The Genetics of Hereditary Retinopathies and Optic Neuropathies

Alessandro Iannaccone, MD, MS


Compr Ophthalmol Update. 2005;6(1):39-62. 

In This Article

Syndromic Disorders

Syndromic eye diseases are complex disorders of ophthalmologic interest in which the involvement of the eye is but one of the cardinal features of the disease. There are myriad syndromic eye disorders and the extent of ocular involvement is also extremely variable in severity. The most common of these syndromes include hearing loss or obesity, as well as retinal degeneration and/or optic atrophy, and some not only severely affect the overall quality of life of patients but also threaten their survival. Awareness of the systemic hallmarks of syndromes of ophthalmologic interest is important and gives the ophthalmologist the opportunity to play a fundamental role in the diagnostic process of these conditions. For sake of brevity, only the genetics of the most common syndromes are reviewed here.

Usher syndrome, which is the most common of the syndromic eye diseases, is an autosomal recessive condition characterized by progressive retinal degeneration of the retinitis pigmentosa family (Figure 3A) and sensorineural hearing loss. Usher syndrome has been estimated to have a prevalence of about one in every 20,000 people in the United States[88] and to account for about 3-6% of congenitally hearing-impaired subjects and 50% of deafness-blindness in the world.[89] Three major clinical Usher syndrome subtypes (i.e., types I, II, and III) can be distinguished on clinical grounds.[90] This distinction is mainly based on the type and severity of hearing loss and presence or absence of vestibular compromise, whereas there are no ophthalmologic criteria known to date to assist in this distinction. Rates of progression of visual field loss have been recently estimated in Usher syndrome type II, in which it is also important to note that the age of onset of symptoms of retinal disease can be as late as the fifth decade of life.[91]

A : Advanced retinitis pigmentosa with bull's eye maculopathy characterizes the fundus of this 56-year-old Caucasian male with Usher syndrome type II, due to compound heterozygous mutations (2299delG and 1724G>C) in the USH2A gene. B : Posterior pole of the right fundus of a 19-year-old Caucasian female with Bardet-Biedl syndrome due to homozygosity for a common BBS1 mutation predicting a methionine-to-arginine amino acid substitution at codon 390 (M390R). Retinal thinning and retinal pigment epithelium dropout are noticeable at and beyond the arcades, as so are waxy pallor of the disk and attenuated retinal vessels, but virtually no bone spicule-like deposits can be found. Atrophic macular changes are also present. Electroretinogram testing showed a severe rod-cone pattern of retinal dysfunction. C : The large area of bull's eye maculopathy and temporal disk pallor shown here were associated in this 10-year-old Caucasian female with nystagmus, light aversion, and a cone-rod pattern of severe retinal dysfunction to electroretinogram testing. These and typical systemic findings corroborated the diagnosis of Alström syndrome. ALMS1 gene mutation screening is in progress.

True Usher syndrome must be differentiated from a newly recognized clinical entity that mimics Usher syndrome. This condition, which we and others recently contributed to identifying and characterizing,[21,22] is inherited as an X-linked trait, with males far more severely and earlier affected than females, has variable degrees and ages of onset of hearing impairment, which—different from true Usher syndrome—can also have a transmissive component due to recurrent otitis media, and in many cases is also associated with recurrent infections of any portion of the upper respiratory tract, similar to what observed in the immotile cilia syndrome. This complex syndrome has been thus far associated only with mutations affecting the integrity of the RCC1-like homology domain of the RPGR gene, the main cause of nonsyndromic X-linked retinitis pigmentosa (see section on rod-cone dystrophies).

The genes that cause genuine Usher syndrome are entirely distinct from those that cause nonsyndromic retinitis pigmentosa, with the exception of one specific mutation in the gene that causes one form of Usher syndrome type II, which has been shown to cause retinitis pigmentosa without hearing loss.[92] Usher syndrome itself is genetically heterogeneous, with many more causal genes than the clinical classification in types I, II, and III could have ever predicted. This is a perfect example of genetic heterogeneity. The genes responsible for Usher syndrome known to date are summarized in Table 7 ( . Accessed October 4, 2004; . Accessed October 4, 2004). Mutations in myosin VIIA (subtype USH1B ) and in usherin (subtype USH2A ) account for most cases of Usher syndrome types I and II, respectively—hence, for the majority of cases of Usher syndrome.

