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lowe syndrome

Lowe syndrome

Lowe syndrome also known as oculocerebrorenal syndrome, is a condition that primarily affects the eyes, brain, and kidneys 1. Lowe syndrome occurs almost exclusively in males. A few affected females with the clinical manifestations of Lowe syndrome have been reported 2.

Male infants with Lowe syndrome are born with thick clouding of the lenses in both eyes (congenital cataracts), often with other eye abnormalities that can impair vision. About half of affected infants develop an eye disease called infantile glaucoma, which is characterized by increased pressure within the eyes. All boys have impaired vision; corrected acuity is rarely better than 20/100.

Many individuals with Lowe syndrome have delayed development, and intellectual ability ranges from normal to severely impaired. Almost all affected males have some degree of intellectual disability; 10%-25% function in the low-normal or borderline range, approximately 25% in the mild-to-moderate range, and 50%-65% in the severe-to-profound range of intellectual disability. Behavioral problems and seizures have also been reported in children with Lowe syndrome. Most affected children have weak muscle tone from birth (neonatal hypotonia), which can contribute to feeding difficulties, problems with breathing, and delayed development of motor skills such as sitting, standing, and walking. Deep tendon reflexes are usually absent.

Hypotonia may slowly improve with age, but normal motor tone and strength are never achieved. Motor milestones are delayed.

Kidney (renal) abnormalities, most commonly a condition known as renal Fanconi syndrome, frequently develop in individuals with Lowe syndrome. The kidneys play an essential role in maintaining the right amounts of minerals, salts, water, and other substances in the body. Affected males have renal Fanconi syndrome with low molecular-weight proteinuria, aminoaciduria, bicarbonate wasting and renal tubular acidosis, phosphaturia with hypophosphatemia and renal rickets, hypercalciuria, sodium and potassium wasting, and polyuria. These kidney problems lead to increased urination, dehydration, and abnormally acidic blood (metabolic acidosis). A loss of salts and nutrients may also impair growth and result in soft, bowed bones (hypophosphatemic rickets), especially in the legs. Progressive kidney problems in older children and adults with Lowe syndrome can lead to life-threatening renal failure and end-stage renal disease (ESRD). The features of symptomatic Fanconi syndrome do not usually become manifest until after the first few months of life, except for low molecular-weight proteinuria. Glomerulosclerosis associated with chronic tubular injury usually results in slowly progressive chronic renal failure and end-stage renal disease between the second and fourth decades of life.

Lowe syndrome is an uncommon condition. It has an estimated prevalence of 1 in 500,000 people 3. Lowe syndrome has been reported in North and South America, Europe, Japan, and India.

Lowe syndrome causes

Mutations in the OCRL gene cause Lowe syndrome. The OCRL gene provides instructions for making an enzyme that helps modify fat (lipid) molecules called membrane phospholipids. By controlling the levels of specific membrane phospholipids, the OCRL enzyme helps regulate the transport of certain substances to and from the cell membrane. This enzyme is also involved in the regulation of the actin cytoskeleton, which is a network of fibers that make up the cell’s structural framework. The actin cytoskeleton has several critical functions, including determining cell shape and allowing cells to move.

Some mutations in the OCRL gene prevent the production of any OCRL enzyme. Other mutations reduce or eliminate the activity of the enzyme or prevent it from interacting with other proteins within the cell. Researchers are working to determine how OCRL mutations cause the characteristic features of Lowe syndrome. Because the OCRL enzyme is present throughout the body, it is unclear why the medical problems associated with this condition are mostly limited to the brain, kidneys, and eyes. It is possible that other enzymes may be able to compensate for the defective OCRL enzyme in unaffected tissues.

Lowe syndrome inheritance pattern

Lowe syndrome is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Most X-linked disorders affect males much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In some cases of Lowe syndrome, an affected male inherits the mutation from a mother who carries one altered copy of the OCRL gene. Other cases result from new mutations in the gene and occur in males with no history of the disorder in their family.

