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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. Lowe syndrome is caused by markedly reduced activity of the enzyme inositol polyphosphate 5-phosphatase OCRL-1, which is encoded by the gene OCRL. The diagnosis is established in affected individuals by demonstrating reduced (<10% of normal) activity of inositol polyphosphate 5-phosphatase OCRL-1 in cultured skin fibroblasts. Such testing is available clinically. Molecular genetic testing of the gene OCRL detects mutations in approximately 95% of affected males and a similar proportion of carrier females. Molecular genetic testing is available clinically.
Management. Treatment of manifestations: early removal of cataracts; nasogastric tube feedings or feeding gastrotomy, with or without fundoplication, to achieve appropriate nutrition; occupational or speech therapy to address feeding problems; standard measures for gastroesophageal reflux; programs to promote optimal psychomotor development, including services for the visually handicapped, beginning in early infancy; behavior modification plan with antidepressant and/or antipsychotic medications as needed. For those with renal Fanconi syndrome/type 2 renal acidosis: oral supplements of sodium and potassium bicarbonate or citrate to correct acidosis and hypokalemia, and oral phosphate and oral calcitriol (1,25-dihydroxyvitamin D3) to correct hypophosphatemia and renal rickets; consider treatment of ESRD with chronic dialysis and renal transplant in selected individuals; consider human growth hormone therapy to improve growth velocity; resection of fibromas and cutaneous cysts if painful or impairing function. Prevention of secondary complications: intravenous fluids, bicarbonate, and electrolytes during illness or when fasting. Surveillance: routine eye evaluations with attention to measurement of intraocular pressure; routine monitoring of kidney function, growth, developmental progress; annual evaluation for scoliosis and joint problems; semiannual dental examinations. Circumstances to avoid: corneal contact lenses because of associated risk of corneal keloid formation and complexities of contact lens care; artificial lens implants because of probable increased risk of glaucoma. Other: Despite appropriate medical and surgical measures, glaucoma is often difficult to control.
Genetic counseling. Lowe syndrome is inherited in an X-linked manner. New mutations have been reported in 32% of affected males with Lowe syndrome. A high risk of germline mosaicism (4.5%) has been identified. When a mother is a carrier, each pregnancy has a 25% chance of resulting in an affected boy, a 25% chance of resulting in a carrier daughter, a 25% chance of resulting in an unaffected boy, and a 25% chance of resulting in a girl who is not a carrier. No affected male is known to have reproduced. Approximately 95% of carrier females over age 15 years have characteristic findings in the lens of the eye when the lens is evaluated by an experienced ophthalmologist through a dilated pupil with a slit-lamp with both direct and retroillumination. Prenatal testing is available. Assay of enzyme activity is the preferred method for prenatal diagnosis for Lowe syndrome. Molecular genetic testing may be used to confirm the enzymatic assay results if the OCRL mutation has been identified in an affected family member; however, such testing is not always necessary.
Males with Lowe syndrome. Varying degrees of severity of the following developmental defects have been noted among affected individuals [Lowe et al 1952, Gropman et al 2000, Nussbaum & Suchy 2001]. The disorder is suspected clinically in males who have 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 varying degrees of bicarbonaturia and acidosis, phosphaturia, aminoaciduria and low molecular-weight proteinuria (including retinol binding protein, N-acetyl glucosaminidase, and albumin); except for low molecular-weight proteinuria, the Fanconi syndrome features do not appear until after the first few months of life.
Other frequently noted findings:
Infantile glaucoma (in ~50% of males)
Seizures
Absent deep tendon reflexes
Maladaptive behaviors, especially stubbornness, tantrums, stranger anxiety, and stereotypy (complex repetitive behaviors)
Short stature
Mild ventriculomegaly and multiple, periventricular, variably sized, small cysts on MRI in approximately one-third of affected individuals [Charnas & Gahl 1991, Demmer et al 1992, Carroll et al 1993]
Hypercalciuria with nephrocalcinosis and nephrolithiasis
Pathologic fractures and bone demineralization in the presence of normal serum concentrations of calcium, phosphorus, and vitamin D metabolites
Dental cysts and dysplastic dentin formation of the teeth
Skin cysts similar to eruptive vellus hair cysts
Female carriers of Lowe syndrome. Approximately 95% of postpubertal carrier females have characteristic findings in the lens of each eye when the lens is evaluated through a dilated pupil with a slit-lamp by an experienced ophthalmologist. The lens findings have correlated with the results of molecular genetic studies in predicting carrier status of postpubertal females [Lin et al 1999, McSpadden 2000, Roschinger et al 2000, Nussbaum & Suchy 2001]. While the lens findings may be present in prepubertal females as well, especially the less common axial posterior central opacity, their absence does not exclude carrier status.
