Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Retinal Disease_Wright, Spiegel, Thompson_2006

FIGURE 5-12. Denaturing gradient gel analysis of a family afflicted with rhodopsin-associated retinitis pigmentosa (Thr-17-Met). Individuals heterozygous for the mutation have four bands on the gel whereas normal individuals have a single band. Closed pedigree symbols indicate clinically affected individuals. There is perfect segregation of the disease phenotype with the molecular genotype. (From Sheffield et al. Am J Hum Genet 1991;49:699–706, with permission.)126

Autosomal Recessive RP

Autosomal recessive RP (ARRP) is probably the most common form of retinitis pigmentosa, although only about 9% of RP patients can be definitely confirmed to have this type of inheritance.23 Many simplex cases are undoubtedly AR. Up to 40% of recessive cases are associated with other systemic pathology or syndromes and 18% have associated hearing loss. Autosomal recessive inheritance of retinitis pigmentosa is suggested when both parents of an affected individual are normal, especially if there is consanguinity. The existence of an affected female (e.g., the patient, a cousin, or sibling), or of male-to-male transmission, helps differentiate this entity from X-linked RP. The clinical course varies widely in age of onset from infancy to the age of 50 or 60143 but may be more severe than most AD cases. A homozygous null mutation in the rhodopsin gene has been demonstrated to cause ARRP in one family.123 Mutations in the RLBP1 gene cause ARRP of the Bothnia type, a childhood-onset RP that may present with intraretinal white dots and has a high

FIGURE 5-14. Fundus photograph of a carrier of X-linked retinitis pigmentosa, from the mother of the patient in Figure 5-13. Note the islands of affected retina that may represent the effect of unfavorable lyonization of clones of retinal cells. This patient is asymptomatic even though she is 20 years older than her son.

RP patients.127 Examination of obligate female carriers (Fig. 5-14) occasionally reveals electroretinographic dysfunction and ophthalmoscopically visible pigmentary degeneration.115 Lyonization may be unfavorably skewed, causing symptoms in some female carriers. A unique, golden metallic reflex is seen in one form of X-linked RP carriers.114

Two distinct loci on the X chromosome are associated with XLRP: RP2 at Xp1119 and RP3 at Xp21.107 The RPGR gene at XP21.1 is mutated in about 20% of families with XLRP.60

DIGENIC RP

With the ability to genotype patients with RP has come the understanding that some patients have mutations of more than one gene causing their disorder. Are these cases autosomal dominant or recessive? Although some phenotypes require mutations of two different genes to cause pathology and mutation of either of these genes alone causes no disorder, others manifest as one type of retinal dystrophy when one gene is mutated and another when a second genetic mutation is added. These forms

are termed digenic. An example is retinitis pigmentosa caused by co-inheritance of a peripherin mutation and a ROM1 mutation.92

LEBER’S CONGENITAL AMAUROSIS

Leber’s congenital amaurosis (LCA) is a group of ocular diseases characterized by severely reduced vision from birth associated with nystagmus or roving eye movements. Most of these children also have high hyperopia,49,140 although a subgroup have myopia.66 Affected infants are often referred to an ophthalmologist when a parent or pediatrician notices that the child does not respond to faces, or when nystagmus or strabismus is noted. Most cases are autosomal recessive; however, autosomal dominant pedigrees have been reported.

Many patients with LCA, as well as other types of infantile blindness, rub or poke their eyes. This phenomenon is called the oculodigital sign of Franceschetti50 and has been purported to cause enophthalmos. Although the apparent cause is an attempt at retinal stimulation, other poorly understood factors contribute, making this behavior a difficult one to stop. Cataracts and keratoconus may be seen in older children. The reported prevalence of neurological abnormalities in LCA varies from 17% to 37%.4,51 Most children with LCA have normal intelligence, and the psychomotor retardation that has been described may have been secondary to sensory deprivation in some cases.111

Rare systemic associations with LCA include deafness, cardiomyopathy, polycystic kidney disease, and osteopetrosis.86a Mutations of at least seven genes can cause LCA. At this writing, 15% to 28% of patients could be genotyped.131 One causative gene is RPGRIP1 on chromosome 14q11, which encodes a protein that interacts with the protein product of the RPGR gene on the X chromosome35; this accounts for approximately 6% of cases of LCA.55 Mutations of the latter cause X- linked RP. Another is the RPE65 gene, for which gene therapy has restored vision in a dog model of LCA.1 RPE65 mutations account for about 5% of human LCA.