A well established metabolic characteristic of this peroxisomal disorder is that affected patients have unusually high circulating levels of a branched-chain fatty acid known as phytanic acid as a result of phytanic acid oxidase deficiency, hence also the name of phytanic-acid storage disease. Prompt recognition of this disorder is important because many of the disease manifestations can be either kept from worsening or reversed with a high-calorie diet devoid of foods rich in phytanic acid (such as butter and animal fat) and plasmapheresis.[93] Therefore, although far less common than Usher syndrome (probably less than one per 500,000 individuals),[94] Refsum disease is one of the most important conditions to be considered in the differential diagnosis of deaf-blinding syndromic diseases like Usher syndrome. The main clinical manifestations of this autosomal recessive disease include pigmentary retinal degeneration, chronic peripheral polyneuropathy, and progressive sensorineural hearing loss ( . Accessed October 4, 2004). Demonstration of elevated levels of circulating phytanic acid is diagnostic. There are two main for ms of Refsum disease: the more common and less severe adult-onset variant, in which anosmia and ichtiosis are also frequent findings, and the infantile-onset form of Refsum disease, which has a broader and typically more severe phenotype ( . Accessed October 4, 2004). Like in Usher syndrome, Refsum disease is more genetically heterogeneous than initially suggested by clinical observations ( Table 8 ) and is also entirely distinct from Usher syndrome ( . Accessed October 4, 2004; . Accessed October 4, 2004).

Features of this very rare autosomal recessive syndrome include fat malabsorption with steatorrhea and low serum cholesterol since childhood (celiac syndrome), pigmentary retinal degeneration of the retinitis pigmentosa type, progressive ataxia, and a characteristic red blood cell shape anomaly called acanthocytosis. Serum beta lipoprotein is absent as a result of defective function in the microsomal triglyceride transfer protein, encoded for by the MTP gene, which is located on the long arm of chromosome 4 (4q23) ( . Accessed October 4, 2004; . Accessed October 4, 2004). The aforementioned clinical and laboratory features allow for differentiation of Bassen-Kornzweig syndrome from Refsum disease. Despite its rarity, awareness of the characteristics of Bassen-Kornzweig syndrome is again important because the syndrome is responsive to supplementation od vitamins A, E, and K.[95,96] Therefore, like for Refsum disease, early diagnosis of Bassen-Kornzweig syndrome is key.

Bardet-Biedl syndrome is the second most common retinal degeneration syndrome after Usher syndrome and one of the most common obesity syndromes of ophthalmologic interest, yet still fairly rare (estimated prevalence of about one instance per 100,000 individuals).[97,98] Infantile-onset obesity, congenitally dystrophic extremities (postaxial polydactyly, syndactyly, and/or brachydactyly of either extremity), kidney abnormalities, some degree of developmental delay, and an early onset retinopathy of the retinitis pigmentosa family (Figure 3B) characterize the vast majority of patients with this autosomal recessive syndrome.[99] Retinopathy is invariably present in all Bardet-Biedl syndrome patients, whereas other features may or may not be present. The retina can appear deceptively normal initially. This may make the diagnosis of Bardet-Biedl syndrome in the clinical setting challenging but electroretinogram testing reveals fairly severe retinal disease early on in most cases. Other features that characterize the eye disease in Bardet-Biedl syndrome patients have been reviewed in detail elsewhere.[99]

