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; Deputy Director, Oregon Clinical and Translational Research Institute; Melissa Wasserstein, MD, Assistant Professor, Departments of Human Genetics 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: Feb 7, 2007

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) 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

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.

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