Helle Høyer

• Prestsæter, Sjur; Koht, Jeanette; Berland, Siren; Høyer, Helle; Selmer, Kaja Kristine & Vedeler, Christian Alexander [Show all 11 contributors for this article] (2026). RFC1 Spectrum Disorder in a Norwegian CANVAS Cohort. Acta Neurologica Scandinavica. ISSN 0001-6314. doi: 10.1155/ane/6613732. Full text in Research Archive Show summary

  Background: Late‐onset cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive neurodegenerative disorder defined by sensory neuropathy, cerebellar ataxia, and bilateral vestibulopathy. While each symptom impairs balance, their combination causes substantial disability. The most common cause is a biallelic intronic repeat expansion in RFC1 , now recognized as a frequent etiology of late‐onset cerebellar ataxia. Objective: The objective of this study is to describe the phenotype, clinical course, and genetic profile of a Norwegian cohort with genetically confirmed CANVAS. Methods: Patients with late‐onset progressive ataxia, without a prior molecular diagnosis, and with at least one additional CANVAS‐associated feature were screened for the RFC1 (AAGGG) repeat expansions. Individuals with confirmed biallelic expansions underwent detailed clinical evaluation. Results: Among the 162 patients tested, 44 (27%) carried biallelic RFC1 expansions. Thirty‐two were clinically assessed, and one additional patient with compound heterozygosity (expansion plus truncating variant) was included. All but one (32/33) exhibited the characteristic triad. Mean age at symptom onset was 50.3 years (range 40–70). All demonstrated additional features beyond the triad, most commonly chronic cough (97%), bulbar dysfunction (85%), and dysautonomia (70%). Limb dystonia, not previously associated with RFC1 ‐related disease, occurred in two patients (6%). Aspiration pneumonia was the predominant cause of death (7/9, 80%). Conclusion: Our results shed light on the clinical course of CANVAS and expand its phenotypic spectrum. They underscore frequent bulbar dysfunction, dysautonomia, and the risk of aspiration pneumonia, while identifying limb dystonia as a novel manifestation of RFC1 ‐related disease.

• Hop, Paul J.; Kooyman, Maarten; Kenna, Brendan J.; Zwamborn, Ramona A. J.; Eijk, Kristel R. van & Wang, Yan [Show all 85 contributors for this article] (2026). Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis. Nature Genetics. ISSN 1061-4036. p. 717–725. doi: 10.1038/s41588-026-02535-9. Full text in Research Archive Show summary

  Amyotrophic lateral sclerosis (ALS) is a heritable disorder where rare variants with low-to-moderate penetrance are thought to dominate genetic risk. To identify such rare variants, we harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases. Rare variant analyses identified several new risk genes, with replication confirming association of YKT6 and supporting HTR3C , GBGT1 and KNTC1 . We also provide strong, independent validation for genes with limited previous evidence: ARPP21 , DNAJC7 and CFAP410 . Notably, in ARPP21 , we identified a new high-effect variant (p.P747L) and confirmed that p.P563L is an ALS-associated variant leading to an aggressive disease course. Beyond new discoveries, our analyses largely recapitulated the known genetic architecture of ALS, identifying risk variants in over 20% of cases and supporting a cumulative oligogenic risk model. These findings highlight new translational targets and show that rare variant analyses capture substantially more genetic risk than common variant genome-wide association studies.

• Vugt, Joke J F A van; Zwamborn, Ramona A J; Dolzhenko, Egor; Eberle, Michael A; Weisburd, Ben & Bekema, Erwin [Show all 20 contributors for this article] (2025). The role of disease-associated short tandem repeats in amyotrophic lateral sclerosis. Brain Communications. 7(6). doi: 10.1093/braincomms/fcaf482. Full text in Research Archive Show summary

