of X-related disorder have a 25% chance of having a carrier daughter like yourself, a 25% chance of having a healthy daughter, a 25% chance of having a son with a disease, and a 25% risk of giving birth to an unaffected son. Of course, each pregnancy does not depend on the last one and does not affect the outcome of the next pregnancy.

Men with Lowe's syndrome have never had children.

Affected populations

Lowe's syndrome is a rare genetic disorder that occurs almost exclusively in men. The estimated prevalence is between 1 and 10 men per 1,000,000 population. The condition has been reported in the Americas, Europe, Japan, and India.

Symptomatic disorders

Signs of the following disorders may be similar to those of Lowe's syndrome. Comparisons can be useful for differential diagnosis:

• Congenital rubella (German measles) is a syndrome that occurs when a fetus becomes infected with the rubella virus in the uterus. It is primarily characterized by disorders of the heart and nervous system, eyes and ears. The fetus is most vulnerable to the virus during the first three months of pregnancy, although pregnant women are advised to avoid contact with the rubella virus at all times. Women who contract rubella during pregnancy have a high risk of having a baby with congenital rubella.
• Violations of the biogenesis of peroxisome spectrum of Zelweger syndrome are a group of genetic disorders of varying severity, characterized by low muscle tone (hypotension), difficulty eating, and abnormal facial features. Other symptoms may include visual and hearing impairment, epilepsy and dysfunction liver. Mutations in several different genes have been found to be associated with the reduction or elimination of cellular structures called peroxisomes, which are necessary for the breakdown of a certain class of fatty acids called very long fatty acids chain. However, congenital cataracts are not a feature of the disease.
• Cataract Dental Syndrome (Nance-Horan syndrome) is an extremely rare genetic disorder that can manifest itself at birth due to cataracts. The syndrome is primarily characterized by dental abnormalities and clouding of the lens of the eyes (congenital cataracts), which leads to impaired vision. Additional eye abnormalities are also often present, such as an unusually small anterior, clear the part of the eye through which light passes (microcornea) and involuntary, rapid, rhythmic eye movements (nystagmus). In some cases, the disorder can also be associated with additional physical abnormalities (ears turned forward, short fourth and fifth fingers and toes, as well as severely abnormal teeth that are barrel-shaped and widely spaced, and possibly intellectual backwardness. The range and severity can vary greatly from person to person, even among affected family members. It is important to note that in women and mothers who are carriers of this condition, which is also associated with X, very characteristic cataracts are also observed, usually with Y-shaped lens sutures, which sometimes worsen vision. Most female carriers also have corneas that are slightly smaller in diameter than normal, but may go unnoticed if the ophthalmologist does not take the initiative to examine them.
• Smith-Lemli-Opitz Syndrome (SLOS) is a highly variable genetic disease characterized by slow growth before and after birth, a small head (microcephaly), mild to moderate developmental disability and multiple birth defects, including certain facial features, accidental cataracts at birth, cleft palate, heart defects, fused second and third fingers, extra fingers and toes and underdeveloped external genital organs in men. The severity of SLOS varies greatly among affected individuals, even within the same family, with some showing normal development and only minor birth defects. SLOS is caused by a deficiency of the enzyme 7-dehydrocholesterol reductase (DHCR7), which leads to disruption of cholesterol synthesis. SLOS is inherited as an autosomal recessive genetic disorder. Aminoaciduria, rickets and other features are absent despite hypotension.
• Dent's disease Is an X-linked disease with overlapping kidney stones (nephrolithiasis), hypophosphatemic rickets, and excess calcium, phosphates, proteins, and amino acids in the urine. Many men with Dent's disease also have mild developmental delays. About two-thirds of men with Dent's disease have mutations in a chloride channel gene called CLCN5but most others have mild mutations in OCRLInterestingly, without the typical face, behavioral features, metabolic acidosis and congenital cataract of the classic Lowe's syndrome.

Diagnostics

Lowe's syndrome is diagnosed when there is a decrease in the activity of the OCRL enzyme phosphatidylinositol polyphosphate 5-phosphatase in cultured skin cells (fibroblasts). Also available and accurately detects more than 95% of affected men molecular genetic testing of gene mutations OCRL.

Testing of female carriers is also available. Approximately 95% of female carriers over the age of 10 have specific and distinctive lens abnormalities that can be diagnosed by an experienced ophthalmologist. Molecular genetic testing for carrier status is available if a specific gene mutation has been identified in a male relative OCRL. Biochemical testing of OCRL enzyme activity of phosphatidylinositol-polyphosphate-5-phosphatase is not reliable for testing carriers for Lowe's syndrome because the range of enzyme activity extends within the normal range range.

Antenatal diagnosis is available using biochemical analysis (enzyme analysis) or molecular genetic testing if gene mutation OCRL was identified in a sick male relative or carrier mother.

Standard treatments

Lowe's syndrome usually requires a team of healthcare professionals, including a pediatric ophthalmologist, nephrologist, geneticist, nutritionist, endocrinologist, neurologist, child development specialist, general surgeon, orthopedist and dentist.

Low muscle tone (hypotension) can sometimes lead to nutritional problems and may require artificial feeding and standard gastroesophageal reflux measures.

Early cataract removal is recommended for optimal vision development. Glasses and contact lenses help improve vision. Glaucoma, which affects half of men, can sometimes be treated with medication (eye drops), but usually requires surgery, which is not always successful with a single operation. Corneal keloids, if they occur, can sometimes be surgically removed, but often recur more aggressively than before. There is no consistent, proven therapy for killing corneal keloids.

Fanconi-type proximal tubular dysfunction is treated with oral sodium bicarbonate or potassium citrate supplements. Doses should be determined individually.

Oral phosphate and oral calcitriol are used to treat (or prevent) rickets. Bone density should be monitored periodically. Seizure disorders are treated with anticonvulsant drugs. Behavior problems are treated with behavior modification and medication.

Early intervention programs are recommended that include physical therapy, occupational therapy, speech and language therapy, special educational services and services for the visually impaired and should start early childhood.

Boys with Lowe's syndrome should be checked regularly for problems with vision (especially late glaucoma), kidney function, growth, development, scoliosis, joint and dental problems.

End-stage renal disease is successfully treated with dialysis and kidney transplantation in late adolescent adult men.

Forecast

The quality of life depends on the degree of neurological and renal manifestations. Life expectancy rarely exceeds 40 years, and death occurs between 20-40 years as a result of renal insufficiency, hypotension, increased susceptibility to infectious diseases, seizures and sudden of death. Glaukoma is often difficult to control.

The oldest recorded patient with Lowe's syndrome died at the age of 54.