AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1952, Lowe and colleagues described an infant with congenital cataracts and mental retardation. When more patients were described, the phenotype was expanded to include the renal tubular defects that comprise Fanconi syndrome, and an X-linked inheritance pattern was noted. The diagnostic triad of the oculocerebrorenal syndrome of Lowe (OCRL) includes congenital cataracts, neonatal or infantile hypotonia with subsequent mental impairment, and renal tubular dysfunction.

Pathophysiology

OCRL is caused by an inherited mutation in OCRL1, which has been mapped to chromosome Xq26. OCRL1 contains 24 exons and encodes the OCRL1 protein. The OCLR1 protein is a phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P2) 5 phosphatase that is localized in the Golgi apparatus and appears to play a role in cytoskeleton remodeling and cellular trafficking. Several mutations have been described in this gene, including truncation mutations, missense mutations, and large deletions. New mutations have been reported, and germline mosaicism is common. OCRL1 deficiency may impair proper intracellular protein sorting, especially within polarized cells such as the renal epithelium and the optic lens. This impairment may explain the epithelial cell phenotype (ie, congenital cataracts and renal tubular dysfunction).

Frequency

International

OCRL is a panethnic disease that has an estimated prevalence of 1 per 500,000 population (Loi, 2006).

Mortality/Morbidity

The high mortality rate observed in the first few months of life is attributed to the severe metabolic derangements associated with Fanconi syndrome. These patients are predisposed to failure to thrive, severe metabolic acidosis, electrolyte imbalances, and dehydration. Patients with OCRL also have a tendency to develop pneumonia due to hypotonia and poor cough reflex. Other causes of death include infection and status epilepticus. Sudden unexplained death can also occur. Death usually occurs in the second or third decade of life. A few patients with OCRL are reported to have survived into the fourth and fifth decades of life with chronic kidney failure.

Sex

OCRL is inherited in an X-linked fashion. Thus, the vast majority of patients are males. Few cases have been reported in females. Most affected females have X-autosomal translocations involving the OCRL1 locus, which permits full expression of the OCRL phenotype.

Age

Although the diagnosis is not always straightforward, virtually all patients have some degree of hypotonia with the absence of deep tendon reflexes and cataracts present at birth. Other nervous system manifestations and mental retardation become obvious later. Renal tubular function may essentially be normal at birth, but the typical abnormalities often are detectable by age 1 year. Serum creatinine levels remain normal, with normal urinary creatinine clearance during the first decade of life. Chronic kidney disease with an increase in the serum creatinine levels develops slowly, starting in the second decade of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Oculocerebrorenal syndrome of Lowe (OCRL) is often diagnosed at birth or in early infancy based on physical characteristics; therefore, history does not usually contribute to the diagnosis. However, a careful review of history is important in documenting disease manifestations, especially neurological and behavioral abnormalities. Obtaining a detailed family history is essential in order to identify any potentially affected male relatives on the maternal side.

• Intelligence
• • Although about 10% of boys with OCRL have intelligence within the low-normal to borderline ranges (intelligence quotient [IQ] of 70 and above), most have more significant intellectual impairment.
  • About one third of patients have profound mental retardation, but most have IQs that fall within the moderate range of 40-54.
  • Socioeconomic status, maternal IQ, OCRL1 mutation, and MRI findings do not correlate with intellectual outcome; thus, prediction of intellectual outcome at birth is not possible. Intelligence is stable over the person's life span.
• Seizures
• • Seizures occur in about one half of all patients with OCRL and typically appear in children younger than 6 years. Seizure types vary widely and include myoclonic seizures, generalized tonic-clonic seizures, infantile spasms, and partial complex seizures.
  • Febrile seizures occur more frequently in persons with OCRL than in the general population (9% vs 1%).
• Behavior
• • Although most patients with OCRL are friendly and sociable, a characteristic pattern of behavioral difficulties is common.
  • Abnormal behavior may include temper tantrums, aggression, unusual repetitive movements, irritability, and rigidity.
  • Individuals may also have unusual preoccupations or obsessions, and self-injurious behavior is not uncommon.
• Gastrointestinal problems: Constipation is common and may be quite severe; severity typically decreases with age.

Physical

The typical facial appearance of patients with OCRL consists of deep-set small eyes, frontal bossing, and an elongated face.

