eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Oculocerebrorenal Dystrophy (Lowe Syndrome)

Amira Al-Uzri, MD, MCR, Associate Professor, Associate Director of Pediatric Clinical Research, Department of Pediatrics, Division of Pediatric Nephrology, Oregon Health & Science University
Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Co-Director: Pediatric and Child Health Research, Oregon Clinical and Translational Research Institute (CTSA).; Melissa P Wasserstein, MD, Associate Professor, Departments of Genetics and Genomic Sciences and Pediatrics, Mount Sinai School of Medicine; Cydney L Fenton, MD, FAAP, Consulting Staff, Department of Pediatric Endocrinology, Children's Hospital Medical Center of Akron

Updated: Jul 14, 2009

Introduction

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), or Lowe syndrome, includes congenital cataracts, neonatal or infantile hypotonia with subsequent mental impairment, and renal tubular dysfunction.

Pathophysiology

Lowe syndrome is caused by an inherited mutations in the OCRL gene, mapped to chromosome Xq 26.1, which encodes the OCRL1 protein. The OCRL1 protein is an inositol polyphosphate 5-phosphatase primarily located in the trans- Golgi network (TGN), on endosomes, and at the endocytic clathrin coated pits. It can also translocate to plasma membrane ruffles upon stimulation with growth-factors.

The main substrates for Lowe syndrome are 2 phosphoinositides (Ptdln): PtdIn4,5P2 and PtdIn3,4,5P3. They are mainly located at the surface membrane of the cell. Lowe syndrome's main function is to couple endocytosis to the dephosphorylation of Ptdln, thereby exerting a tight control on the availability of these PtdIn at the surface membrane. Mutations in OCRL ultimately lead to disruption in membrane trafficking, cellular homeostasis, cell migration and polarization, actin cytoskeleton remodeling, and other cellular functions. For a more thorough review of the role of phosphatidylinositol in the regulation of cellular function, please see the following: McCrea HJ, De Camilli P. Mutations in phosphoinositide metabolizing enzymes and human disease. Physiology (Bethesda). Feb 2009;24:8-16.¹  

Membrane trafficking defects caused by mutation in OCRL may explain renal tubular defects observed in Lowe syndrome, including the inability of proximal tubular cells (PTC) to reabsorb low molecular weight (LMW) proteins and other solutes such as phosphorus and bicarbonate from the glomerular filtrate. The absorption of LMW proteins occurs in the PTC through clathrin-mediated endocytosis via 2 multiligand receptors (megalin and cubilin) present in the PTC brush border. These receptors undergo proteolytic cleavage at the apical membrane of the PTC and appear normal in the urine. Proteomic analysis of urine from patients with Lowe syndrome typically show low levels of megalin and cubilin denoting a decrease in the number of these multiligand receptors in the PTC.

Several mutations in the OCRL gene have been described, including truncation mutations, missense mutations, and large deletions. New mutations do occur and germline mosaicism is not uncommon. As mentioned previously, deficiency in Lowe syndrome may impair proper intracellular protein sorting, especially within polarized cells such as the renal epithelium and the optic lens. This may explain the epithelial cell phenotype (ie, congenital cataracts and renal tubular dysfunction).

Frequency

International

Lowe syndrome is an uncommon, panethnic disorder with the prevalence of 1:200,000-1:500,000 births. In the United States, 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.

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 Lowe syndrome 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 Lowe syndrome are reported to have survived into the fourth and fifth decades of life with chronic kidney failure.

Sex

Lowe syndrome 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 Lowe syndrome 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 in some patients.

Clinical

History

Oculocerebrorenal syndrome of Lowe (OCRL), or Lowe syndrome, 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 Lowe syndrome 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 Lowe syndrome and typically appear in children younger than 6 years. Seizure types vary widely and include myoclonic seizures, generalized tonic-clonic seizures, infantile spasms, partial complex seizures, and atonic seizures.
  • Febrile seizures are more common in persons with Lowe syndrome than in the general population (9% vs 1%).
• Behavior
  • Although most patients with Lowe syndrome 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.
• GI problems: Constipation is common and may be quite severe; severity typically decreases with age.
• Renal: Glomerulosclerosis associated with chronic tubular injury usually results in slowly progressive chronic renal failure and end-stage renal disease after age 20 years.