Bardet-Biedl syndrome presents a remarkable degree of genetic heterogeneity and complexity. Eight different genes responsible for this syndrome have been localized and cloned to date ( Table 9 ) ( . Accessed October 4, 2004; . Accessed October 4, 2004). Mutations in BBS1 and BBS2 account for the majority of Bardet-Biedl syndrome cases reported to date. Recent studies have shown that most Bardet-Biedl syndrome proteins colocalize at the basal body of ciliated cells and have provided evidence that a generalized ciliary dysfunction is certainly an important aspect of Bardet-Biedl syndrome pathophysiology.[100,101,102] Consistent with this hypothesis, abnormal olfaction has recently emerged as a novel feature of the syndrome.[103,104] To complicate matters further, it appears possible that the severity of the clinical manifestations may be modulated by coinheritance of one or more additional Bardet-Biedl syndrome mutated alleles (i.e., an epistatic effect, as discussed in the Introduction—see Badano et al[105] for example). Some investigators even proposed that three or four mutated alleles may be necessary to cause disease in some cases,[106] but this hypothesis has not been confirmed by others.[107]

Although significantly rarer than Bardet-Biedl syndrome (less than 300 cases have been identified worldwide to date), ( Accessed October 4, 2004). Alström syndrome represents the main differential diagnostic issue with Bardet-Biedl syndrome when confronted with an obese patient affected with a retinal degenerative disease. Alström syndrome shares a number of phenotypical features with Bardet-Biedl syndrome, but some important distinctive features of Alström syndrome that facilitate its differentiation from Bardet-Biedl syndrome are the type of retinal dystrophy observed in Alström syndrome, which is of the cone-rod dystrophy type by both clinical (Figure 3C) and electroretinogram criteria with severe early visual acuity compromise and, often, congenital nystagmus; the presence of dilated infantile-onset cardiomyopathy in Alström syndrome children, which is very often the presenting symptom and the main cause for fatalities; postverbal (i.e., noncongenital) progressive sensorineural hearing loss; late-onset diabetes mellitus, typically preceded by hyperinsulinemia; and the absence of polydactyly (or any other dystrophic aspect of the extremities), which is instead a cardinal sign of Bardet-Biedl syndrome.[108] Alström syndrome patients typically do not have developmental delay, except for patients affected with the French-Acadian variant of the syndrome that has been observed in Louisiana ( . Accessed October 4, 2004). To date, Alström syndrome and Bardet-Biedl syndrome appear to be genetically distinct. The gene responsible for Alström syndrome, called ALMS1 (2p13.1), was cloned recently. ( . Accessed October 4, 2004; . Accessed October 4, 2004). To date, the function of the ALMS1 protein remains unknown and so does the pathophysiology of Alström syndrome.

This rare autosomal recessive syndrome is characterized by an early onset rod-cone retinal dystrophy of the Leber congenital amaurosis type and multicystic renal dysplasia leading to progressive kidney damage (nephronophthisis) and failure. In addition to these cardinal features, other findings typical of children with Senior-Loken syndrome are liver fibrosis, cone-shaped deformity of long bone epiphyses, cerebellar ataxia, sensorineural hearing loss, and vasopressin-resistant diabetes insipidus ( . Accessed October 4, 2004). The estimated prevalence of Senior-Loken syndrome is approximately one in every 250,000 individuals, accounting for nearly 20% of patients affected with familial juvenile nephronophthisis ( . Accessed October 4, 2004). Despite the similar clinical ocular presentation with Leber congenital amaurosis, the far-reaching systemic implications of Senior-Loken syndrome warrant a thorough work-up with focus on kidney ultrasounds and functional laboratory work. Accordingly, the genetics of Senior-Loken syndrome are distinct from those of Leber congenital amaurosis. Three distinct genes are known to date to cause Senior-Loken syndrome, which share expression in the tissues targeted by the disease, where they appear to be associated with ciliary structures ( Table 10 ) ( . Accessed October 4, 2004; . Accessed October 4, 2004). Therefore, similar to Bardet-Biedl syndrome, ciliary dysfunction is suspected to play an important role in at least part of the manifestations of Senior-Loken syndrome.