Most carrier 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 wrapping 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 carriers (~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.
For laboratories offering biochemical testing, see
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Low molecular-weight (LMW) proteinuria. LMW 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 Allelic Disorders), and many other diseases associated with the Fanconi syndrome. In Lowe syndrome, LMW 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, LMW may be the most sensitive marker of the renal dysfunction that occurs in this disorder.
Inositol polyphosphate 5-phosphatase OCRL-1 activity
Males. Activity of the enzyme inositol polyphosphate 5-phosphatase OCRL-1 (phosphatidylinositol polyphosphate 5-phosphatase OCRL-1) can be measured in cultured skin fibroblasts to confirm the diagnosis in affected males [Suchy et al 1995, Zhang et al 1995]. Affected males have less than 10% normal activity of the enzyme. Such testing is abnormal in more than 99% of affected males.
Note: Peripheral blood samples cannot be used because the enzyme is not present in lymphocytes [Nussbaum & Suchy 2001].
Carrier females. Measurement of activity of the enzyme inositol polyphosphate 5-phosphatase OCRL-1 is not accurate for carrier detection because of lyonization (random X-chromosome inactivation), which results in a wide range of "normal" activity in females [Lin et al 1999].
Karyotype. Translocations between an autosome and an X chromosome with a breakpoint through the OCRL locus (Xq26.1) have been observed [Hodgson et al 1986, Mueller et al 1991].
Other. No specific findings are noted on muscle biopsy, nerve conduction testing, or electromyography [McSpadden 2000, Nussbaum & Suchy 2001].
Gene. OCRL is the only gene known to be associated with Lowe syndrome.
Clinical uses
Confirmatory diagnostic testing
Clinical testing
Sequence analysis of the OCRL gene identifies mutations in approximately 95% of males with Lowe syndrome. There are no common mutations. Although a few mutations have been noted in more than one affected individual, most mutations are unique to a family.
FISH analysis can detect large (partial or whole-gene) deletions. The detection frequency of this testing is unknown.
Linkage analysis is available on a clinical basis for families in whom an exact DNA mutation or deletion cannot be identified [Reilly et al 1988, Wadelius et al 1989, Lin et al 1999]. Linkage studies are based upon accurate diagnosis of Lowe syndrome in the affected family members (e.g., with enzyme assay confirmation), understanding of the genetic relationships in the family, and the availability and willingness of family members to be tested. The markers used for Lowe syndrome linkage are highly informative and tightly linked to the OCRL locus [Nussbaum et al 1997]. In informative families, linkage analysis and a dilated slit-lamp eye examination may be used to establish a female's carrier status with approximately 94% accuracy.
Note: (1) Linkage analysis may be considered in families with only one affected male; however, the possibility of a new mutation in the affected family member makes interpretation challenging. (2) Germline mosaicism, which can confound studies that rely on linkage alone for carrier detection, has also been documented in Lowe syndrome [Satre et al 1999, Monnier et al 2000].
| Test Method | Mutations Detected | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|
| Sequence analysis | OCRL sequence variants | ~95% 1 | Clinical
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| FISH | Large (partial or whole-gene) deletions of OCRL | Unknown |
1. In affected males
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Establishing the diagnosis in a male proband
Testing of inositol polyphosphate 5-phosphatase OCRL-1 activity in cultured skin fibroblasts is the diagnostic test of choice.
Sequence analysis of OCRL can be used for confirmation of diagnosis; it is necessary for identification of the disease-causing mutation in a family for purposes of carrier testing and prenatal diagnosis.
Consider FISH testing if sequence analysis of some or all exons fails to generate any sequence information (suggesting a partial or whole-gene deletion in a hemizygous male).
Establishing the diagnosis in a female proband. All females suspected of having the Lowe syndrome should have detailed cytogenetic studies in addition to enzymatic and molecular testing for the disorder because of the possibility of an X;autosome translocation.
Mutations in the OCRL gene have been found in five of 13 families with Dent disease who did not demonstrate mutations in CLCN5. Mutations in OCRL can therefore occur within individuals with the isolated renal phenotype of Dent disease who lack the cataracts, renal tubular acidosis, and neurologic abnormalities that are characteristic of Lowe syndrome [Hoopes et al 2005].
The major clinical manifestations found in males with Lowe syndrome involve the eyes, central nervous system, and kidneys. As molecular genetic testing and biochemical studies of the OCRL gene have become more widespread, phenotypic heterogeneity appears to be substantially greater than previously suspected, such that individuals who lack certain features of Lowe syndrome can still have mutations in the OCRL gene.