  Short tandem repeats (STRs) are recognized contributors to various neurodegenerative disorders, with evidence supporting genetic pleiotropy among these STRs. Multiple STRs have been associated with amyotrophic lateral sclerosis (ALS), although the strength of evidence supporting each association varies. To establish the role of disease-associated repeat expansions as pleiotropic risk factors in ALS susceptibility and progression, we genotyped a panel of 39 STRs, known to cause neurological diseases, within Project MinE in 6519 patients and 2412 controls, utilizing 100 and 150 bp short-read sequencing technology. Pathogenic allele frequencies were compared to those in a control cohort comprising 4930 Genome Aggregation Database (gnomAD) genomes. Repeat sizes and motif changes were detected using ExpansionHunter and ExpansionHunter Denovo. We developed a model to predict genotyping failures in STRs and established a best-practice protocol for assessing the accuracy of STR genotyping in short-read sequencing data. Following our genotyping assessment, 11 out of the 39 STRs exhibited insufficient genotyping accuracy, warranting caution in studying these STRs using these tools in combination with short-read sequencing. Furthermore, the observed differences in STR genotyping accuracy across studies applying different sequencing technologies and genotyping tools in control cohorts highlight the importance of a carefully designed experimental setup when interpreting potential disease-associated STR findings. Pathogenic C9orf72 and premutated ATXN2 expansions were confirmed to be significantly associated with ALS susceptibility. Additionally, pathogenic C9orf72 expansions were significantly associated with reduced mean ALS survival by 11.5 months and an earlier mean age at onset by 2.4 years. Premutation expansions in ATXN1 showed a nominally significant association with ALS susceptibility, while pathogenic expansions in NIPA1 displayed a nominally significant association with ALS survival. Previously reported ALS-associated pleiotropy in HTT and STMN2 could not be confirmed. Motif changes were identified in BEAN1, RFC1, ATXN8, C9orf72, DAB1, FXN and SAMD12; however, none of the motif changes were linked to ALS. Re-evaluation of clinical data from patients with ALS and a repeat expansion typically associated with another disease revealed that 7% of these patients’ diagnoses had to be reclassified to the disease associated with the repeat expansion (e.g. Kennedy’s disease or spinocerebellar ataxia). This underscores the value of broad STR screening in neurodegenerative cases. Pathogenic and premutation STRs were also found in controls in unexpected high frequencies, suggesting reduced penetrance or underdiagnosis, and highlighting the need for caution when interpreting genetic associations with disease without a proper control cohort.

• Olsen, Cathrine Goberg; Malmberg, Vetle Nilsen; Fahlström, Maria; Alstadhaug, Karl Bjørnar; Bjørnå, Ingrid Kristine & Braathen, Geir Julius [Show all 24 contributors for this article] (2024). Amyotrophic lateral sclerosis caused by the C9orf72 expansion in Norway–prevalence, ancestry, clinical characteristics and sociodemographic status. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. ISSN 2167-8421. 26(1-2), p. 132–140. doi: 10.1080/21678421.2024.2405118. Full text in Research Archive Show summary

  Objective: The most common genetic cause of amyotrophic lateral sclerosis (ALS) is the C9orf72 expansion. A high incidence of this expansion has been detected in Sweden and Finland. This Norwegian population-based study aimed to identify the prevalence, geographic distribution, ancestry, and relatedness of ALS patients with a C9orf72 expansion (C9pos). Further, we compared C9pos and C9neg patients' clinical presentation, family history of ALS and other neurodegenerative disorders, and sociodemographic status. Methods: We recruited ALS patients from all 17 Departments of neurology in Norway. Blood samples and questionnaires regarding clinical characteristics, sociodemographic status and family history of ALS, and other neurodegenerative disorders were collected. The C9orf72 expansion was examined for all patients. Results: The study enrolled 500 ALS patients, 8.8% of whom were C9pos, with half being sporadic ALS cases. The proportion of C9pos cases differed between regions, ranging from 17.9% in the Northern

• 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. 6(2), p. 1–10. doi: 10.1093/braincomms/fcae087. Full text in Research Archive Show summary

  Genetic repeat expansions cause neuronal degeneration in amyotrophic lateral sclerosis as well as other neurodegenerative disorders such as spinocerebellar ataxia, Huntington’s disease and Kennedy’s disease. Repeat expansions in the same gene can cause multiple clinical phenotypes. We aimed to characterize repeat expansions in a Norwegian amyotrophic lateral sclerosis cohort. Norwegian amyotrophic lateral sclerosis patients (n = 414) and neurologically healthy controls adjusted for age and gender (n = 713) were investigated for repeat expansions in AR, ATXN1, ATXN2 and HTT using short read exome sequencing and the ExpansionHunter software. Five amyotrophic lateral sclerosis patients (1.2%) and two controls (0.3%) carried ≥36 repeats in HTT (P = 0.032), and seven amyotrophic lateral sclerosis patients (1.7%) and three controls (0.4%) carried ≥29 repeats in ATXN2 (P = 0.038). One male diagnosed with amyotrophic lateral sclerosis carried a pathogenic repeat expansion in AR, and his diagnosis was revised to Kenne

