From the Department of Ophthalmology (EMV, SS, PLG), A. Fiorini Hospital, Polo Pontino, University of Rome, La Sapienza, Italy; The Jackson Laboratory (JDM), Bar Harbor, Maine; and the Department of Medical and Surgical Sciences (PM, GM), University of Padua, Padua, Italy.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Serena Salvatore, MD, Via Terni 38 E 13, 00182 Rome, Italy.
Alström syndrome (Online Mendelian Inheritance in Man [OMIN] 203800) is an autosomal recessive inherited disorder first described in 1959 by Alström et al.1 The gene, ALMS1, was mapped to chromosome 2p13, and several disease-causing mutations have been identified.2 The cardinal features of this disorder are cone–rod dystrophy, hearing loss, obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy, and progressive hepatic and renal dysfunction.3
The ALMS1 gene encodes a protein lacking previously described domains. The protein is found primarily in centrosomes and basal bodies of ciliated cells, suggesting a function in cilia formation, maintenance, and function.4
Ocular manifestations occurring in the first years of life include nystagmus and photophobia with diminished visual acuity. Narrowing of the retinal vessels, chorioretinal atrophy, bone spicula pigmentary changes, and optic atrophy are seen in the fundus, and posterior subcapsular cataracts may be present.5,6
The current study focuses on the evaluation of retinal ultrastructure in a young boy with Alström syndrome by means of microperimetry and high-resolution spectral domain optical coherence tomography (OCT).
A 5-year-old boy was referred to the Department of Ophthalmology of the University of Rome, La Sapienza, Polo Pontino, with a complaint of progressive vision loss with decreasing visual acuity since birth. The patient had a normal gestation and birth and no medical record of inflammatory or other acute ocular disease. He was obese and had dilated cardiomyopathy. His familial medical history was unremarkable.
Informed consent was obtained from the patient’s parents for further medical and genetic investigations. Genomic DNA was extracted from peripheral blood for mutation screening for Alström syndrome. The homozygous mutation, 8938C>T Gln2980Ter, was found on exon 10 in the ALMS1 gene, which confirmed Alström syndrome.
The patient underwent a complete ophthalmologic evaluation including assessment of best-corrected visual acuity, slit-lamp biomicroscopy examination, indirect ophthalmoloscopy, visual field examination, color vision testing, electroretinogram and visual evoked potentials, microperimetry (MP-1; Nidek Technologies, Italy), and high-resolution OCT (OCT Spectralis; Heidelberg Engineering, Heidelberg, Germany).
Best-corrected visual acuity was 0.52 logarithm of the minimum angle of resolution in both eyes (+2.00 = +1.00/120 in the right eye; +3.00 = +1.00/45 in the left eye) and there was both photophobia and pendular nystagmus. Fundus examination revealed pale optic discs with drusen, cone–rod dystrophy, and narrowing of the retinal vessels in both eyes.
Visual fields were examined with Goldmann kinetic perimetry using standardized targets III:4e and I:4e with white light stimulus. The patient had severely constricted visual fields to approximately 20° and 10° with the III:4e target and to 10° and 5° with the I:4e target in the right and left eyes, respectively. Color vision was tested using the Farnsworth D-15 color vision test. The patient had confusion regarding color discs that were close together, which is not considered significant, and the lines in both eyes remained along the outside of the circle.
The mixed cone–rod electroretinogram was reduced in both eyes. The visual evoked potential amplitudes were reduced in the right eye and normal in the left eye.
Microperimetry demonstrated a central absolute scotoma in the right eye and two paracentral scotomas in the left eye. Retinal sensitivity was 14.8 dB in the right eye and 16 dB in the left eye. Fixation behavior was relatively unstable in both eyes (77% of the fixation points were inside the 4° diameter circle in the right eye and 79% of the fixation points were inside the 4° diameter circle in the left eye).7
High-definition spectral domain OCT scans showed a slight thinning of the central retina and persistent inner retinal layers (similar to paramacular scans) within the fovea. The connecting cilium in the outer retina was absent, and there was no alteration of the retinal pigment epithelium and Bruch’s membrane.