Physical

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

• Ophthalmologic examination
  • Cataracts are a hallmark of Lowe syndrome and are always present at birth. Pathologic changes in the ocular lens occur prenatally and have been described in fetuses with Lowe syndrome at 20 weeks' gestation and 24 weeks' gestation.
  • Glaucoma, with or without buphthalmos, occurs in about 50-60% of boys with Lowe syndrome 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 Lowe syndrome develop strabismus.
  • All boys have impaired vision; corrected acuity is rarely better than 20/100.
• Examination of the nervous system
  • Neonatal generalized hypotonia due to CNS (brain) 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.
  • Decreased motor tone also results in delayed motor milestones. Independent ambulation occurs in approximately 25% of boys aged 3-6 years and in 75% by age 6-13 years. Some never walk and require the use of a wheelchair for mobility.⁴
  • Orthopedic complications include hypophosphatemia and metabolic acidosis, which are causative factors in the development of bone disease. This bone disease includes rickets, osteomalacia, and osteopenia. Osteopenia is a consistent finding despite maintenance of normal serum phosphorus levels with therapy. Aside from osteopenia, the other bone manifestations can be prevented or ameliorated with treatment.
  • Fractures are common in boys with Lowe syndrome and often occur when they are learning how to walk. The femur is most often affected. About one third of patients with Lowe syndrome 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 Lowe syndrome and may progress after puberty.
  • Both joint hypermobility and decreased movement that causes joint contractures have been reported.
• Growth
  • Patients with Lowe syndrome 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 Lowe syndrome.
  • 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.
  • Delayed eruption of permanent teeth, crowding, hypoplastic enamel, constricted palate, taurodontism of the molars, dental caries, gingival inflammation due to mouth breathing, and excessive calculus deposits on teeth have been reported. Abnormal dentition due to excessive vertical facial length has been described in adult patients with Lowe syndrome. Dental cysts may occur.

Causes

• Lowe syndrome 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.³ 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 encephalomyopathies such as cytochrome oxidase deficiency can present similarly with hypotonia, mental retardation, cataracts, and renal tubular dysfunction.

Differential Diagnoses

Cystinosis
Fanconi Syndrome
Hypophosphatemic Rickets

Other Problems to Be Considered

• Congenital cataracts
• Renal tubular acidosis
• Hypotonia at birth
• Mito disease
• Dent disease
• Peroxisomal disorders
• Fanconi syndrome: Lowe syndrome has been described for many years as one of the causes of Fanconi syndrome in children. However, growing opinion among experts suggests that the 2 conditions may be quite different.⁵

Workup

Laboratory Studies

The following studies may be indicated in oculocerebrorenal syndrome of Lowe (OCRL), or Lowe syndrome:

• Urinalysis, urinary electrolyte levels (including urine phosphorous and calcium levels), urinary amino acid levels, urine osmolality, and urinary carnitine levels
  • Renal tubular dysfunction (commonly described as Fanconi syndrome) is a cardinal manifestation of Lowe syndrome, but severity widely varies.
  • Proximal renal tubular acidosis due to bicarbonate loss in the urine has been reported.
  • Aminoaciduria varies in Lowe syndrome but is typically present.
  • Low molecular weight (LMW) proteinuria, such as retinol-binding protein and β2 microglobulin, are elevated in urine.
  • Albuminuria may be noted.
  • Hypercalcuria has been reported in patients with Lowe syndrome 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. Whether carnitine wasting in the urine from severe Fanconi syndrome is the etiology of carnitine deficiency has not been studied adequately in Lowe syndrome.
  • Glycosuria is absent in the majority of patients with Lowe syndrome. 
• 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 estimation of creatinine clearance: Progressive renal failure is heralded by a gradual increase in plasma creatinine and a decrease in creatinine clearance. The calculated glomerular filtration rate (GFR) using widely published formulas such as the Schwartz or the Schwartz Haycock formulas in children with Lowe syndrome were found to overestimate the true GFR due to low muscle mass. A lower k value in the corresponding formulas was suggested for use in patients with Lowe syndrome; for example, a k of .30 is used when creatinine is measured in mg/dL, and a k of 26 is used when creatinine is measured in mmol/L. Direct measurement of GFR using a renal glomerular marker such as iohexol or iothalamate is the preferred and accurate method to measure kidney function in patients with Lowe syndrome.
• 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.
  • α -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.
  • Thrombocytopenia has been reported in Lowe syndrome and can be explained by the homology of the human OCRL protein to the phosphatidylinositol biphosphate 5-phosphatase present in human platelets, resulting in some functional overlap between these proteins.  
• Diagnostic testing: Measurement of enzyme activity in cultured fibroblasts has been the preferred diagnostic test. Mutation analysis may be confirmatory and is increasingly used as the main diagnostic test.

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. Tigroid pattern of white matter demyelination has been reported on MRI imaging and is thought to represent areas of normal white matter signaling interspersed with demyelinated areas.
• 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 Lowe syndrome.

