Helle Høyer

• Novy, Camilla; Busk, Øyvind; Tysnes, Ole-Bjørn; Landa, Sigve Strand; Aanjesen, Tori Navestad & Alstadhaug, Karl Bjørnar [Show all 29 contributors for this article] (2024). Repeat expansions in AR, ATXN1, ATXN2 and HTT in Norwegian patients diagnosed with amyotrophic lateral sclerosis. Brain Communications. ISSN 2632-1297. 6(2). doi: 10.1093/braincomms/fcae087.
• Olsen, Cathrine Goberg; Busk, Øyvind; Holla, Øystein Lunde; Tveten, Kristian; Holmøy, Trygve & Tysnes, Ole-Bjørn [Show all 7 contributors for this article] (2023). Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. ISSN 2167-8421. doi: 10.1080/21678421.2023.2270705. Full text in Research Archive Show summary

  Objective: In Norway, 89% of patients with Amyotrophic lateral sclerosis (ALS) lacks a genetic diagnose. ALS genes and genes that cause other neuromuscular or neurodegenerative disorders extensively overlap. This population-based study examined whether patients with ALS have a family history of neurological disorders and explored the occurrence of rare genetic variants associated with other neurodegenerative or neuromuscular disorders. Methods: During a two-year period, blood samples and clinical data from patients with ALS were collected from all 17 neurological departments in Norway. Our genetic analysis involved exome sequencing and bioinformatics filtering of 510 genes associated with neurodegenerative and neuromuscular disorders. The variants were interpreted using genotype-phenotype correlations and bioinformatics tools. Results: A total of 279 patients from a Norwegian population-based ALS cohort participated in this study. Thirty-one percent of the patients had first- or second-degree relatives with other neurodegenerative disorders, most commonly dementia and Parkinson's disease. The genetic analysis identified 20 possible pathogenic variants, in ATL3, AFG3L2, ATP7A, BICD2, HARS1, KIF1A, LRRK2, MSTO1, NEK1, NEFH, and SORL1, in 25 patients. NEK1 risk variants were present in 2.5% of this ALS cohort. Only four of the 25 patients reported relatives with other neurodegenerative or neuromuscular disorders. Conclusion: Gene variants known to cause other neurodegenerative or neuromuscular disorders, most frequently in NEK1, were identified in 9% of the patients with ALS. Most of these patients had no family history of other neurodegenerative or neuromuscular disorders. Our findings indicated that AFG3L2, ATP7A, BICD2, KIF1A, and MSTO1 should be further explored as potential ALS-causing genes.

• Løseth, Sissel; Høyer, Helle; LE, KIM MAI; Delpire, Eric; Kinge, Einar & Lande, Asgeir [Show all 10 contributors for this article] (2022). Late-onset sensory-motor axonal neuropathy, a novel SLC12A6-related phenotype. Brain. ISSN 0006-8950. 146(3), p. 912–922. doi: 10.1093/brain/awac488. Full text in Research Archive Show summary

  We describe five families from different regions in Norway with a late onset autosomal dominant hereditary polyneuropathy sharing a heterozygous variant in the SLC12A6 gene. Mutations in the same gene have previously been described in infants with autosomal recessive hereditary motor and sensory neuropathy with corpus callosum agenesis and mental retardation (Andermann syndrome), and in a few case-reports describing dominantly acting de novo mutations, most of them with onset in childhood. The phenotypes in our families demonstrated heterogeneity. Some of our patients only had subtle to moderate symptoms and some individuals even no complaints. None had central nervous system manifestations. Clinical and neurophysiological evaluations revealed a predominant sensory axonal polyneuropathy with slight to moderate motor components. In all ten patients the identical SLC12A6 missense variant, NM_001365088.1 c.1655G > A p.(Gly552Asp), was identified. For functional characterization, the mutant potassium chloride cotransporter 3 was modelled in Xenopus oocytes. This revealed a significant reduction in potassium influx for the p.(Gly552Asp) substitution. Our findings further expand the spectrum of SLC12A6 disease, from biallelic hereditary motor and sensory neuropathy with corpus callosum agenesis and mental retardation and monoallelic early-onset hereditary motor and sensory neuropathy caused by de novo mutations, to late onset autosomal dominant axonal neuropathy with predominant sensory deficits.