High-speed and high-resolution spectral domain OCT allowed a detailed analysis of retinal layers in a young patient with Alström syndrome for the first time. Instead of the typical alterations observed in cone–rod dystrophies, the characteristics of the central foveal tissue (Figs. 1 and 2) suggest signs of retinal immaturity, with only a single layer of short, thick cones and rods and immature short outer segments.8
Figure 1. Infrared Fundus Image of the (A) Left Eye and (C) Right Eye. Arrows Indicate the Direction of Scans. High-Definition Spectral Domain Optical Coherence Tomography Horizontal Scans (OCT Spectralis; Heidelberg Engineering, Heidelberg, Germany) Showing Retinal Immaturity in the (B) Left Eye and (D) Right Eye.
Figure 2. (A1) Infrared Fundus Image of the Left Eye. Arrow Indicates the Direction of Scan. (B1) High-Definition Spectral Domain Optical Coherence Tomography Horizontal Scan (OCT Spectralis; Heidelberg Engineering, Heidelberg, Germany). The Detail Inside the Black Rectangle Has Been Enlarged in C1. (C1) Enlarged Detail of the Horizontal Optical Coherence Tomography Scan in the Left Eye. The Central Retina Exhibits the Persistence of Inner Retinal Layers (similar to Paramacular Scans) Within the Fovea, Indicated by ^. The Connecting Cilium in the Outer Retina Is Absent and There Is No Alteration of the Retinal Pigment Epithelium and Bruch’s Membrane.
On a superficial analysis, our data seem to contradict the results of the necropsy findings of Sebag et al.5 They found that the retina had a markedly hypocellular ganglion cell and inner and outer nuclear cell layers, rod and cone outer segments were absent, the retinal pigment epithelium was disrupted throughout, and there was optic nerve atrophy and giant drusen of the optic disc in both eyes.
This discrepancy of results may be attributed to the progressive nature of retinal degeneration in Alström syndrome. Furthermore, they state that histopathologic findings in this disease differ from the histopathologic characteristics of primary retinitis pigmentosa, and this could be explained by our findings. In fact, the in vivo imaging of retinal derangement by OCT suggests that although the ocular features of this syndrome have always been explained as a cone–rod dystrophy, Alström syndrome is characterized by the arrest of macular development and abnormal persistence of the early retinal structural organization. This finding could explain why these patients experienced an earlier and more severe visual loss than typical cone–rod dystrophies. Our results are limited to one case only, but shed new light on the ocular characteristics of this syndrome and can serve as a future reference to establish its pathophysiology.
- Alström CH, Hallgren B, Nilsson LB, Asander A. Retinal degeneration combined with obesity, diabetes mellitus and neurogenous deafness: a specific syndrome (not hitherto described) distinct from the Laurence-Moon-Bardet-Biedl syndrome: a clinical, endocrinological and genetic examination based on a large pedigree. Acta Psychiatr Neurol Scand Suppl. 1959;129:1–35.
- Malm E, Ponjavic V, Nishina PM, et al. Full-field electroretinography and marked variability in clinical phenotype of Alström syndrome. Arch Ophthalmol. 2008;126:51–57. doi:10.1001/archophthalmol.2007.28 [CrossRef]
- Marshall JD, Beck S, Maffei P, Naggert JK. Alström syndrome. Eur J Hum Genet. 2007;15:1193–1202. doi:10.1038/sj.ejhg.5201933 [CrossRef]
- Hearn T, Spalluto C, Phillips VJ, et al. Subcellular localization of ALMS1 supports involvement of centrosome and basal body dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. Diabetes. 2005;54:1581–1587. doi:10.2337/diabetes.54.5.1581 [CrossRef]
- Sebag J, Albert DM, Craft JL. The Alström syndrome: ophthalmic histopathology and retinal ultrastructure. Br J Ophthalmol. 1984;68:494–501. doi:10.1136/bjo.68.7.494 [CrossRef]
- Russell-Eggitt IM, Clayton PT, Coffey R, Kriss A, Taylor DS, Taylor JF. Alström syndrome: report of 22 cases and literature review. Ophthalmology. 1998;105:1274–1280. doi:10.1016/S0161-6420(98)97033-6 [CrossRef]
- Fujii GY, de Juan E Jr, Sunness J, Humayun MS, Pieramici DJ, Chang TS. Patient selection for macular translocation surgery using the scanning laser ophthalmoscope. Ophthalmology. 2002;109:1737–1744. doi:10.1016/S0161-6420(02)01120-X [CrossRef]
- Hendrickson AE, Yuodelis C. The morphological development of the human fovea. Ophthalmology. 1984;91:603–612.