Analysis of Suspected Achromatopsia by Multimodal Diagnostic Testing

Abstract

Background Achromatopsia (ACHM) as a hereditary cone disease might manifest in a stationary and progressive manner. The proper clinical and genetic diagnosis may allow an individual prognosis, accurate genetic counselling, and the optimal choice of low vision aids. The primary aim of the study was to determine the spectrum of clinical and genetic diagnostics required to characterize the ACHM.

Methods A retrospective analysis was performed in 8 patients from non-related families (5 ♀,3 ♂); age at diagnosis: 3 – 56 y, mean 18.13 (SD ± 18.22). Clinical phenotyping, supported by colour vision test, fundus photography-, autofluorescence- (FAF), infra-red- (IR), OCT imaging and electroretinography provided information on the current status and the course of the disease over the years. In addition, genetic examinations were performed with ACHM relevant testing (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H and the transcription factor ATF6).

Results All patients suffered photophobia and reduced visual acuity (mean: 0.16 [SD ± 0.08]). Nystagmus was identified in 7 from 8 subjects and in one patient a head-turn right helped to reduce the nystagmus amplitude. Colour vision testing confirmed complete achromatopsia in 7 out of 8 patients. Electrophysiology found severely reduced photopic- but also scotopic responses. Thinning and interruption of the inner segment ellipsoid (ISe) line within the macula but also FAF- and IR abnormalities in the fovea and/or parafovea were characteristic in all ACHM patients. Identification of pathogenic mutations in 7 patients helped to confirm the diagnosis of ACHM (3 adults, 4 children; 3 ♀ and 4 ♂). Achromatopsia was linked to CNGA3 (2 ♀, 1 ♂) and CNGB3 variants (2 ♀, 3 ♂). The youngest patient (♀, 10 y) had 3 different CNGB3 variants on different alleles. In a patient (♂, 29 y) carrying 2 pathogenic digenic-triallelic CNGA3- and CNGB3-mutations, a severe progression of ISe discontinuity to coloboma-like macular atrophy was observed during the 12-year follow-up. The oldest female (67 y) showed a compound homozygous CNGA3- and heterozygous CNGB3-, as well as a heterozygous GUCY2D variants. The destruction of her ISe line was significantly enlarged and represented a progressive cone-rod phenotype in comparison to other ACHM patients. In a patient (♂, 45 y) carrying a pathogenic CNGB3 and USH2 mutation, a severe macular oedema and a rod-cone phenotype was observed. In addition, two variants in C2ORF71 considered as VOS were found. One patient showed the rare ATF6 mutation, where a severe coloboma-like macular atrophy was observed on the left eye as early as at the age of three years.

Conclusion Combining multimodal ophthalmological diagnostics and molecular genetics when evaluating patients with ACHM helps in characterizing the disease and associated modifiers, and is therefore strongly recommended for such patients.

Zusammenfassung

Hintergrund Achromatopsie (ACHM) als eine erbliche Zapfenerkrankung kann sich als stationäre oder als progressive Erkrankung manifestieren. Die genaue klinische und genetische Diagnostik kann eine individuelle Prognose, akkurate genetische Beratung und eine optimale Wahl von Sehhilfen erlauben. Das primäre Ziel der Studie war, das Spektrum der klinischen und genetischen Diagnostik zu ermitteln, um das Krankheitsbild der ACHM zu charakterisieren.

Methoden Eine retrospektive Analyse wurde bei 8 Patienten von nicht verwandten Familien (5 ♀,3 ♂) durchgeführt; das Alter war zum Zeitpunkt der Diagnosestellung: 5 – 56 Jahre, Mittelwert 18,13 (SD ± 18,22). Die klinische Phänotypisierung, unterstützt durch Farbsehtests, Fundusfotografie, Autofluoreszenz- (FAF), Infrarot- (IR), OCT-Bildgebung und Elektroretinografie lieferten Informationen über den aktuellen Status und den Verlauf der Erkrankung über Jahre. Zusätzlich wurden für ACHM relevante genetische Tests durchgeführt (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H und der Transcription Factor ATF6).

