Lowe Syndrome

From EyeWiki



Disease Entity

Disease

Lowe syndrome or oculocerebrorenal syndrome of Lowe (OCRL) is a rare disorder characterized by multiple features occurring mainly in males. Its prevalence is approximately 1 in 500,000. Its systemic manifestations include mental retardation, hypotonia, and kidney dysfunction in the form of Fanconi syndrome. Specifically, its ocular manifestations include congenital cataracts, corneal keloid, and infantile glaucoma.[1]

Etiology

Lowe Syndrome is an X-linked recessive disorder with the key mutation in the OCRL gene. A male may inherit mutation from mother who has mutated OCRL gene copy or may develop a new mutation spontaneously without any previous family history.

Risk Factors

Male gender is a risk factor as well as mother being carrier of OCRL mutation.

Pathophysiology

The key mutation is in the OCRL which encodes for the enzyme OCRL-1. This enzyme is an inositol 5-phosphatase which fits with a substrate PI (4,5)P2. When OCRL-1 levels are low, levels of PI (4,5)P2 rise. The enzyme is mainly focused in the organelles such as the golgi apparatus and endosomes. Thus, proper PI (4,5)P2 substrate concentration is essential for cell functions such as protein trafficking, signaling, and actin cytoskeleton polymerization. Phosphoinositides play an essential role in cellular physiology and cellular functioning including cytokinesis, actin cytoskeleton remodeling, and movement. Phosphoinositides regulate cellular functions via effector protein substrates. Most mutations in Lowe syndrome occur in the phosphatase domain of OCRL-1. This enzyme also works with clathrin and various enzymes essential for membrane trafficking and endosome actions. Faulty protein trafficking may explain defects at the level of the kidney. The mechanisms behind the ocular abnormalities are poorly understood but altered OCRL-1 activity and localization may be needed for epithelial cell movement and ability to differentiate in the eye.

Diagnosis

The definite diagnosis of Lowe Syndrome is based on genetic testing and physical exam findings upon birth.

History

Lowe Syndrome should be suspected in a newborn male patient with congenital cataracts, central hypotonia, and central nervous system delay. Family history may be positive for male relatives with similar findings. Mothers of affected children (carriers) may have radial cortical lenticular opacities in the shape of snowflakes.

Physical examination

Ophthalmological Abnormalities

  • Visual prognosis is overall poor in patients with Lowe Syndrome due to various visual abnormalities. Vision is rarely better than 20/100. [2]
  • Cataracts: are often noted even at 20 weeks gestation. Newborn physical examination will reveal this abnormality and Lowe syndrome should be considered in any male infant with bilateral cataracts.
  • Glaucoma: Present in around 50% of patients. Present with increased intraocular pressure with possible buphthalmos. Distorted anatomical configuration of the angle as noted via gonioscopy. Decreased visibility of both scleral spur and a narrow ciliary body band is noted. Despite intervention, the glaucoma is often aggressive and non-responsive to medical therapy. Vision loss often leads to blindness in these patients.
  • Nystagmus: May be a result of aphakia and possible retinal abnormalities from the genetic mutation.
  • Keloids: About 25% of patients present with corneal or conjunctival Keloids which can further reduce visual prognosis.


Nervous Systemic Abnormalities

  • Severe hypotonia is often present at birth with loss of deep tendon reflexes. This may complicate vital functions such as breathing at birth. Motor function is severely delayed in these patients. Mental retardation may be noted and a majority develop maladaptive behaviors such as temper tantrums, irritability, and non-finalised behavior. Patients may also develop seizures or febrile convulsions.


Kidney Abnormalities

  • Fanconi Syndrome: the key dysfunction in Lowe Syndrome often develops with age and may be not present with symptoms at birth. Failure to thrive may present due to mineral wasting. Renal bicarbonate along with water and salt wasting. Chronic renal failure often develops as time progresses. Overall, the specific renal tubular dysfunction is characterized by aminoaciduria, hypercalciuria, and low-molecular-weight proteinuria with occasional renal tubular acidosis.

