Novel Mutations in Two Saudi Patients with Congenital Retinal Dystrophy.

UNLABELLED: To report novel mutations in two Saudi children with clinical features of Leber congenital amaurosis (LCA) and Alström syndrome. CASE REPORTS: Case 1 was a child with phenotypic features of LCA including oculodigital sign, bilateral enophthalmos, nystagmus, pale disc, and retinal changes. Direct sequencing of the coding sequence of GUCY2D revealed a missense mutation affecting highly conserved position (c. 743C > T; p.S248 L). Case 2 describes a girl with marked nystagmus, photophobia, and retinal changes in both eyes with short and stubby fingers tapering at the distal phalanges. The electroretinograms were nonrecordable in each eye. She had a hearing aid in the left ear, mid-facial hypoplasia, bilateral enophthalmos, and insulin dependent diabetes. Mutation screening of candidates genes revealed a pathogenic mutation in ALMS1 gene (c. 8441C > A, p.S2814). Two novel mutations causing phenotypic LCA and Alström syndrome in Saudi patients from consanguineous families expand the genotypic spectrum of congenital retinal dystrophies.

INTRODUCTION

Leber congenital amaurosis (LCA) is a global name for a set of early-onset retinal dystrophies characterized by severe vision loss and poorly recordable electroretinographic responses as early in life as tested.12 Alström syndrome is a recessive, monogenic ciliopathy with multisystem involvement including early cone-rod retinal dystrophy and visual impairment, hearing loss, childhood obesity, acquired type 2 diabetes mellitus, cardiomyopathy, and ultimately multiple organ failure.3 We here report novel mutations in the GUCY2D and ALMS1 gene in each of two Saudi female patients who presented more than 20 years ago with clinical features of LCA and Alström syndrome, respectively. These were research patients from an Institutional Review Board approved study at the King Khaled Eye Specialist Hospital in Riyadh, Saudi Arabia.

CASE REPORTS

Case 1

This patient was brought to Neuro-ophthalmology Clinic at the King Khaled Eye Specialist Hospital in Riyadh on 27 November 1991. She was a 6-month-old female with normal gestation, full term, and normal delivery in a hospital. There were two normal siblings, one stillbirth. The parents, first cousins, had noted rapid synchronous eye movements of both eyes of the child at 40 days of age, but no clinically apparent hearing impairment. Eye movements decreased after that, but head nodding with eye movements persisted. The child also manifested the oculodigital sign, pushing the eyes intermittently. Prior medical and surgical history was negative.

An eye examination on the 3rd of December 1991 revealed that the infant did not follow the light. Extraocular movements revealed jerky nystagmus to the left with ocular digital reflex. The cornea was clear, anterior chamber of normal depth, and media clear in both eyes. Examination of the fundus showed the normal color of the optic disc of oval shape with a cup-to-disc ratio of 0.3 with some pallor temporally.

Eighteen months later, her examination revealed classical oculodigital sign, moderate bilateral enophthalmos, irregular nystagmus, disc with temporal pallor, mild neuroepithelial atrophy, and mild retinal vascular attenuation. Based on the clinical signs and course, the child was diagnosed with LCA. The family pedigree is shown in Figure 1. After genetic testing, the family never returned for follow-up examination and discussions.

Figure 1

Family pedigree of Case 1. Arrow point to the affected proband

Direct sequencing of the coding sequence of GUCY2D revealed a missense mutation affecting a highly conserved position (c.743C>T; p.S248 L). This novel mutation occurs in a previously reported position but with different amino acid change. Pathogenicity of this mutation was checked with prediction software such as PolyPhen and SIFT. Additionally, this variant was absent from 300 ethnically matching controls, which excluded this variant from being a rare polymorphism and makes it more likely to be disease-causing.

Case 2

This is a 5 ½-year-old girl who was seen on November 22, 1986, because of poor visual acuity in each eye. There was a history of nystagmus and visual impairment, which had been noticed, when she was 6 months old. Medical history was unremarkable. The parents were first cousins.

