Ocular evaluation and genetic test for an early Alström Syndrome diagnosis

Abstract

Purpose: We present 3 cases of Alström syndrome (ALMS) that highlight the importance of the ophthalmic exam, as well as the diagnostic challenges and management considerations of this ultra-rare disease.

Observations: The first case is of a 2-year-old boy with history of spasmus nutans who presented with head bobbing and nystagmus. The second patient is a 5-year-old boy with history of infantile dilated cardiomyopathy status post heart transplant, Burkitt lymphoma status post chemotherapy, obesity, global developmental delay, and high hyperopia previously thought to have cortical visual impairment secondary to heart surgery/possible ischemic event. This patient presented with nystagmus, photophobia, and reduced vision. The third case involves a 8-year-old boy with history of obesity, bilateral optic nerve atrophy, hyperopic astigmatism, exotropia, and nystagmus. Upon presentation to the consulting pediatric ophthalmologist, none of the patients had yet been diagnosed with ALMS. All 3 cases were subsequently found to have an electroretinogram (ERG) that exhibited severe global depression and to carry ALMS1 pathogenic variants.

Conclusions and importance: ALMS is an autosomal recessive disease caused by ALMS1 variations, characterized by cone-rod dystrophy, obesity, progressive sensorineural hearing loss, cardiomyopathy, insulin resistance, and multiorgan dysfunction. Retinal dystrophy diagnosis is critical given clinical criteria and detection rates of genetic testing. Early diagnosis is extremely important because progression to flat ERG leads to the inability to differentiate between rod-cone or cone-rod involvement, either of which have their own differential diagnoses. In our series, the ophthalmic exam and abnormal ERG prompted further genetic testing and the subsequent diagnosis of ALMS. Multidisciplinary care ensures the best possible outcome with the ophthalmologist playing a key role.

Keywords: ALMS, Alström Syndrome; ALMS1 gene; APD, Afferent pupillary defect; Alström syndrome; Autosomal recessive; BMI, Body mass index; CHF, Congestive heart failure; CLIA, Clinical Laboratory Improvement Amendments; Cone-rod dystrophy; DA, Dark-adapted; DFE, Dilated fundus exam; EEG, Electroencephalogram; ERG, Electroretinogram; EUA, Exam under anesthesia; FAF, Fundus autofluorescence; IGF, Insulin-like growth factor; IR, Insulin resistance; ISCEV, International Society for Clinical Electrophysiology of Vision; LA, Light-adapted; MRI, Magnetic resonance imaging; OCT, Optical coherence tomography; OD, Right eye; OPs, Oscillatory potentials; OS, Left eye; OU, Both eyes; RPE, Retinal pigment epithelium; T2DM, Type II diabetes mellitus; VA, Visual acuity; VEP, Visual evoked potential; VGB, Vigabatrin; cDNA, complementary DNA.

Fig. 1

Light-adapted (LA) and dark-adapted (DA) electroretinogram ERGs recorded under anesthesia from a 2.3-year-old boy taking vigabatrin (VGB) who has shown no evidence of toxicity (A), and Case 1 tested at 2.25 years of age (B). Right and left eye ERGs are superimposed. The cone-mediated ERGs (LA 3.0, LA OPs, LA 30 Hz, and DA Red) are non-recordable in Case 1 (B) whereas corresponding cone ERGs are robust in the VGB patient (A). In addition, the DA 0.01 rod-mediated ERG, mixed DA 3.0, and the DA OPs are robust in the VGB patient but are markedly diminished in Case 1. The bright DA 3.0 cd-s m⁻² flash elicited comparatively small amplitude A- and B-waves and markedly diminished DA OPs. ERG amplitude calibration: 100 μV, except OPs, which are 20 μV. ERG time calibration: 50 ms marked from onset of flash. Bottom two panels show binocular flash visual evoked potential (VEP) recorded unsedated within a month of the ERG recordings for each patient. Compared with the VGB patient, the negative/positive flash VEP complex is delayed and diminished in amplitude for Case 1. VEP vertical calibration: 8 μV; horizontal calibration: 100 ms from flash onset (single flash ERGs begin recording 20 ms pre-flash).

Fig. 2

Bilateral fundus photograph, fundus autofluorescence (FAF), and optical coherence tomography (OCT) images for Case 3. (A) Fundus photographs showing mild diffuse pallor of the optic disc, blunted foveal reflex, severe vascular attenuation, and diffuse hypopigmented mottling bilaterally. (B) FAF demonstrating a circular region of decreased autofluorescence encompassing the macula surrounded by a ring of increased autofluorescence bilaterally. (C) OCT with distorted foveal contour with loss of the outer retina, specifically the photoreceptor layer, within the macula bilaterally.