• Ophthalmologic examination
• • Cataracts are a hallmark of OCRL and are always present at birth. Pathologic changes in the ocular lens occur prenatally and have been described in fetuses with OCRL at 20 weeks' gestation and 24 weeks' gestation.
  • Glaucoma, with or without buphthalmos, occurs in about 50-60% of boys with OCRL and is usually bilateral. Glaucoma is typically diagnosed in the first year of life but may present at any age.
  • Keloids may spontaneously form over the cornea or the conjunctiva in one or both eyes without preceding trauma. They may cause significant visual impairment. Corneal keloids occur in about 25% of patients, usually develop in children older than 5 years, and are bilateral in about one half of patients.
  • Many children with OCRL develop strabismus.
• Examination of the nervous system
• • Neonatal hypotonia due to CNS dysfunction is a consistent feature of OCRL. Feeding difficulties and delayed motor development may occur.
  • Although tone improves with age, most patients never achieve normal muscular tone and have consequential problems such as scoliosis and hernias.
  • Areflexia may also be present.
• Orthopedic complications
• • Hypophosphatemia and metabolic acidosis are causative factors in the development of bone disease, which includes rickets, osteomalacia, and osteopenia. Osteopenia is a consistent finding despite maintenance of normal serum phosphorus levels with therapy.
  • Fractures are common in boys with OCRL and often occur when they are learning how to walk. The femur is most often affected. About one third of patients with OCRL have more than one fracture. Osteopenia or osteoporosis may play a causative role in this propensity to fracture.
  • Joint swelling, arthritis, and tenosynovitis are common and typically occur in the late teenaged years and early adulthood. Nontender swelling of the small and large joints may occur. Plantar masses have also been reported. The cause of these abnormalities is unknown, and treatment is merely supportive.
  • Scoliosis is frequently present in patients with OCRL and may progress after puberty.
  • Both joint hypermobility and decreased movement that causes joint contractures have been reported.
• Growth
• • Patients with OCRL have normal birth weights and lengths. By age 1-3 years, growth parameters fall below the third percentile.
  • The average final adult height is 5'1".
  • Adult head circumferences are typically within the reference range.
  • Sexual development progresses at a normal pace.
• Other significant physical examination findings
• • Cryptorchidism occurs in 15-40% of boys with OCRL.
  • Dermatologic and mucosal cysts may occur in multiple sites including the mouth, teeth (blue dome cysts), buttocks, and lower back. They can be painful and may become superinfected.

Causes

OCRL is an inherited condition caused by mutations in the OCRL1 gene, which encodes PtdIns[4,5]P2 5 phosphatase. This enzyme appears to play a role in regulating protein trafficking, second messengers, and other aspects of cellular metabolism.

OCRL1 mutation was recently reported in 23% of kindreds with Dent disease-2, which is another X-linked renal tubulopathy characterized by hypercalcuria and nephrocalcinosis (Hoopes, 2005). A defect in the OCRL1 protein may cause the mildly elevated creatine kinase and lactate dehydrogenase (LDH) serum levels observed in this subgroup of patients, without the presence of cataract. Mitochondrial abnormalities such as cytochrome oxidase deficiency can have a similar presentation.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Congenital cataracts
Renal tubular acidosis
Hypotonia at birth
Mito disease
Dent disease
Peroxisomal disorders

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Urinalysis, urinary electrolyte levels (including urine phosphorous and calcium levels), urinary amino acid levels, urine osmolality, and urinary carnitine levels
• • Renal tubular dysfunction (Fanconi syndrome) is a cardinal manifestation of oculocerebrorenal syndrome of Lowe (OCRL), but severity widely varies.
  • Proximal renal tubular acidosis due to bicarbonate loss in the urine is reported.
  • Aminoaciduria, phosphaturia, and proteinuria are typically present. Hypercalcuria has been reported in patients with OCRL as part of the proximal tubulopathy or as a result of vitamin D treatment, leading to nephrocalcinosis or nephrolithiasis/urolithiasis.
  • Water resorption is impaired, resulting in high urine volume and low urine osmolality. Dehydration may be life threatening in the first years of life.
  • Hyperphosphaturia may lead to osteomalacia or rickets.
  • L-carnitine is lost in the urine.
• Plasma electrolyte levels
• • Clinically significant hypokalemia due to urinary losses is rare but may require replacement therapy.
  • Clinically significant hyponatremia and hypocalcemia are extremely rare.
• Plasma alkaline phosphatase, calcium, and phosphorus levels
• • Urinary losses of calcium and phosphorus predispose to the development of rickets and osteomalacia.
  • A rise in alkaline phosphatase levels is usually the first biochemical indicator of rickets.
• Blood gas levels: Significant metabolic acidosis is caused by the urinary loss of bicarbonate.
• Plasma carnitine levels: As carnitine is lost in the urine, plasma levels may be low and oral replacement therapy may be necessary.
• Plasma creatinine levels and urine 24-hour creatinine clearance: Progressive renal failure is heralded by a gradual increase in plasma creatinine levels and a decrease in creatinine clearance.
• Other serum markers
• • Serum aspartate aminotransferase (AST), LDH, and creatine kinase levels are often elevated. AST and LDH levels may be 2-3 times the reference range.
  • Serum acid phosphatase levels may be elevated.
  • a-2 globulin levels may be abnormally elevated on serum protein electrophoresis findings.
  • Thyroxine (T4) levels, thyroxine-binding globulin (TBG) levels, and erythrocyte sedimentation rate (ESR) may be high.
• Diagnostic testing: Measurement of enzyme activity in cultured fibroblasts is the diagnostic test. Mutation analysis may be confirmatory.