• Høyer, Helle; Busk, Øyvind Løvold; Esbensen, Qin Ying; Røsby, Oddveig; Hilmarsen, Hilde Tveitan & Russell, Michael Bjørn [Show all 9 contributors for this article] (2022). Clinical characteristics and proteome modifications in two Charcot-Marie-Tooth families with the AARS1 Arg326Trp mutation. BMC Neurology. ISSN 1471-2377. 22(1). doi: 10.1186/s12883-022-02828-6. Full text in Research Archive Show summary

  Background: Aminoacyl tRNA-synthetases are ubiquitously-expressed enzymes that attach amino acids to their cognate tRNA molecules. Mutations in several genes encoding aminoacyl tRNA-synthetases, have been associated with peripheral neuropathy, i.e. AARS1, GARS1, HARS1, YARS1 and WARS1. The pathogenic mechanism underlying AARS1-related neuropathy is not known. Methods: From 2012 onward, all probands presenting at Telemark Hospital (Skien, Norway) with peripheral neuropathy were screened for variants in AARS1 using an "in-house" next-generation sequencing panel. DNA from patient's family members was examined by Sanger sequencing. Blood from affected family members and healthy controls were used for quantification of AARS1 mRNA and alanine. Proteomic analyses were conducted in peripheral blood mononuclear cells (PBMC) from four affected family members and five healthy controls. Results: Seventeen individuals in two Norwegian families affected by Charcot-Marie-Tooth disease (CMT) were characterized in this study. The heterozygous NM_001605.2:c.976C > T p.(Arg326Trp) AARS1 mutation was identified in ten affected family members. All living carriers had a mild to severe length-dependent sensorimotor neuropathy. Three deceased obligate carriers aged 74-98 were reported to be unaffected, but were not examined in the clinic. Proteomic studies in PBMC from four affected individuals suggest an effect on the immune system mediated by components of a systemic response to chronic injury and inflammation. Furthermore, altered expression of proteins linked to mitochondrial function/dysfunction was observed. Proteomic data are available via ProteomeXchange using identifier PXD023842. Conclusion: This study describes clinical and neurophysiological features linked to the p.(Arg326Trp) variant of AARS1 in CMT-affected members of two Norwegian families. Proteomic analyses based on of PBMC from four CMT-affected individuals suggest that involvement of inflammation and mitochondrial dysfunction might contribute to AARS1 variant-associated peripheral neuropathy.

• Olsen, Cathrine Goberg; Busk, Øyvind Løvold; Aanjesen, Tori Navestad; Alstadhaug, Karl Bjørnar; Bjørnå, Ingrid Kristine & Braathen, Geir Julius [Show all 28 contributors for this article] (2022). Genetic Epidemiology of Amyotrophic lateral Sclerosis in Norway: A 2-Year Population-Based Study. Neuroepidemiology. ISSN 0251-5350. 56(4), p. 271–282. doi: 10.1159/000525091. Full text in Research Archive Show summary

  Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons. In Europe, disease-causing genetic variants have been identified in 40-70% of familial ALS patients and approximately in 5% of sporadic ALS patients. In Norway, the contribution of genetic variants to ALS has not yet been studied. In light of the potential development of personalized medicine, knowledge of genetic causes of ALS in a population is becoming increasingly important. The present study provides clinical and genetic data on familial and sporadic ALS patients in a Norwegian population-based cohort. Methods: Blood samples and clinical information from ALS patients were obtained at all 17 neurological departments throughout Norway during a 2-year period. Genetic analysis of the samples involved expansion analysis of C9orf72 and exome sequencing targeting 30 known ALS-linked genes. The variants were classified using genotype-phenotype correlations and bioinformatics tools. Results: A total of 279 ALS patients were included in the study. Of these, 11.5% had one or several family members affected with ALS, whereas 88.5% had no known family history of ALS. A genetic cause of ALS was identified in 31 individuals (11.1%), among which 18 (58.1%) were familial and 13 (41.9%) were sporadic. The most common genetic cause was the C9orf72 expansion (6.8%), which was identified in 8 familial and 11 sporadic ALS patients. Pathogenic or likely pathogenic variants of SOD1 and TBK1 were identified in 10 familial and 2 sporadic cases. C9orf72 expansions dominated in patients from the Northern and Central regions, whereas SOD1 variants dominated in patients from the South-Eastern region. Conclusion: In the present study, we identified several pathogenic gene variants in both familial and sporadic ALS patients. Restricting genetic analysis to only familial cases would miss more than 40 percent of those with a disease-causing genetic variant, indicating the need for genetic analysis in sporadic cases as well.