An ophthalmologist confronted with an infant with congenital nystagmus must rule out a sensory disturbance as the cause. In one study, 74 of 81 prospectively studied patients (91%) with congenital nystagmus were eventually found to have one

of the following diagnoses: albinism, LCA or “early-onset RP,” achromatopsia, or CSNB.141 Albinism and LCA were the most commonly observed. All these diagnoses, as well as idiopathic congenital nystagmus, are consistent with very poor visual responses in infancy. All but LCA/early-onset RP usually show improvement in visual responses with age. Fundus examination often does not aid in diagnosis. As many as one-half of patients with LCA retain a normal fundus appearance at least until 1 year of age, with arteriolar attenuation and optic nerve pallor more prevalent by age 2 to 3 years. Unusual ophthalmoscopic variants include the presence of a macular “coloboma-like lesion,”66,95 yellow flecks or white dots, a “marbleized” pattern, salt-and- pepper pigmentary changes, and a nummular pattern.

Electrophysiological testing is essential to establishing the proper diagnosis. The ERG is typically extinguished in LCA/early-onset RP, differentiating these from syndromes with similar initial presentation. One caveat is that, because the ERG may be normally reduced in early infancy,53 one should repeat the ERG at a later time, especially if vision seems to be improving. For example, congenital stationary night blindness has been reported to present as blindness in infancy with a nonrecordable ERG that improves with age along with acuity.88,145 Children with CSNB are often myopic rather than hyperopic, whereas the reverse is true for most LCA patients.

Joubert syndrome can also mimic LCA. This syndrome is characterized by neonatal tachypnea, mental retardation, agenesis of the cerebellar vermis, oculomotor apraxia, brainstem malformation, and a congenital retinal dystrophy.72,83,87 The correct diagnosis can be made by demonstrating hypoplasia of the cerebellar vermis with neuroimaging. Patients with oculomotor apraxia (OMA) cannot make voluntary horizontal saccades, which leads to the impression the child cannot fix and follow. Following objects with the use of head thrusts differentiates this condition from true vision loss. Patients who do not have pigmentary retinopathy, but only OMA, may have good vision.

Delayed visual maturation is another challenging clinical problem that may present similar to LCA. Infants with delayed visual maturation have normal eyes without nystagmus, but they do not exhibit appropriate fixation responses for age. The visual evoked potential (VEP) may be attenuated but the ERG is normal. Many of these children have a good prognosis for development of normal vision.41,88,142

Multisystem metabolic syndromes such as infantile phytanic acid storage disease and infantile neuronal ceroid lipofuscinosis should also be considered in the differential of a young child with poor vision and an abnormal ERG. Most, but not all, of these children have neurological abnormalities at the time of presentation. Intrauterine infections should also be considered (see Congenital Retinal Disease section in Chapter 13).

RETINITIS PIGMENTOSA ASSOCIATED WITH SYSTEMIC DISEASES

A more detailed and systematic approach to RP associated with systemic disease can be found in Chapter 13. Only the most common examples of RP associated with major systemic syndromes are discussed here.

Usher Syndrome

When retinitis pigmentosa is associated with sensorineural hearing loss, the disorder is termed Usher syndrome. This condition is the most common cause of combined deaf-blindness in the United States, and represents a heterogeneous group of autosomal recessively inherited diseases. Of children born with hearing impairment, 3% to 6% have Usher syndrome. Lack of recognition of the coexistence of RP in deaf children may lead to years of frustration, with visual field decrease mistaken as clumsiness. For this reason, all deaf children should have a screening ERG at about age 7 or 8 years, earlier if there are any symptoms of RP. Studies by Merin et al. and Fishman et al. have suggested two common types, and a third rarer subtype; these subtypes are termed USH1, USH2, and USH3.47,99

Type I Usher’s patients have profound congenital sensorineural hearing loss, usually resulting in unintelligible speech, and mild nonprogressive ataxia associated with absent vestibular function. Slowly progressive retinal degeneration is often noted in early adolescence, with severe impairment of vision around the age of 40. Type II patients have a moderate to profound, nonprogressive, congenital sensorineural impairment, generally intelligible speech, and normal vestibular responses. Visual deficits tend to occur in later adolescence, and good vision is likely to be preserved until 50 to 60 years of age.117