Imaging Studies

• Brain MRI may demonstrate white matter abnormalities, particularly in the periventricular area. These signal abnormalities are caused by fluid-filled cysts, which appear to have no clinical significance.
• Radiographs of the wrists and long bones may demonstrate changes that are typical of rickets, including metaphyseal flaring and osteopenia.
• Renal imaging studies include the following:
• • Renal ultrasonography may show evidence of nephrocalcinosis or even nephrolithiasis.
  • Poor renal uptake of technetium 99 m (Tc99m) dimercaptosuccinic acid is reported in patients with OCRL.

Histologic Findings

Typical renal findings include atrophic tubular epithelial cells and interstitial fibrosis. The tubular lumina may be filled with proteinaceous material. In older patients, the glomerular basement membranes appear thickened with fusion of the podocytes. In later stages of the disease, sclerosis of the glomeruli is evident.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Management of renal tubular acidosis includes the following:
• • Careful monitoring of acid-base status and electrolyte levels is required. Alkali supplements, such as sodium bicarbonate, sodium citrate and citric acid (Bicitra), or sodium citrate and potassium citrate (Polycitra), are administered to maintain plasma bicarbonate levels at more than 20 mEq/L. The dose of sodium bicarbonate can vary from 1-10 mEq/kg/d divided into 3 or 4 doses. Potassium citrate is preferable in patients with hypercalcuria to decrease nephrocalcinosis and urinary calcium excretion.
  • Potassium and calcium supplementation may be required to offset renal losses.
  • Oral carnitine supplementation may be necessary if plasma levels are abnormally low.
• Neutral phosphate and vitamin D supplementation and careful maintenance of normal acid-base status are necessary to avoid rickets and osteomalacia.
• Acute illness with attendant risk of dehydration and electrolyte abnormalities should be treated with aggressive intravenous fluid and electrolyte therapy.
• Cryptorchidism may improve with hormonal therapy.

Surgical Care

• Ophthalmologic intervention
• • Removal of cataracts as early as possible, even within the first weeks of life, is indicated in order to provide the optimal visual stimulation to the developing brain. Implantation of artificial lenses is not recommended because of the growth potential of the infant eye and because of the propensity to develop glaucoma.
  • Glaucoma develops in about one half of all patients with oculocerebrorenal syndrome of Lowe (OCRL) and is typically difficult to treat. Surgical implantation of artificial valves to control the release of intraocular fluid is often required
  • Corneal keloids can interfere with vision. Treatment may consist of surgical removal of the scar tissue or radiation therapy. Corneal transplantation is problematic because of the difficulty in administering the required intensive postoperative care.
  • Surgical correction of strabismus is sometimes required.
• Other procedures
• • If testes do not spontaneously descend in boys with cryptorchidism by age 5 years, surgical correction may be necessary.
  • Nasogastric tube feeding or gastrostomy (sometimes with fundoplication) may be indicated.

Consultations

• Ophthalmologist: Because eye complications are a primary manifestation of OCRL, meticulous management by an ophthalmologist is necessary. Cataract surgery is usually performed within the first few weeks of life. In addition, close monitoring of intraocular pressure is necessary because glaucoma is common and requires treatment. Corrective contact lenses or glasses, with or without eye patches, are required to manage the visual deficits caused by cataracts and strabismus.
• Nephrologist: Renal Fanconi syndrome typically develops in children aged 1 year and requires replacement therapy to offset renal losses. Renal failure gradually develops within the second decade of life.
• Orthopedist: Scoliosis and lone-bone deformities due to rickets and contractures may require orthopedic consultation.

