Genetic screening for Huntington disease phenocopies in Sweden: A tertiary center case series focused on short tandem repeat (STR) disorders

Martin Paucar; José Laffita-Mesa; Valter Niemelä; Helena Malmgren; Inger Nennesmo; Kristina Lagerstedt-Robinson; Magnus Nordenskjöld; Per Svenningsson

doi:10.1016/j.jns.2023.120707

Genetic screening for Huntington disease phenocopies in Sweden: A tertiary center case series focused on short tandem repeat (STR) disorders

J Neurol Sci. 2023 Aug 15:451:120707. doi: 10.1016/j.jns.2023.120707. Epub 2023 Jun 10.

Authors

Martin Paucar¹, José Laffita-Mesa², Valter Niemelä³, Helena Malmgren⁴, Inger Nennesmo⁵, Kristina Lagerstedt-Robinson⁶, Magnus Nordenskjöld⁷, Per Svenningsson⁸

Affiliations

¹ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Neurology, Karolinska University Hospital, Stockholm, Sweden. Electronic address: martin.paucar-arce@regionstockholm.se.
² Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: jose.laffita@ki.se.
³ Institute for Medical Sciences, Uppsala University, Uppsala, Sweden.
⁴ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. Electronic address: helena.malmgren@regionstockholm.se.
⁵ Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. Electronic address: inger.nennesmo@regionstockholm.se.
⁶ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. Electronic address: kristina.lagerstedt-robinson@regionstockholm.se.
⁷ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. Electronic address: magnus.nordenskjold@ki.se.
⁸ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Neurology, Karolinska University Hospital, Stockholm, Sweden. Electronic address: per.svenningsson@ki.se.

PMID: 37379724
DOI: 10.1016/j.jns.2023.120707

Abstract

Objective: To perform a screening for Huntington disease (HD) phenocopies in a Swedish cohort.

Methods: Seventy-three DNA samples negative for HD were assessed at a tertiary center in Stockholm. The screening included analyses for C9orf72-frontotemporal dementia/amyotrophic lateral sclerosis (C9orf72-FTD/ALS), octapeptide repeat insertions (OPRIs) in PRNP associated with inherited prion diseases (IPD), Huntington's disease-like 2 (HDL2), spinocerebellar ataxia-2 (SCA2), spinocerebellar ataxia 3 (SCA3) and spinocerebellar ataxia-17 (SCA17). Targeted genetic analysis was carried out in two cases based on the salient phenotypic features.

Results: The screening identified two patients with SCA17, one patient with IPD associated with 5-OPRI but none with nucleotide expansions in C9orf72 or for HDL2, SCA2 or SCA3. Furthermore, SGCE-myoclonic-dystonia 11 (SGCE-M-D) and benign hereditary chorea (BHC) was diagnosed in two sporadic cases. WES identified VUS in STUB1 in two patients with predominant cerebellar ataxia.

Conclusions: Our results are in keeping with previous screenings and suggest that other genes yet to be discovered are involved in the etiology of HD phenocopies.

Keywords: Chorea; Huntington's disease phenocopies; Huntington's disease-like.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis* / genetics
C9orf72 Protein / genetics
DNA Repeat Expansion
Frontotemporal Dementia* / genetics
Genetic Testing
Humans
Huntington Disease* / diagnosis
Huntington Disease* / genetics
Microsatellite Repeats
Prion Diseases*
Prions*
Sweden
Ubiquitin-Protein Ligases / genetics

Substances

C9orf72 Protein
Prions
STUB1 protein, human
Ubiquitin-Protein Ligases

Supplementary concepts

Spinocerebellar Ataxia 17