Visual fields and dark adaptation are abnormal in Usher’s syndrome, often by adolescence. The ERG is typically extinguished or very reduced at presentation in type I. In Type II the ERG is usually recordable. Consultation with otolaryngology is essential because vestibular dysfunction is the best way to distinguish between the two types of Usher syndrome. A rapid initial screen may be performed in the office by having the child or an affected relative attempt toe-to-heel walking. Patients with type I Usher’s syndrome usually have difficulty with this maneuver. The differential diagnosis of Usher syndrome includes Alstrom disease, Bardet–Biedl syndrome, Refsum disease, Cogan syndrome, retinal-renal syndromes, and Leber’s congenital amaurosis, as well as the mitochondrial myopathies and mucopolysaccharidoses. There are at least six different genetic loci for USH1; one of the common causative genes is MYO7A. One of the genes causing USH2 is the USH2A gene.4a,18,91 Cochlear implant surgery can restore hearing to many children with Usher syndrome.

Alstrom Syndrome

Alstrom disease103 presents with impaired vision from the first year of life with nystagmus, photoaversion, and an atypical pigmentary retinopathy, which progresses to bare light perception by the second decade. Bull’s-eye maculopathy may be present, and the cone portion of the ERG is abnormal before the rods. Childhood obesity, insulin-resistant diabetes mellitus, sensorineural deafness, and normal mentation are characteristically present. Variably present associations include acanthosis nigricans, baldness, hypogonadism, and life-threatening renal failure. Alstrom syndrome has been mapped to chromosome 2p and is autosomal recessive.30

Bardet–Biedl Syndrome

Bardet–Biedl syndrome is an autosomal recessive, multisystem disease characterized by obesity, polydactyly, hypogenitalism, mental retardation, and pigmentary retinopathy. Macular pigment mottling is present with relatively little of the typical bone spicule-like hyperpigmentation. When recordable, a rod–cone dystrophy appears to be most common. Postaxial polydactyly, brachydactyly, and syndactyly, which are common in Bardet–Biedl patients, may be subtle and easily overlooked, par-

ticularly if surgery was performed early in life. Diagnosis requires examination of feet and hands and may require radiography. Various authors have argued for distinguishing Bardet–Biedl from the entity of Laurence–Moon syndrome. Patients with the latter develop spastic paresis and extensive choroidal atrophy but lack polydactyly and obesity.26 Mutations in the MKKS gene cause Bardet–Biedl syndrome.78,129

Retinal-Renal Syndromes

Retinitis pigmentosa may be associated with renal failure. Juvenile nephronophthisis or Senior–Loken syndrome is an autosomal recessively inherited disease that features a retinal pigmentary degeneration which may be sectoral, and juvenileonset renal failure, often requiring renal transplant.125 The Saldino–Mainzer syndrome features congenital blindness and renal disease.94

Neuronal Ceroid Lipofuscinosis

The neuronal ceroid lipofuscinoses or lipopigment storage diseases (e.g., Batten’s disease) are lysosomal storage diseases that are associated with retinal degeneration and neurological deterioration. The infantile form (Haltia–Santavuori) is an autosomal recessive disorder characterized by delayed mental and motor development after a normal first 6 months of life. Patients have nonrecordable ERGs and are totally blind by 2 to 3 years of age. The mean age of death is 6.5 years. The late infantile form (Jansky–Bielschowsky) generally occurs between 2 to 4 years of age and begins with seizures, followed by ataxia, delayed mental and motor development, and decerebrate rigidity before death. Optic atrophy and pigmentary retinopathy accompany the visual loss. Unlike the first two forms, the juvenile type (Batten’s, or Spielmeyer–Batten–Vogt) begins with visual loss before the onset of neurological deterioration. Central visual loss begins between the ages of 3 and 7, with death from neurological complications by 20 years.119,132 The diagnosis of infantile ceroid lipofuscinosis may be aided by the finding of electrondense bodies within neurons from a rectal biopsy or sural nerve, lymphocytes, brain, or conjunctiva. However, these changes are somewhat nonspecific.24 Mutations in the CLN1, CLN2, and CLN3 genes cause infantile NCL, late infantile NCL, and juvenile NCL, respectively.148