Usually only males have the disorder. A few affected females with the clinical manifestations of Lowe syndrome have been reported (see Karyotype).
Eyes. Dense congenital cataracts, formed as a result of abnormal metabolism or migration of the embryonic lens epithelium, are found in all affected boys. Microphthalmos and enophthalmos, related to the lens abnormality, are noted occasionally. Although present at birth, the cataracts may not be detected until a few weeks of life.
Infantile glaucoma, present in approximately 50% of affected males, is difficult to control and often results in buphthalmos (enlarged eyes) and progressive visual loss [McSpadden 2000, Nussbaum & Suchy 2001]. The glaucoma is severe and requires surgical management.
Strabismus, retinal dystrophy, secondary corneal scarring, and calcific band keratopathy with keloid formation [Cibis et al 1982] may cause additional visual impairment [McSpadden 2000, Nussbaum & Suchy 2001].
All boys have impaired vision; corrected acuity is rarely better than 20/100 [McSpadden 2000, Nussbaum & Suchy 2001]. 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 and require the use of a wheelchair for mobility [McSpadden 2000].
Approximately 50% of affected boys have seizure disorders, most often of the generalized type and usually starting before age six years [McSpadden 2000].
Behavior problems, i.e., self-stimulation or stereotypic and obsessive-compulsive behaviors, are frequent and include many problems common to visually and mentally handicapped individuals. Occasionally, violent tantrums or aggressive and self-abusive behaviors occur [Charnas & Gahl 1991, Kenworthy et al 1993].
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 and approximately 25% function in the mild-to-moderate range of intellectual disability. The remainder functions in the severe-to-profound range of mental handicap [Kenworthy et al 1993]. 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 talkative [McSpadden 2000]. 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 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 (LMW) proteinuria (see Testing). LMW proteinuria has been identified as early as just after birth [Laube et al 2004] and may be the most sensitive marker for renal involvement of Lowe syndrome.
Albumin can also be handled like a LMW protein. The molecular size of albumin is at the upper end of the size range for LMW proteins, so the small percentage of albumin that is normally filtered by the glomerulus is reabsorbed by the proximal tubule via the LMW protein transport process. In Lowe syndrome, proximal renal tubular dysfunction often leads to clinically apparent albuminuria (urine dipstick albumin 1-4+), while serum albumin remains normal. 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.
Some boys develop full-blown Fanconi syndrome with bicarbonaturia and renal tubular acidosis, phosphaturia with hypophosphatemia and renal rickets, aminoaciduria, LMW proteinuria, sodium and potassium wasting, and polyuria with an apparent urine concentrating defect from the massive solute loss in the urine. Other boys have little or no bicarbonaturia and phosphaturia, but LMW proteinuria and hypercalciuria with nephrocalcinosis and nephrolithiasis [Sliman et al 1995] as seen in Dent disease.
Progressive glomerulosclerosis likely results from progressive renal tubular injury, which eventually may lead to chronic renal failure and end-stage renal disease (ESRD) between the second and fourth decades of life [McSpadden 2000, Nussbaum & Suchy 2001].
Most males do not live past age 40 years. In older individuals, death has been related to progressive renal failure or scoliosis. Death from dehydration, pneumonia, and infections occurs at all ages [McSpadden 2000].
Other clinical manifestations. 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 [McSpadden 2000]. Chronic renal disease and acidosis along with rickets may contribute to the short stature.
Bone disease in affected boys may be related to Fanconi syndrome with phosphaturia, inadequate renal production of 1,25-dihydroxyvitamin D and chronic acidosis, and 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 repeated pathologic bone fractures with poor healing and bone demineralization on radiographs or bone densitometry [E Brewer, personal observation]. 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.
Undescended testes (cryptorchidism) are noted in approximately one-third of affected boys [McSpadden 2000].
Failure to thrive 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.
Decreased truncal motor tone increases the risk of developing scoliosis, present in approximately 50% of affected boys [McSpadden 2000].
Hypermobile joints may result in joint dislocation, especially of the hips and knees.
Puberty may be delayed in onset; otherwise, male secondary sexual development is normal.
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 [Athreya et al 1983, Elliman & Woodley 1983].
Dental malformations with decreased dentin formation may also be related to a primary dental abnormality in Lowe syndrome.
Superficial cysts may occur in the mouth and on the skin. In one report of an individual with a clinical diagnosis of Lowe syndrome who had not had definitive laboratory diagnosis by enzyme assay or molecular genetic testing, biopsy of the cysts showed the histologic findings of an eruptive vellus hair cyst [Nandedkar et al 2004]. Those on the lower back and buttocks can become painful and occasionally infected. 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 [McSpadden 2000, Nussbaum & Suchy 2001].
