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Shaking Up Ataxia : FGF14 and RFC1 Repeat Expansions in Affected and Unaffected Members of a Chilean Family

2023; Wiley; Volume: 38; Issue: 6 Linguagem: Inglês

10.1002/mds.29390

1531-8257

Paula Saffie Awad, Katja Lohmann, Yasmin Hirmas, Frauke Hinrichs, Mirja Thomsen, Marcelo A. Kauffman, Theresa Lüth, Joanne Trinh, Ana Westenberger, Pedro Chaná‐Cuevas, Christine Klein,

Endoplasmic Reticulum Stress and Disease

The very recent discovery of intronic GAA monoallelic repeat expansions in the FGF14 (fibroblast growth factor 14) gene,1, 2 as well as the previously described biallelic repeat expansions in the RFC1 (replication factor C subunit 1) gene,3, 4 causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome, have greatly enhanced the diagnostic yield in ataxia, which was previously limited to <50% even with exome sequencing.5 We describe a Chilean nonconsanguineous family with ataxia from a rural area (Fresia). Seven affected women and five affected men were identified, including 11/20 affected among the offspring in the three younger generations, suggesting high penetrance of an autosomal dominantly inherited cause. Age at onset (AAO) ranged from 17 to 50 years, with seemingly genetic anticipation (Fig. 1A). The index patient is a 29-year-old man who presented with cramps and leg pain at 21 years of age. He progressively developed vertigo, clumsiness, and gait ataxia. He had a history of rapid eye movement sleep behavior disorder (RBD), constipation, and depressive symptoms. His physical examination showed dysarthria, gait and limb ataxia, and absence of deep tendon reflexes. Oculomotor abnormalities or pyramidal features were absent. A sensorimotor chronic moderate-to-severe polyneuropathy was diagnosed by nerve conduction studies, and superior vermis brain atrophy was seen on magnetic resonance imaging. All affected family members shared this phenotype (Video S1), with additional features in his grandmother, ie, orolingual dyskinesias, choreoathetosis, and dementia. Genetic testing for ATXN1/2/3/7, CACNA1A, TBP, ATN1, FXN, HTT, and exome sequencing was negative. FGF14 testing demonstrated an expanded allele (~325 repeats) in three of the four affected and in one unaffected (aged 62 years) family member (Fig. 1A,B). Incomplete segregation could not be explained by a sample mix-up as relationship and sex were tested by nine polymorphic microsatellite markers, including two markers each on the X and Y chromosomes. Notably, repeat-primed PCR suggested repeat interruption in all four tested FGF14 expansion carriers in the Chilean family (Figure 1C). Due to vertigo in one affected, we also tested for RFC1 expansions in all available family members revealing a biallelic repeat expansion in one unaffected family member, aged 18 years, ie, well younger than the average AAO of RFC1 patients (Fig. 1A,C). This is the first Latin American family in whom an expanded FGF14 repeat was found. Although the definitive range for normal vs. intermediate/reduced penetrance vs. pathogenic/full penetrance alleles has not yet been determined, 250 and 300 repeats have been suggested as the respective boundaries.2 Importantly, however, the GAA repeat in our family is interrupted, and only pure expanded alleles have currently been identified in affected individuals.1 The phenotype in this family with the interrupted FGF14 repeat expansion of uncertain clinical relevance differs from the two series published to date, as ocular abnormalities were absent and additional features were consistently observed, such as polyneuropathy, RBD, constipation, and depression. Notably, there is co-occurrence of an only heterozygous RFC1 repeat expansion in at least one affected and one unaffected family member with an additional heterozygous expansion in FGF14 (Fig. 1A). However, at this stage, it is unclear whether there is an additive effect of expanded repeats in both genes. Interestingly, patient L-14997 appears to be the most severely affected in this family. Since the role of the interrupted FGF14 repeat expansion could not be determined