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Ceroid lipofuscinosis type 5: novel pathogenic variants and unexpected phenotypic findings
  1. Anderson Rodrigues Brandão de Paiva1,2,3,
  2. André Luiz Santos Pessoa4,5,
  3. Paulo Ribeiro Nóbrega2,6,
  4. Cristiane Araujo Martins Moreno1,2,
  5. David S Lynch7,8,
  6. Lucas Mitsuo Taniguti1,
  7. João Paulo Kitajima1,
  8. Fernando Freua2,9,
  9. Bruno Della-Ripa1,2,
  10. Paulina Cunha2,10,
  11. Isabella Peixoto de Barcelos2,11,
  12. Lúcia Inês Macedo-Souza12,
  13. Carlos Augusto Takeuchi13,
  14. Antônio Milton Silva Garcia14,
  15. Flávia Nardes15,
  16. Ramiro Fontão16,
  17. Sérgio Antônio Antoniuk17,
  18. Monica Troncoso18,
  19. Norma Spécola19,
  20. Consuelo Durand20,
  21. Bianca de Aguiar Coelho Silva Madeiro21,
  22. Maria Juliana Rodovalho Doriqui22,
  23. Diane Vergara18,
  24. Henry Houlden7,8,
  25. Fernando Kok1,2
  1. 1Mendelics Genomic Analysis, São Paulo, SP, Brazil
  2. 2Neurology Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
  3. 3Neurology Department, Hospital São Rafael - Rede D'or São Luiz, Salvador, BA, Brazil
  4. 4Hospital Infantil Albert Sabin, Fortaleza, CE, Brazil
  5. 5Universidade Estadual do Ceara, Fortaleza, CE, Brazil
  6. 6Neurology Department, Universidade Federal do Ceará, Fortaleza, CE, Brazil
  7. 7Department of Neurogenetics, National Hospital for Neurology & Neurosurgery, Queen Square, London, UK
  8. 8Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
  9. 9Neurology Department, Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
  10. 10Institut du Cerveau (ICM), APHP, Pitié Salpêtrière Hospital, Paris, France
  11. 11Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  12. 12Centro de Estudos do Genoma Humano, Universidade de São Paulo, Sao Paulo, SP, Brazil
  13. 13Sabará Hospital Infantil, São Paulo, SP, Brazil
  14. 14Hospital Regional Dom Moura, Garanhuns, PE, Brazil
  15. 15Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
  16. 16Neuropediatrics, Penna Hospital, Bahía Blanca, Buenos Aires, Argentina
  17. 17Universidade Federal do Paraná, Curitiba, PR, Brazil
  18. 18Pediatric Neurology Department, Hospital Clínico San Borja Arriarán, University of Chile, Santiago, Chile
  19. 19Hospital de Niños Sor María Ludovica, La Plata, Argentina
  20. 20Laboratorio de Neuroquímica Dr. N.A. Chamoles, Buenos Aires, Argentina
  21. 21Hospital Universitário Oswaldo Cruz, Universidade de Pernambuco, Recife, PE, Brazil
  22. 22Public Health Department, Universidade Federal do Maranhão, São Luís, MA, Brazil
  1. Correspondence to Dr Anderson Rodrigues Brandão de Paiva, Neurology Department, Hospital São Rafael, Salvador, BA, Brazil; arbrandaopaiva{at}gmail.com

http://dx.doi.org/10.1136/jnnp-2022-330135

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    The neuronal ceroid lipofuscinoses (NCLs) are genetic disorders characterised by accumulation of autofluorescent material resembling lipofuscin or ceroid. Most patients present with cognitive and motor decline, seizures and visual loss. NCLs are the most prevalent neurodegenerative disorders of childhood. CLN5 encodes ceroid lipofuscinosis neuronal protein 5, which has three major putative functions: trafficking lysosomal sorting receptors, lysosomal and non-lysosomal palmitoyl thioesterase activity.1

    CLN5 variants were described mainly in Caucasians, but patients from several populations were already reported. Here, we describe 17 South American patients harbouring ten CLN5 pathogenic variants, including five novel variants, one with a founder effect. This case series broadens the phenotype of CLN5 by describing an unusual adult-onset patient.

    Patients were identified through a search for pathogenic variants in the CLN5 gene in the database of a commercial laboratory and by contacting centres for neurogenetic diseases in South America. Genetic analysis was performed using next-generation sequencing through whole-exome sequencing (WES) or epilepsy gene panels. Variants were classified according to American College of Medical Genetics (ACMG) guidelines. Haplotype analysis was performed in four phased-VCFs (variant call format) using a custom script.

    We identified 19 patients from 17 families. Two were excluded because of insufficient clinical data. Table 1 shows a summary of clinical details and genetic profiles.

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    Table 1

    Clinical and genetic features of CLN5 patients in South America

    We analysed 17 patients from 16 families with age of onset varying between 1 and 40 years, 5 males and 12 females. All patients presented with cognitive and motor decline, ataxia and seizures. Most patients (14/17) had visual impairment. All patients had behaviour abnormalities ranging from anxiety and inattention to stereotypic behaviour, in most cases initiated in the first years of disease. Seizures were the presenting feature in nine patients and language disorders in other six.

    Cerebellar, cortical and subcortical …

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    Footnotes

    • Correction notice This article has been corrected since it was published online. Spelling error for author "Monica Troncoso" has been corrected.

    • Contributors ARBdP: designed and conceptualised the study; analysed and interpreted the data; drafted the manuscript. ALSP: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. PRN: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. DSL: major role in the acquisition of data; revised the manuscript for intellectual content. CAMM: major role in the acquisition of data; revised the manuscript for intellectual content. LMT: major role in the acquisition of data; revised the manuscript for intellectual content. JPK: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. FF: major role in the acquisition of data; revised the manuscript for intellectual content. BD-R: major role in the acquisition of data; revised the manuscript for intellectual content. PC: major role in the acquisition of data; revised the manuscript for intellectual content. IPB: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. LIM-S: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. CAT: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. AMSG: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. FNS: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. RF: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. SAA: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. MT: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. NS: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. CD: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. BdACSM: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. MJRD: major role in the acquisition of data; interpreted the data; revised the manuscript for intellectual content. DV: analysed the data; revised the manuscript for intellectual content. HH: analysed the data; revised the manuscript for intellectual content. FK: designed and conceptualised the study; analysed and interpreted the data; drafted the manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.