Elevated serum concentration of high-density cholesterol, creatinine kinase, AST, and LDH are occasionally noted and are of uncertain significance [McSpadden 2000, Nussbaum & Suchy 2001].
Decreased plasma carnitine concentration has been reported in approximately one-third of individuals with Lowe syndrome and may normalize with oral carnitine therapy [Gahl et al 1988]. Whether carnitine wasting in the urine from severe Fanconi syndrome is the etiology of carnitine deficiency has not been studied adequately in Lowe syndrome.
To date, correlation of genotype with phenotype has not been established. Differing clinical courses have been noted in unrelated individuals with the same OCRL mutation [Leahey et al 1993]. It is also now apparent that highly deleterious mutations in the OCRL gene that result in total loss of OCRL gene expression occur both in individuals with Lowe syndrome and in individuals with Dent disease, but intrafamilial variability has not been documented.
Penetrance is complete, with similar phenotype in affected males within any given family.
Oculocerebrorenal syndrome is the formal term for this disorder.
Oculocerebrorenal syndrome is synonymous with Lowe syndrome, but may be preferred in order to avoid the use of eponymous syndrome nomenclature.
Lowe syndrome is an uncommon, pan ethnic disorder with the prevalence of only a few individuals per 100,000 births. In the USA, as of the year 2000, 190 living affected males were known to the Lowe Syndrome Association (LSA), which estimates this number to represent approximately 50% of all cases.
The disorder has been seen in Europe, Japan, and India and is believed to occur worldwide, although it has not been documented in many populations in Africa, South America, or much of the mainland of Asia.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Low molecular-weight (LMW) proteinuria is a feature of Fanconi syndrome and can also be seen in, for example, cystinosis, nephrotoxic drug injury to the tubules (e.g., aminoglycosides) and acute tubulointerstitial renal transplant rejection with tubular injury. However, the LMW proteinuria seems to be a more prominent feature of renal tubular dysfunction in Lowe syndrome and Dent disease than in these other disorders.
Disorders with congenital or neonatal-onset cataracts, hypotonia, proximal renal tubular dysfunction, and delayed development may be considered in the differential diagnosis. These include the following:
Generalized congenital infections (e.g., rubella)
Peroxisomal biogenesis disorders, Zellweger syndrome spectrum. Affected children are hypotonic, feed poorly, and have distinctive facies. Neonatal seizures are common. Bony stippling (chondrodysplasia punctata) of the patella(e) and other long bones may occur. Older children have retinal dystrophy, sensorineural hearing loss, developmental delay with hypotonia, and liver dysfunction. Measurement of plasma very-long-chain fatty acid (VLCFA) levels is the most commonly used and most informative initial screen. Elevation of C26:0 and C26:1 and the ratios C24/C22 and C26/C22 is consistent with a defect in peroxisomal fatty acid metabolism. Mutations in 12 different PEX genes (which encode peroxins, the proteins required for normal peroxisome assembly) have been identified.
Nance-Horan syndrome (OMIM 302350) is an X-linked syndrome of dense cataracts and microcornea associated with dental anomalies including cone-shaped incisors, supernumerary teeth, and facial dysmorphisms such as anteverted pinnae. Female carriers have Y-shaped sutural cataracts and may have dental anomalies as well. Renal abnormalities are not seen, nor is the facial appearance of sunken orbits and bitemporal hallowing seen frequently in Lowe syndrome. Mutations at a novel X-linked gene, NHS, at Xp22, are responsible for the Nance-Horan syndrome.
Smith-Lemli-Opitz syndrome (OMIM 270400) is a congenital multiple anomaly syndrome caused by an abnormality in cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol reductase. It is characterized by prenatal and postnatal growth retardation, microcephaly, moderate to severe mental retardation, and multiple major and minor malformations. The malformations include distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, and 2-3 syndactyly of the toes. The clinical spectrum is wide and individuals have been described with normal development and only minor malformations. The diagnosis relies upon elevated serum concentration of 7-dehydrocholesterol (7-DHC) or an elevated 7-dehydrocholesterol:cholesterol ratio. Molecular genetic testing for mutations of the DHCR7 gene is available and is used primarily for carrier detection and prenatal diagnosis.
Congenital myotonic dystrophy type 1 (DM1) (OMIM 160900) is characterized by hyptonia and severe generalized weakness at birth, often with respiratory insufficiency and early death; mental retardation is common. It is caused by expansion of a cTG trinucleotide repeat in the gene DMPK. The diagnosis of DM1 is suspected in individuals with characteristic muscle weakness and is confirmed by molecular genetic testing of DMPK. Although CTG repeat length exceeding 35 repeats is abnormal, the development of congenital myotonic dystrophy requires repeat lengths greater than 2000.