unambiguously in this family, another, as yet unidentified genetic variant/repeat expansion could contribute to the disease. Furthermore, it is important to not only determine the length of the FGF14 repeat but also its architecture in unexplained spinocerebellar ataxia. This project was supported by the Global Parkinson's Genetics Program (GP2). GP2 is funded by the Aligning Science Against Parkinson's (ASAP) initiative and implemented by the Michael J. Fox Foundation for Parkison's Research (https://www.gp2.org). For a complete list of GP2 members see https://gp2.org. We thank the authorities of Fresia, especially Mauro González Villarroel, who gave financial and logistic support to the index patient to seek medical assistance. Josefa Correa, Catalina Figueroa, and Belén Cortés traveled to Fresia and helped with collecting samples and videotaping. Paula Saffie Awad: design, execution, analysis, writing, and editing of final version of the manuscript. Katja Lohmann: repeat analyses (design, execution, analysis), writing, and editing of final version of the manuscript. Yasmin Hirmas: execution and editing of final version of the manuscript. Frauke Hinrichs: repeat analyses (execution) and reviewing the manuscript. Mirja Thomsen: repeat analyses (establishing the pipeline) and reviewing the manuscript. Marcelo Kauffman: execution, analysis, and editing of final version of the manuscript. Theresa Lüth: exome analysis (execution) and reviewing the manuscript. Joanne Trinh: exome analysis (design) and reviewing the manuscript. Ana Westenberger: exome analysis (analysis) and reviewing the manuscript. Pedro Chaná-Cuevas: execution, analysis, and editing of final version of the manuscript. Christine Klein: supervision, design, execution, analysis, writing, and editing of final version of the manuscript. Paula Saffie Awad: Grants: The Michael J. Fox Foundation (MJFF); Employment: Centro de Trastornos del Movimiento (CETRAM)/Clínica Santa María. Katja Lohmann: Grants: German Research Foundation, MJFF (GP2), Damp foundation, and Parkinson's Foundation; Employment: University of Lübeck. Yasmin Hirmas: Employment: cesfam "Dr. Miguel Solar" Paine, Chile. Frauke Hinrichs: Employment: Institute of Neurogenetics, University of Lübeck. Mirja Thomsen: Employment: University Hospital Schleswig-Holstein. Marcelo Kauffman: Employment: Hospital General de Agudos José Maria Ramos Mejía, employee of CONICET. Theresa Lüth: Grants: German Research Foundation (FOR2488). Joanne Trinh: Grants: German Research Foundation and Else Kroener Fresenius Stiftung; Employment: UKSH, Institute of Neurogenetics. Ana Westenberger: Grants: German Research Foundation; Employment: University Clinic Schleswig-Holstein. Christine Klein: Consultancies: medical advisor to Centogene and Retromer Therapeutics; Honoraria: speaking honoraria from Desitin and Bial; Grants: German Research Foundation, the BMBF, MJFF, and ASAP; Employment: University of Lübeck and University Hospital of Schleswig-Holstein; Royalties: Oxford University Press. Pedro Chaná-Cuevas: Employment: CETRAM/USACH. Video S1. Chilean ataxia family with repeat expansions in FGF14 and RFC1 genes. Video showing the clinical phenotype of five affected family members. A pedigree with an arrow indicating which family member will be shown precedes the individual record of each one of them. The exact pedigree position is labeled with Roman and Arabic numbers (first generation: I.1, I.2 etc., second generation: II.1, II.2, etc. from left to right), and laboratory codes are given for those family members who could be included in the genetic analyses. Patient IV.1 (L-14995) with ataxic gait and difficulties performing tandem gait. Patient III.2 (L-14997), the most severely affected family member, shows postural instability, a severely ataxic gait with the need for support, and dysdiadochokinesia. Patient III.9 has a wide-based ataxic gait and dysmetria. Patient IV.4 also presents with an ataxic gait. Patient II.6 (L-14994) features orolingual dyskinesia and difficulties performing the Luria test. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.