Choroideremia (CHM) is characterized by progressive chorioretinal degeneration in affected males and milder signs in heterozygous (carrier) females. Typically, symptoms in affected males evolve from night blindness to peripheral visual field loss, with central vision preserved until late in life. Although carrier females are generally asymptomatic, signs of chorioretinal degeneration can be reliably observed with fundus autofluorescence imaging, and – after age 25 years – with careful fundus examination.

Gyrate atrophy of the choroid and retina (GACR) due to deficiency of ornithine aminotransferase is clinically characterized by a triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy. Characteristic chorioretinal atrophy with progressive constriction of the visual fields leads to blindness at the latest during the sixth decade of life. Patients generally have normal intelligence (summary by Peltola et al., 2002). See 238970 for another hyperornithinemia syndrome.

Adult Refsum disease (ARD is associated with elevated plasma phytanic acid levels, late childhood-onset (or later) retinitis pigmentosa, and variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis. Onset of symptoms ranges from age seven months to older than age 50 years. Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life.

Retinitis pigmentosa (RP) refers to a heterogeneous group of inherited ocular diseases that result in a progressive retinal degeneration affecting 1 in 3,000 to 5,000 people (Veltel et al., 2008). Symptoms include night blindness, the development of tunnel vision, and slowly progressive decreased central vision starting at approximately 20 years of age. Upon examination, patients have decreased visual acuity, constricted visual fields, dyschromatopsia (tritanopic; see 190900), and the classic fundus appearance with dark pigmentary clumps in the midperiphery and perivenous areas ('bone spicules'), attenuated retinal vessels, cystoid macular edema, fine pigmented vitreous cells, and waxy optic disc pallor. RP is associated with posterior subcapsular cataracts in 39 to 72% of patients, high myopia, astigmatism, keratoconus, and mild hearing loss in 30% of patients (excluding patients with Usher syndrome; see 276900). Fifty percent of female carriers of X-linked RP have a golden reflex in the posterior pole (summary by Kaiser et al., 2004). Juvenile Retinitis Pigmentosa Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis (see 204000), whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (Gu et al., 1997). Autosomal recessive forms of juvenile retinitis pigmentosa can be caused by mutation in the SPATA7 (609868), LRAT (604863), and TULP1 (602280) genes (see LCA3, 604232, LCA14, 613341, and LCA15, 613843, respectively). An autosomal dominant form of juvenile retinitis pigmentosa (see 604393) is caused by mutation in the AIPL1 gene (604392).

Mucopolysaccharidosis type III (MPS III) is a multisystem lysosomal storage disease characterized by progressive central nervous system degeneration manifest as severe intellectual disability (ID), developmental regression, and other neurologic manifestations including autism spectrum disorder (ASD), behavioral problems, and sleep disturbances. Disease onset is typically before age ten years. Disease course may be rapidly or slowly progressive; some individuals with an extremely attenuated disease course present in mid-to-late adulthood with early-onset dementia with or without a history of ID. Systemic manifestations can include musculoskeletal problems (joint stiffness, contractures, scoliosis, and hip dysplasia), hearing loss, respiratory tract and sinopulmonary infections, and cardiac disease (valvular thickening, defects in the cardiac conduction system). Neurologic decline is seen in all affected individuals; however, clinical severity varies within and among the four MPS III subtypes (defined by the enzyme involved) and even among members of the same family. Death usually occurs in the second or third decade of life secondary to neurologic regression or respiratory tract infections.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the RP1 gene.

Cohen syndrome is characterized by failure to thrive in infancy and childhood; truncal obesity in the teen years; early-onset hypotonia and developmental delays; microcephaly developing during the first year of life; moderate to profound psychomotor retardation; progressive retinochoroidal dystrophy and high myopia; neutropenia in many with recurrent infections and aphthous ulcers in some; a cheerful disposition; joint hypermobility; and characteristic facial features.

This form of fleck retina disease (see 228980) is characterized by discrete uniform white dots over the entire fundus with greatest density in the midperiphery and no macular involvement. Night blindness occurs. Both autosomal dominant and autosomal recessive inheritance had been suggested (Krill and Folk, 1962; Krill, 1977).

Mevalonate kinase deficiency is a condition characterized by recurrent episodes of fever, which typically begin during infancy. Each episode of fever lasts about 3 to 6 days, and the frequency of the episodes varies among affected individuals. In childhood the fevers seem to be more frequent, occurring as often as 25 times a year, but as the individual gets older the episodes occur less often.\n\nMevalonate kinase deficiency has additional signs and symptoms, and the severity depends on the type of the condition. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria (MVA).\n\nDuring episodes of fever, people with HIDS typically have enlargement of the lymph nodes (lymphadenopathy), abdominal pain, joint pain, diarrhea, skin rashes, and headache. Occasionally they will have painful sores called aphthous ulcers around their mouth. In females, these may also occur around the vagina. Rarely, people with HIDS develop a buildup of protein deposits (amyloidosis) in the kidneys that can lead to kidney failure. Fever episodes in individuals with HIDS can be triggered by vaccinations, surgery, injury, or stress. Most people with HIDS have abnormally high levels of immune system proteins called immunoglobulin D (IgD) and immunoglobulin A (IgA) in the blood. It is unclear why some people with HIDS have high levels of IgD and IgA and some do not. Elevated levels of these immunoglobulins do not appear to cause any signs or symptoms. Individuals with HIDS do not have any signs and symptoms of the condition between fever episodes and typically have a normal life expectancy.\n\nPeople with MVA have signs and symptoms of the condition at all times, not just during episodes of fever. Affected children have developmental delay, problems with movement and balance (ataxia), recurrent seizures (epilepsy), progressive problems with vision, and failure to gain weight and grow at the expected rate (failure to thrive). Individuals with MVA typically have an unusually small, elongated head. In childhood or adolescence, affected individuals may develop eye problems such as inflammation of the eye (uveitis), a blue tint in the white part of the eye (blue sclera), an eye disorder called retinitis pigmentosa that causes vision loss, or clouding of the lens of the eye (cataracts). Affected adults may have short stature and may develop muscle weakness (myopathy) later in life. During fever episodes, people with MVA may have an enlarged liver and spleen (hepatosplenomegaly), lymphadenopathy, abdominal pain, diarrhea, and skin rashes. Children with MVA who are severely affected with multiple problems may live only into early childhood; mildly affected individuals may have a normal life expectancy.

Lowry-Wood syndrome (LWS) is characterized by multiple epiphyseal dysplasia and microcephaly. Patients exhibit intrauterine growth retardation and short stature, as well as developmental delay and intellectual disability. Retinal degeneration has been reported in some patients (Farach et al., 2018; Shelihan et al., 2018). Microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710) and Roifman syndrome (RFMN; 616651), the features of which overlap with those of Lowry-Wood syndrome, are also caused by biallelic mutation in the RNU4ATAC gene.

