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

Oculocerebrorenal Dystrophy (Lowe Syndrome)

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
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).; 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
Contributor Information and Disclosures

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).

Recently, mutations in the OCRL gene have also been identified with renal tubular reabsorption defects in a subset of patients with another X-linked disease called Dent disease, which is characterized by LMW proteinuria, hypercalciuria, and nephrocalcinosis.2,3 Classic Dent disease (also called Dent disease 1) typically does not include renal tubular acidosis or extra renal manifestations. It occurs due to a mutation in the CLCN5 gene located in Xp11.22 and encodes the chloride channel 5 (ClC-5). These CIC-5 channels are predominantly expressed in the proximal tubule and in the intercalated cells of the distal nephron.

The genetic heterogeneity of Dent disease was recently described by identifying a subset of patients who lacked the CLCN5 mutations but exhibited OCRL1 mutations.3 Those patients with OCRL1 mutations are defined as having Dent disease 2 and can be easily differentiated from patients with Lowe syndrome by their lack of major extra-renal manifestations such as cataracts and hypotonia. However, mildly elevated serum muscle enzyme levels, mild cognitive or behavioral impairment, growth retardation, and cryptorchidism have been reported in Dent disease 2. Despite recent advances in molecular genetics, the exact mechanism by which the mutations in OCRL gene causes the phenotypic characteristics of Lowe syndrome or the limited renal manifestations of Dent disease 2 remains unknown.

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.

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References
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References

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Further Reading

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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

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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
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

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
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting

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
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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