Ergebnisse Alle Patienten litten an Photophobie und reduzierter Sehschärfe (Mittelwert: 0,16 (SD ± 0,08). Nystagmus wurde bei 7 von 8 Patienten festgestellt und bei einem Patienten half es, mit einer Rechts-Kopfdrehung, die Nystagmusamplitude zu verringern. Farbsehtests bestätigten die komplette Achromatopsie bei 7 von 8 Patienten. Bei der Elektrophysiologie wurden stark reduzierte photopische, aber auch skotopische Antworten gefunden. Eine Ausdünnung und Unterbrechung der ISe-Line innerhalb der Makula, aber auch FAF- und IR-Auffälligkeiten in der Fovea und/oder Parafovea waren charakteristisch bei allen ACHM-Patienten. Die Identifizierung von pathogenen Mutationen bei 7 Patienten half, die Diagnose der ACHM (3 Erwachsene, 4 Kinder; 3 ♀ and 4 ♂) zu bestätigen. Achromatopsie war verknüpft mit CNGA3- (2 ♀, 1 ♂) und CNGB3-Varianten (2 ♀, 3 ♂). Der jüngste Patient (♀, 10 Jahre) hatte 3 verschiedene CNGB3-Varianten auf verschiedenen Allelen. Bei einem Patienten (♂, 29 Jahre), der 2 pathogene digenisch-triallelische CNGA3- and CNGB3-Mutationen trug, wurde eine schwerwiegende Progression der ISe-Unterbrechung zu einer Coloboma-artigen Makulaatrophie beobachtet während der 12 Jahre Follow-up-Zeit. Die älteste weibliche Patientin (67 Jahre) zeigte eine kombinierte homozygote CNGA3- und heterozygote CNGB3-Variante sowie eine heterozygote GUCY2D-Variante. Die Zerstörung ihrer ISe-Line war signifikant vergrößert und repräsentierte einen progressiven Zapfen-Stäbchen-Phänotyp im Vergleich zu anderen ACHM-Patienten. Bei einem Patienten (♂, 45 Jahre), der pathogene CNGB3- und USH2-Mutation trug, wurde ein schwerwiegendes Makulaödem und ein Stäbchen-Zapfen-Phänotyp beobachtet. Zusätzlich wurden bei ihm 2 Varianten in C2ORF71 mit unklarer Bedeutung (VOS) gefunden. Eine Patientin (♀, 26 Jahre) zeigte eine seltene ATF6-Mutation, assoziiert mit monolateraler Coloboma-artiger Makulaatrophie.

Schlussfolgerung Die Kombination von multimodaler ophthalmologischer Diagnostik und Molekulargenetik bei der Evaluierung von Patienten mit ACHM hilft bei der Charakterisierung der Erkrankung und deren assoziierten Modifikatoren und ist aus diesem Grund für solche Patienten empfehlenswert.

Conclusion Box

Already known:

Achromatopsia as hereditary cone disease may manifest in a stationary and progressive manner. Apart from typical, also atypical manifestations of ACHM are described.

Newly described:

The present study highlights the importance of combined multimodal ophthalmological diagnostics and molecular genetics when evaluating patients with ACHM. This approach is of importance not only in characterizing the ACHM disease, but also the possible effect of future therapies, associated disease modifiers, as well as in family counselling, and is therefore strongly recommended for our ACHM patients.

Key words

inherited cone disorder - genetics - achromatopsia - cone dystrophy - colour vision discrimination - cone photoreceptor function - foveomacular degeneration

Schlüsselwörter

vererbte Zapfenerkrankung - Genetik - Achromatopsie - Zapfendystrophie - Farbseh-Unterscheidung - Zapfen-Photorezeptor-Funktion - foveomakuläre Degeneration

Publication History

Received: 23 June 2023

Accepted: 15 September 2023

Accepted Manuscript online:
15 September 2023

Article published online:
23 October 2023

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