Saul-Wilson syndrome (SWS) is a skeletal dysplasia characterized by profound short stature, distinctive craniofacial features, short distal phalanges of fingers and toes, and often clubfoot. Early development (primarily speech and motor) is delayed; cognition is normal. Other findings can include hearing loss (conductive, sensorineural, and mixed), lamellar cataracts, and/or rod-cone retinal dystrophy. To date, 16 affected individuals have been reported.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the FAM161A gene.

Usher syndrome type II (USH2) is characterized by the following: Congenital, bilateral sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies. Intact or variable vestibular responses. Retinitis pigmentosa (RP); progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision) and eventually includes decreased central visual acuity; the rate and degree of vision loss vary within and among families.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the PRPF3 gene.

Retinitis pigmentosa-17 (RP17) is characterized by relatively mild disease, with decreased visual acuity, visual field constriction, nyctalopia, and slow progression. Many affected individuals have preserved central vision and acuity until the sixth or seventh decades of life (de Bruijn et al., 2020). For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the NRL gene.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the SNRNP200 gene.

Cone dystrophy with supernormal rod responses (CDSRR) is characterized by onset in the first or second decade of life of very marked photophobia, myopia, reduced color vision along the red-green axis with relatively preserved tritan discrimination, and central scotomata with peripheral widespread sensitivity loss predominating in the superior visual field. Nyctalopia is a later feature of the disorder. There is often retinal pigment epithelium disturbance at the macula with a normal retinal periphery. Autofluorescence (AF) imaging shows either a perifoveal ring or a central macular area of relative increased AF (summary by Michaelides et al., 2005).

A retinitis pigmentosa that has material basis in variation in the chromosome region 1p21.3-p13.3.

Posterior column ataxia with retinitis pigmentosa (AXPC1) is an autosomal recessive neurologic disorder characterized by childhood-onset retinitis pigmentosa and later onset of gait ataxia due to sensory loss (summary by Ishiura et al., 2011).

Early-onset neurodegeneration in the human retina can lead to Leber congenital amaurosis (LCA), the most severe human form of inherited photoreceptor-neuron degeneration resulting in congenital blindness, with an incidence of approximately 1 in 80,000 (summary by Koenekoop et al., 2012). NMNAT1 mutations have been observed to cause severe and rapidly progressive macular degeneration, leading to severe central atrophy with an appearance of congenital macular coloboma in the neonatal period, as well as an unusual early-onset atrophy of the optic nerve (Perrault et al., 2012). Some patients present with later onset and milder phenotype than typical LCA (Kumaran et al., 2021). For a general discussion of the phenotypic and genetic heterogeneity in Leber congenital amaurosis, see LCA1 (204000).

Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of retinal dystrophies characterized by a progressive degeneration of photoreceptors, eventually resulting in severe visual impairment. For a discussion of genetic heterogeneity of RP, see 268000.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the TULP1 gene.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the CRB1 gene.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the PRPF8 gene.

A retinitis pigmentosa that has material basis in variation in the chromosome region Xp21.3-p21.2.

A retinitis pigmentosa that has material basis in mutation in the PRPH2 gene on chromosome 6p21.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the FSCN2 gene.

Newfoundland rod-cone dystrophy (NFRCD) is a severe retinal dystrophy in which night blindness is present from infancy. Progressive loss of peripheral, central, and color vision begins in childhood and results in severe visual loss by the second to fourth decade of life (Eichers et al., 2002).

Bothnia retinal dystrophy is an autosomal recessive disorder with onset of night blindness in childhood. The fundus has a characteristic appearance with yellow-white spots, and at later stages patients develop widespread retinal degeneration with areas of chorioretinal atrophy (summary by Granse et al., 2001).

X-linked cone-rod dystrophy is a rare, progressive visual disorder primarily affecting cone photoreceptors (Demirci et al., 2002). Affected individuals, essentially all of whom are males, present with decreased visual acuity, myopia, photophobia, abnormal color vision, full peripheral visual fields, decreased photopic electroretinographic responses, and granularity of the macular retinal pigment epithelium. The degree of rod photoreceptor involvement is variable, with increasing degeneration. Although penetrance appears to be nearly 100%, there is variable expressivity with respect to age at onset, severity of symptoms, and findings (Hong et al., 1994). Genetic Heterogeneity of X-linked Cone-Rod Dystrophy Additional forms of X-linked cone-rod dystrophy include CORDX2 (300085), mapped to chromosome Xq27, and CORDX3 (300476), caused by mutation in the CACNA1F gene (300110) on chromosome Xp11.23. For a discussion of autosomal forms of cone-rod dystrophy, see CORD2 (120970).

X-linked intellectual disability-retinitis pigmentosa syndrome is characterized by moderate intellectual deficit and severe, early-onset retinitis pigmentosa. It has been described in five males spanning three generations of one family. Some patients also had microcephaly. It is transmitted as an X-linked recessive trait.

X-linked retinitis pigmentosa (XLRP) is a severe form of inherited retinal degeneration that primarily affects the rod photoreceptors (Demirci et al., 2002). It typically causes an early-onset night blindness and loss of peripheral vision, often causing patients to become legally blind by the age of 30 to 40 years. In RP3, affected males have a severe phenotype, and carrier females show a wide spectrum of clinical features ranging from completely asymptomatic to severe RP (Jin et al., 2007). Mutation in the RPGR gene is believed to account for approximately 70% of XLRP (Vervoort et al., 2000). For a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.

Cone-rod dystrophy-10 (CORD10) is characterized by progressive loss of visual acuity and color vision, followed by night blindness and loss of peripheral vision. Patients may experience photophobia and epiphora in bright light (Abid et al., 2006). Mutation in SEMA4A can also cause a form of retinitis pigmentosa (RP35; 610282). For a general phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy, see 120970.

A syndrome with characteristics of immune deficiency and neurological disorders in females and neonatal death in males. The syndrome has been described in only one family with nine affected individuals (five males and four females) spanning two generations. Symptomatic females present slowly progressive proximal muscle weakness, leg hyperreflexia, pes cavus, increased muscle tone in the legs, poor bladder function, static reduced night vision and frequent sinopulmonary infections associated with IgG2 deficiency. Males present with low birth weight and severe hypotonia that leads to death in the neonatal period. The gene locus has been mapped to Xq26-qter.

An autosomal recessive retinopathy in which patients have increased sensitivity to blue light; perception of blue light is mediated by what is normally the least populous cone photoreceptor subtype, the S (short wavelength, blue) cones. Characteristics include visual loss, with night blindness occurring from early in life, varying degrees of L (long, red)- and M (middle, green)-cone vision, and retinal degeneration.

Autosomal recessive congenital stationary night blindness is a disorder of the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this condition typically have difficulty seeing and distinguishing objects in low light (night blindness). For example, they may not be able to identify road signs at night or see stars in the night sky. They also often have other vision problems, including loss of sharpness (reduced acuity), nearsightedness (myopia), involuntary movements of the eyes (nystagmus), and eyes that do not look in the same direction (strabismus).\n\nThe vision problems associated with this condition are congenital, which means they are present from birth. They tend to remain stable (stationary) over time.

Retinitis pigmentosa-35 (RP35) is characterized by night blindness with progressive loss of vision. Pigment deposits and narrowing of vasculature are seen in the retina (Abid et al., 2006). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.

