Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver peroxisomal enzyme alanine:glyoxylate-aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is absent, glyoxylate is converted to oxalate, which forms insoluble calcium oxalate crystals that accumulate in the kidney and other organs. Individuals with PH1 are at risk for recurrent nephrolithiasis (deposition of calcium oxalate in the renal pelvis / urinary tract), nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma), or end-stage renal disease (ESRD). Age at onset of symptoms ranges from infancy to the sixth decade. Approximately 10% of affected individuals present in infancy or early childhood with nephrocalcinosis, with or without nephrolithiasis, and failure to thrive related to renal failure. The majority of individuals with PH1 present in childhood or early adolescence, usually with symptomatic nephrolithiasis and normal or reduced kidney function. The remainder of affected individuals present in adulthood with recurrent renal stones and a mild-to-moderate reduction in kidney function. The natural history of untreated PH1 is one of progressive decline in renal function as a result of calcium oxalate deposits in kidney tissue and complications of nephrolithiasis (e.g., obstruction and infection) with eventual progression to oxalosis (widespread tissue deposition of calcium oxalate) and death from ESRD and/or complications of oxalosis.

Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and vascular system. Individuals most commonly present with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage and/or characteristic papules in the skin. The most frequent cause of morbidity and disability in PXE is reduced vision due to complications of subretinal neovascularizations and macular atrophy. Other manifestations include premature gastrointestinal angina and/or bleeding, intermittent claudication of arm and leg muscles, stroke, renovascular hypertension, and cardiovascular complications (angina/myocardial infarction). Most affected individuals live a normal life span.

Age-related macular degeneration-3 (ARMD3) is characterized by numerous small round yellow lesions visible at the temporal edge of the macula. Larger, less distinct yellow areas near the center of the macula are also observed, which represent areas of pigment epithelial detachment (Stone et al., 2004). For a phenotypic description and a discussion of genetic heterogeneity of age-related macular degeneration, see 603075.

Adult-onset foveomacular vitelliform dystrophy, also known as adult vitelliform macular dystrophy, adult-type foveomacular dystrophy, adult vitelliform macular degeneration, pseudovitelliform macular degeneration, and adult-onset foveomacular pigment epithelial dystrophy, is characterized by a solitary, oval, slightly elevated yellowish subretinal lesion of the fovea that is similar in appearance to the vitelliform or egg-yolk stage of Best disease (153700). Initially the yellow lesion may be present in only one eye. The size is generally one-third to one disc diameter, and small yellow flecks are seen in the paracentral lesion. Patients usually become symptomatic in the fourth or fifth decade of life with a protracted decrease of visual acuity and mild metamorphopsia. Electrooculographic testing reveals a normal or only slightly reduced Arden ratio, which is intensely abnormal in Best disease. The prognosis is optimistic, as most patients retain reading vision throughout life (Felbor et al., 1997; Yamaguchi et al., 2001). For a discussion of genetic heterogeneity of vitelliform macular dystrophy, see VMD1 (153840).

Late-onset retinal degeneration (LORD) is an autosomal dominant disorder characterized by onset in the fifth to sixth decade with night blindness and punctate yellow-white deposits in the retinal fundus, progressing to severe central and peripheral degeneration, with choroidal neovascularization and chorioretinal atrophy (Hayward et al., 2003).

Age-related macular degeneration (ARMD) is a progressive degeneration of photoreceptors and underlying retinal pigment epithelium (RPE) cells in the macula region of the retina. It is a highly prevalent disease and a major cause of blindness in the Western world. Drusen, pale excrescences of variable size, and other deposits accumulate below the RPE on the Bruch membrane; clinical and histopathologic investigations have shown that these extracellular deposits are the hallmark of early ARMD. As ARMD advances, areas of geographic atrophy of the RPE can cause visual loss, or choroidal neovascularization can occur to cause wet, or exudative, ARMD with accompanying central visual loss (summary by De et al., 2007). Genetic Heterogeneity of Age-Related Macular Degeneration ARMD2 (153800) is associated with mutation in the ABCR gene (601691) on chromosome 1p, and ARMD3 (608895) is caused by mutation in the FBLN5 gene (604580) on chromosome 14q31. Up to 50% of the attributable risk of age-related macular degeneration (ARMD4; 610698) appears to be explained by a polymorphism in the CFH gene (134370.0008). ARMD5 (613761) and ARMD6 (613757) are associated with mutation in the ERCC6 (609413) and RAX2 (610362) genes, respectively. ARMD7 (610149) and ARMD8 (613778), which both represent susceptibility linked to chromosome 10q26, are associated with single-nucleotide polymorphisms in the HTRA1 (602194) and ARMS2 (611313) genes, respectively. ARMD9 (611378) is associated with single-nucleotide polymorphisms in the C3 gene (120700). ARMD10 (611488) maps to chromosome 9q32 and may be associated with a polymorphism in the TLR4 gene (603030). ARMD11 (611953) is association with variation in the CST3 gene (604312); ARMD12 (613784) with variation in the CX3CR1 gene (601470); and ARMD13 (615439) with variation in the CFI gene (217030). ARMD14 (615489) is associated with variation in or near the C2 (613927) and CFB (138470) genes on chromosome 6p21. ARMD15 (615591) is associated with variation in the C9 gene (120940). There is evidence for a form of ARMD caused by mutation in the mitochondrial gene MTTL1 (590050). A haplotype carrying deletion of the complement factor H-related genes CFHR1 (134371) and CFHR3 (605336) is also associated with reduced risk of ARMD. Lotery and Trump (2007) reviewed the molecular biology of age-related macular degeneration and tabulated the genes associated with ARMD, including those with only positive findings versus genes for which conflicting results have been found.

