Laura Kytövuori

Background: Neurodegeneration with Brain Iron Accumulation (NBIA) rarely manifests after the age of 50 years. The phenotype in these cases is most often parkinsonism. Objectives: To present the case with the oldest age of NBIA onset reported so far. Methods: Clinico‐pathological case. Results: A female patient presented at 84 years of age with wobbling of the head that had started approximately 2 years ago. Choreiform movements of the head and upper body were observed and these abated when she focused on doing something else or lay down but started again when she was talking or moving. There were no cerebellar signs, abnormal reflexes or sensory disturbance. Cognitive screening tests were abnormal but significant cognitive symptoms absent. Magnetic Resonance Imaging (MRI) showed extensive iron accumulation in the basal ganglia and upper pons. Extensive analyses yielded no genetic diagnosis. She died suddenly 19 months after her first appointment. In neuropathological analysis the basal ganglia, especially the lenticular nuclei, were macroscopically darker than normal with notable iron accumulation in the arterial walls in these areas. Prominent axonal ballooning was observed especially in the internal globus pallidus. Globus pallidus displayed iron accumulation, observed to a slightly lesser extent also in the substantia nigra pars reticulata. The neuropathological phenotype resembled classical pantothenate kinase‐associated neurodegeneration (PKAN). Concomitant beta‐amyloid, hyperphosphorylated tau protein (consistent with primary age‐related tauopathy, or PART) and TDP‐43 (consistent with LATE‐NC) pathologies were also evident. Conclusions: NBIA may manifest at a very advanced age with a mild phenotype, likely influenced by coexisting neuropathology.

Several heterozygous variants of the glucocerebrosidase gene (GBA1) have been reported to increase the risk of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). GBA1-associated PD has been reported to be more severe than idiopathic PD, and more deleterious variants are associated with more severe clinical phenotypes. We report a family with a heterozygous p.Pro454Leu variant in GBA1. The variant was associated with a severe and rapidly progressive neurodegenerative disease with Lewy bodies that were clinically and pathologically diverse. Pathogenicity prediction algorithms and evolutionary analyses suggested that p.Pro454Leu is deleterious.

Background and Purpose: The biallelic repeat expansion (AAGGG)_exp in the replication factor C subunit 1 gene (RFC1) is a frequent cause of cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) as well as late‐onset ataxia. The clinical spectrum of RFC1 disease has expanded since the first identification of biallelic (AAGGG)_exp and includes now various nonclassical phenotypes. Biallelic (AAGGG)_exp in RFC1 in patients with clinically confirmed Parkinson's disease (PD) has recently been found.Methods: A nationwide cohort of 273 Finnish patients with early‐onset PD was examined for the biallelic intronic expansion in RFC1. The expansion (AAGGG)_exp was first screened using extra long polymerase chain reactions (Extra Large‐PCRs) and flanking multiplex PCR. The presence of biallelic (AAGGG)_exp was then confirmed by repeat‐primed PCR and, finally, the repeat length was determined by long‐read sequencing.Results: Three patients were found with the biallelic (AAGGG)_exp in RFC1 giving a frequency of 1.10% (0.23%–3.18%; 95% confidence interval). The three patients fulfilled the diagnostic criteria of PD, none of them had ataxia or neuropathy, and only one patient had a mild vestibular dysfunction. The age at onset of PD symptoms was 40–48 years and their disease course had been unremarkable apart from the early onset.Conclusions: Our results suggest that (AAGGG)_exp in RFC1 is a rare cause of early‐onset PD. Other populations should be examined in order to determine whether our findings are specific to the Finnish population.

An intronic expansion (AAGGG)_exp in the RFC1 gene has recently been shown to cause recessively inherited cerebellar ataxia, neuropathy, and vestibular areflexia syndrome and, furthermore, a few patients with ataxia and parkinsonism have been reported. We investigated 569 Finnish patients with medicated parkinsonism for RFC1 and found biallelic (AAGGG)_exp in three non-consanguineous patients with clinically confirmed Parkinson’s disease without ataxia suggesting that RFC1-related disorders include Parkinson’s disease as well.

Background: The genetics of cerebellar ataxia is complex. Hundreds of causative genes have been identified, but only a few cause more than single cases. The spectrum of ataxia-causing genes differs considerably between populations. The aim of the study was to investigate the molecular epidemiology of ataxia in the Finnish population. Patients and methods: All patients in hospital database were reviewed for the diagnosis of unspecified ataxia. Acquired ataxias and nongenetic ataxias such as those related to infection, trauma or stroke were excluded. Sixty patients with sporadic ataxia with unknown etiology and 36 patients with familial ataxia of unknown etiology were recruited in the study. Repeat expansions in the SCA genes (ATXN1, 2, 3, 7, 8/OS, CACNA1A, TBP), FXN, and RFC1 were determined. Point mutations in POLG, SPG7 and in mitochondrial DNA (mtDNA) were investigated. In addition, DNA from 8 patients was exome sequenced. Results: A genetic cause of ataxia was found in 33 patients (34.4%). Seven patients had a dominantly inherited repeat expansion in ATXN8/OS. Ten patients had mitochondrial ataxia resulting from mutations in nuclear mitochondrial genes POLG or RARS2, or from a point mutation m.8561C > G or a single deletion in mtDNA. Interestingly, five patients were biallelic for the recently identified pathogenic repeat expansion in RFC1. All the five patients presented with the phenotype of cerebellar ataxia, neuropathy, and vestibular areflexia (CANVAS). Moreover, screening of 54 patients with Charcot-Marie-Tooth neuropathy revealed four additional patients with biallelic repeat expansion in RFC1, but none of them had cerebellar symptoms. Conclusions: Expansion in ATXN8/OS results in the majority of dominant ataxias in Finland, while mutations in RFC1 and POLG are the most common cause of recessive ataxias. Our results suggest that analysis of RFC1 should be included in the routine diagnostics of idiopathic ataxia and Charcot-Marie-Tooth polyneuropathy.

Background: We have previously suggested that some of the mutations defining mitochondrial DNA (mtDNA) haplogroups J and K produce an uncoupling effect on oxidative phosphorylation and thus are detrimental for elite endurance performance. Here, the association between haplogroups J and K and physical performance was determined in a population-based cohort of 1036 Finnish military conscripts.Results: Following a standard-dose training period, excellence in endurance performance was less frequent among subjects with haplogroups J or K than among subjects with non-JK haplogroups (p = 0.041), and this finding was more apparent among the best-performing subjects (p < 0.001).Conclusions: These results suggest that mtDNA haplogroups are one of the genetic determinants explaining individual variability in the adaptive response to endurance training, and mtDNA haplogroups J and K are markers of low-responders in exercise training.