A cone-rod dystrophy that has material basis in variation in the chromosome region 1q12-q24.

Retinitis pigmentosa with or without skeletal anomalies (RPSKA) is characterized by retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurologic defects. Night blindness occurs around 10 years of age, followed by restriction of visual fields. Brachydactyly affects primarily the distal phalanges. Craniofacial abnormalities include frontal bossing, downslanting palpebral fissures, large columella, hypoplastic nares, micrognathia, and large low-set ears (summary by Xu et al., 2017).

Familial benign fleck retina is an autosomal recessive condition associated with a distinctive retinal appearance and no apparent visual or electrophysiologic deficits. Affected individuals are asymptomatic, but fundus examination reveals a striking pattern of diffuse, yellow-white, fleck-like lesions extending to the far periphery of the retina but sparing the foveal region (summary by Sergouniotis et al., 2011).

Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, eccentric fixation, and reduced or complete loss of color discrimination. All individuals with achromatopsia (achromats) have impaired color discrimination along all three axes of color vision corresponding to the three cone classes: the protan or long-wavelength-sensitive cone axis (red), the deutan or middle-wavelength-sensitive cone axis (green), and the tritan or short-wavelength-sensitive cone axis (blue). Most individuals have complete achromatopsia, with total lack of function of all three types of cones. Rarely, individuals have incomplete achromatopsia, in which one or more cone types may be partially functioning. The manifestations are similar to those of individuals with complete achromatopsia, but generally less severe. Hyperopia is common in achromatopsia. Nystagmus develops during the first few weeks after birth followed by increased sensitivity to bright light. Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia and may be as high as 20/80 in incomplete achromatopsia. Visual acuity is usually stable over time; both nystagmus and sensitivity to bright light may improve slightly. Although the fundus is usually normal, macular changes (which may show early signs of progression) and vessel narrowing may be present in some affected individuals. Defects in the macula are visible on optical coherence tomography.

Impaired intellectual development, truncal obesity, retinal dystrophy, and micropenis syndrome (MORMS) is an autosomal recessive disorder characterized by these findings (Hampshire et al., 2006).

Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis (LCA), whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (Gu et al., 1997). Various intermediate phenotypes between LCA and retinitis pigmentosa are known and are sometimes described as 'early-onset severe rod-cone dystrophy' or 'early-onset retinal degeneration' (Booij et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000; for cone-rod dystrophy, see 120970.

Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis, whereas the less aggressive forms are usually considered retinitis pigmentosa (Gu et al., 1997). SPATA7-associated retinopathy shows a variable age at onset, ranging from infancy to adulthood, as well as phenotypic variability, including intrafamilial differences (Wang et al., 2009; Avila-Fernandez et al., 2011; Feldhaus et al., 2018; Sengillo et al., 2018). Mackay et al. (2011) concluded that SPATA7 retinopathy is an infantile-onset severe cone-rod dystrophy with early extensive peripheral retinal atrophy but with variable foveal involvement. For a general phenotypic description and a discussion of genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000. Reviews Kannabiran (2020) reviewed reported SPATA7 mutations and the associated phenotypes. The author noted that there were no clear-cut correlations between genotype and phenotype, and that phenotypic heterogeneity had been observed among patients with the same mutation. Clinical variability was also often seen in patients with SPATA7 mutations, with some phenotypes resembling cone-rod dystrophy or choroideremia.

Bardet-Biedl syndrome-3 (BBS3) is a rare autosomal recessive disorder characterized by retinal dystrophy, polydactyly, renal structural abnormalities, and history of obesity. Although mental retardation has been considered part of the BBS phenotype, several patients with BBS3 and normal intelligence have been reported. Additionally, the obesity in several BBS3 patients has been reversible with caloric restriction and exercise (Young et al., 1998; Ghadami et al., 2000). For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900).

RPE65-related Leber congenital amaurosis / early-onset severe retinal dystrophy (RPE65-LCA/EOSRD) is a severe inherited retinal degeneration (IRD) with a typical presentation between birth and age five years. While central vision varies, the hallmark of this disorder is the presence of severe visual impairment with a deceptively preserved retinal structure. Vision is relatively stable in the first decade of life, but begins to decline in adolescence. Most affected individuals are legally blind (visual acuity 20/200 and/or visual fields extending <20 degrees from fixation) by age 20 years. After age 20 years, visual acuity declines further and by the fourth decade all affected individuals are legally blind and many have complete loss of vision (i.e., no light perception). Milder disease phenotypes have been described in individuals with hypomorphic alleles.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the EYS gene.

Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, eccentric fixation, and reduced or complete loss of color discrimination. All individuals with achromatopsia (achromats) have impaired color discrimination along all three axes of color vision corresponding to the three cone classes: the protan or long-wavelength-sensitive cone axis (red), the deutan or middle-wavelength-sensitive cone axis (green), and the tritan or short-wavelength-sensitive cone axis (blue). Most individuals have complete achromatopsia, with total lack of function of all three types of cones. Rarely, individuals have incomplete achromatopsia, in which one or more cone types may be partially functioning. The manifestations are similar to those of individuals with complete achromatopsia, but generally less severe. Hyperopia is common in achromatopsia. Nystagmus develops during the first few weeks after birth followed by increased sensitivity to bright light. Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia and may be as high as 20/80 in incomplete achromatopsia. Visual acuity is usually stable over time; both nystagmus and sensitivity to bright light may improve slightly. Although the fundus is usually normal, macular changes (which may show early signs of progression) and vessel narrowing may be present in some affected individuals. Defects in the macula are visible on optical coherence tomography.

There are more than 30 types of cone-rod dystrophy, which are distinguished by their genetic cause and their pattern of inheritance: autosomal recessive, autosomal dominant, and X-linked. Additionally, cone-rod dystrophy can occur alone without any other signs and symptoms or it can occur as part of a syndrome that affects multiple parts of the body.\n\nThe first signs and symptoms of cone-rod dystrophy, which often occur in childhood, are usually decreased sharpness of vision (visual acuity) and increased sensitivity to light (photophobia). These features are typically followed by impaired color vision (dyschromatopsia), blind spots (scotomas) in the center of the visual field, and partial side (peripheral) vision loss. Over time, affected individuals develop night blindness and a worsening of their peripheral vision, which can limit independent mobility. Decreasing visual acuity makes reading increasingly difficult and most affected individuals are legally blind by mid-adulthood. As the condition progresses, individuals may develop involuntary eye movements (nystagmus).\n\nCone-rod dystrophy is a group of related eye disorders that causes vision loss, which becomes more severe over time. These disorders affect the retina, which is the layer of light-sensitive tissue at the back of the eye. In people with cone-rod dystrophy, vision loss occurs as the light-sensing cells of the retina gradually deteriorate.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the ABCA4 gene.

A retinitis pigmentosa that is characterized pigmentary retinal degeneration with onset in the teens leading to blindness in the sixth ans seventh decades of life.