Disorders of mitochondrial oxidative phosphorylation (see Mitochondrial Disorders Overview). Common clinical features of mitochondrial disease include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. The central nervous system findings are often fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutations of nuclear or mitochondrial DNA (mtDNA). In some individuals, the clinical picture is characteristic of a specific mitochondrial disorder, and the diagnosis can be confirmed by molecular genetic testing of DNA extracted from a blood sample. In many individuals, however, a more structured approach is required for diagnosis, including family history, blood and/or CSF lactate concentration, neuroimaging, cardiac evaluation, and muscle biopsy for histologic or histochemical evidence of mitochondrial disease, and molecular genetic testing for an mtDNA mutation.
Cystinosis (OMIM 219800) is characterized by poor growth, renal tubular Fanconi syndrome, renal glomerular failure, and involvement of other tissues and organ systems. In untreated individuals, failure to grow is generally noticed at age six to nine months. Cystine-depleting therapy begun just after birth can attenuate the Fanconi syndrome. In untreated individuals, glomerular function gradually deteriorates, resulting in renal failure at approximately age ten years. A slit-lamp examination of the cornea showing typical cystine crystals is diagnostic for cystinosis. This should be confirmed by measurement of leucocyte cystine, which is best performed using the cystine binding protein assay. Mutations in CTNS cause cystinosis.
To establish the extent of disease in an individual diagnosed with Lowe syndrome, the following evaluations are recommended:
Infants should be evaluated for feeding problems and gastroesophageal reflux, including a pH probe study.
Growth parameters should be measured and plotted on a growth chart.
An ophthalmologic evaluation is needed to assess for cataract and glaucoma. Behavior problems may necessitate the use of anesthesia for eye examinations.
Renal tubular function should be assessed by measurement of serum electrolytes, calcium, phosphorus and creatinine, and simultaneous urinalysis and random urine pH, electrolytes, calcium, phosphorus, creatinine, amino acids, protein and retinol binding protein, and/or N-acetyl glucosaminidase, if available. 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), low molecular-weight proteinuria, and renal glomerular insufficiency (serum creatinine).
If acidosis or phosphaturia is present, serum concentration of 1,25-dihydroxyvitamin D and parathyroid hormone should be measured and bone radiographs should be obtained to evaluate for renal rickets.
If hematuria or hypercalciuria is present, a renal ultrasound examination should be performed to screen for nephrocalcinosis and nephrolithiasis.
Plasma carnitinine may be measured to evaluate for carnintine deficiency.
Developmental and behavioral evaluations should be completed.
An electroencephalogram (EEG) is often needed to document the exact type of seizures and to determine appropriate anticonvulsant therapy.
Management of the varying clinical problems usually requires more than one medical specialist; experts in pediatric ophthalmology, nephrology, clinical biochemical genetics, metabolism, nutrition, endocrinology, neurology, child development, behavior, rehabilitation, general surgery, orthopedics, or dentistry may be involved.
Eyes. Treatment of the eye problems usually requires an experienced (preferably pediatric) ophthalmologist; cataract surgeons and glaucoma specialists may also be needed.
Early removal of cataracts is recommended to promote proper visual stimulation and development. Postoperatively, eyeglasses or contact lenses help to improve vision. Surgical implantation of artificial lenses is not recommended because of the high prevalence of infantile glaucoma.
Despite management with medical and surgical measures, glaucoma is often difficult to control.
Special services for the visually handicapped should be included in any rehabilitation plan.
Central nervous system. In infancy, feeding and nutrition problems related to hypotonia may be substantial. Occasionally, nasogastric tube feedings or feeding gastrotomy, with or without fundoplication, may be necessary to achieve appropriate nutrition. Occupational or speech therapists who specialize in feeding problems may be of assistance.
Gastroesophageal reflux usually responds to standard anti-reflux measures such as thickened feedings and elevation of the head of the bed. Some individuals need medications to control gastric acidity and to promote gastric emptying; others require surgery.
Most seizure disorders can be controlled with anticonvulsant therapy.
Programs to promote optimal psychomotor development should be started in early infancy. Early childhood and preschool intervention programs, e.g., First Steps or Head Start, and later public or private school programs should evaluate the abilities and specific needs of the child and formulate an individualized educational plan (IEP). Physical therapy, occupational therapy, speech and language therapy, special education services, and services for the visually impaired are usually included in the plan.
A behavior modification plan along with antidepressant and/or antipsychotic medications may be needed for behavior control.