• Høyer, Helle; Hilmarsen, Hilde T; Sunder-Plassmann, Raute; Braathen, Geir Julius; Andersen, Peter M. & Beetz, Christian [Show all 17 contributors for this article] (2022). A polymorphic AT-repeat causes frequent allele dropout for an MME mutational hotspot exon. Journal of Medical Genetics. ISSN 0022-2593. doi: 10.1136/jmedgenet-2021-108281.
• Kliest, Tessa; van Eijk, Ruben P. A.; Al-Chalabi, Ammar; Albanese, Alberto; Andersen, Peter M. & Amador, Maria Del Mar [Show all 57 contributors for this article] (2022). Clinical trials in pediatric ALS: a TRICALS feasibility study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. ISSN 2167-8421. 23(7-8), p. 481–488. doi: 10.1080/21678421.2021.2024856. Full text in Research Archive Show summary

  Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA). Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe. Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS. Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS. Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

• Høyer, Helle; Amor-Barris, Silvia; Brauteset, Lin; De Vriendt, Els; Strand, Linda & Jordanova, Albena [Show all 8 contributors for this article] (2021). HINT1 neuropathy in Norway: clinical, genetic and functional profiling. Orphanet Journal of Rare Diseases. ISSN 1750-1172. 16(1). doi: 10.1186/s13023-021-01746-z. Full text in Research Archive Show summary

  Background: Autosomal recessive axonal neuropathy with neuromyotonia has been linked to loss of functional HINT1. The disease is particularly prevalent in Central and South-East Europe, Turkey and Russia due to the high carrier frequency of the c.110G > C (p.Arg37Pro) founder variant. Results: In a cohort of 748 Norwegian patients with suspected peripheral neuropathy, we identified two seemingly unrelated individuals, compound heterozygous for a new variant (c.284G > A, p.Arg95Gln) and the most common pathogenic founder variant (c.110G > C, p.Arg37Pro) in the HINT1 gene. Probands presented with motor greater than sensory neuropathy of various onset, accompanied by muscle stiffness and cramps in the limbs. Furthermore, they displayed non-classical symptoms, including pain in the extremities and signs of central nervous system involvement. Haplotype analysis in both patients revealed a common chromosomal background for p.Arg95Gln; moreover, the variant was identified in Swedish carriers. Functional characterization in HINT1-knockout and patient-derived cellular models, and in HNT1-knockout yeast, suggested that the new variant is deleterious for the function of HINT1 and provided mechanistic insights allowing patient stratification for future treatment strategies. Conclusion: Our findings broaden the genetic epidemiology of HINT1-neuropathy and have implications for molecular diagnostics of inherited peripheral neuropathies in Scandinavia.

• Senderek, Jan; Lassuthova, Petra; Kabzinska, Dagmara; Abreu, Lisa; Baets, Jonathan & Beetz, Christian [Show all 57 contributors for this article] (2020). The genetic landscape of axonal neuropathies in the middle-Aged and elderly: Focus on MME. Neurology. ISSN 0028-3878. 95(24). doi: 10.1212/WNL.0000000000011132.
• Fabrizi, Gian Maria; Høyer, Helle; Taioli, Federica; Cavallaro, Tiziana; Hilmarsen, Hilde T & Squintani, Giovanna Maddalena [Show all 8 contributors for this article] (2020). Inherited motor-sensory neuropathy with upper limb predominance associated with the tropomyosin-receptor kinase fused gene. Neuromuscular Disorders. ISSN 0960-8966. 30(3), p. 227–231. doi: 10.1016/j.nmd.2019.12.007. Show summary

  The Tropomyosin-receptor kinase fused gene (TFG) encodes TFG which is expressed in spinal motor neurons, dorsal root ganglia and cranial nerve nuclei, and plays a role in the dynamics of the endoplasmic reticulum. Two dominant missense TFG mutations have previously been reported in limited geographical areas (Far East, Iran, China) in association with hereditary motor sensory neuropathy with proximal involvement (HMSN-P) of the four limbs, or with Charcot-Marie-Tooth disease type 2 (CMT2). The 60-year-old female proband belonging to a three-generation Italian family presented with an atypical neuropathy characterized by diffuse painful cramps and prominent motor-sensory impairment of the distal upper limbs. Her sural nerve biopsy showed chronic axonal neuropathy without active degeneration or regeneration. Targeted next-generation sequencing of a panel with 98 genes associated with inherited peripheral neuropathies/neuromuscular disorders identified three candidate genes: TFG, DHTKD1 and DCTN2. In the family, the disease co-segregated with the TFG p.(Gly269Val) variant. TFG should be considered in genetic testing of patients with heterogeneous inherited neuropathy, independently of their ethnic origin.