Retinitis pigmentosa-10 (RP10) is characterized in most patients by early onset and rapid progression of ocular symptoms, beginning with night blindness in childhood, followed by visual field constriction. Some patients experience an eventual reduction in visual acuity. Funduscopy shows typical changes of RP, including optic disc pallor, retinal vascular attenuation, and bone-spicule pattern of pigmentary deposits in the retinal midperiphery. Electroretinography demonstrates equal reduction in rod and cone responses (Jordan et al., 1993; Bowne et al., 2002; Bowne et al., 2006). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.

Autosomal dominant retinitis pigmentosa (ADRP) is characterized by a typical fundus appearance, narrowed retinal vessels, and changes in the electrophysiological responses of the eye. Early signs are night blindness and constriction of the visual fields with a variable ages of onset (summary by Jay et al., 1992).

A rare genetic eye disease with characteristics of congenital profound excavation of the optic nerve head with diminished visual field, in the absence of elevated intraocular pressure. Many patients lack a well-formed retinal artery and have multiple radial cilioretinal arteries instead. The condition is mostly bilateral, may worsen progressively, and is often complicated by serous macular detachment with profound visual loss.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the NR2E3 gene.

Microphthalmia-retinitis pigmentosa-foveoschisis-optic disc drusen syndrome is a rare, genetic, non-syndromic developmental defect of the eye disorder characterized by the association of posterior microphthalmia, retinal dystrophy compatible with retinitis pigmentosa, localized foveal schisis and optic disc drusen. Patients present high hyperopia, usually adult-onset progressive nyctalopia and reduced visual acuity, and, on occasion, acute-angle glaucoma.

Cone-rod dystrophy is a group of related eye disorders that causes vision loss, which becomes more severe over time. These disorders affect the retina, which is the layer of light-sensitive tissue at the back of the eye. In people with cone-rod dystrophy, vision loss occurs as the light-sensing cells of the retina gradually deteriorate.\n\nThe first signs and symptoms of cone-rod dystrophy, which often occur in childhood, are usually decreased sharpness of vision (visual acuity) and increased sensitivity to light (photophobia). These features are typically followed by impaired color vision (dyschromatopsia), blind spots (scotomas) in the center of the visual field, and partial side (peripheral) vision loss. Over time, affected individuals develop night blindness and a worsening of their peripheral vision, which can limit independent mobility. Decreasing visual acuity makes reading increasingly difficult and most affected individuals are legally blind by mid-adulthood. As the condition progresses, individuals may develop involuntary eye movements (nystagmus).\n\nThere are more than 30 types of cone-rod dystrophy, which are distinguished by their genetic cause and their pattern of inheritance: autosomal recessive, autosomal dominant, and X-linked. Additionally, cone-rod dystrophy can occur alone without any other signs and symptoms or it can occur as part of a syndrome that affects multiple parts of the body.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the PROM1 gene.

Retinitis pigmentosa is characterized by constriction of the visual fields, night blindness, and fundus changes, including 'bone corpuscle' lumps of pigment. RP unassociated with other abnormalities is inherited most frequently (84%) as an autosomal recessive, next as an autosomal dominant (10%), and least frequently (6%) as an X-linked recessive in the white U.S. population (Boughman et al., 1980). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.

Adult Refsum disease (ARD is associated with elevated plasma phytanic acid levels, late childhood-onset (or later) retinitis pigmentosa, and variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis. Onset of symptoms ranges from age seven months to older than age 50 years. Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life.

Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis, whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (Gu et al., 1997). For a general phenotypic description and a discussion of genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the BEST1 gene.

Leber congenital amaurosis is also associated with other vision problems, including an increased sensitivity to light (photophobia), involuntary movements of the eyes (nystagmus), and extreme farsightedness (hyperopia). The pupils, which usually expand and contract in response to the amount of light entering the eye, do not react normally to light. Instead, they expand and contract more slowly than normal, or they may not respond to light at all.\n\nA specific behavior called Franceschetti's oculo-digital sign is characteristic of Leber congenital amaurosis. This sign consists of affected individuals poking, pressing, and rubbing their eyes with a knuckle or finger. Poking their eyes often results in the sensation of flashes of light called phosphenes. Researchers suspect that this behavior may contribute to deep-set eyes in affected children.\n\nIn very rare cases, delayed development and intellectual disability have been reported in people with the features of Leber congenital amaurosis. Because of the visual loss, affected children may become isolated. Providing children with opportunities to play, hear, touch, understand and other early educational interventions may prevent developmental delays in children with Leber congenital amaurosis.\n\nAt least 20 genetic types of Leber congenital amaurosis have been described. The types are distinguished by their genetic cause, patterns of vision loss, and related eye abnormalities.\n\nLeber congenital amaurosis, also known as LCA, is an eye disorder that is present from birth (congenital). This condition primarily affects the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this disorder typically have severe visual impairment beginning at birth or shortly afterward. The visual impairment tends to be severe and may worsen over time.

Syndrome with characteristics of progressive pigmentary retinal degeneration (with nyctalopia and visual field restriction), cystic macular degeneration and angle closure glaucoma. It has been described in seven members of one family. Patients also have hyperopia and nanophthalmos. The mode of transmission is autosomal recessive.

Bardet-Biedl syndrome is an autosomal recessive and genetically heterogeneous ciliopathy characterized by retinitis pigmentosa, obesity, kidney dysfunction, polydactyly, behavioral dysfunction, and hypogonadism (summary by Beales et al., 1999). Eight proteins implicated in the disorder assemble to form the BBSome, a stable complex involved in signaling receptor trafficking to and from cilia (summary by Scheidecker et al., 2014). Genetic Heterogeneity of Bardet-Biedl Syndrome BBS2 (615981) is caused by mutation in a gene on 16q13 (606151); BBS3 (600151), by mutation in the ARL6 gene on 3q11 (608845); BBS4 (615982), by mutation in a gene on 15q22 (600374); BBS5 (615983), by mutation in a gene on 2q31 (603650); BBS6 (605231), by mutation in the MKKS gene on 20p12 (604896); BBS7 (615984), by mutation in a gene on 4q27 (607590); BBS8 (615985), by mutation in the TTC8 gene on 14q32 (608132); BBS9 (615986), by mutation in a gene on 7p14 (607968); BBS10 (615987), by mutation in a gene on 12q21 (610148); BBS11 (615988), by mutation in the TRIM32 gene on 9q33 (602290); BBS12 (615989), by mutation in a gene on 4q27 (610683); BBS13 (615990), by mutation in the MKS1 gene (609883) on 17q23; BBS14 (615991), by mutation in the CEP290 gene (610142) on 12q21, BBS15 (615992), by mutation in the WDPCP gene (613580) on 2p15; BBS16 (615993), by mutation in the SDCCAG8 gene (613524) on 1q43; BBS17 (615994), by mutation in the LZTFL1 gene (606568) on 3p21; BBS18 (615995), by mutation in the BBIP1 gene (613605) on 10q25; BBS19 (615996), by mutation in the IFT27 gene (615870) on 22q12; BBS20 (619471), by mutation in the IFT172 gene (607386) on 9p21; BBS21 (617406), by mutation in the CFAP418 gene (614477) on 8q22; and BBS22 (617119), by mutation in the IFT74 gene (608040) on 9p21. The CCDC28B gene (610162) modifies the expression of BBS phenotypes in patients who have mutations in other genes. Mutations in MKS1, MKS3 (TMEM67; 609884), and C2ORF86 also modify the expression of BBS phenotypes in patients who have mutations in other genes. Although BBS had originally been thought to be a recessive disorder, Katsanis et al. (2001) demonstrated that clinical manifestation of some forms of Bardet-Biedl syndrome requires recessive mutations in 1 of the 6 loci plus an additional mutation in a second locus. While Katsanis et al. (2001) called this 'triallelic inheritance,' Burghes et al. (2001) suggested the term 'recessive inheritance with a modifier of penetrance.' Mykytyn et al. (2002) found no evidence of involvement of the common BBS1 mutation in triallelic inheritance. However, Fan et al. (2004) found heterozygosity in a mutation of the BBS3 gene (608845.0002) as an apparent modifier of the expression of homozygosity of the met390-to-arg mutation in the BBS1 gene (209901.0001). Allelic disorders include nonsyndromic forms of retinitis pigmentosa: RP51 (613464), caused by TTC8 mutation, and RP55 (613575), caused by ARL6 mutation.