Kidney. Those individuals with renal Fanconi syndrome and type 2 renal acidosis should be treated with oral supplements of sodium and potassium bicarbonate or citrate to correct acidosis and hypokalemia. Doses need to be titrated to individual needs based on "trough" blood concentrations of serum electrolytes (sodium, potassium, chloride, and total carbon dioxide). (Trough levels are blood concentrations measured just before a scheduled dose.)
Treatment with oral phosphate, along with oral calcitriol (1,25-dihydroxyvitamin D3), is needed to correct hypophosphatemia and renal rickets of the Fanconi syndrome. Doses should also be titrated to individual needs based on trough blood concentration for phosphorus and serum concentrations of 1,25-dihydroxyvitamin D, calcium, and intact parathyroid hormone.
An increased requirement for fluids, along with the electrolyte and bicarbonate requirements, places affected individuals at high risk for metabolic imbalance during illness (especially those associated with vomiting or diarrhea) or when fasting, e.g., with surgical procedures. At such times, intravenous replacement of fluids, bicarbonate, and electrolytes is important and may need to be done in anticipation of problems to prevent severe electrolyte disturbances and dehydration.
Progressive glomerulosclerosis likely results from progressive renal tubular injury, which eventually may lead to chronic renal failure and end-stage renal disease (ESRD) between the second and fourth decades of life [McSpadden 2000, Nussbaum & Suchy 2001]. Treatment of ESRD with chronic dialysis and renal transplant may be successful in selected patients [Tricot et al 2003]. Although experience is limited, at least seven adult men with Lowe syndrome and ESRD have been treated successfully over a few years, including three with chronic hemodialysis, one with chronic home peritoneal dialysis, and three with renal transplants [E Brewer, personal observation].
Other. Human growth hormone therapy has been used successfully to improve growth velocity in some boys [McSpadden 2000]. The potential benefits of such therapy must be weighed against its costs/limitations.
Most undescended testes descend with time into the scrotum; some require hormone therapy and/or surgical correction.
In older individuals, bracing or surgery may be needed to arrest or correct severe or progressive scoliosis and joint hypermobility.
Resection of fibromas and cutaneous cysts may be needed if they are painful, have recurrent infections, or limit function.
Eye evaluations should be done at regular intervals, depending upon the type and severity of abnormality. No formal guidelines exist. Because approximately 50% of males either present with glaucoma or develop glaucoma in time, regardless of cataract surgery, intraocular pressure should be monitored at least every six months life-long. Presence of clinical findings suggestive of increased intraocular pressure (e.g., excessive tearing, eye rubbing, change in the clarity/transparency of the cornea) warrant prompt evaluation.
Kidney function should be assessed at least yearly with measurement of serum concentrations of electrolyte, blood urea nitrogen (BUN), creatinine, calcium, phosphorus, albumin, intact parathyroid hormone, and 1,25-dihydroxyvitamin D.
If the patient has Fanconi syndrome requiring therapy with supplemental bicarbonate or citrate, serum concentrations of phosphate or calcitriol should be measured every three to six months or more often after dose changes.
BUN and serum creatinine are appropriate screening tests to detect the onset of chronic renal failure and to monitor its progression.
Urinalysis and random urine protein, calcium, and creatinine are useful to follow proteinuria and hypercalciuria.
If the patient has renal Fanconi syndrome and bone disease, radiographs of the long bones and growth plates should be obtained at regular intervals as needed, but no more than every six months.
Growth should be monitored regularly with height/length and weight plotted on growth charts for age. Height/length and weight should be measured more frequently in infants (every 2-3 months) than in older children and adolescents who are still growing (every 3-6 months). If patients are treated with growth hormone, growth assessment every three months is indicated.
Developmental progress should be assessed and the educational plan updated twice yearly for the first three years and annually after that. Any regression in abilities should be investigated with high-resolution imaging studies of the central nervous system.
Scoliosis and joint problems should be monitored as part of a routine annual physical examination.
Dental examinations should be performed twice a year by a pediatric dentist experienced in treating children with developmental delay.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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 and with careful and continuing monitoring of intraocular pressures, even with examinations under anesthesia.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
To date, no effective treatment for the conjunctival and corneal keloids has been found.
Families of affected individuals are often among the most knowledgeable about the problems and needs of their son(s) and must be advocates for them. Interested professionals, families, and other caregivers may contact the Lowe Syndrome Association for literature and additional information.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Lowe syndrome is inherited in an X-linked manner.
Parents of a proband
The father of an affected male will not have the disease nor will he be a carrier of the mutation.
In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier, have germline mosaicism, or the affected male may have a de novo gene mutation, in which case the mother is not a carrier. New mutations have been reported in approximately 32% of males with Lowe syndrome [Satre et al 1999, Monnier et al 2000].