• Arntzen, Kjell Arne; Høyer, Helle; Ørstavik, Kristin; Tallaksen, Chantal; Vedeler, Christian A. & Østern, Rune André Helland [Show all 9 contributors for this article] (2018). Charcot-Marie-Tooth disease type 4C in Norway: Clinical characteristics, mutation spectrum and minimum prevalence. Neuromuscular Disorders. ISSN 0960-8966. 28(8), p. 639–645. doi: 10.1016/j.nmd.2018.06.004.
• Holla, Øystein Lunde; Busk, Øyvind; Tveten, Kristian; Hilmarsen, Hilde T; Strand, Linda & Høyer, Helle [Show all 9 contributors for this article] (2015). Diagnostisk eksomsekvensering – norske erfaringer :. Tidsskrift for Den norske legeforening. ISSN 0029-2001. 135(20), p. 1833–1837. doi: 10.4045/tidsskr.14.1442.
• Høyer, Helle; Busk, Øyvind; Holla, Øystein Lunde; Strand, Linda; Russell, Michael Bjørn & Skjelbred, Camilla Furu [Show all 7 contributors for this article] (2015). Arvelige perifere nevropatier diagnostisert ved dypsekvensering :. Tidsskrift for Den norske legeforening. ISSN 0029-2001. 135(20), p. 1838–1843. doi: 10.4045/tidsskr.14.1002.
• Braathen, Geir Julius; Høyer, Helle; Busk, Øyvind; Tveten, Kristian; Skjelbred, Camilla Furu & Russell, Michael Bjørn (2015). Variants in the genes DCTN2, DNAH10,LRIG3, and MYO1A are associated with intermediate Charcot–Marie–Tooth disease in a Norwegian family. Acta Neurologica Scandinavica. ISSN 0001-6314. doi: 10.1111/ane.12515.
• Høyer, Helle; Braathen, Geir Julius; Eek, Anette Kildal; Namløs, Gry Beate; Skjelbred, Camilla Furu & Russell, Michael Bjørn (2015). Copy Number Variations in a Population-Based Study of Charcot-Marie-Tooth Disease. BioMed Research International. ISSN 2314-6133. doi: 10.1155/2015/960404.
• Vogel, Lotte K.; Sæbø, Mona; Høyer, Helle; Kopp, Tine Iskov; Vogel, Ulla & Godiksen, Sine [Show all 12 contributors for this article] (2014). Intestinal PTGS2 mRNA Levels, PTGS2 Gene Polymorphisms, and Colorectal Carcinogenesis. PLOS ONE. ISSN 1932-6203. 9(8). doi: 10.1371/journal.pone.0105254.
• Høyer, Helle; Braathen, Geir Julius; Busk, Øyvind; Holla, Øystein Lunde; Svendsen, Marit & Hilmarsen, Hilde T [Show all 9 contributors for this article] (2014). Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing. BioMed Research International. ISSN 2314-6133. 2014. doi: 10.1155/2014/210401.
• Høyer, Helle; Braathen, Geir Julius; Eek, Anette Kildal; Skjelbred, Camilla Furu & Russell, Michael Bjørn (2011). Charcot-Marie-Thooth caused by a copy number variation in myelin protein zero. European Journal of Medical Genetics. ISSN 1769-7212. 54, p. 580–583. doi: 10.1016/j.ejmg.2011.06.006.
• Braathen, Geir Julius; Sand, Jette Christensen; Lobato, Pascual Ana; Høyer, Helle & Russell, Michael Bjørn (2011). Genetic epidemiology of Charcot-Marie-Tooth in the general population. European Journal of Neurology. ISSN 1351-5101. 18(1), p. 39–48. doi: 10.1111/j.1468-1331.2010.03037.x.
• Braathen, Geir Julius; Sand, Jette Christensen; Lobato Pascual, Ana; Høyer, Helle & Russell, Michael Bjørn (2010). MFN2 point mutations occur in 3.4% of Charcot-Marie-Tooth families. An investigation of 232 Norwegian CMT families. BMC Medical Genetics. ISSN 1471-2350. 11(48). doi: 10.1186/1471-2350-11-48.