Females who carry one mutated copy of the OCRL gene do not have the characteristic features of Lowe syndrome. Most female carriers, however, have changes in the lens of the eye that can be observed with a thorough eye examination. These changes typically do not impair vision.

Figure 1. Lowe syndrome X-linked inheritance pattern

Lowe syndrome X-linked inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

Lowe syndrome symptoms

Lowe syndrome signs and symptoms:

  • Cataracts in both eyes, found at birth or shortly after
  • Glaucoma (in about half the cases)
  • Poor muscle tone and delayed motor development
  • Cognitive delays, ranging from borderline to severe
  • Seizures (in about half the cases)
  • Severe behavior problems (in some cases)
  • Kidney involvement (“Leaky” kidneys, or renal tubular acidosis)
  • Short stature
  • Tendency to develop rickets, bone fractures, scoliosis and joint problems

The major clinical manifestations found in males with Lowe syndrome involve the eyes, central nervous system, and kidneys. Nearly all post-pubertal heterozygous females have lens opacities; a few will have additional findings. With the wide availability of molecular genetic testing, phenotypic heterogeneity appears to be substantially greater than previously suspected, such that individuals who lack certain features of Lowe syndrome can still have pathogenic variants in OCRL.

Boys with Lowe syndrome have cataracts that are present at birth in each eye (and detectable by high resolution ultrasound prenatally in suspect cases). With only extremely rare exceptions, these require surgery early in life, as soon as health allows for anesthesia to perform it. But even in optimal circumstances, corrected visual acuities when recordable are rarely better than 20/100. Approximately half of eyes will develop high pressure in the eye (glaucoma) that can damage the optic nerve and lead to blindness if not controlled. Infants with Lowe syndrome have poor muscle tone (hypotonia) at birth and experience delayed motor development. Almost all boys with Lowe syndrome have developmental and intellectual disability that can range from mild (~10%-25%) to severe (~50%-65%). Seizures occur in approximately half of those by six years of age, and behavioral problems are present in some boys with Lowe syndrome. A fraction of affected males develop growths on the corneas of one or both eyes called keloids during late childhood and adolescence. These growths are progressive and can lead to blindness.

The kidney problem associated with Lowe syndrome is called proximal tubular dysfunction of the Fanconi type. This abnormality results in the loss of certain substances (amino acids, bicarbonates, and phosphates) into the urine that are normally filtered prior to excretion into the urine or reabsorbed by the body. However, as mentioned, the spilling or leakage of amino acids into the urine seldom begins until the end of the first year of life, sometimes delaying and confounding the diagnosis. The filters in the kidney (glomeruli) usually begin to fail in boys with Lowe syndrome after 10 years of age. Kidney failure is slow and progressive and results in a reduced life expectancy of approximately 30-40 years.

Other signs frequent in boys with Lowe syndrome include short stature, dental cysts and abnormal dentin formation of the teeth, skin cysts, and vitamin D deficiency that can lead to soft bones, skeletal changes (rickets), bone fractures, scoliosis, and non-inflammatory degenerative joint disease. Some patients have shown a delayed bleeding diathesis following surgery characterized by normal hemostasis and clot formation, only to be followed a few hours later by sudden recurrence of bleeding. This may be an important consideration with any surgery but especially both cataract surgery and glaucoma surgery in which bleeding inside the eye may have considerable consequences.

Males

Eyes

Dense congenital cataracts, formed as a result of abnormal metabolism or migration of the embryonic lens epithelium, are found in all affected boys. Although present at birth, the cataracts may not be detected until a few weeks of life. Rarely, the lens opacities are so mild that they do not affect visual development, even into the teen years.

  • Microphthalmos and enophthalmos, related to the lens abnormality, are noted occasionally.
  • Infantile glaucoma, present in approximately 50% of affected males, is difficult to control and often results in buphthalmos (enlarged eyes) and progressive visual loss 4. Often the glaucoma is not detected until after the lenses have been removed. The glaucoma is severe and requires surgical, rather than medical, management.
  • Strabismus, retinal dystrophy, secondary corneal scarring, and calcific band keratopathy with keloid formation 5 may cause additional visual impairment 4.

