The genetic spectrum of congenital ocular motor apraxia type Cogan: an observational study, continued

Schröder et al. Orphanet Journal of Rare Diseases (2023) 18:101 https://doi.org/10.1186/s13023-023-02706-5 Orphanet Journal of Rare Diseases Open Access RESEARCH The genetic spectrum of congenital ocular motor apraxia type Cogan: an observational study, continued Simone Schröder1, Gökhan Yigit2, Yun Li2, Janine Altmüller3,14,15, Hans‑Martin Büttel4, Barbara Fiedler5, Christoph Kretzschmar6, Peter Nürnberg3, Jürgen Seeger7, Valentina Serpieri8, Enza Maria Valente9,10, Bernd Wollnik11,12, Eugen Boltshauser13 and Knut Brockmann1*    Abstract Background The term congenital ocular motor apraxia (COMA), coined by Cogan in 1952, designates the incapacity to initiate voluntary eye movements performing rapid gaze shift, so called saccades. While regarded as a nosologi‑ cal entity by some authors, there is growing evidence that COMA designates merely a neurological symptom with etiologic heterogeneity. In 2016, we reported an observational study in a cohort of 21 patients diagnosed as having COMA. Thorough re-evaluation of the neuroimaging features of these 21 subjects revealed a previously not recog‑ nized molar tooth sign (MTS) in 11 of them, thus leading to a diagnostic reassignment as Joubert syndrome (JBTS). Specific MRI features in two further individuals indicated a Poretti–Boltshauser syndrome (PTBHS) and a tubulinopa‑ thy. In eight patients, a more precise diagnosis was not achieved. We pursued this cohort aiming at clarification of the definite genetic basis of COMA in each patient. Results Using a candidate gene approach, molecular genetic panels or exome sequencing, we detected causative molecular genetic variants in 17 of 21 patients with COMA. In nine of those 11 subjects diagnosed with JBTS due to newly recognized MTS on neuroimaging, we found pathogenic mutations in five different genes known to be associated with JBTS, including KIAA0586, NPHP1, CC2D2A, MKS1, and TMEM67. In two individuals without MTS on MRI, pathogenic variants were detected in NPHP1 and KIAA0586, arriving at a diagnosis of JBTS type 4 and 23, respectively. Three patients carried heterozygous truncating variants in SUFU, representing the first description of a newly identi‑ fied forme fruste of JBTS. The clinical diagnoses of PTBHS and tubulinopathy were confirmed by detection of causa‑ tive variants in LAMA1 and TUBA1A, respectively. In one patient with normal MRI, biallelic pathogenic variants in ATM indicated variant ataxia telangiectasia. Exome sequencing failed to reveal causative genetic variants in the remaining four subjects, two of them with clear MTS on MRI. Conclusions Our findings indicate marked etiologic heterogeneity in COMA with detection of causative mutations in 81% (17/21) in our cohort and nine different genes being affected, mostly genes associated with JBTS. We provide a diagnostic algorithm for COMA. Keywords Congenital ocular motor apraxia, Cogan syndrome, Joubert syndrome, Molar tooth sign, Ciliopathy, Poretti–Boltshauser syndrome *Correspondence: Knut Brockmann Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Schröder et al. Orphanet Journal of Rare Diseases (2023) 18:101 Background When David C. Cogan in a Jackson Memorial Lecture in 1952 described four children with a distinct disturbance of voluntary horizontal gaze characterized by the “inability to turn the eyes voluntarily in a direction for which there is full involuntary … control” accompanied by compensatory, jerky head movements, he coined the term congenital ocular motor apraxia (COMA) [1]. Ocular apraxia designates the incapacity to initiate eye movements performing rapid gaze shift, so called saccades. In most patients, COMA affects horizontal, occasionally also vertical saccades. In 2016 we reported an observational study aiming at the nosological delineation of congenital ocular motor apraxia type Cogan [2]. We had recruited a cohort of 21 previously unreported patients (8 female, 13 male, ages at that time ranging from 2 to 24 years) diagnosed as having COMA. Inclusion criteria comprised early-onset OMA (diagnostic recognition within the first year of life), availability of an MRI in technical quality adequate for assessment of especially brainstem and cerebellum, and written informed consent of the parents or the patient or both. Patients with already established diagnosis of Joubert Syndrome (JBTS) based on presence of the molar tooth sign (MTS) on MRI were not included. Re-evaluation of MRI data sets of all 21 subjects disclosed a so far unrecognized molar tooth sign diagnostic for JBTS in 11 patients, neuroimaging features of Poretti-Boltshauser syndrome (PTBHS) in one subject and cerebral malformation suspicious of a tubulinopathy in another individual. MRI revealed hypo-/dysplasia of the vermis cerebelli in four and no abnormalities in the remaining four patients. These results provided strong evidence for the notion, that COMA does not designate a nosological entity, but rather a neurological symptom with heterogeneous etiology [2]. Pursuing this cohort of 21 patients with COMA, we aimed at clarification of the definite genetic etiology in all subjects. Here, we report the molecular genetic findings in 17 individuals with conclusive genetic diagnoses. Methods This study was approved by the ethics committee of the University Medical Center, Göttingen, Germany (file no. 19/5/14). All participating families provided written informed consent. Patient cohort Recruitment of the 21 patients with COMA was described previously [2]. Briefly, an email based acquisition of rare neurological disorders in childhood [3] was used to collect subjects with early-onset OMA Page 2 of 11 (diagnostic recognition within the first year of life), who had received MRI in technical quality adequate for assessment of brainstem and cerebellum in particular. Genetic testing The genetic findings reported here were obtained pa (...truncated)