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

Medical Care

• Management of renal tubular acidosis in patients with oculocerebrorenal syndrome of Lowe (OCRL), or Lowe syndrome, 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 22 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.
• Human growth hormone therapy may be used in patients with short stature to improve growth velocity.

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.
  • Avoid corneal contact lenses because of associated risk of corneal keloid formation and complexities of contact lens care; artificial lens implants should also be avoided because of probable increased risk of glaucoma. 
  • Glaucoma develops in about one half of all patients with Lowe syndrome 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.
  • Resection of fibromas and cutaneous cysts is indicated if they are painful or impair function.

Consultations

• Ophthalmologist: Because eye complications are a primary manifestation of Lowe syndrome, 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.
• Clinical geneticist/metabolic disease specialist: A clinical geneticist/metabolic disease specialist is typically familiar with this very rare disorder and can help facilitate and interpret diagnostic testing. The specialist should work with the nephrologist and ensure proper genetic counseling.

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

Medications are necessary in oculocerebrorenal syndrome of Lowe (OCRL), or Lowe syndrome, to offset the renal losses of electrolytes and other substances.

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.

Calcitriol (Rocaltrol)

Used to manage rickets and osteomalacia. A synthetic vitamin D analog (1 a, 25-dihydroxycholecalciferol or 1 a, 25-dihydroxyvitamin D3) that is active in regulating the absorption of calcium from the intestinal tract and its utilization in the body.

Dosing

Adult

0.25-2 mcg/d PO

Pediatric

0.01-0.05 mcg/kg/d PO; titrate in 0.005-0.01 mcg/kg/d increments q4-8wk based on clinical response

Interactions

Cholestyramine and colestipol decrease absorption of calcitriol; magnesium-containing antacids and thiazide diuretics can increase calcitriol effects

Contraindications

Documented hypersensitivity; hypercalcemia; malabsorption syndrome

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Measure serum calcium levels at least twice weekly when initiating therapy or increasing dose; if hypercalcemia is noted, discontinue medication until the patient is normocalcemic; overdose can cause symptoms of hypercalcemia manifested initially as weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain, and a metallic taste (later effects of hypercalcemia include polyuria, polydipsia, anorexia, weight loss, calcific conjunctivitis, pancreatitis, elevated liver function tests, ectopic calcifications, cardiac arrhythmias, and, rarely, overt psychosis)

Sodium citrate and citric acid (Bicitra)

Systemic alkalizer solution used to treat renal tubular acidosis. Following ingestion, citrate salts are oxidized to bicarbonate. Each mL contains 1 mEq sodium ion and is equivalent to 1 mEq bicarbonate.

Dosing

Adult

Initial dose: 1-2 mEq/kg/d PO divided pc and hs; adjust prn to keep plasma bicarbonate level >22 mEq/L
Dilute in water or juice

Pediatric

Initial dose: 2 mEq/kg/d PO divided pc and hs; doses of up to 10 mEq/kg/d may be required; adjust prn to keep plasma bicarbonate level >22 mEq/L
Dilute in water or juice

Interactions

Decreases therapeutic levels of lithium, chlorpropamide, methotrexate, tetracyclines, and salicylates owing to urinary alkalinization; increases toxicity of amphetamines, ephedrine, quinine, and quinidine owing to urinary alkalinization

Contraindications

Renal insufficiency; sodium-restricted diet

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Patients with hypertension, heart failure, impaired renal function, or edema or those on sodium-restricted diets should undergo periodic serum electrolyte evaluations; dilute with water or juice to avoid a laxative effect; periodic monitoring of serum electrolyte levels is necessary to avoid alkalosis

Phosphate salts (Neutra-Phos)

Increases serum phosphate levels and is used to manage rickets and osteomalacia. Serum phosphate is important in regulating serum calcium concentration. In patients with increased urinary excretion of phosphorus and calcium, neutral phosphorus is necessary to offset these losses and to prevent osteomalacia and rickets. One g of phosphorus equals 32.29 mmol.

Dosing

Adult

1-2 g phosphorus/d PO divided qid with food; dilute with water prior to administration

Pediatric

<4 years: 30-90 mg phosphorus/kg/d PO divided qid with food
>4 years: 1 g phosphorus/d PO divided qid with food
Dilute with water prior to administration

Interactions

Magnesium- and aluminum-containing antacids or sucralfate can act as phosphate binders and decrease serum phosphate levels; potassium-sparing diuretics, ACE inhibitors, and salt substitutes may increase serum phosphate levels; calcium-containing preparations and/or vitamin D may antagonize the effects of phosphates in the treatment of hypercalcemia

Contraindications

Hyperphosphatemia; hypocalcemia; hypomagnesemia; hyperkalemia; renal failure

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Neutral phosphorus preparations may contain potassium and sodium; periodically monitor potassium and sodium serum levels; may act as a laxative; patients with kidney stones may pass old stones when phosphate therapy is started
Exercise caution when neutral phosphorus is administered in patients with cardiac disease, severe adrenal or renal insufficiency, acute dehydration, extensive tissue breakdown, myotonia congenita, cirrhosis, liver disease, edema, hypernatremia, hypertension, toxemia of pregnancy, hypoparathyroidism, and acute pancreatitis

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.