BBS2 is an autosomal recessive ciliopathy characterized by retinal degeneration, polydactyly, renal disease, hypogonadism, obesity, dysmorphic features, and variable degrees of cognitive impairment (Innes et al., 2010). Mutation in the BBS2 gene is the third most frequent cause of BBS, accounting for approximately 8% of cases (Zaghloul and Katsanis, 2009). For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900).

BBS4 is a rare multisystemic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, and renal dysfunction that accounts for less than 3% of BBS (Katsanis et al., 2002). Anosmia has been described in patients with BBS4 (Iannaccone et al., 2005), as well as polydactyly confined to the hands (Carmi et al., 1995). For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900).

Retinitis pigmentosa-54 (RP54) is characterized by typical signs of RP, including poor night vision and peripheral field loss, retinal bone spicule-type pigment deposits, pale optic discs, and markedly reduced or extinguished responses on electroretinography. Atypical features that have been observed include early degeneration of the cone photoreceptor system with macular abnormalities, and ring scotoma on the visual field (Collin et al., 2010). Patients may exhibit an early-onset form of cone-rod dystrophy (CORD23), with central vision loss and ring scotoma around the fovea that progresses to marked chorioretinal atrophy in the macular area (Serra et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000. For a general phenotypic description and discussion of genetic heterogeneity of cone-rod dystrophy, see CORD2 (120970).

Any retinitis pigmentosa in which the cause of the disease is a mutation in the TTC8 gene.

Retinitis pigmentosa-56 (RP56) is an early-onset form of RP with progressive visual-field loss and deterioration of visual acuity (Bandah-Rozenfeld et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the ZNF513 gene.

Cone-rod dystrophy-15 (CORD15) is characterized by onset of reduced vision in the third to fifth decades of life. Visual acuity progressively worsens, and most patients exhibit reduced color vision and central scotomas (Cohen et al., 2012; Sobolewska et al., 2023). Retinitis pigmentosa-65 (RP65) is an adult-onset form of RP, with night blindness developing in the second to fourth decades of life. In addition to constriction of visual fields, patients may experience photophobia, reduced visual acuity, and difficulties with color vision (Henderson et al., 2010; Bessette et al., 2018; Dawood et al., 2021). Retinal macular dystrophy-5 (MCDR5) is a late-onset form of macular dystrophy, with most patients noting symptoms in the fourth to sixth decades of life. Symptoms include reduced visual acuity, glare, poor contrast vision, and metamorphopsia; night blindness is uncommon (Stingl et al., 2017; Charbel Issa et al., 2019; Ba-Abbad et al., 2021). Macular atrophy is a characteristic feature in all patients, and early involvement may be observed even in patients with RP who exhibit relatively preserved visual acuity (Malechka et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy, see 120970; for retinitis pigmentosa, see 268000; for retinal macular dystrophy, see 136550. Reviews Bessette et al. (2018) reviewed published reports of patients with disease-causing mutations in the CDHR1 gene. The median age of patients was 36 years, and the majority retained visual acuity of 20/70 or better in at least one eye. Most patients developed symptoms between the first and third decades of life (range, infancy through fourth decade). Night blindness was the most common presenting symptom (54%), followed by photosensitivity (39%) and decreased vision (31%). Macular atrophy was the most common fundus feature reported (96%), followed by vascular attenuation (69%) and peripheral bone spicules (54%). The authors noted significant inter- and intrafamilial phenotypic variability among patients with CDHR1 mutations.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the RHO gene.

Retinitis pigmentosa-49 (RP49) is characterized by onset of night blindness in childhood, followed by progressive loss of visual fields and reduced visual acuity. Typical fundus features are present, including pale optic disc, attenuated vasculature, and pigment deposits in the midperiphery (Zhang et al., 2004; Katagiri et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.

Retinitis pigmentosa-47 (RP47) is characterized by relatively late-onset visual decline, although most patients experience night blindness in childhood. A characteristic golden sheen, considered to be pathognomonic for Oguchi disease (258100), may be observed in the periphery on ultra-widefield fundus images (Nishiguchi et al., 2019). For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the CNGB1 gene.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the RPE65 gene.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the PDE6B gene.

Retinitis pigmentosa-43 (RP43) is characterized by night blindness in the first decade of life, with progressive loss of peripheral visual fields and reduction in visual acuity. Examination reveals typical features of RP, including waxy pallor of optic disc, attenuated retinal vessels, and bone-spicule pigment in midperipheral retina. Macular edema and/or atrophy has been observed in some patients. Electroretinographic responses are markedly reduced or absent (summary by Huang et al., 1995 and Corton et al., 2010).

Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis, whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (summary by Gu et al., 1997). Mutation in TULP1 can also cause a form of autosomal recessive retinitis pigmentosa (RP14; 600132). For a general phenotypic description and a discussion of the genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the DHDDS gene.

Retinitis pigmentosa (RP) describes a group of disorders with progressive degeneration of rod and cone photoreceptors in a rod-cone pattern of dysfunction. RP has a prevalence of 1 in 3,500, and is genetically and phenotypically heterogeneous (summary by Mackay et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the PRPF6 gene.

Retinitis pigmentosa-61 (RP61) is an autosomal recessive photoreceptor degenerative disorder initially characterized by impairment of night vision and midperipheral visual field loss. Bone spicule pigmentation in the retinal periphery is present, and loss of rod function is detected by electroretinography (ERG) (Khan et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa (RP), see 268000.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the MAK gene.