All boys have impaired vision; corrected acuity is rarely better than 20/100 4. With decreased visual acuity, nystagmus develops early in life, even with early and uncomplicated surgery. Self-stimulatory activity also increases, i.e., rhythmic flapping of the hands, eye rubbing, and repetitive rocking movements. Despite aggressive intervention, visual disability may progress to blindness.

Central nervous system

Generalized infantile hypotonia is noted soon after birth and is of central origin. Deep tendon reflexes are usually absent. Hypotonia may slowly improve with age, but neither normal motor tone nor strength is ever achieved.

  • Feeding difficulties in infancy associated with poor head control, sucking, or swallowing may be a consequence of the hypotonia.
  • Decreased motor tone also results in delayed motor milestones. Independent ambulation occurs in approximately 25% of boys between age three and six years and in 75% by age six to 13 years. Some never walk, requiring the use of a wheelchair for mobility 6.

Approximately 50% of affected boys have seizure disorders, most often of the generalized type and usually starting before age six years 6.

Behavior problems (i.e., self-stimulation or stereotypic and obsessive-compulsive behaviors) are frequent and include many problems common to visually and intellectually handicapped individuals. Occasionally, violent tantrums or aggressive and self-abusive behaviors occur 7.

Almost all affected males have some degree of intellectual impairment. Between 10% and 25% of affected males function in the low-normal or borderline range, approximately 25% function in the mild-to-moderate range, and 50%-65% function in the severe-to-profound range of intellectual disability 7. Delayed language development is evident in early childhood. Most individuals learn to communicate verbally to some extent by age seven years; some eventually become quite verbal 6. Love of music and rhythm are notable.

As adults, most affected men reside with their families. A few are functional enough to live in a group home or even independently with appropriate assistance and guidance.

Kidneys

Affected boys have varying degrees of proximal renal tubular dysfunction of the renal Fanconi type. The features of symptomatic Fanconi syndrome do not usually become manifest until after the first few months of life, except for low molecular-weight (low molecular-weight) proteinuria.

  • Low molecular-weight proteins are normally filtered by the glomerulus, then reabsorbed in the proximal tubule through endocytosis and metabolized in lysosomes in proximal tubular cells.
  • When reabsorption and/or metabolism are dysfunctional, low molecular-weight proteins, including retinol-binding protein, beta-2-microglobulin, and the lysosmal enzyme N-acetyl glucosaminidase, are lost in the urine. low molecular-weight proteinuria has been identified as early as just after birth 8 and may be the most sensitive early marker for renal involvement of Lowe syndrome.

The molecular size of albumin is at the upper end of the size range for low molecular-weight proteins, so the small percentage of albumin that is normally filtered by the glomerulus is also reabsorbed and metabolized by the proximal tubule via the low molecular-weight protein transport process.

In Lowe syndrome, proximal renal tubular dysfunction often leads to clinically apparent albuminuria (urine dipstick albumin 1-4+; nephrotic range proteinuria >1 g/m2/day in more than half), while serum albumin remains normal 9. Albuminuria is better known as a marker of glomerular injury in other diseases such as diabetes mellitus; in Lowe syndrome it likely reflects proximal tubular dysfunction, especially early in life before chronic renal failure occurs.

All boys have low molecular-weight proteinuria and albuminuria, likely due to downstream disordered endocytosis and postendocytic membrane trafficking in the proximal tubular cell 10. Most boys have aminoaciduria 9. Some boys develop full-blown renal Fanconi syndrome with bicarbonaturia and renal tubular acidosis, phosphaturia with hypophosphatemia and renal rickets, sodium and potassium wasting, and polyuria with an apparent urine-concentrating defect from the massive solute loss in the urine. Few of these boys have renal glucose wasting, which is frequently observed in other diseases with full-spectrum renal Fanconi syndrome 11. Other boys have little or no bicarbonaturia and phosphaturia, but low molecular-weight proteinuria and hypercalciuria with nephrocalcinosis and nephrolithiasis (calcium oxalate and calcium phosphate stones) similar to Dent disease 9.