Diagnostic procedures

Neurologic findings may warrant neuroimaging. MRI may show light ventriculomegaly and periventricular cystic lesions.[2]

Laboratory test

The diagnosis of Lowe Syndrome can be made based off of reduced inositol polyphosphate-5-phosphatase activity of OCRL-1 in cultured skin fibroblasts. In addition, genetic analysis can be performed for OCLR. Neurologic and musculoskeletal findings may warrant electroencephalography or electromyography. Serologic testing may reveal metabolic acidosis, reduced GFR, hypokalemia, vitamin D deficiency, and elevated CPK and liver transaminases. Urinalysis may reveal aminoaciduria and proteinuria.

Differential diagnosis

Presence of cataracts with hypotonia requires ruling out mitochondrial disorders such as Leber congenital optic neuropathy (LHON), peroxisomal disorders like Zellweger syndrome, and congenital infections including but not limited to rubella or toxoplasmosis. Hypotonia is a feature of OCRL which may be seen in congenital myotonic dystrophies or congenital myopathy such as Muscle-Eye-Brain Disease. It is important to note that presence of renal pathology will generally rule out these other differential diagnoses. Joubert syndrome is another inherited cerebrorenal syndrome with characteristic cerebellar and brainstem abnormalities.

Management

General treatment

Eye Abnormalities

As with other forms of congenital cataracts, cataract surgery is recommended within the first three months of life to avoid amblyopia. Due to the increased risk of complications and need for further surgeries, infants are traditionally left aphakic. Aphakic spectacles or contacts lenses are important for visual development. Children with Lowe's syndrome and glaucoma often require surgery to treat their glaucoma. There is no consensus on preferred glaucoma surgeries. Options include goniotomy, trabeculotomy, and tube shunt procedures are the mainstay of management for glaucoma. Children should be screened at regular intervals for glaucoma.

Systemic Abnormalities

Hypotonia requires early physical therapy intervention. Maladaptive behaviors may be controlled by antipsychotics. Clomipramine, paroxetine, and risperidone have been shown to have some beneficial effects with nervous abnormalities. Kidney pathology often presents in the form of renal tubular acidosis and may be treated with sodium bicarbonate or other alkali. Intravenous fluids may be required for infants that have resultant dehydration. Additionally, supplementation with vitamin D is essential to prevent occurrence of rickets with adjustment based on close monitoring of both parathyroid hormone and calcium levels.

Complications and Prognosis

Prognosis is variable and early diagnosis is important to prevent life threatening complications due to renal pathology, hypotonia, or infection. Importantly, quality of life is highly dependent on extent of nervous and renal compromise. Visual acuity is rarely better than 20/100 and is highly dependent on the degree and treatment of amblyopia and complications from glaucoma.

Additional Resources

References

  1. Loi M. Lowe syndrome. Orphanet J Rare Dis. 2006;1(1).
  2. 2.0 2.1 Bokenkamp A, Ludwig M. The oculocerebrorenal syndrome of Lowe: an update. Pediatr Nephrol. 2016. 31(12): 2201–2212
  1. Erdmann KS, Mao Y, McCrea HJ, et al. A Role of the Lowe Syndrome Protein OCRL in Early Steps of the Endocytic Pathway. Dev Cell. 2007;13(3):377-390.
  2. Mehta ZB, Pietka G, Lowe M. The cellular and physiological functions of the lowe syndrome protein OCRL1. Traffic. 2014;15(5):471-487.
  3. Schurman SJ, Scheinman SJ. Inherited cerebrorenal syndromes. Nat Rev Nephrol. 2009;5(9):529-538.
  4. Lowe M. Structure and function of the Lowe syndrome protein OCRL1. Traffic. 2005;6(9):711-719.
  5. Kenworthy L, Charnas L. Evidence for a discrete behavioral phenotype in the oculocerebrorenal syndrome of Lowe. Am J Med Genet. 1995;59(3):283-290.