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• Høyer, Helle; Nakken, Ola & Holmøy, Trygve (2023). A Novel SPAST Variant Associated with Isolated Spastic Paraplegia. Case Reports in Genetics. ISSN 2090-6552. doi: 10.1155/2023/4553365. Show summary

  Genetic variants in SPAST are the most common cause of hereditary spastic paraplegia (HSP), entitled spastic paraplegia type 4 (SPG4). Inheritance is autosomal dominant, and age of onset can vary from childhood to adulthood. Pathogenic SPAST variants are often observed in isolated cases, likely due to reduced penetrance and clinical variability. We report an isolated case of SPG4 associated with a novel likely pathogenic variant in SPAST. A 38-year-old woman presented with an eight-year history of progressive difficulty walking. Neurological examination revealed spastic paraparesis in the absence of upper motor neuron dysfunction, sensory deficits, or intellectual disability. Magnetic resonance imaging (MRI) of the brain and spinal cord was normal. No family members had similar complaints. Genetic analysis revealed a novel heterozygous sequence variant in SPAST, c.1751A > G p.(Asp584Gly) (NM_014946.4). The affected amino acid is highly conserved among orthologue and paralogue species. Four other nucleotide substitutions predicted to affect the same amino acid, a "hot spot", have been reported previously in adult-onset HSP. This report describes a novel SPAST variant in a female with HSP without a known family history of the disorder.

• Ali, Amanuel Hassen; Høyer, Helle; Rugland, Eyvind & Holmøy, Trygve (2022). A. H. Ali og medarbeidere svarer. Tidsskrift for Den norske legeforening. ISSN 0029-2001. 142(13). doi: 10.4045/tidsskr.22.0560.
• Ali, Amanuel Hassen; Høyer, Helle; Rugland, Eyvind & Holmøy, Trygve (2022). En kvinne i 50-årene med økende gangvansker. Tidsskrift for Den norske legeforening. ISSN 0029-2001. 142(11), p. 984–987. doi: 10.4045/tidsskr.21.0522.
• Glover, Joel; Tysnes, Ole-Bjørn; Myhr, Kjell-Morten; Bråthen, Geir; Sandvig, Ioanna & Høyer, Helle [Show all 9 contributors for this article] (2019). Hvor står ALS-forskningen i Norge? VG : Verdens gang. ISSN 0805-5203.
• Arntzen, Kjell Arne; Høyer, Helle; Ørstavik, Kristin; Tallaksen, Chantal; Vedeler, Christian A. & Østern, Rune André Helland [Show all 9 contributors for this article] (2018). Clinical characteristics, minimum prevalence and spectrum of SH3TC2 mutations in Norway.
• Høyer, Helle; Tveten, Kristian; Røsby, Oddveig; Hilmarsen, Hilde T; Busk, Øyvind & Svendsen, Marit [Show all 12 contributors for this article] (2018). A novel AARS variant identified in three CMT2 families.
• Høyer, Helle; Strand, Linda; Helås, Tormod; Holla, Øystein Lunde; Hilmarsen, Hilde T & Busk, Øyvind [Show all 9 contributors for this article] (2017). Late-onset polyneuropathy and MME variants – a Norwegian study.
• Arntzen, Kjell Arne; Høyer, Helle; Ingebrigtsen, Monica; Busk, Øyvind Løvold; Holla, Øystein Lunde & Tveten, Kristian [Show all 13 contributors for this article] (2016). Prevalence and spectrum of SH3TC2 mutations in Norway.
• Høyer, Helle; Braathen, Geir Julius; Busk, O.L.; Holla, OL; Strand, Linda & Skjelbred, Camilla Furu [Show all 7 contributors for this article] (2012). Charcot-Marie-Tooth families analysed with high-throughput sequencing. European Journal of Neurology. ISSN 1351-5101. 19, p. 734–734.
• Braathen, Geir Julius; Eek, Anette Kildal; Høyer, Helle; Bergsaker, D. K. & Russell, Michael Bjørn (2010). Syndromic Charcot-Marie-Tooth is easily neglected in ordinary diagnostics of Charcot-Marie-Tooth disease. European Journal of Neurology. ISSN 1351-5101. 17, p. 607–607.
• Høyer, Helle; Eek, A; Russell, Michael Bjørn & Braathen, Geir Julius (2010). Charcot-Marie-Tooth disease (CMT) caused by a novel copy-number variation (CNV) in the MPZ gene. European Journal of Neurology. ISSN 1351-5101. 17(supp. 3), p. 599–599.
• Høyer, Helle; Eek, A K; Russell, Michael Bjørn & Braathen, Geir Julius (2010). Charcot-Marie-Tooth disease (CMT) and novel mutations in Connexin 32 and LITAF. European Journal of Neurology. ISSN 1351-5101. 17, p. 608–608.
• Høyer, Helle; Russell, Michael Bjørn; Braathen, Geir Julius & Skjelbred, Camilla Furu (2015). Molecular diagnosis of Charcot-Marie-Tooth disease in Norway. Akademika forlag. ISSN 9788283330380.

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