Progressive glomerulosclerosis likely results from progressive renal tubular injury, which eventually may lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD) between the second and fourth decades of life 11.

Short stature

Although birth length is usually normal, linear growth velocity is below normal and short stature becomes evident by age one year. The average adult height is approximately 155 cm 6. Chronic kidney disease and acidosis along with renal rickets or other bone disease may contribute to the short stature. Some boys have been treated with growth hormone, resulting in an increase in height but persistence of short stature for age 11.

Feeding and gastrointestinal concerns

  • Slow weight gain may occur because of insufficient caloric intake.
  • Gastroesophageal reflux, most common in infancy, may be seen at any age.
  • Aspiration of food along with a decreased ability to cough effectively to clear lung fields may lead to atelectasis, pneumonia, or chronic lung disease.
  • Poor abdominal muscle tone increases the risk for chronic constipation and the development of (predominantly inguinal) hernias.

Bone disease

Bone disease in affected boys may be related to Fanconi syndrome with phosphaturia, inadequate renal production of 1,25-dihydroxyvitamin D, and chronic acidosis as well as chronic kidney disease. The bone disease may appear as classic changes of rickets on bone radiographs.

However, even in the presence of well-corrected Fanconi syndrome and no findings of rickets, some boys have repeat pathologic bone fractures with poor healing and bone demineralization on radiographs or bone densitometry.

Whether some of the bone disease is related to inactivity resulting from muscle hypotonia and immobilization in severely affected boys or to a primary defect in bone mineralization/molecular transport requires further study.

Other musculoskeletal concerns

  • Decreased truncal motor tone increases the risk of developing scoliosis, present in approximately 50% of affected boys 6.
  • Hypermobile joints may result in joint dislocation, especially of the hips and knees.
  • In affected teenagers and adults, joint swelling, arthritis, tenosynovitis, and subcutaneous benign fibromas, often on the hands and feet and most especially in areas of repeated trauma, are noted frequently 12.
  • Elevated serum creatine kinase (CK), AST, and LDH are typical in Lowe syndrome and likely due to abnormal muscle metabolism 9.
  • Decreased plasma carnitine concentration has been reported in approximately one third of individuals with Lowe syndrome 13, but the need for or efficacy of carnitine supplementation has never been studied, and therapy continues to be individualized.

Genitourinary issues

  • Undescended testes (cryptorchidism) are noted in approximately one third of affected boys 14. Isolated LH elevation at baseline and on GnRH stimulation testing was observed in an infant with undescended testes 15.
  • Puberty may be delayed in onset; otherwise, male secondary sexual development is normal.

Teeth and skin findings

Dental malformations and generalized mobility of primary teeth with decreased or dysplastic dentin formation may also be related to a primary dental abnormality in Lowe syndrome 16.

Superficial cysts may occur in the mouth and on the skin, especially the scalp, lower back and buttocks.The skin cysts may become painful and occasionally infected. Histologic examination revealed epidermal cysts in which the dermis was lined by several layers of stratified squamous epithelium with a granular layer and filled with keratin flakes 17. Cysts have also been found in imaging studies of the kidneys and brain. These findings suggest that an abnormality in connective tissue may also be involved in the pathogenesis of the disorder 18.

Coagulation disorder

The OCRL-1 protein is found in human platelets. Prolonged or delayed bleeding following surgery, such as cataract extraction has been reported. An intrinsic platelet defect in these individuals that can be detected using a platelet function analyzer (PFA-100) was identified; other coagulation profile related tests, including platelet counts, gave normal results 19. In another study, thrombocytopenia/low normal platelets were found in about 20% 14.

Life span

Most males do not live past age 40 years. The oldest reported patient to live with Lowe syndrome died at age 54 years 20. In older individuals, death has been related to progressive renal failure or scoliosis. Death from dehydration, pneumonia, and infections occurs at all ages 6.