Leber congenital amaurosis is also associated with other vision problems, including an increased sensitivity to light (photophobia), involuntary movements of the eyes (nystagmus), and extreme farsightedness (hyperopia). The pupils, which usually expand and contract in response to the amount of light entering the eye, do not react normally to light. Instead, they expand and contract more slowly than normal, or they may not respond to light at all.\n\nA specific behavior called Franceschetti's oculo-digital sign is characteristic of Leber congenital amaurosis. This sign consists of affected individuals poking, pressing, and rubbing their eyes with a knuckle or finger. Poking their eyes often results in the sensation of flashes of light called phosphenes. Researchers suspect that this behavior may contribute to deep-set eyes in affected children.\n\nIn very rare cases, delayed development and intellectual disability have been reported in people with the features of Leber congenital amaurosis. Because of the visual loss, affected children may become isolated. Providing children with opportunities to play, hear, touch, understand and other early educational interventions may prevent developmental delays in children with Leber congenital amaurosis.\n\nAt least 20 genetic types of Leber congenital amaurosis have been described. The types are distinguished by their genetic cause, patterns of vision loss, and related eye abnormalities.\n\nLeber congenital amaurosis, also known as LCA, is an eye disorder that is present from birth (congenital). This condition primarily affects the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this disorder typically have severe visual impairment beginning at birth or shortly afterward. The visual impairment tends to be severe and may worsen over time.

Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.

A retinitis pigmentosa that has material basis in variation in the chromosome region 6q23.

Cone-rod dystrophy (CORD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. RP is characterized initially by rod photoreceptor dysfunction, giving rise to night blindness, which is followed by progressive rod and cone photoreceptor dystrophy, resulting in midperipheral vision loss, tunnel vision, and sometimes blindness. In contrast to RP, CORD is characterized by a primary loss of cone photoreceptors and subsequent or simultaneous loss of rod photoreceptors. The disease in most cases becomes apparent during primary-school years, and symptoms include photoaversion, decrease in visual acuity with or without nystagmus, color vision defects, and decreased sensitivity of the central visual field. Because rods are also involved, night blindness and peripheral vision loss can occur. The diagnosis of CORD is mainly based on electroretinogram (ERG) recordings, in which cone responses are more severely reduced than, or equally as reduced as rod responses (summary by Estrada-Cuzcano et al., 2012).

Cone-rod dystrophy (CORD) characteristically leads to early impairment of vision. An initial loss of color vision and of visual acuity is followed by nyctalopia (night blindness) and loss of peripheral visual fields. In extreme cases, these progressive symptoms are accompanied by widespread, advancing retinal pigmentation and chorioretinal atrophy of the central and peripheral retina (Moore, 1992). In many families, perhaps a majority, central and peripheral chorioretinal atrophy is not found (Tzekov, 1998). Genetic Heterogeneity of Autosomal Cone-Rod Dystrophy There are several other autosomal forms of CORD for which the molecular basis is known. CORD3 (604116) is caused by mutation in the ABCA4 gene (601691) on chromosome 1p22. CORD5 (600977) is caused by mutation in the PITPNM3 gene (608921) on chromosome 17p13. CORD6 (601777) is caused by mutation in the GUCY2D gene (600179) on chromosome 17p13.1. CORD9 (612775) is caused by mutation in the ADAM9 gene (602713) on chromosome 8p11. CORD10 (610283) is caused by mutation in the SEMA4A gene (607292) on chromosome 1q22. CORD11 (610381) is caused by mutation in the RAXL1 gene (610362) on chromosome 19p13. CORD12 (612657) is caused by mutation in the PROM1 gene (604365) on chromosome 4p15. CORD13 (608194) is caused by mutation in the RPGRIP1 gene (605446) on chromosome 14q11. CORD14 (see 602093) is caused by mutation in the GUCA1A gene (600364) on chromosome 6p21. CORD15 (613660) is caused by mutation in the CDHR1 gene (609502) on chromosome 10q23. CORD16 (614500) is caused by mutation in the C8ORF37 gene (614477) on chromosome 8q22. CORD18 (615374) is caused by mutation in the RAB28 gene (612994) on chromosome 4p15. CORD19 (615860) is caused by mutation in the TTLL5 gene (612268) on chromosome 14q24. CORD20 (615973) is caused by mutation in the POC1B gene (614784) on chromosome 12q21. CORD21 (616502) is caused by mutation in the DRAM2 gene (613360) on chromosome 1p13. CORD22 (619531) is caused by mutation in the TLCD3B gene (615175) on chromosome 16p11. CORD23 (see 613428) is caused by mutation in the C2ORF71 gene (PCARE; 613425) on chromosome 2p23. CORD24 (620342) is caused by mutation in the UNC119 gene (604011) on chromosome 17q11. A diagnosis of CORD was made in an individual with a mutation in the AIPL1 gene (604392.0004) on chromosome 17p13.1, as well as in an individual with a mutation in the UNC119 gene (604011.0001) on chromosome 17q11.2. Other mapped loci for autosomal CORD include CORD1 (600624) on chromosome 18q21.1-q21.3; CORD7 (603649) on chromosome 6q14; CORD8 (605549) on chromosome 1q12-q24; and CORD17 (615163) on chromosome 10q26. For a discussion of X-linked forms of cone-rod dystrophy, see CORDX1 (304020).

Jalili syndrome is an autosomal recessive disorder consisting of cone-rod dystrophy and amelogenesis imperfecta. Significant visual impairment with nystagmus and photophobia is present from infancy or early childhood and progresses with age. Enamel of primary and secondary dentitions is grossly abnormal and prone to rapid posteruptive failure, in part reflecting hypomineralization (summary by Parry et al., 2009).

An X-linked retinal dystrophy characterized by choroideremia, causing in affected males progressive nyctalopia and eventual central blindness. Obesity, moderate intellectual disability and congenital mixed (sensorineural and conductive) deafness are also observed. Female carriers show typical retinal changes indicative of the choroideremia carrier state.

Autosomal recessive congenital stationary night blindness is a disorder of the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this condition typically have difficulty seeing and distinguishing objects in low light (night blindness). For example, they may not be able to identify road signs at night or see stars in the night sky. They also often have other vision problems, including loss of sharpness (reduced acuity), nearsightedness (myopia), involuntary movements of the eyes (nystagmus), and eyes that do not look in the same direction (strabismus).\n\nThe vision problems associated with this condition are congenital, which means they are present from birth. They tend to remain stable (stationary) over time.

Progressive retinal dystrophy due to retinol transport defect is a rare, genetic, metabolite absorption and transport disorder characterized by progressive rod-cone dystrophy, usually presenting with impaired night vision in childhood, progressive loss of visual acuity and severe retinol deficiency without keratomalacia. Association with ocular colobomas, severe acne and hypercholesterolemia has been reported.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the RBP3 gene.

Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).

Any retinitis pigmentosa in which the cause of the disease is a mutation in the SLC7A14 gene.

Bestrophinopathies, the spectrum of ophthalmic disorders caused by pathogenic variants in BEST1, are typically characterized by retinal degeneration. The four recognized phenotypes are the three autosomal dominant disorders: Best vitelliform macular dystrophy (BVMD), BEST1 adult-onset vitelliform macular dystrophy (AVMD), and autosomal dominant vitreoretinochoroidopathy (ADVIRC); and autosomal recessive bestrophinopathy (ARB). Onset is usually in the first decade (except AVMD in which onset is age 30 to 50 years). Slow visual deterioration is the usual course. Choroidal neovascularization can occur in rare cases. ADVIRC is also associated with panophthalmic involvement including nanophthalmos, microcornea, hyperopia, and narrow anterior chamber angle with angle closure glaucoma.