Levocarnitine (Carnitor)

A carrier molecule involved in the transport of long-chain fatty acids across the inner mitochondrial membrane.

Dosing

Adult

1-3 g/d PO divided bid/tid

Pediatric

50-100 mg/kg/d PO divided bid/tid; not to exceed 3 g/d

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Various mild GI symptoms including diarrhea, nausea, and vomiting have been reported with long-term use; mild myasthenia has been described in uremic patients

Follow-up

Further Outpatient Care

• Hypotonia and mental retardation in oculocerebrorenal syndrome of Lowe (OCRL), or Lowe syndrome, 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.

Inpatient & Outpatient Medications

• 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 22 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

• In childhood, death may occur as a result of renal dysfunction with electrolyte problems, hypotonia, seizures, infections (respiratory or enteric), or sudden death while sleeping.
• Death in patients with Lowe syndrome that occurs between the second to fourth decades of life is usually due to progressive renal failure. The decision to initiate dialysis in patients with Lowe syndrome is medically and ethically complex and depends on the degree of mental retardation, the medical condition of patient, quality of life, and family and social system support. Successful dialysis and renal transplantation has been reported in few adult patients with Lowe syndrome.

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.
• The Lowe Syndrome Association website http://www.lowesyndrome.org/ is an excellent resource for information and support to families of children with Lowe syndrome.

Miscellaneous

Medicolegal 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.
    
    

    

    The classic lenticular opacities in a female carrier for Lowe syndrome. Note the punctate cortical opacities in radical wedges. (Photo courtesy of Otis Paul, MD)

    
    
  • 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, or Lowe syndrome, 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.

Multimedia

Media file 1: The classic lenticular opacities in a female carrier for Lowe syndrome. Note the punctate cortical opacities in radical wedges. (Photo courtesy of Otis Paul, MD)

References

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Keywords

oculocerebrorenal dystrophy, Lowe syndrome, Lowe's syndrome, oculocerebrorenal syndrome of Lowe, OCRL, Fanconi syndrome, Fanconi's syndrome, renal tubular defects, congenital cataracts, neonatal hypotonia, infantile hypotonia, mental retardation, mental impairment, renal tubular dysfunction, OCRL1, Lowe-Terrey-MacLachlan syndrome, cryptorchidism, metabolic acidosis, pneumonia, status epilepticus, temper tantrums, aggression, constipation, glaucoma, treatment, diagnosis, rickets, osteomalacia, osteopenia

Contributor Information and Disclosures

Author

Amira Al-Uzri, MD, MCR, Associate Professor, Associate Director of Pediatric Clinical Research, Department of Pediatrics, Division of Pediatric Nephrology, Oregon Health & Science University
Amira Al-Uzri, MD, MCR is a member of the following medical societies: American Society of Pediatric Nephrology and American Society of Transplantation
Disclosure: Nothing to disclose.

Coauthor(s)

Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Co-Director: Pediatric and Child Health Research, Oregon Clinical and Translational Research Institute (CTSA).
Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research
Disclosure: Genzyme Honoraria Speaking and teaching; Genzyme Grant/research funds Other; Shire Honoraria Speaking and teaching; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Speaking and teaching; Biomarin Consulting fee Consulting

Melissa P Wasserstein, MD, Associate Professor, Departments of Genetics and Genomic Sciences and Pediatrics, Mount Sinai School of Medicine
Melissa P Wasserstein, MD is a member of the following medical societies: American Society of Human Genetics
Disclosure: Nothing to disclose.

Cydney L Fenton, MD, FAAP, Consulting Staff, Department of Pediatric Endocrinology, Children's Hospital Medical Center of Akron
Cydney L Fenton, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Ian Krantz, MD, Department of Pediatrics, Assistant Professor, University of Pennsylvania and Children's Hospital of Philadelphia
Ian Krantz, MD is a member of the following medical societies: American Society of Human Genetics
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Managing Editor

Leonard G Feld, MD, PhD, MMM, FAAP, Sara H Bissell and Howard C Bissell Endowed Chair in Pediatrics, Chief Medical Officer, Levine Children's Hospital, Carolinas Medical Center
Leonard G Feld, MD, PhD, MMM, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
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Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
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