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Genetic Factors for Leber Congenital Amaurosis (LCA)

2486 words (10 pages) Essay in Biology

18/05/20 Biology Reference this

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Introduction

ABC News Nightline recently aired a story about six-year-old Monroe, twenty-five-year-old Heather and then twelve-year old Christian who all suffered from a severe ocular impairment disease called Leber Congenital Amaurosis or LCA. This rare disease causes retinal dystrophy and is inherited. The eye disorder causes severe vision loss at birth, or within the first few years of life, and is the common cause of all inherited childhood blindness cases.

According to studies done at University of California San Francisco Health, “LCA affects both the peripheral rod cells, which allow you to see at night, and the central cone cells, responsible for fine detail and color vision.” (University of California San Francisco Health, n.d., para. 1). All three subjects in the Nightline dossier could not see anything at night and needed assistance to see clearly during the day, but as drug-trial subjects, could now improve vision due to the type of LCA they have.

There are at least thirteen variations of LCA distinguishable by cause, eye abnormalities and severity of loss of vision. Because LCA can result from mutations of 14 or more genes that have several pertinent roles in the function, development of the retina, and normal vision, these variations of the disease occur. (“Genetics Home Reference: Your Guide to Understanding Genetic Conditions,” Reviewed August 2010, Published July16, 2019, Causes p. 1).

Patients that suffer from one of two mutations of the RPE65 gene, have an opportunity to improve the affects of LCA through new breakthroughs in gene therapy. Mutations of the RPE65 gene are linked to approximately 6% of LCA diagnoses. (University of California San Francisco Health, n.d., Treatment Tab)

I. Cause. A genetic mutation, inheritance of a recessive or dominate gene?

LCA is commonly inherited through families by autosomal recessive genes. Confirmation of genetic heterogeneity was done in 1995 when the disease-causing gene was linked to chromosome 17p13. By 1996, LCA1 mutations we discovered in the photoreceptor-specific guanylate cyclase gene (retGC1), an essential protein for phototransduction (ability for eyes to recover in the dark). Mutations in a specific retinal pigment epithelium gene (RPE65) was discovered in 1997. (Perrault et al., Received 2 July 1999, Revised 21 July 1999, Available online 25 May 2002.).

The protein RPE65 (LCA2) metabolizes vitamin A; failures in this process are link to 5% of all retinal dystrophies and up to 18% of congenital blindness. Symptoms of LCA are poor visual function, usually with nystagmus (involuntary eye movement), nyctalopia (night blindness), photophobia (light sensitivity), diminished electroretinogram, high hyperopia (farsightedness), keratoconus (coning corneas), abnormal pupillary responses and occasionally, Franceschetti’s oculo-digital indicating eye poking, pressing, and rubbing.” (“Blueprint Genetics / Tests / Panels / Ophthalmology / Leber Congenital Amaurosis,” 2019).

 

 

 

 

 

 

 

This table was compiled from database called the Human Phenotype Ontology (HPO). HPO collects information on symptoms that have been described in medical resources. (Genetic and Rare Diseases Information Center (GARD), n.d., Symptoms Table 1)

II. Trait in families. Passing genes to children. Prevalence male/female.

Risks for children to have this recessive gene disorder increases with parents who are close relatives (consanguineous) as they have a higher chance than unrelated parents to each carry the same abnormal gene. Since both parents must carry a defective gene to pass LCA on to their children, offspring have a 25% chance of inheriting two LCA genes (one from each parent). Both male and female offspring share equal risks of inheriting the disorder from the parents. (National Organization for Rare Disorders (NORD), 1986, 1987, 1990, 1996, 1997, 2001, 2010, 2017), (University of California San Francisco Health, n.d.), (https://www.ucsfhealth.org/conditions/leber_congenital_amaurosis/).

III. Dominant or Recessive-Autosomal or Sex-linked or a Mitochondrial disorder

Leber congenital amaurosis is typically an autosomal recessive gene disorder, but some autosomal dominant inheritance cases have been recording. According to a March 2002 article from Human Molecular Genetics:

Since 1996, six genes involved in LCA have been identified, that is, aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) (6), Crumbs homolog 1 (CRB1) (7,8), cone–rod homeobox (CRX) (9), guanylate cyclase 2D (GUCY2D, RETGC1) (10), RPE65 (11), and retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) (12). In addition, linkage studies have revealed LCA loci on 14q24 (LCA3) (13) and 6q11-q16 (LCA5) (14). Other genes that have been associated with early-onset retinal dystrophy, including LRAT, MERTK, PROML1, and TULP1, are not considered LCA genes since the associated phenotypes are typical of juvenile or early-onset retinitis pigmentosa (RP) rather than LCA (15–18).” (Cremers, Van den Hurk, & Den Hollander, May 15, 2002)

