Cone-Rod Synaptic Disorder, Congenital Nonprogressive

A number sign (#) is used with this entry because of evidence that congenital nonprogressive cone-rod synaptic disorder (CRSD) is caused by mutation in the gene encoding calcium-binding protein-4 (CABP4; 608965) on chromosome 11q13.

Description

Congenital nonprogressive cone-rod synaptic disorder is characterized by stable low vision, nystagmus, photophobia, a normal or near-normal fundus appearance, and no night blindness. Electroretinography shows an electronegative waveform response to scotopic bright flash, near-normal to subnormal rod function, and delayed and/or decreased to nonrecordable cone responses (Traboulsi, 2013; Khan, 2014).

Clinical Features

Zeitz et al. (2006) studied 3 patients from 2 unrelated families who exhibited electroretinographic (ERG) findings consistent with congenital stationary night blindness (CSNB; see 310500). The first family consisted of the index patient and his affected brother, 4 unaffected sibs, and their unaffected parents. The 2 patients presented with nystagmus and decreased visual acuity in early childhood. In both patients at age 15 years, best corrected visual acuity was 20/100 in both eyes. The disease course in the index patient was stationary for 30 years; however, he experienced a decrease in visual acuity near the time of the report. Neither patient complained about night blindness, and only the index patient developed moderate photophobia accompanied by a mild decrease in visual acuity. The 2 brothers were 39 and 45 years old at the time of the report. The index patient of the second family was the only affected member. He reported decreased visual acuity and night blindness at age 15 years. Visual acuity was reduced to 20/30 in both eyes. ERG showed a pattern typical for CSNB in general, with a well developed a-wave but a minimal b-wave.

Littink et al. (2009) described a Dutch brother and sister who had decreased visual acuity and nystagmus since early childhood, associated with photophobia but not with night blindness. Examination at ages 12 and 10 years, respectively, showed visual acuities of 20/200 to 20/400, which had not changed over a 6-year period. Slit-lamp examination and funduscopy were unremarkable. Both sibs showed severely abnormal deutan color vision. Dark-adaptation curves were biphasic, with a slightly elevated final threshold. ERGs showed rod responses that were normal in the brother and low normal in the sister; both had absent cone a-waves and an electronegative configuration with absent b-waves. Cone responses were severely reduced, and 30-Hz photopic flicker responses showed the double-peak waveform characteristic of CSNB2. Rod responses showed an intact slow sensitive rod pathway, but an absent or severely abnormal fast insensitive rod pathway. Because the patients did not experience night blindness, Littink et al. (2009) designated the phenotype 'congenital cone-rod synaptic disorder.'

Aldahmesh et al. (2010) reported 4 sibs, born of first-cousin Bedouin parents, who had very poor vision since infancy with nystagmus and lack of fixation or tracking. The proband was a 15-year-old girl who had a history of photophobia but not night blindness, with normal color vision. Examination revealed nystagmus and eccentric fixation, with a best-corrected visual acuity of 20/400 in both eyes; the visual acuity measurement was unchanged from early childhood, indicating the nonprogressive nature of the vision loss. Funduscopy was normal except for decreased foveal reflex, and ERG was extinguished under both photopic and scotopic conditions. The patient's 3 affected sibs exhibited a strikingly similar clinical profile; however, in 1 sister the ERG was not extinguished, but rather severely decreased under photopic conditions with normal implicit time on photopic flicker, and her scotopic ERG was borderline with a normal oscillatory potential. Two of the affected sibs had strabismus, which was surgically corrected. All 4 affected sibs had normal intellect and growth, and systemic evaluation was unremarkable. Aldahmesh et al. (2010) considered the phenotype to be 'LCA-like' (see 204000).

Khan et al. (2013) studied 7 affected individuals from 3 consanguineous Saudi families with early-onset retinal dysfunction. Including the 4 previously reported Bedouin sibs by Aldahmesh et al. (2010), Khan et al. (2013) noted that all 11 patients had congenital nystagmus, low vision that was considered stable, and photophobia. All denied night blindness upon specific questioning, and all had a normal or near-normal fundus appearance. Affected individuals in the Saudi families had recordable ERGs similar to those of the 1 Bedouin sister, with an electronegative waveform to scotopic flash, near-normal or subnormal rod function, and decreased and delayed cone responses to photopic flash.