BBS5 is a ciliopathy associated with severe and early-onset retinal dystrophy, postaxial polydactyly, obesity, renal dysfunction, hypogonadism, and learning difficulties (summary by Scheidecker et al., 2015). Patients described by Young et al. (1999) and Moore et al. (2005) with mutations in the BBS5 gene did not have polydactyly. The contribution of BBS5 mutations to all cases of BBS has been estimated at 2% (Li et al., 2004) and 0.40% (Zaghloul and Katsanis, 2009). For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900).

Tubular aggregates in muscle, first described by Engel (1964), are structures of variable appearance consisting of an outer tubule containing either one or more microtubule-like structures or amorphous material. They are a nonspecific pathologic finding that may occur in a variety of circumstances, including alcohol- and drug-induced myopathies, exercise-induced cramps or muscle weakness, and inherited myopathies. Tubular aggregates are derived from the sarcoplasmic reticulum (Salviati et al., 1985) and are believed to represent an adaptive mechanism aimed at regulating an increased intracellular level of calcium in order to prevent the muscle fibers from hypercontraction and necrosis (Martin et al., 1997; Muller et al., 2001). Genetic Heterogeneity of Tubular Aggregate Myopathy See also TAM2 (615883), caused by mutation in the ORAI1 gene (610277) on chromosome 12q24.

Retinitis pigmentosa (RP), also designated rod-cone dystrophy, is characterized by initial night blindness due to rod dysfunction, with subsequent progressive constriction of visual fields, abnormal color vision, and eventual loss of central vision due to cone photoreceptor involvement (summary by El Shamieh et al., 2014). For a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the PRPF4 gene.

Retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies is a rare, genetic, retinal dystrophy disorder characterized by decreased central retinal sensitivity associated with hyper-reflectivity of ganglion cells and nerve fiber layer with loss of optic nerve fibers manifesting with photophobia, optic disc pallor and progressive loss of central vision with preservation of peripheral visual field.

A rare genetic syndromic rod-cone dystrophy disorder with characteristics of psychomotor developmental delay from early childhood, intellectual disability, short stature, mild facial dysmorphism (e.g. upslanted palpebral fissures, hypoplastic alae nasi, malar hypoplasia, attached earlobes), excessive dental spacing and malocclusion, juvenile cataract and ophthalmologic findings of atypical retinitis pigmentosa (i.e. salt-and-pepper retinopathy, attenuated retinal arterioles, generalised rod-cone dysfunction, mottled macula, peripapillary sparing of retinal pigment epithelium).

Any cone-rod dystrophy in which the cause of the disease is a mutation in the DRAM2 gene.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the HGSNAT gene.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the ZNF408 gene.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the IFT172 gene.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the REEP6 gene.

Any retinitis pigmentosa in which the cause of the disease is a mutation in the POMGNT1 gene.

Bardet-Biedl syndrome-20 (BBS20), a rare autosomal recessive disorder associated with ciliary dysfunction, is characterized by rod-cone dystrophy, postaxial polydactyly, truncal obesity, renal anomalies, and learning disability, as well as hypogonadism in males and genital abnormalities in females (Saida et al., 2014). For a general phenotypic description and discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900).

Congenital stationary night blindness type 1H (CSNB1H) is an unusual and unique stationary retinal disorder with a dual anomaly in visual processing, characterized by a partial or severe degree of ON bipolar dysfunction and variably reduced cone sensitivity. Patients present with childhood-onset night blindness and middle age-onset photophobia, but have near-normal vision and do not exhibit nystagmus or high myopia (Vincent et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of congenital stationary night blindness, see CSNB1A (310500).

Any retinitis pigmentosa in which the cause of the disease is a mutation in the AGBL5 gene.

TRNT1 deficiency encompasses what was first thought to be two separate disorders, a severe disorder called sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) and a milder disorder called retinitis pigmentosa with erythrocytic microcytosis (RPEM), each named for its most common features. SIFD begins in infancy, and affected individuals usually do not survive past childhood. RPEM, on the other hand, is recognized in early adulthood, and the microcytosis usually does not cause any health problems. However, it has since been recognized that some individuals have a combination of features that fall between these two ends of the severity spectrum. All of these cases are now considered part of TRNT1 deficiency.\n\nFeatures that occur less commonly in people with TRNT1 deficiency include hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss), recurrent seizures (epilepsy), and problems with the kidneys or heart.\n\nNeurological problems are also frequent in TRNT1 deficiency. Many affected individuals have delayed development of speech and motor skills, such as sitting, standing, and walking, and some have low muscle tone (hypotonia).\n\nEye abnormalities, often involving the light-sensing tissue at the back of the eye (the retina), can occur in people with TRNT1 deficiency. Some of these individuals have a condition called retinitis pigmentosa, in which the light-sensing cells of the retina gradually deteriorate. Eye problems in TRNT1 deficiency can lead to vision loss.\n\nIn addition, many individuals with TRNT1 deficiency have recurrent fevers that are not caused by an infection. These fever episodes are often one of the earliest recognized symptoms of TRNT1 deficiency, usually beginning in infancy. The fever episodes are typically accompanied by poor feeding, vomiting, and diarrhea, and can lead to hospitalization. In many affected individuals, the episodes occur regularly, arising approximately every 2 to 4 weeks and lasting 5 to 7 days, although the frequency can decrease with age.\n\nMany people with TRNT1 deficiency have an immune system disorder (immunodeficiency) that can lead to recurrent bacterial infections. Repeated infections can cause life-threatening damage to internal organs. The immunodeficiency is characterized by low numbers of immune system cells called B cells, which normally help fight infections by producing immune proteins called antibodies (or immunoglobulins). These proteins target foreign invaders such as bacteria and viruses and mark them for destruction. In many individuals with TRNT1 deficiency, the amount of immunoglobulins is also low (hypogammaglobulinemia).\n\nA common feature of TRNT1 deficiency is a blood condition called sideroblastic anemia, which is characterized by a shortage of red blood cells (anemia). In TRNT1 deficiency, the red blood cells that are present are unusually small (erythrocytic microcytosis). In addition, developing red blood cells in the bone marrow (erythroblasts) can have an abnormal buildup of iron that appears as a ring of blue staining in the cell after treatment in the lab with certain dyes. These abnormal cells are called ring sideroblasts.\n\nTRNT1 deficiency is a condition that affects many body systems. Its signs and symptoms can involve blood cells, the immune system, the eyes, and the nervous system. The severity of the signs and symptoms vary widely.

Retinitis pigmentosa-78 (RP78) is an autosomal recessive retinal dystrophy that presents in the third to fourth decade with central visual disturbance, visual field defects, and nyctalopia. Fundus examination reveals optic disc pallor, attenuated retinal vessels, and irregular midperipheral intraretinal pigment migration (Arno et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.

