Leber Congenital Amaurosis

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Disease Entity

Disease

Leber congenital amaurosis (LCA) is a family of congenital retinal dystrophies that results in severe vision loss at an early age. Patients present usually with nystagmus, sluggish or near-absent pupillary responses, severely decreased visual acuity, photophobia and high hyperopia.


The disease was first described by Theodor Karl Gustav von Leber (February 29, 1840 - April 17, 1917) in 1869. It should not be confused with Leber Hereditary Optic Neuropathy described by the same physician in 1871.

Etiology

Leber congenital amaurosis is a a group of hereditary (usually autosomal recessive) retinal diseases. Currently, there are 14 know genetic mutations known to cause LCA. The most most common gene mutations are CEP290, GUDY2D, and CRB1.

Risk Factors

Cosanguinity is the only known risk factor.

Pathophysiology

The pathophysiology of LCA is related to the inability of the eye to undergo phototransduction due to a disruption of the Visual Cycle. The Visual Cycle is a series of enzymatic reactions between the retinal pigment epithelium (RPE)and the neurosensory retina to metabolize dietary vitamin A into 11-cis retinal to generate photopigment. Without 11-cis retinal, the phototransduction cascade cannot be initialized; thus, visual neuronal signals are not propagated to the visual cortex. A dysfunctional mutation of any of the genes encoding for proteins that catalyze any of the series of enzymatic reactions to generate 11-cis retinal can block the Visual Cycle and lead to symptoms of LCA. As such, there are over eleven known variants of this disease, each linked to a specific genetic mutation.

The link between the hindrance of innate vitamin A metabolism within the eye and photoreceptor degeneration remains unclear and is currently an active area of biomedical research.

Epidemiology

The estimated birth prevalence of LCA is two to three per 100,000 births. The condition is the most common cause of inherited blindness in childhood and constitutes more than 5% of all retinal dystrophies. LCA accounts for blindness in more than 20% of children attending schools for the blind.

Diagnosis History

LCA is characterized by significant vision loss in infancy. It may be suspected in a young child with decreased visual response, nystagmus, poorly reactive pupils and an extinguished ERG. Family history typically consistent with autosomal recessive inheritance.

Physical examination Signs

  • Abnormal or absent pupillary response
  • High hyperopia
  • Keratoconus
  • Nystagmus noticed early in live, present from birth
  • Photophobia
  • Vision loss (typically ranging from 20/200 to bare LP

Retinal exam

  • The retina appears normal initially. Later, a variety of abnormalities may develop either in isolation or combination. They include: chorioretinal degeneration and atrophy centered about the fovea, “bone-spicule" like pigmentation, subretinal flecks, "marbled" fundus, pigmented nummular lesions at the level of the retinal pigment epithelium (RPE), optic disc abnormalities and “Coats like” reaction.
  • Oculo-digital sign comprising eye poking, pressing, and rubbing likely producing mechanical retinal stimulation. The major sequelum is enophthalmos, a physical defect in which the eye recedes into the orbit, presumably from atrophy of orbital fat.
  • Intellectual Disability. Rarely, LCA is seen in association with neurodevelopmental delay, intellectual disability, and oculomotor apraxia-type behavior.

Symptoms Visual impairment

Profound visual impairment is usually present from birth. One-third of individuals with LCA have no perception of light. Visual acuity is, with rare exceptions, 20/400 and below. The visual impairment is generally stable or very slowly progressive. Occasionally in the early stages, a mild degree of visual improvement is observed, followed by progressive degradation. Clinical diagnosis is based on clinical findings and ERG. LCA has retinal, ocular, and extraocular features and occasionally, systemic associations (2).

Diagnostic procedures 

Nonrecordable/Extinguished or severely reduced scotopic and photopic electroretinogram (ERG). Normal ERG responses rule out a diagnosis of LCA. Visual evoked responses are variable.

Laboratory test Genetic testing available - combined mutation detection rate of 40%-50%. For details http://www.ncbi.nlm.nih.gov 

Differential diagnosis

Senior-Loken syndrome: Juvenile nephronophthisis (medullary cystic renal disease)

  • Early-onset retinal dystrophy
  • Conorenal syndrome: Cone-shaped digital epiphyses
  • Cerebellar hypoplasia,
  • Early-onset retinal dystrophy
  • Joubert syndrome: Nephronophthisis (a juvenile-onset cystic kidney disease)
  • Hypoplasia of the cerebellar vermis *Early-onset retinal dystrophy, and *Either or both of the following: Episodic hyperpnea and/or apnea
  • Atypical eye movements Peroxisomal biogenesis disorders, Zellweger syndrome a spectrum three phenotypes described before the biochemical and molecular bases of the disorders were known: Zellweger syndrome (ZS) - retinal dystrophy, sensorineural hearing loss, developmental delay with hypotonia, and liver dysfunction. Usually letal during the first year of life. Neonatal adrenoleukodystrophy (NALD) - Retinal degeneration associated with congenital liver and renal abnormalities. Infantile Refsum disease (IRD) – same Infantile neuronal ceroid-lipofuscinosis (CLN1, Santavuori-Haltia disease) *Normal at birth *Develop retinal vision impairment, loss of milestones, and progressive microcephaly by age six to 12 months *blindness by age two years, seizures and progressive mental deterioration *death generally occurs between ages three and 11 years
  • Disorders of mitochondrial dysfunction *ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy *diabetes mellitus
    Early-onset retinitis pigmentosa (RP) *later age of onset, *better preservation of central visual acuity *no nystagmus. *ERG: in the early stages of RP, the photopic component of the ERG typically shows some degree of sparing, while in LCA both the photopic and scotopic ERG are profoundly abnormal
    "SECORD" (severe early-childhood onset retinal dystrophy)
  • Achromatopsia *Photophobia *Specific ERG
    Congenital stationary night-blindness *Myopia *Specific ERG pattern *Better visual acuity Abetalipoproteinemia
  • Hyperthreoninemia

Management

To date no substantial treatment or cure for LCA exists. Affected individuals benefit from correction of refractive error, use of low-vision aids when possible, and optimal access to educational and work-related opportunities.


There are several clinical trials, in different phases, involving specific mutation treatment (3) by gene replacement therapy or photo pigment supplementation. For details http://www.clinicaltrials.gov 


Medical therapy
No effective therapy proven so far. Reduction in light exposure is recommended to avoid photophobia.

Medical follow up

Close follow-up of infants with LCA is recommended with diagnostic ERG. Fundus photos and detailed retinal examination may be helpful. Low vision referral may be warranted. Genetic counseling is recommended for families and patients. At conception, each sibling of an individual with recessively inherited LCA has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk may be possible if the disease-causing mutation in the family are known. Pre-implantation genetics may be considered in this patient population.

Surgery

There are no surgical treatment available for LCA. Gene therapy is a promising treatment, which is currently being research. With this technique, the genes are delivered through vector virus injected subretinaly. Gene therapy has been found to restore some vision in a dog model of LCA>

1. Leber Congenital Amaurosis Richard G Weleber, MD, FACMG, Peter J Francis, FRCOphth, PhD, and Karmen M Trzupek, MS, CGC. Genereview http://www.ncbi.nlm.nih.gov/books/NBK1298/ 

2. Fazzi E, Signorini SG, Scelsa B, Bova SM, Lanzi G. Leber's congenital amaurosis: an update. Eur J Paediatr Neurol. 2003;7:13–22.
3. Maguire AM, Simonelli F, Pierce EA, Pugh EN, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008;358:2240–8.