Diet

• Some physicians have tried low-protein diets in an attempt to offset the renal disease, but a clear benefit from this diet has not been demonstrated.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medications are necessary to offset the renal losses of electrolytes and other substances.

Drug Category: Minerals and electrolytes

These agents are used to correct disturbances in fluid and electrolyte homoeostasis or acid-base balance. They are also used to reestablish osmotic equilibrium of specific ions. Renal losses of calcium and phosphate may predispose to the development of osteomalacia and rickets.

Drug Category: Amino acids

These are essential cofactors of fatty acid metabolism. Oral carnitine may be used to replace urinary losses. Its efficacy in altering the outcome of patients with oculocerebrorenal syndrome of Lowe is unclear.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Hypotonia and mental retardation necessitate physical, speech, and feeding therapy.
• Physical therapy should be initiated in infancy. The initial goals may be head control, sitting, rolling over, and locomotion.
• Speech delays are common and are multifactorial in origin. Contributing factors include hypotonia, high palate, and intellectual delays.
• Hypotonia often causes feeding difficulties. Sucking, swallowing, and chewing may be impaired, and therapy may be helpful.
• Services for the visually handicapped can be helpful.

In/Out Patient Meds

• Replacement of renal losses is essential.
• Sodium citrate and citric acid (Bicitra) is an alkalizing agent used to manage metabolic acidosis. The therapeutic goal is to maintain serum bicarbonate levels at more than 20 mEq/L.
• Neutral phosphate and vitamin D may be necessary to prevent the development of osteomalacia or rickets caused by phosphaturia and calciuria.
• Carnitine may be used if renal losses are substantial enough to cause abnormally low blood levels.
• Anticonvulsants are necessary in patients with seizures.
  However, anticonvulsants can interfere with vitamin D metabolism; therefore, caution is necessary.

Complications

• Dental problems may occur.

Prognosis

• Progressive renal failure is the major cause of morbidity and death and usually occurs in the second or third decade of life. The decision to initiate dialysis in patients with oculocerebrorenal syndrome of Lowe (OCRL) is medically and ethically complex and depends on the degree of mental retardation, the medical condition of patient, and family and social system support. Successful dialysis and renal transplantation has been reported in few adult patients with OCRL.

Patient Education

• Education is directed toward self-help skills and must be tailored to meet the individual strengths and weakness of each patient. Physical therapy should focus on encouraging walking and preventing secondary effects of hypotonia. Occupational therapy is directed toward personal hygiene. Behavioral difficulties may interfere with education, and specialized plans may be necessary to deal with these difficulties and maximize the child's learning.
• For excellent patient education resources, visit eMedicine's Eye and Vision Center. Also, see eMedicine's patient education article Cataracts.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to monitor intraocular pressure may lead to blindness.