SHRF is an autosomal recessive disorder characterized by short stature, brachydactyly, dysmorphic facial features, hearing loss, and visual impairment. Onset of the hearing and visual abnormalities, including retinitis pigmentosa, varies from birth to the second decade. Patients have mild intellectual disability and mild cerebellar atrophy with myelination defects on brain imaging (summary by Di Donato et al., 2016).

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.

An atypical form of Usher syndrome, here designated type IV (USH4), is an autosomal recessive disorder characterized by late onset of retinitis pigmentosa and usually late-onset of progressive sensorineural hearing loss without vestibular involvement (summary by Khateb et al., 2018). For a discussion of genetic heterogeneity of Usher syndrome, see 276900.

Joubert syndrome-35 (JBTS35) is an autosomal recessive disorder characterized by brain malformations that result in developmental delay, oculomotor apraxia, and hypotonia. Some patients have renal and retinal involvement (Alkanderi et al., 2018). For a discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (213300).

Retinitis pigmentosa-83 (RP83) is characterized by onset of night blindness in the first decade of life, with decreased central vision in the second decade of life in association with retinal degeneration. The retinal dystrophy is associated with cataract, and macular edema has also been reported in some patients (Holtan et al., 2019).

Intellectual developmental disorder and retinitis pigmentosa (IDDRP) is characterized by mildly to moderately impaired intellectual development and typical features of RP. Patients experience reduced night vision, constriction of visual fields, and reduced visual acuity; optic disc pallor, attenuated retinal blood vessels, and bone-spicule pigmentation are seen on funduscopy. Attention-deficit/hyperactivity disorder is observed in some patients (Tatour et al., 2017).

Congenital stationary night blindness type 1I (CSNB1I) is characterized by night blindness from infancy or early childhood. Visual acuity is preserved, but some patients have color vision and/or visual field defects. Older patients may show retinitis pigmentosa-like retinal degeneration (Stunkel et al., 2018).

Retinitis pigmentosa-86 (RP86) is characterized by night blindness followed by progressive narrowing of visual fields and decline in visual acuity, with typical findings of RP on fundus examination, including attenuated retinal vessels, waxy pallor of the optic disc, and bone spicule-like pigmentation (de Bruijn et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.

Usher syndrome type 1M (USH1M) is characterized by prelingual sensorineural hearing loss, vestibular dysfunction, and retinitis pigmentosa (Ahmed et al., 2018). For a general phenotypic description and discussion of genetic heterogeneity of Usher syndrome, see USH1 (276900).

Retinitis pigmentosa-88 (RP88) is characterized by night blindness and constriction of peripheral visual fields, with mildly reduced visual acuity. Examination shows typical findings of RP, including attenuated retinal vessels, pale optic discs, and pigment deposits in the peripheral retinal pigment epithelium (Zobor et al., 2018; Hu et al., 2019; Albarry et al., 2019). For a discussion of genetic heterogeneity of RP, see 268000.

Retinitis pigmentosa-89 (RP89) is characterized by classic features of RP as well as features of ciliopathy, including postaxial polydactyly and renal and hepatic disease. Onset of symptoms is within the first decade of life (Cogne et al., 2020). For a general phenotypic description and discussion of genetic heterogeneity of RP, see 268000.

Retinitis pigmentosa-90 (RP90) is characterized by early-onset night blindness, within the first decade of life. Patients exhibit other typical features of RP, including retinal vessel attenuation, optic disc pallor, and retinal pigment epithelium (RPE) atrophy and pigmentation abnormalities. Macular pseudocoloboma and cystoid macular edema have also been observed (Pierrache et al., 2017). For a discussion of genetic heterogeneity of RP, see 268000.

Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies (GKAF) is characterized by microcephaly, congenital alopecia, distinctive craniofacial features, severe congenital sensorineural hearing loss, global developmental delay, hydrocephalus, hypoplastic kidneys with renal insufficiency, genital hypoplasia, and early mortality (Ito et al., 2018).

Infantile-onset multisystem neurologic, endocrine, and pancreatic disease-2 (IMNEPD2) is an autosomal recessive multisystemic disorder characterized by cholestatic hepatitis, poor feeding associated with poor overall growth, and hypoglycemia apparent from infancy. Most, but not all, patients have variable global developmental delay. Additional common features include sensorineural deafness, retinal abnormalities with visual defects, and hypotonia. Some patients have endocrine abnormalities, including hyperinsulinemic hypoglycemia, pancreatic dysfunction, hypothyroidism, and primary amenorrhea. Additional features may include hypertriglyceridemia, anemia, proteinuria, increased lactate, and recurrent infections. Brain imaging often shows dysmyelination, thin corpus callosum, cerebral atrophy, and white matter abnormalities. Although the clinical manifestations and severity of the disorder are highly variable, death in early childhood may occur (summary by Williams et al., 2019 and Zeiad et al., 2021). For a discussion of genetic heterogeneity of IMNEPD, see IMNEPD1 (616263).

Retinitis pigmentosa-92 (RP92) is characterized by relatively mild disease, with onset of night blindness and vision loss in the third to sixth decades of life. Patients show abnormal pigmentation of the retina and have reduced scotopic responses on electroretinography (Zhang et al., 2018). For a general phenotypic description and discussion of genetic heterogeneity of RP, see 268000.

Chromosome 16q12 duplication syndrome is characterized by early-onset progressive cone dystrophy, with early blue cone involvement. Patients report reduced visual acuity in the first decade of life, as well as difficulty differentiating colors, photophobia, and reduced night vision (Kohl et al., 2021). Tritanopia can also be caused by heterozygous mutation in the OPN1SW gene (613522) on chromosome 7q32 (see 190900).

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).

Any Usher syndrome in which the cause of the disease is a mutation in the CLRN1 gene.

Cone-rod dystrophy-24 (CORD24) is characterized by night blindness, defective color vision, and reduced visual acuity. Macular atrophy, macular pigmentation deposits, and drusen-like deposits in the macula have been observed. Age at onset varies widely, from the first to the sixth decades of live (Kobayashi et al., 2000; Huang et al., 2013; Zenteno et al., 2023). For a general phenotypic description and discussion of genetic heterogeneity of CORD, see CORD2 (120970).

Retinitis pigmentosa-97 (RP97) is characterized by onset of night blindness and visual field defects in the first decade of life, with later onset of reduced visual acuity (Kong et al., 2023). For a general phenotypic description and a discussion of genetic heterogeneity of RP, see 268000.

Neurodevelopmental disorder with progressive movement abnormalities (NEDPM) is an autosomal recessive complex neurologic disorder characterized by global developmental delay apparent from infancy, moderately to severely impaired intellectual development, poor or absent speech, behavioral abnormalities, and various hyperkinetic movement disorders, including dystonia, spasticity, and cerebellar ataxia, that interfere with gait and cause a stooped posture. The disorder appears to be progressive with age-related deterioration of cognitive and motor function; parkinsonism may develop in older patients. Additional more variable features include seizures, dysmorphic facial features, oculomotor defects, and brain imaging abnormalities (Kaiyrzhanov et al., 2024).