If a woman has more than one affected son and the disease-causing mutation cannot be detected in DNA extracted from her leukocytes, she has germline mosaicism. In two linkage studies using flanking markers, two of 44 (4.5%) women were found to have germline mosaicism [Satre et al 1999, Monnier et al 2000].
Approximately 30% of affected males have no family history of Lowe syndrome [R Lewis, personal observation]. If an affected male represents a single occurrence in a family, several possibilities regarding his mother's carrier status and carrier risks of extended family members need to be considered:
He has a de novo disease-causing mutation in the OCRL gene and his mother is not a carrier.
His mother has a de novo disease-causing mutation in the OCRL gene, either a) as a "germline mutation" (i.e., present at the time of her conception and thus present in every cell of her body); or b) as "germline mosaicism" (i.e., present in a certain percentage of her germ cells only).
His maternal grandmother has a de novo disease-causing mutation in the OCRL gene.
The mother of child with Lowe syndrome who represents a simplex case (i.e., a single occurrence in a family) should be thoroughly evaluated by an experienced ophthalmologist for the characteristic punctate lens opacities seen in female carriers. The family should be offered the opportunity to go beyond biochemical enzyme testing in the proband and have molecular genetic testing.
Sibs of a proband
The risk to sibs of a proband depends upon the carrier status of the mother.
If the mother is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually be unaffected.
Germline mosaicism has been demonstrated in this condition. Thus, even if the disease-causing mutation has not been identified in DNA extracted from the mother's leukocytes, the sibs are still at increased risk. In two linkage studies with flanking markers, two of 44 (4.5%) women with sons or carrier daughters with Lowe syndrome were found to have germline mosaicism [Satre et al 1999, Monnier et al 2000].
Offspring of a proband. No affected male has reproduced.
Other family members of the proband. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending upon their gender, may be at risk of being carriers or of being affected.
Carrier testing of at-risk female relatives by mutation analysis is available on a clinical basis if the mutation has been identified in the proband.
Approximately 95% of carrier females older than age 15 years are observed to have characteristic findings in the lens of the eye on slit-lamp examination by an experienced ophthalmologist using both direct and retroillumination (see Diagnosis); thus, ophthalmologic exam may be used as a method of carrier detection.
When the mutation is not known, linkage analysis in informative families may be helpful in determining which at-risk female relatives are carriers.
Biochemical enzymatic assays for inositol polyphosphate 5-phosphatase OCRL-1 activity are not accurate for carrier detection because of lyonization (random X-chromosome inactivation) in females [Lin et al 1999].
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is relevant in situations in which the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Biochemical genetic testing. Prenatal testing is possible for pregnancies of women who are known or suspected carriers. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15-18 weeks' gestation. If the karyotype is 46,XY, measurement of inositol polyphosphate 5-phosphatase OCRL-1 activity in cultured chorionic villi or cultured amniotic fluid cells is performed. Assay of enzymatic activity is the preferred method for prenatal diagnosis of Lowe syndrome unless the mutation in the family has been defined previously and can be tested for specifically in the fetus. Deficient activity of the enzyme inositol polyphosphate 5-phosphatase OCRL-1 should be documented in the proband prior to offering prenatal testing so that correct interpretation of the prenatal testing results can be made. The major disadvantage of biochemical testing is the sporadic commercial availability of the substrate used for the in vitro enzyme assay.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Molecular genetic testing of the OCRL gene may be used to confirm the enzymatic assay results if the OCRL mutation has been identified in the proband; however, such testing is not always necessary.
Direct molecular genetic testing may be done if the OCRL disease-causing mutation in the family is known.
Linkage analysis may also be used in informative families.
Because of the relatively high rate (4.5%) of germline mosaicism, every mother of a male with Lowe syndrome, even with a negative family history, should be offered prenatal testing by enzymatic analysis or DNA testing if the mutation in her son is known, even if the results of dilated slit-lamp examination or DNA testing suggest that she is not a carrier [McSpadden 2000].
Preimplantation genetic diagnosis (PGD). Preimplantation genetic diagnosis may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|
| OCRL | Xq26.1 | Inositol polyphosphate 5-phosphatase OCRL-1 | Lowe Syndrome Mutation Database | OCRL |
Lowe syndrome results from mutations in the OCRL gene, which encodes for inositol polyphosphate 5-phosphatase OCRL-1 (phosphatidylinositol polyphosphate 5-phosphatase OCRL-1). The enzyme is thought to be involved with regulation of intracellular phosphatidylinositol (4,5) bisphosphate concentration. In an as-yet-unexplained manner, the enzyme deficiency interferes with normal fetal development and postnatal functioning of various organ systems, resulting in the birth defects and other abnormalities found in individuals with Lowe syndrome.