Special Concerns

• Carrier detection
• • As many as 94% of female carriers may be detected using slit-lamp examination. The typical findings include numerous punctate lenticular opacities or a single dense posterior cataract. If the mother has normal eye examination findings, mutation analysis should still be obtained because some women (rarely) are nonpenetrant carriers and do not have the typical eye manifestations.
  • Molecular analysis of the OCRL1 gene is a more specific way to diagnose female carriers if the mutation in the proband is known.
• Prenatal testing
• • Prenatal testing is possible for at-risk pregnancies, using either molecular analysis or biochemical testing, in which the activity of PtdIns[4,5]P2 5-phosphatase is measured in cultured chorionic villi (at 9-11 weeks' gestation) or cultured amniocytic fluid cells (at 15-20 weeks' gestation).
  • Genetic mutations should be documented first in the proband.
• Genetic counseling
• • The recurrence risk for the family of a patient with oculocerebrorenal syndrome of Lowe (OCRL) depends on whether the proband carries a new mutation.
  • If the mother of the proband is a carrier (determined with mutation analysis optimally or with ophthalmologic examination if mutation analysis is not available), each male offspring has a 50% chance of being affected, and each female has a 50% chance of being a carrier. If the mother does not have the typical eye findings and no mutations are found in the OCRL1 locus, then the mutation may be new, and the recurrence risk is low but finite because of the possibility of gonadal mosaicism.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Charnas LR, Gahl WA. The oculocerebrorenal syndrome of Lowe. Adv Pediatr. 1991;38:75-107. [Medline].
• Charnas LR, Bernardini I, Rader D, et al. Clinical and laboratory findings in the oculocerebrorenal syndrome of Lowe, with special reference to growth and renal function. N Engl J Med. May 9 1991;324(19):1318-25. [Medline].
• Charnas LR, Nussbaum RL. The Oculocerebrorenal Syndrome of Lowe (Lowe syndrome). In: Beaudet AL, Scriver CR, Sly WS, Valle DL, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. McGraw-Hill Health Professions Division;1995:3705-3716.
• Cibis GW, Tripathi RC, Tripathi BJ. Lowe's oculocerebrorenal syndrome. In: Gold DH, Weingeist TA, eds. The Eye in Systemic Disease. Lippincott-Raven Publishers;1990:504.
• Cifelli PM, Hargreaves I, Grunewald S. Cytochrome oxidase deficiency in Lowe syndrome. J Inherit Metab Dis. Sep 2002;25(5):411-2. [Medline].
• Dressman MA, Olivos-Glander IM, Nussbaum RL, Suchy SF. Ocrl1, a PtdIns(4,5)P(2) 5-phosphatase, is localized to the trans-Golgi network of fibroblasts and epithelial cells. J Histochem Cytochem. Feb 2000;48(2):179-90. [Medline]. [Full Text].
• Erneux C, Govaerts C, Communi D, Pesesse X. The diversity and possible functions of the inositol polyphosphate 5- phosphatases. Biochim Biophys Acta. Dec 8 1998;1436(1-2):185-99. [Medline].
• Hoopes RR, Shrimpton AE, Knohl SJ, et al. Dent Disease with mutations in OCRL1. Am J Hum Genet. Feb 2005;76(2):260-7. [Medline]. [Full Text].
• Kenworthy L, Park T, Charnas LR. Cognitive and behavioral profile of the oculocerebrorenal syndrome of Lowe. Am J Med Genet. May 15 1993;46(3):297-303. [Medline].
• Kim DW, Kim CG, Park SA. Poor Renal Uptake of Tc-99m DMSA in a Patient With Oculocerebrorenal Dystrophy (Lowe syndrome). Clin Nucl Med. Jan 2007;32(1):49-50. [Medline].
• Lin T, Orrison BM, Leahey AM, et al. Spectrum of mutations in the OCRL1 gene in the Lowe oculocerebrorenal syndrome. Am J Hum Genet. Jun 1997;60(6):1384-8. [Medline]. [Full Text].
• Loi M. Lowe syndrome. Orphanet J Rare Dis. 2006;1:16. [Medline]. [Full Text].
• Nussbaum RL, Orrison BM, Janne PA, et al. Physical mapping and genomic structure of the Lowe syndrome gene OCRL1. Hum Genet. Feb 1997;99(2):145-50. [Medline].
• Ono J, Harada K, Mano T, et al. MR findings and neurologic manifestations in Lowe oculocerebrorenal syndrome. Pediatr Neurol. Feb 1996;14(2):162-4. [Medline].
• Roschinger W, Muntau AC, Rudolph G, et al. Carrier assessment in families with lowe oculocerebrorenal syndrome: novel mutations in the OCRL1 gene and correlation of direct DNA diagnosis with ocular examination. Mol Genet Metab. Mar 2000;69(3):213-22. [Medline].
• Sonmez F, Temocyn AK, Ozkan SB, et al. Lowe syndrome with anal atresia: a possible variant of OCRL?. Pediatr Int. Apr 2003;45(2):201-4. [Medline].
• Suchy SF, Lin T, Horwitz JA, et al. First report of prenatal biochemical diagnosis of Lowe syndrome. Prenat Diagn. Nov 1998;18(11):1117-21. [Medline].
• Tricot L, Yahiaoui Y, Teixeira L, et al. End-stage renal failure in Lowe syndrome. Nephrol Dial Transplant. Sep 2003;18(9):1923-5. [Medline].
• Ungewickell AJ, Majerus PW. Increased levels of plasma lysosomal enzymes in patients with Lowe syndrome. Proc Natl Acad Sci U S A. Nov 9 1999;96(23):13342-4. [Medline]. [Full Text].

Article Last Updated: Feb 7, 2007