Where LCA was inherited via autosomal dominant genes, mutations in CRX, IMPDH1, and OTX2 genes were noted. The abnormal gene comes from either parent or results from new mutation. Risk of passing the disorder from parent to offspring from an autosomal dominant inheritance increases to 50% vice the 25% in autosomal recessive inheritance. Again, the risk of offspring inheritance is equal for both females and males. (National Organization for Rare Disorders (NORD), 1986, 1987, 1990, 1996, 1997, 2001, 2010, 2017)

IV. Statistics of LCA in the general population? (How many people have it?)

Leber congenital amaurosis occurs equally in males and females, affecting 2 to 3 per 100,000 newborns, and approximately 1:50,000 people worldwide. LCA is the most common cause of childhood blindness cases. (“Genetics Home Reference: Your Guide to Understanding Genetic Conditions,” Reviewed August 2010, Published July16, 2019), (National Organization for Rare Disorders (NORD), 1986, 1987, 1990, 1996, 1997, 2001, 2010, 2017), (Duijkers et al., 2018)

V. Is LCA fatal? Are there treatments (or cure) available?

LCA is not fatal standalone but can increase mortality due to the symptoms and debilitations it causes. Because multiple genetic mutations that can cause LCA have been identified and located on chromosomes, scientists world-wide have been developing and improving gene therapies for LCA. An FDA approved gene therapy drug called “Luxturna” from Spark Therapeutics, is available for LCA caused by RPE65 gene mutations (night blindness). According to the makers of this drug, only certain patient profiles are optimal for this treatment:

“LUXTURNA (voretigene neparvovec-rzyl) is a prescription gene therapy product used for the treatment of patients with inherited retinal disease due to mutations in both copies of the RPE65 gene, which can only be confirmed through genetic testing. You must also have enough remaining cells in your retina (the thin layer of tissue in the back of your eyes) as determined by your healthcare professional”. (Spark Therapeutics and design, LUXTURNA, n.d., Webpage Overview)

These early treatments with Luxturna also seems to be more effective in younger patients. Unfortunately, for the other 14 or so possible mutations that can cause LCA, treatments are still being researched and investigated. For patients that do not yet have gene therapy available, adaptive training skills, vision aids, orientation and mobility training, job placement or income assistance have proved beneficial. (University of California San Francisco Health, n.d.)

VI. Timing of Onset

Leber Congenital Amaurosis typically causes severe vision loss at birth or within the first few years of life, but it can progress slowly as an individual ages, as with Heather and Christian from ABC News’ Nightline report. LCA in infants is typically discovered by parents as the babies do not respond to visual cues, have unnatural eye movements and may habitually press their eyes causing eyes to look sunken-in. Monroe parents knew something was wrong with Monroe’s eyes early-on as they knew they both had an abnormal LCA gene. Monroe was missing key developmental milestones and was officially diagnosed with LCA at the age of 3. Christian and his parents didn’t figure out there were issues with blindness until he was about 5-years old. Heather had been told all her life that her vison was going to go away, so she has been able to find ways to modify her lifestyle to deal with increasing loss to her vision. (University of California San Francisco Health, n.d.), (Winn, Ordonez, & Walker, 10 July 2019)

VII. Heterozygous offspring as carriers and symptoms

Although LCA is usually inherited in an autosomal recessive manner, a genetically heterogeneous disorder, autosomal dominant inheritance cases have been recorded. Heterozygotes or carriers are typically asymptomatic, but because the disorder can mutate in various configurations to cause the disorder, uncharacteristic situations can occur. (Weleber, Francis, Trzupek, & Beattie, Initial Posting: July 7, 2004; Last Update: May 2, 2013.), (“Blueprint Genetics / Tests / Panels / Ophthalmology / Leber Congenital Amaurosis,” 2019)

Conclusion

 There are many things that can happen in the creation of another being, the miracle of life, losing one of the five senses can be devastating and is always life altering. Though testing is available to determine if parents have an abnormal gene that can cause LCA, often the severity or version of the visual disorder cannot be determine until the child is born.

Gene therapy is a promising treatment for some patients with certain types of LCA, and so far, appear to be the most effective in younger patients. Monroe, the six-year-old, and Christian the thirteen-year-old, both treated with Luxturna saw remarkable and quick improvement to their vision, especially nighttime vision. In contrast to Heather, the 25-year-old, who struggled to see improvements with her vision at first but was able to finally see some objects at night, especially if the objects reflected light. She was able to see the white parts of waves at the beach, and the moon, and stars through a microscope. She hopes to be able to see her fiancé’s and her future children’s eyes and eye color. As scientific milestones continue, more gene therapies may be obtainable for not only other LCA types, but genetic disorders in general.

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