What is the patho physiology of Achromatopsia?

April 21 22:53 2019 Print This Article

The electro retinography helps to diagnose the hemeralopic aspect of this condition. It is a non invasive technique. The response at the low and medium light levels is normal but the response at the high light level is absent. The medium light level is referred as mesotopic. The high light level is referred as phototopic. The medium light level is 100 times lower than the high light level. This condition mainly occurs due to the saturation in neural portion of retina and is not related to the absence of photo receptors.

The patho mechanism of this condition is generally the inability to respond to the variations in the altered cGMP levels. It is an important factor in the visual perception. It regulates the opening of cyclic nucleotide gated ion channel which is referred as CNGs. As the concentration of cGMP decreases the closure of CNGs occurs which leads to the hyper polarization and stops the release of glutamate. The retinal CNGs are native and are made up of 2 alpha and 2 beta subunits which are referred as CNGA3 and CNGB3 respectively. They are present in the cone cells. The CNGB3 do not have the ability to perform independently while the CNGA3 have the ability to perform independently.

The combination of both of them forms channels which alter the membrane expression and the permeability of ion. They also affect the efficacy of cAMP and cGMP. They decrease the outward rectification and cause the current to flicker. They are sensitive to L cis diltiazem. There is a loss of CNGB3 function as a result of mutation and there is a gain of function of CNGA3. The cone cell transducin activity controls the functions of cGMP. The mutations in the GNAT2 result in a truncated and non functional protein. It prevents the alteration of cGMP levels by photons. The relation between the mutations in proteins and the achromatopsia phenotype is positive.

As a result of mutations in the CNGA3 non functional and truncated channels are formed. Only one mutation results in the functional channels out of all the mutations. These all are linked to the ACHM2. The mutation of T369S produces the alterations when it is expressed without the CNGB3. It also leads to the decreased affinity for cyclic guanosine mono phosphate. There is an introduction of single channel gating kinetics and increased calcium permeability. The mutant T369S combines with the CNGB3 and leads to increase calcium permeability. It is not clear how it leads to increase in the calcium permeability. This may occur due to the increase current and decrease in the signal to noise ratio.

There is another mutation which involves the Y181C and S1. It decreases the density of current due to the inability of channel to traffic to the surface. This function negates the cone cells ability to respond to visual input and produce achromatopsia. The other mutation in outside of the S1 region may lead to the loss of function. In the case of ACHM3, there are very few mutations in the CNGB3 which forms truncated channels which are non functional. This results in haploin sufficiency. In few cases the truncated proteins can combine with the wild type channels. This combination is of wide and dominant negative fashion. The most prevalent mutation is the ACHM3 and forms a non functional truncated protein which does not properly traffic to the cell membrane.

There are certain mutations which are mis sense and in the study done on they showed that there are many aberrant properties. The pore region of channel has a R403Q mutation which increases the outward current rectification. It is in competition with the large linear current voltage relationship involving the wild type channels. They are in a direct relation with the cGMP affinity. There is another mutation of S435F which may increase or decrease the surface expression. It also increases the affinity for cAMP and cGMP. It causes the disease causing change with increased affinity for cAMP and cGMP.

This increased affinity forms the channels which are not sensitive to the concentration changes in the cGMP as the light enters in the retina. . In the case of ACHM4, the activation of light the rhodopsin changes the GDP to GTP. It occurs in the guanine nucleotide binding protein which is referred as a G protein. An alpha transducing activity polypeptide 2 is refered as a GNAT2. There is a release of activated alpha sub unit from the inhibhited beta sub units. The alpha sub unit activates the phosphor di esterase which changes the cyclic GMPP to GMP. It reduces the current through the cng3 channels. This process is necessary for the proper processing of color. The mutations in the GNAT2 lead to achromatopsia. The mutations in the GNAT2 result in a truncated and non functional protein. It prevents the alteration in cGMP levels. It does not alter the photo receptor membrane hyper polarization.

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