Mapping

In a Dutch brother and sister with congenital nonprogressive cone-rod synaptic disorder, Littink et al. (2009) performed genomewide homozygosity mapping and identified 2 homozygous regions, the largest of which was a 9-Mb region on 11q13.1-q13.5 that encompassed the CABP4 gene.

In 4 Bedouin sibs with decreased visual acuity from infancy and extinguished or markedly reduced ERG responses, Aldahmesh et al. (2010) found only 1 shared block of homozygosity, with a minimal 3.29-Mb area of overlap on chromosome 11q13, encompassing 157 genes, including CABP4.

Molecular Genetics

In 2 Swiss brothers who had decreased visual acuity without night blindness and who exhibited ERG findings consistent with CSNB2 (300071) but were negative for mutation in the CACNA1F gene (300110), Zeitz et al. (2006) identified homozygosity for a 2-bp deletion in the CABP4 gene (800delAG; 608965.0001). In addition, a 15-year-old boy from an unrelated family of Swiss ancestry, who did experience night blindness and whose ERG showed a pattern typical for CSNB in general, was compound heterozygous for the 2-bp deletion and a missense mutation in CABP4 (R124C; 608965.0002). He was also hemizygous for an N735T missense mutation in the CACNA1F gene, as was his unaffected brother, and his mother was a heterozygous carrier of the variant. Zeitz et al. (2006) concluded that the CACNA1F variant was not itself disease-causing but might modify the phenotype. Zeitz et al. (2006) showed that these mutations reduced CABP4 transcript levels to 30 to 40% of those in controls. On the basis of haplotype reconstruction and the Swiss ancestry of both families, a common origin of the 2-bp deletion in all 3 apparently unrelated individuals was considered possible.

In a Dutch brother and sister with congenital nonprogressive cone-rod synaptic disorder mapping to chromosome 11q13.1-q13.5, Littink et al. (2009) sequenced the CABP4 gene and identified homozygosity for a nonsense mutation (R216X; 608965.0003). Their unaffected parents were heterozygous for the mutation, which was not found in 300 ethnically matched alleles. Sequence analysis of all coding exons of CABP4 in 85 additional Dutch patients with cone or cone-rod dystrophy did not reveal any mutations, suggesting that CABP4 mutations are not a major cause for those progressive retinal dystrophies.

In 4 Bedouin sibs with decreased visual acuity from infancy and extinguished or markedly reduced ERG responses mapping to chromosome 11q13, Aldahmesh et al. (2010) directly sequenced the CABP4 gene and identified homozygosity for a 1-bp insertion (608965.0004); their unaffected first-cousin parents and 1 unaffected brother were heterozygous carriers of the mutation.

In 7 patients from 3 consanguineous Saudi families with early-onset retinal dysfunction, Khan et al. (2013) identified homozygosity for the same 1-bp insertion that had been identified in 4 Bedouin sibs by Aldahmesh et al. (2010). Haplotype analysis confirmed a shared haplotype surrounding the mutation for all 4 families. Khan et al. (2013) noted that all reported patients with homozygous mutations in the CABP4 gene had congenital nystagmus, low vision that was considered stable, photophobia, no night blindness, a normal or near-normal fundus, and a typically hyperopic refraction. The authors stated that the best designation for the CABP4 phenotype is 'congenital cone-rod synaptic disorder.'

Among a cohort of 101 Dutch patients diagnosed with congenital stationary night blindness, Bijveld et al. (2013) analyzed 6 known CSNB-related genes and identified the R216X mutation in the CABP4 gene in 1 female patient. However, Bijveld et al. (2013) noted that this patient, as well as the previously reported Dutch sibs (Littink et al., 2009) who were also homozygous for R216X, exhibited a phenotype distinct from CSNB: their problems were almost exclusively cone-related, including relatively low visual acuity, hyperopia, severe nonspecific color vision defects, and photophobia, with a slightly elevated (1.0 log) dark adaptation threshold.