Age-related macular degeneration (ARMD) is a multifactorial disorder of the central retina that is the most prevalent cause of progressive vision loss in the developed world. As in other chronic age-related diseases, most cases result from interplay between multiple environmental and genetic factors, with a resultant spectrum of phenotypes. In rare cases, ARMD may manifest early, but there is an exponential rise in prevalence after the age of 60 years (summary by Pras et al., 2015). For a phenotypic description and a discussion of genetic heterogeneity of age-related macular degeneration (ARMD), see 603075.

Patterned macular dystrophy-3 (MDPT3), also called Martinique crinkled retinal pigment epitheliopathy, appears in the fourth or fifth decade of life and is characterized by a 'dry desert land' pattern of the fundus, involving the posterior pole initially and progressing from the temporal fovea to the periphery of the retina. Polypoid choroidal vasculopathy, choroidal neovascularization, or atrophic fibrous macular scarring can cause reduced visual acuity after age 50. Late-stage MDPT3 consists of a retinitis pigmentosa (RP; see 268000)-like phenotype due to death of retinal pigment epithelium (RPE) and photoreceptor cells. The dry desert land pattern observed on fundus examination corresponds to an irregular thickness of the Bruch membrane and the RPE, with a scalloped elevation ('crinkling') of the RPE observed on optical coherence tomography (OCT). Full-field electroretinography may be normal at preclinical and early stages of the dystrophy, but later cone and rod responses are severely reduced, consistent with progressive photoreceptor cell dysfunction and death at the final state (summary by Meunier et al., 2016). For a general phenotypic description and discussion of genetic heterogeneity of patterned macular dystrophy, see MDPT1 (169150).

Patterned dystrophies of the retinal pigment epithelium (RPE) refer to a heterogeneous group of macular disorders, characterized by an abnormal accumulation of lipofuscin in the RPE. The lipofuscin is most apparent in the macular area, and its distribution can show various sizes and shapes. High inter- and intrafamilial variability has been described, and retinitis pigmentosa (RP; see 268000)-like changes have sometimes been observed in association with patterned dystrophies (summary by Vaclavik et al., 2012). Three main varieties of patterned dystrophy of the RPE have been described: reticular ('fishnet-like') dystrophy (see 179840 and 267800), macroreticular ('spider-shaped') dystrophy, and butterfly-shaped pigment dystrophy of the fovea. Genetic Heterogeneity of Patterned Macular Dystrophy Also see MDPT2 (608970), caused by mutation in the CTNNA1 gene (116805) on chromosome 5q31; and MDPT3 (617111), caused by mutation in the MAPKAPK3 gene (602130) on chromosome 3p21.

CLCN2-related leukoencephalopathy is characterized by nonspecific neurologic findings, mild visual impairment from chorioretinopathy or optic atrophy, male infertility, and characteristic findings on brain MRI. Neurologic findings include mild ataxia (action tremor and gait instability following initially normal motor development; occasionally, mild spasticity), cognitive impairment in some (typically mild, rarely severe), psychiatric symptoms in some (depression and schizophrenia-like symptoms), headaches in some (usually intermittent, severe, and diffuse) and auditory symptoms in some (hearing loss, tinnitus, vertigo). Affected individuals remain ambulatory, do not require support for walking, and rarely become blind. To date CLCN2-related leukoencephalopathy has been reported or identified in 31 individuals from 30 families. It is not yet known if the findings occurring in a few individuals (i.e., epilepsy and paroxysmal kinesigenic dyskinesia) are part of the phenotypic spectrum or unrelated findings.

Retinal macular dystrophy-4 (MCDR4) is characterized by late-onset macular degeneration, with multiple drusen-like deposits, macular geographic atrophy, and choroidal neovascularization. Patients also exhibit extensive retinal dysfunction with impaired rod function (Zhou et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of retinal macular dystrophy, see MCDR1 (136550).