Normal allelic variants: The gene contains 5152 nucleotide base pairs and consists of 24 exons, of which 23 are coding. There is also one small (24 bp) alternatively-spliced exon, 18a, which encodes an additional eight amino acids and is expressed in neurologic tissues [Nussbaum et al 1997, Nussbaum & Suchy 2001].
Pathologic allelic variants: More than 120 mutations are known. Most are unique to a single family; a few have been noted in more than one unrelated individual. The majority are nucleotide nonsense substitutions or small deletions that result in frameshift and premature termination. Missense mutations and partial or complete genomic deletions also have been reported. Of the identified mutations, 93% have been located in exons 10-18 and exons 19-23 of the OCRL gene, especially in exon 15 [Satre et al 1999, Monnier et al 2000, Nussbaum 2001, Nussbaum & Suchy 2001]. The majority (93%) of known mutations are nonsense, missense, frameshift, or splice junction mutations affecting exons 10-18 and exons 19-23 of the OCRL gene, especially exon 15. Seven percent of known mutations involve partial or complete genomic deletions [Lin et al 1998, Satre et al 1999, Monnier et al 2000, Nussbaum 2001]. The paucity of detectable mutations in exons 1-9 remains unexplained, but recent data suggest that the frequency of mutations may be increased in the first eight exons of the OCRL gene in Dent disease [Steven Scheinman, personal communication].
Normal gene product: The OCRL gene encodes a 105-kd Golgi protein (inositol polyphosphate 5-phosphatase OCRL-1) that has phosphatidylinositol polyphosphate 5-phosphatase activity [Suchy et al 1995, Zhang et al 1995]. The enzyme is present in the trans-Golgi network and the endosomal compartment of a variety of cell types, including brain, skeletal muscle, heart, kidney (cultured proximal renal tubular cells), lung, ovary, testis, cultured fibroblasts, placenta, chorionic villi samples, and cultured amniocytes. It is involved with regulation of intracellular phosphatidylinositol (4,5) bisphosphate concentration and is highly homologous to inositol polyphosphate 5-phosphatase [Nussbaum & Suchy 2001]. Phosphatidylinositol (4,5) bisphosphate is a critical membrane phospholipid that is known to regulate many intracellular processes including protein kinase C activity and intracellular calcium release via its cleavage into diacylglycerol and inositol triphosphate, actin cytoskelon organization, and vesicle trafficking between the endoplasmic reticulum, Golgi, endosomal compartment, and cell surface.
Abnormal gene product: Reduced activity or absence of the gene product, inositol polyphosphate 5-phosphatase OCRL-1, leads to elevated intracellular levels of its substrate, phosphatidylinositol (4,5) bisphosphate [PtdIns (4,5) P2] [Zhang et al 1998]. PtdIns (4,5) P2 appears to be involved in the regulation of vesicular formation and protein trafficking in the Golgi and with actin-cytoskeleton assembly. The loss of inositol polyphosphate 5-phosphatase OCRL-1 causes a defect in intracellular protein trafficking. Thus, for example, the apical surface protein megalin is markedly reduced both in Lowe syndrome and in Dent disease caused by mutations in the CLCN5 gene, suggesting abnormal renal apical epithelial trafficking of this protein [Norden et al 2002]. Actin cytoskeleton organization is also abnormal in fibroblasts from persons with Lowe syndrome [Suchy & Nussbaum 2002]. Although the exact mechanisms are unclear, the elevated PtdIns (4,5) P2 levels may affect these processes, which may influence cell membrane composition, actin cytoskeletal organization, or both, and ultimately lead to abnormal cell migration and differentiation in certain cell types, i.e., renal tubule or lens epithelium. Such changes could result in the birth defects and other clinical manifestations of Lowe syndrome [Zhang et al 1995, Suchy & Nussbaum 2002, Ungewickell et al 2004].
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Eileen D Brewer, MD (2007-present)
Richard A Lewis, MD, MS (2007-present)
Robert L Nussbaum, MD (2007-present)
Rebecca S Wappner, MD, FAAP, FACMG; Indiana University School of Medicine (2001-2007)
12 March 2008 (cd) Revision: FISH analysis available on a clinical basis
16 November 2007 (cd) Revision: mutation scanning no longer available on a clinical basis
5 January 2007 (me) Comprehensive update posted to live Web site
19 September 2003 (me) Comprehensive update posted to live Web site
24 July 2001 (me) Review posted to live Web site
13 April 2001 (rw) Original submission