Lowe syndrome females

Approximately 95% of postpubertal heterozygous females have characteristic findings in the lens of each eye on slit lamp examination through a dilated pupil by an experienced ophthalmologist. The lens findings have correlated with the results of molecular genetic studies in predicting heterozygosity for the pathogenic variant in OCRL in postpubertal females 4. While the lens findings may appear in prepubertal females as well (especially the less common axial posterior central opacity), their absence does not exclude the possibility of heterozygosity.

Most heterozygous females show numerous irregular, punctate, smooth, off-white (white to gray) opacities, present in the lens cortex, more in the anterior cortex than the posterior cortex, and distributed in radial bands that wrap around the lens equator. Classically, the nucleus is spared. On retroillumination, the opacities are distributed in a radial, spoke-like pattern and can be relatively dense in a wedge shape comparable to an hour or two on the face of a clock, alternating with a similar-sized wedge with few to no opacities.

A few heterozygous females (~10%) have a dense central precapsular dead-white cataract at the posterior pole of the lens that may be visually significant if it is large. Similarly, the cataracts in some heterozygous females may become visually significant by the fourth decade and require surgery without the diagnostic importance being recognized.

The manifestations of Lowe syndrome besides those seen in the lens are not observed in heterozygous females unless there is either rare X;autosome translocation with the X chromosome breakpoint at OCRL or extremely skewed X inactivation. In an example of the latter, a female with two structurally normal X chromosomes showed classic, severe Lowe syndrome as a result of a familial defect in X inactivation inherited from her father. The paternally derived X chromosome containing a normal OCRL gene remained inactive in 100% of cells, while the maternally derived X chromosome carrying a pathogenic variant of ORCL was active in 100% of cells tested 2.

Lowe syndrome diagnosis

Lowe syndrome should be suspected in an index case (proband) with a combination of the following features:

  • Bilateral dense congenital cataracts
  • Infantile congenital hypotonia
  • Delayed development
  • Proximal renal tubular transport dysfunction of the Fanconi type characterized by low molecular-weight (low molecular-weight) proteinuria (including retinol binding protein, N-acetyl glucosaminidase, and albumin), aminoaciduria and varying degrees of bicarbonaturia and acidosis, phosphaturia and hypophosphatemia, and hypercalciuria.

Note: low molecular-weight proteinuria, characterized by the excretion of proteins such as retinal binding protein and N-acetyl glucosaminidase, is seen in Lowe syndrome, the allelic disorder Dent disease (see Genetically Related Disorders), and many other diseases associated with the Fanconi syndrome. In Lowe syndrome, low molecular-weight proteinuria can be seen early in life even in the absence of clinically significant aminoaciduria or other renal tubular abnormalities [Laube et al 2004]. Thus, low molecular-weight may be the most sensitive early marker of the renal dysfunction occurring in this disorder.

Lowe syndrome is diagnosed when a reduced activity of the phosphatidylinositol polyphosphate 5-phosphatase OCRL enzyme is demonstrated in cultured skin cells (fibroblasts). Molecular genetic testing for OCRL gene mutations is also available and accurately detects more than 95% of affected males.

Carrier testing for female relatives is available. Approximately 95% of carrier females older than 10 years of age have specific and distinctive abnormalities of the lens of the eye that can be diagnosed by an experienced ophthalmologist. Molecular genetic testing for carrier status is available if a specific OCRL gene mutation has been identified in a male relative. Biochemical testing for phosphatidylinositol polyphosphate 5-phosphatase OCRL enzyme activity is not reliable for carrier testing for Lowe syndrome because the range of enzyme activity spreads over the normal range.

Prenatal diagnosis is available with biochemical testing (enzyme assay) or molecular genetic testing if the OCRL gene mutation has been determined in an affected male relative or carrier mother.