OTHER PHOTORECEPTOR DISORDERS

Congenital Stationary Night Blindness

Congenital stationary night blindness (CSNB), similar to RP, is characterized by abnormal scotopic vision. Three main forms of CSNB have been described: (1) X-linked, the most common; (2) autosomal dominant, typified by the large French Nougaret pedigree; and (3) autosomal recessive, which is rare. Most cases of the latter have been in consanguineous or Jewish families. Snellen visual acuities of CSNB patients range from normal to 20/200, with most cases of severely decreased vision associated with myopia.64,101 Khouri and colleagues reported a family of X- linked CSNB and hyperopia.80 Unlike RP patients, the visual function remains stable throughout life, with rare reports of slowly progressive loss of vision.5 With the exception of myopic changes, the fundus appearance of CSNB patients is normal. Although dark adaptometry curves are typically 2 to 3 log units above normal, some CSNB patients do not complain of nyctalopia.118 The most common reasons for presentation in childhood are nystagmus, decreased vision, and myopia. Patients with the latter signs invariably have the X-linked or autosomal recessive forms of the disease, because in the autosomal dominant or Nougaret form of CSNB the vision is normal and there is no nystagmus.

Electroretinography is important in the diagnosis of CSNB, and there are several classifications of patients based on these studies. The negative ERG in X-linked and autosomal recessive CSNB, characterized by a selective loss of the b-wave amplitude, is called the Schubert–Bornschein type.124 The photopic a-wave may also be squared off secondary to a lesser contribution of the early components of the oscillatory potentials. The much rarer Riggs type121 appears to be associated with autosomal dominant forms of CSNB and has a relatively normal a- and b-wave configuration, with absent rod responses and subnormal cone responses.

Miyake et al. classified the more prevalent Schubert– Bornschein patients into “complete” and “incomplete” types.105 Patients with the “complete” type of CSNB have poor rod function and absolute psychophysical thresholds that are mediated by cones. Rod responses are selectively diminished on the electroretinogram. Patients with the “incomplete” type of CSNB still have rods mediating threshold but the threshold is elevated.

Interestingly, the ERG reveals marked cone dysfunction in incomplete CSNB, whereas in the complete type cone function is not as severely affected. The validity of Miyake’s subtyping is indirectly supported by the lack of any reports finding both subtypes within the same pedigree.

The rate of rhodopsin turnover following a bright light bleach is normal in AD CSNB.27 Alpern and associates studied pupillary responses and found that rod bleaching signals were normal in spite of poor rod vision, further suggesting that the defect in CSNB is postreceptoral.3 X-linked CSNB has been mapped to Xp11.108 Mutations in the NYX gene cause X-linked complete congenital stationary night blindness.11 Mutations in the CACNA1F gene on Xp11.23 cause another, incomplete form.10 Autosomal dominant CSNB of the Nougaret type has been attributed to mutations in the GNAT1 gene on 3p22.37 Various forms of CSNB have been shown to be caused by a number of genes including those which encode rhodopsin, the alpha subunit of rod transducin, the beta subunit of rod cGMP phosphodiesterase, rhodopsin kinase, arrestin, 22 cis retinol dehydrogenase, and a retinal L-type calcium channel.34 In these disorders the rods are present and function, but abnormally.

There are several rare forms of autosomal recessive CSNB which feature very prolonged recovery of absolute threshold of light sensitivity. These forms differ from the more typical types discussed previously in that they do not have a normal fundus appearance. Fundus albipunctatus is characterized by fine yellow-white dots scattered throughout the retina except for the fovea. There are no other gross abnormalities of the optic nerve, retinal vessels or pigment. Mutations in the RDH5 gene on chromosome 12q13–q14 have been reported in this disorder.147 Patient’s with Oguchi disease may exhibit the Mizuo-Nakamura phenomenon under the proper circumstances. This phenomenon is the appearance of an unusual yellow iridescent sheen in the retina following light exposure which gradually resolves in the dark.106 Mutations of the SAG(arrestin) and RHOK (Rho kinase) genes cause Oguchi disease.52,147 The fleck retina of Kandori is a very rare condition which features larger, more irregular yellow flecks than seen in fundus albipunctatus. Electrophysiologic and psychophysical findings are similar to fundus albipunctatus.76 Although Oguchi disease and fundus albipunctatus are considered stationary, some patients lose vision in late adulthood.