Neuronal ceroid lipofuscinoses, more commonly termed Batten disease, represent a group of autosomal recessive severe progressive and typically deadly neurodegenerative lysosomal disorders. Although the most frequent age of onset is between 5 and 10 years of age, which is typical of the so-called type III (juvenile) form, there are several neuronal ceroid lipofuscinosis types, most of which have a phenotype of ophthalmologic interest and are characterized by specific ages of onset and distinct genetic etiologies ( Table 11 ) ( . Accessed October 4, 2004; . Accessed October 4, 2004). Overall, the estimated prevalence of neuronal ceroid lipofuscinosis is as high as one in every 12,500 individuals, making them the most common group of neurogenetic pediatric storage diseases.[109]

The typical presenting signs of neuronal ceroid lipofuscinosis are fast deterioration of vision as a result of a rapidly progressive pigmentary retinopathy and optic atrophy, along with a slower but progressive cognitive deterioration, followed by seizures and psychotic behavior, which result from progressive cerebral damage. All neuronal ceroid lipofuscinosis causal genes ( Table 11 ) are important for lysosomal function, a defect that leads to progressive accumulation of lipofuscin deposits in neural tissues and progressive retinal and cerebral atrophy. Laboratory studies often show vacuolated lymphocytes with fingerprint-like inclusions, which are also seen on skin biopsy. In type I, granular osmiophilic deposits are also characteristically seen. New insights regarding the pathophysiology of retinopathy and optic neuropathy in Batten disease have become available very recently, including the finding that the electroretinogram in children with Batten disease can be, at least initially, markedly electronegative.[110] Further details about the neuropathology of this common group of neurodegenerative disorders can be found elsewhere.[111,112]

The full spectrum of this rare autosomal recessive syndrome includes diabetes insipidus, insulin-dependent diabetes mellitus, optic atrophy, and deafness, in the form of progressive sensorineural hearing loss. (This disorder is also known by the acronym of DIDMOAD). Optic atrophy and diabetes mellitus are typically the earliest and often the only signs of the disease and a pigmentary retinopathy can also be present. The exact prevalence of this rare disease is not well defined, with estimates ranging from one in every 100,000 individuals in U.S. studies to one in every 770,000 individuals in U.K. studies.[113] Patients with this disorder appear to be exquisitely prone to developing also neuropsychiatric disorders, as are heterozygous carriers of the trait.[114] In addition to diabetic complications, affected patients are at risk for premature death from progressive brainstem atrophy and complications of urinary tract atony. One causal gene, WFS1 (4p16.1 locus), has been recently cloned ( . Accessed October 4, 2004; . Accessed October 4, 2004). The product of WFS1 , wolframin, appears to be important for mitochondrial function, thereby leading to this protean array of symptoms and to the accumulation of multiple mitochondrial DNA deletions in the target tissues. A second gene, WFS2 , has been mapped to 4q22-q24 in families of Jordanian descent, but the gene has not been cloned yet. Vitamin B1 (thiamine) supplementation may reduce the insulin needs of these patients, but it is unknown if this may be of benefit also for the other features of the disease.[115]

Although osteopetrosis is also known as marble bone disease, its most serious consequences are seen in the nervous system. The main features of the rare but severe pediatric variants of ophthalmologic interest, which are transmitted as an autosomal recessive trait and have an estimated prevalence of one per 200,000 individuals, ( . Accessed October 4, 2004) are macrocephaly, progressive hearing and vision loss, hepatosplenomegaly, and severe anemia ( . Accessed October 4, 2004). Vision loss is typically caused by optic nerve compression in the optic nerve canal. However, cases also affected by retinal dystrophy have been reported.[116] Autosomal recessive osteopetrosis is genetically heterogeneous, with more genes responsible for the observed phenotype than suggested by clinical observation alone ( Table 12 ) ( . Accessed October 4, 2004). The underlying pathogenetic mechanism of these forms of osteopetrosis is defective resorption of immature bone due to abnormal acidification of the bone surface beneath the osteoclasts. Bone marrow transplantation has been shown to be highly effective in ameliorating the entire spectrum of the disease,[117] specifically visual outcomes.[118]


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