Lowe syndrome treatment

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

Table 1. Recommended evaluations following initial diagnosis in individuals with Lowe syndrome

System/
Concern
EvaluationComment
EyesOphthalmologic exam to assess for cataract & glaucomaBehavior problems may necessitate use of anesthesia for exam.
CNS
  • Developmental & behavior assessments
  • EEG if seizures present to optimize therapy
KidneysAssess renal tubular function.Tests should include:
  • Serum electrolytes, glucose, calcium, phosphorus & creatinine
  • Simultaneous urinalysis, urine pH, sodium, potassium, chloride, calcium, phosphorus, creatinine, amino acids, protein & retinol-binding protein, &/or N-acetyl glucosaminidase (if available) 1
If hematuria or hypercalciuria is present, renal ultrasound to look for nephrolithiasis or nephrocalcinosis.
If aciduria or phosphaturia present, test serum 1,25-dihydroxy vitamin D & parathyroid hormone plus bone radiographs to evaluate for renal rickets.
Growth/
Feeding
  • Growth parameters
  • Infants assessed for feeding problems & gastroesophageal reflux, incl a pH probe study
SkeletalRadiographs for bone pain or point tenderness to evaluate for fractures
DentalThorough clinical exam after tooth eruptionGeneralized mobility of all primary teeth as well as subrachitic changes due to renal rickets
HematologicAlert providers performing any surgical interventions of risk for delayed bleeding after apparent hemostasis in immediate post-op period.
OtherConsultation w/a clinical geneticist &/or genetic counselor

Footnote: 1. Interpretation of these results allows diagnosis of type 2 renal tubular acidosis, hypokalemia, phosphate wasting with decreased tubular reabsorption of phosphate (TRP), hypercalciuria (urine calcium/creatinine ratio >0.02), amino aciduria, albuminuria (urine dipstick-positive albumin and urine protein/creatinine ratio >0.2), LMW proteinuria, and CKD (serum creatinine).

[Source 1 ]

Low muscle tone (hypotonia) can sometimes result in feeding problems and may require tube feeding and standard measures for gastroesophageal reflux.

Early removal of cataracts is recommended to promote optimum development of vision. Eyeglasses and contact lenses help to improve vision. Glaucoma occurring in half of males sometimes may be treated with medication (eyedrops) but usually requires surgery, which is not always successful with a single operation. If they occur, corneal keloids can sometimes be removed surgically but often recur more aggressive than before. There is no consistent proven therapy to eradicate corneal keloids.

Proximal tubular dysfunction of the Fanconi type is treated with oral supplements of sodium and potassium bicarbonate or citrate. Doses must be determined on an individual basis.

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

Early intervention programs that include physical therapy, occupational therapy, speech and language therapy, special education services, and services for visually impaired are recommended and should begin in early infancy.

Boys with Lowe syndrome should be monitored regularly for vision problems (especially later onset glaucoma), kidney function, growth, developmental progress, scoliosis, and joint problems, and dental problems.

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

Surveillance

Intraocular pressure monitoring every six months for life, other eye evaluations at intervals determined by specialist; at least annual assessment of kidney function, growth, developmental progress; annual evaluation for scoliosis and joint problems; semiannual dental examinations.

Circumstances to avoid

  • Corneal contact lenses. Because of the associated risks of corneal keloid formation and the inherent difficulties that the person with Lowe syndrome has in managing personal contact lens care, conventional eye glasses seem safer than corneal contact lenses.
  • Artificial lens implants. Although some infants have had primary intraocular lens implantation at the time of cataract surgery, the associated risk of glaucoma appears higher in those infants with artificial lens implants. Therefore, artificial lens implants should be used with extreme caution, with intraocular pressure carefully monitored (under anesthesia if required) on a continual basis.

Lowe syndrome prognosis

Currently, there is no correlation between the genotype and phenotypes, so clinical severity of disease cannot be correlated with certain variants. However, affected males within the same family have similar phenotypes, as intrafamilial variability has not yet been reported 21.

Most males do not live past age 40 years. The oldest reported patient to live with Lowe syndrome died at age 54 years 20. In older individuals, death has been related to progressive renal failure or scoliosis. Death from dehydration, pneumonia, and infections occurs at all ages 6.

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Health Jade Team

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