• Novy, Camilla; Tysnes, Ole-Bjørn; Busk, Øyvind; Jaioun, Keson; Holmøy, Trygve & Holla, Øystein Lunde [Show all 7 contributors for this article] (2024). Association of UNC13A with increased amyotrophic lateral sclerosis risk, bulbar onset, and lower motor neuron involvement in a Norwegian ALS cohort. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. ISSN 2167-8421. doi: 10.1080/21678421.2024.2447922. Full text in Research Archive Show summary

  Objective: Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by the loss of motor neurons, has limited treatment options available. Treatments targeting specific ALS genes, including UNC13A, have attracted considerable attention. The UNC13A rs12608932 variant has been associated with an increased risk of ALS, shorter survival, and more frequent bulbar onset. Methods: In this study, we investigated the allele frequency of rs12608932 among 500 Norwegian ALS patients, divided into three groups: patients with a genetic cause, patients without a genetic cause, and the entire ALS population.The three groups were compared to two independent control groups.The patients carrying UNC13A genotypes AA, AC, and CC were further clinically characterized and compared using additive, recessive, and dominant models. Results: The frequency of the rs12608932 C allele was higher in the patients with ALS (0.438) than in the controls (0.365; p<0.001). Among ALS patients without a known genetic cause, individuals with the CC genotype exhibited higher frequencies of bulbar onset (p¼0.015) and prominent lower motor neuron involvement (p¼0.007) than those with the AA and AC genotypes. Conclusions: The CC genotype of rs12608932 is associated with an increased risk of ALS. Additionally, it acts as a modifier of the ALS phenotype, increasing the risk of bulbar onset and dominant lower motor neuron involvement, specifically in patients without a genetic cause in known ALS genes.

• 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.

• 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. Full text in Research Archive 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.

• 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. 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.

• 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; 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. Full text in Research Archive
• 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.

• Kliest, Tessa; Eijk, Ruben P. A. van; 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; Vriendt, Els De; 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. 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. Full text in Research Archive
• 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. Full text in Research Archive 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. Full text in Research Archive
• 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 (Tidsskriftet). ISSN 0029-2001. 135(20), p. 1833–1837. doi: 10.4045/tidsskr.14.1442. Full text in Research Archive
• 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. Full text in Research Archive
• 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 (Tidsskriftet). ISSN 0029-2001. 135(20), p. 1838–1843. doi: 10.4045/tidsskr.14.1002. Full text in Research Archive
• 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. Full text in Research Archive
• 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. 9(8). doi: 10.1371/journal.pone.0105254. Full text in Research Archive
• 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. Full text in Research Archive
• 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. Full text in Research Archive
• 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. Full text in Research Archive
• Braathen, Geir Julius; Sand, Jette Christensen; Pascual, Ana Lobato; 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. 11(48). doi: 10.1186/1471-2350-11-48. Full text in Research Archive Show summary

  Background Point mutations in the mitofusin 2 (MFN2) gene has been identified exclusively in Charcot-Marie-Tooth type 2 (CMT2), and in a single family with intermediate CMT. MFN2 point mutations are probably the most common cause of CMT2. Methods Two-hundred and thirty-two consecutive unselected and unrelated CMT families with available DNA from all regions in Norway were included. We screened for point mutations in the MFN2 gene. Results We identified four known and three novel point mutations in 8 unrelated CMT families. The novel point mutations were not found in 100 healthy controls. This corresponds to 3.4% (8/232) of CMT families have point mutations in the MFN2 gene. The phenotypes were compatible with CMT1 in two families, CMT2 in four families, intermediate CMT in one family and distal Hereditary Motor Neuropathy (dHMN) in one family. This corresponds to 2.3% of CMT1, 5.5% of CMT2, 12.5% of intermediate CMT and 6.7% of dHMN families have a point mutation in the MFN2 gene. Point mutations in the MFN2 gene is likely to be the fourth most common cause to CMT after duplication of the peripheral myelin protein 22 (PMP22) gene, and point mutations in the Connexin32 (Cx32) and myelin protein zero (MPZ) genes. Conclusions The identified known and novel point mutations in the MFN2 gene expand the clinical spectrum from CMT2 and intermediate CMT to also include possibly CMT1 and the dHMN phenotypes. Thus, genetic analyses of the MFN2 gene should not be restricted to persons with CMT2.

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• Ali, Amanuel Hassen; Høyer, Helle; Rugland, Eyvind & Holmøy, Trygve (2022). A. H. Ali og medarbeidere svarer. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 142(13). doi: 10.4045/tidsskr.22.0560. Full text in Research Archive
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• 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? Full text in Research Archive
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