The eye examination revealed visual acuities of fixing and following objects with each eye. The refraction in the right and left eye was +5.50 +0.50 at 90 and +5.50 +5.50 at 90, respectively. The examination of the cornea, iris, lens, and vitreous was within normal limits. There was a marked nystagmus and slight photophobia. The fundus examination revealed a peppery mottling of the fundus. The discs were flat with optic atrophy and attenuated arterioles in both eyes.

Systemic examination revealed that the fingers were short and stubby but tapering at the distal phalanges; there was no polydactyly in the fingers or the toes. A working diagnosis was “tapetoretinal degeneration of both eyes” with nystagmus; not surprisingly, the responses of the electroretinogram were nonrecordable in each eye. No medication was ordered, and the doctor prescribed new glasses for the patient.

On a subsequent examination on December 7, 1993, the then 12-year-old patient spoke just words at the age of 3, had a hearing aid in the left ear, mild mid-facial hypoplasia, bilateral enophthalmos, and diabetes which was discovered 4 years prior to the examination. She has been on insulin. After genetic testing, the family was lost to follow-up.

The family pedigree appears as Figure 2. Mutation screening of candidates genes revealed a pathogenic mutation in ALMS1 gene (c.8441C>A, p.S2814*). This mutation is predicted to terminate the 4169 amino acid protein, losing almost one-third of the protein, which is predicted to go through nonsense-mediated decay.

Figure 2

Family pedigree of Case 2. Arrow point to the affected proband

DISCUSSION

We describe novel mutations in genes for the Alström syndrome and LCA in two unrelated consanguineous families from Saudi Arabia. The two novel mutations contribute to the previously reported heterogeneity in each disorder in the Saudi population.4

LCA usually presents before 6 months of age, but milder forms can present after 1 year.5 The disease-causing mutation in our case was located in the GUCY2D gene which is expressed in cone and rod photoreceptors and is essential for their functional integrity. The gene is located on chromosome 17p13.1 and encodes retGC-1, which is essential for the recovery of the dark state after light excitation of photoreceptors (phototransduction).6 Autosomal recessive mutations in GUCY2D, as in our case, are a major cause of LCA.7 The clinical picture of GUCY2D mutations includes cone-predominant retinal dystrophy with glare, color vision, dark adaptation deficits, and neuroepithelial atrophy.8 Phenotypic characterization in our proband included disturbance of the retinal pigment epithelium, mild enophthalmos, and temporal optic disc pallor.

Alström syndrome has been described previously as an example of a rare autosomal recessive disorder with allelic heterogeneity in the highly inbred population such as in Saudi Arabia.4 ALMS1 localizes to centrosomes and to basal bodies of ciliated cells in numerous organs. ALMS1 may function in the biogenesis or maintenance of cilia.9 Until recently, 120 unambiguous disease-causing mutations in ALMS1 gene have been reported in patients with Alström syndrome.1011 Most described disease-causing alleles are nonsense and frameshift mutations, that would lead to premature protein truncation and are predicted to undergo nonsense-mediated decay of the corresponding mRNA, which indicates that disease manifestation is likely due to loss of protein function.11 Clinical signs typical in early childhood are cone-rod retinal dystrophy leading to blindness, sensorineural hearing loss, metabolic abnormalities, and obesity, all of which were present in our patient. The retinitis pigmentosa in Alström syndrome is often severe and of early-onset, associated with nystagmus.12 Despite the fact that founder effects are more likely events in Saudi population, this report further supports that allelic heterogeneity is expected to occur in inbred populations just as any other population.

In summary, we describe novel mutations causing phenotypic LCA and Alström syndrome in Saudi patients coming from consanguineous families. These two novel mutations expand the genotypic spectrum of congenital retinal dystrophies in the Saudi population.

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Conflicts of interest

There are no conflicts of interest.