Paula and Bobby
Parents of Lillie
What is Achromatopsia 3?
Achromatopsia 3 is a rare disease. It is also known as Achm1, Formerly ACHM2 ACHM3 ACHM4 Achromatopsia With Myopia Pingalese colour blindness Pingelapese Blindness Rod Monochromacy 1, Formerly; Rmch1, Formerly Rod Monochromatism 1, Formerly Total Colorblindness With Myopia.
Achromatopsia is the inability to distinguish colours - the world is perceived in monochrome. Functional cones are absent from the retina. Features are reduced central vision, nystagmus, poor colour vision and photophobia. Vision is better in dim illumination. Achromatopsia is congenital and stationary and usually the fundus examination is normal. It occurs in typical and atypical forms which may be complete or incomplete. (This abstract refers only to the form of achromatopsia where the defect is at the retinal receptor level as distinct from central loss of colour perception due to lesions of the ventromedial occipital cortex).
Typical rod achromats lack all sensitivity mediated by cone pigments, but have normal rod function with normal levels of rhodopsin. Incidence is of the order of 3 per 100,000. All colours can be matched to shades of gray. It has been suggested that rhodopsin may be active not only in their rods but also in their cones, cone pigments being absent. In complete achromatopsia. Vision is reduced from infancy, particularly in bright illumination, with acuity loss of the order of 6/60. The nystagmus often becomes less marked in adolescence and may evolve from predominantly pendular to jerk. Pupil reactions to light may be paradoxical (smaller in dim than bright lighting). There is photophobia and in some cases the foveal light reflex is absent. Reduced iris pigmentation and optic disc pallor have been reported. There is a very small, approximately 0.3 degrees, central scotoma.
Visual function may be improved and some relief from photophobia obtained by dark red tinted glasses. Side shielding is necessary to avoid darkly tinted lenses acting as mirrors and to reduce dazzle. The dark adaptation curve is monophasic. A scotopic ERG can be detected, but there is no response to a red flash or flicker stimulus. Histologically the central cones are abnormal in morphology and peripheral cones very reduced in number. There has been a single report with a translocation that suggests a locus on chromosome 14 (Pentao et al., 1992). This locus has been confirmed. Note the patient reported by Wiszniewski et al., (2007) with maternal isodisomy 14.
Atypical achromats also behave as if they have only rod vision, but reflection densitimetry shows normal levels of cone pigments. The defect must be distal to the point of light absorption. Both forms have poor to no colour discrimination and similar acuity levels. Usually the retina appears normal.
Partial achromatopsia has a similar phenotype to complete achromatopsia, but the acuity is often better at 6/24 to 6/36 and there is some colour discrimination. It may be due to mutation of the same gene with only partial loss of function. Partial achromats may be helped with a dark yellow brown (ie red plus yellow) tint in their glasses. In the early stages it is often not possible to distinguish from progressive cone dystrophy - but the latter usually occurs as an autosomal dominant or sporadic trait and is often associated with a Bull's eye macula. In occasional sibships, followed over many years (Hayashi et al., 2004), both complete and incomplete achromatopsia might occur. The sister in this sibship had an atrophic looking macula and was myopic, whereas her brother was hypermetropic and had normal fundi.
Achromatopsia is relatively common in Jewish Moroccan, Iranian and Iraqi families and the gene in Iranian Jewish families has been mapped to chromosome 2 (Arbour et al., 1997). The incidence on the island of Fur in Denmark is 1% (Madsen, 1967). Mutations have been found in the alpha subunit of the cone photoreceptor cGMP-gated cation channel (Kohl et al., 1998, Wissenger et al., 2001). These latter authors found that mutations in their Scandinavian familes and those in Northern Italy have a common origin. The gene is also common in the Pingelapese people of the Eastern Caroline Islands - see separate entry. Eksandh et al., (2002) found both CNGA3 and CNGB3 mutations in a Swedish population. The phenotype in the two genes was similar. Another locus at 1p13 has been identified by Kohl et al., (2002) and mutations found in the cone photoreceptor G-protein alpha-subunit gene (GNAT2). Further mutations were reported by Michaelides et al., (2003). Mutations at this locus account for fewer than 2% of the disease mutations. Two cousins reported by Rosenberg et al., (2004) with GNAT2 mutations had different phenotypes. One could be clssified as having incomplete achromatopsia, whereas the other had oligocone trichromacy. In a study of 22 UK families, Johnson et al., (2004), 41% had CNGA3 mutations and 36% had CNGB3 involvement.In eighteen of the 22 families a mutation was detected. Kohl et al., (2005), reported that 50% of all cases have a CNGB3 mutation. The figure in another study showed that the CNGB3, p.T383fsX mutation accounted for 75% of the disease associated alleles (Wiszniewski et al., 2007).
Differentiation from blue-cone monochromatopsia is difficult particularly in children.
Autosomal recessive incomplete achromatopsia can also be caused by mutations in PDE6H (Kohl et al., 2012) and ATF6 (Kohl et al., 2015, Ansar et al., 2015).
* This information is courtesy of the L M D.
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What gene changes cause Achromatopsia 3?
The syndrome is inherited in the following inheritance pattern/s:
Autosomal Recessive - Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms but have a 25% chance of passing the copies of the gene mutations onto each of their children.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
OMIM Number - 262300 (please check the OMIM page for updated information)
The syndrome can be caused by mutations in the following gene/s location/s:
CNGB3 - 8q21.3
What are the main symptoms of Achromatopsia 3?
The typical symptoms of the syndrome are:
Cataract, Horizontal pendular nystagmus, High myopia, Achromatopsia, Severely reduced visual acuity, Photophobia, Autosomal recessive inheritance, Monochromacy
How does someone get tested for Achromatopsia 3?
The initial testing for Achromatopsia 3 can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
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