Leber Congenital Amaurosis

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Article summary goes here.

Disease Entity: Leber congenital amaurosis (LCA), ICD code ICD 9 362.76, is a congenital retinal dystrophy.

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Disease: Leber congenital amaurosis (LCA) is a congenital retinal dystrophy that results in severe vision loss at an early age. Patients present usually with nystagmus, sluggish or near-absent pupillary responses, severly 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's hereditary optic neuropathy described by the same physician in 1871.

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Etiology: LCA is inherited in an autosomal recessive manner. Rarely, LCA is inherited in an autosomal dominant manner. The diagnosis of LCA is established by clinical findings. Molecular genetic testing is clinically available for the 12 genes currently known to be associated with LCA (1).

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Risk Factors: cosanguinity is the only known risk factor

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General Pathology

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Pathophysiology: 

The disease affects the function of retinal photoreceptor cells. The various genetic mutations result in truncation or alteration of the protein with a complete or partial loss of normal protein function. The result is impairment of phototransduction cascade at various levels, the alteration of photopigments and ion channels which lead to photoreceptors malfunction and subsequent death.

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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.

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Diagnosis

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History: Young child with decreased visual responses and nystagmus. Family history typically consistent with autosomal recessive inheritance.

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Physical examination

Signs:

• Abnormal or absent pupillary response
• High hyperopia
• Keratoconus
• Nystagmus noticed early in live, present from birth
• Photophobia

• 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.

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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.

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Clinical diagnosis is based on clinical findings and ERG. LCA has retinal, ocular, and extraocular features and occasionally, systemic associations (2).

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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.

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Laboratory test:

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

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Differential diagnosis:

Senior-Loken syndrome:
• Juvenile nephronophthisis (medullary cystic renal disease) and
• Early-onset retinal dystrophy


Conorenal syndrome:
• Cone-shaped digital epiphyses,
• Cerebellar hypoplasia, and
• 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:
     o Episodic hyperpnea and/or apnea
     o 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

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Management

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General treatment:

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

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Medical therapy:

No effective therapy proven so far. Reduction in light exposure is recommended.

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Medical follow up:

Yearly, more often if keratoconus present.

Genetic counseling - Is recommended for families and patients. At conception, each sib 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 mutations in the family are known.

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Surgery:

No surgical treatment available. For gene replacement therapy, the genes are delivered through vector virus injected subretinaly

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Surgical follow up

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Complications:

Enophthalmos. Children should be discouraged from repeatedly poking and pressing on their eyes, although attempts to alter such behavior are not always successful.
Inflammatory "Coats like" reactions.

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Prognosis: visual prognosis is reserved at this point although current clinical trials show promising results.

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Additional Resources

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References:

= 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.

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