Cognitive impairment is not uncommon in patients with biallelic RFC1 AAGGG repeat expansion, but the expansion is rare in patients with cognitive disease.

INTRODUCTION: The biallelic repeat expansion (AAGGG)exp in RFC1 causes cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). Recently, cognitive impairment has been reported in patients with CANVAS and a broader neurodegenerative process associated with RFC1 has been suggested. Furthermore, rare cases of multiple system atrophy, Parkinson's disease, amyotrophic lateral sclerosis or CANVAS with features of dementia with Lewy bodies have been found. OBJECTIVE: We hypothesized that the biallelic (AAGGG)exp is associated with neurodegeneration manifested as cognitive symptoms and that atypical RFC1 disease may be found among patients with cognitive disorder. METHODS: Clinical data on nine patients with biallelic (AAGGG)exp were reviewed and 564 patients with Alzheimer's disease or frontotemporal dementia (FTD) were investigated for biallelic RFC1 (AAGGG)exp. RESULTS: Five patients with biallelic (AAGGG)exp were found with a cognitive impairment and in four of them the phenotype resembled FTD. However, biallelic (AAGGG)exp was not detected among patients with Alzheimer's disease or FTD. CONCLUSION: Cognitive impairment is a feature in patients with the biallelic (AAGGG)exp, but the pathogenic expansion seems to be rare in patients with dementia. Studies on patients with diverse phenotypes would be useful to further explore the involvement of RFC1 in neuronal degeneration and to identify atypical phenotypes, which should be taken into account in clinical practice.

Phenotype of Patients With Charcot-Marie-Tooth With the p.His123Arg Mutation in GDAP1 in Northern Finland.

BACKGROUND AND OBJECTIVES: Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene cause autosomal dominant or autosomal recessive forms of Charcot-Marie-Tooth disease (CMT). Our aim was to study the clinical phenotype of patients with CMT caused by heterozygous p.His123Arg in GDAP1. METHODS: Twenty-three Finnish patients were recruited from a population-based cohort and through family investigation. Each patient was examined clinically and electrophysiologically. The Neuropathy Symptom Score and the Neuropathy Disability Score (NDS) were used in clinical evaluation. RESULTS: The median age at onset of symptoms was 17 years among patients with p.His123Arg in GDAP1. Motor symptoms were markedly more common than sensory symptoms at onset. All patients had distal weakness in lower extremities, and 17 (74%) patients had proximal weakness. Muscle atrophy and pes cavus were also common. Nineteen (82%) patients had sensory symptoms such as numbness or pain. The disease progressed with age, and the NDS increased 8.5 points per decade. Electrodiagnostic testing revealed length-dependent, sensory and motor axonal polyneuropathy. EDx findings were asymmetrical in 14 patients. Genealogic study of the families suggested a founder effect. DISCUSSION: We found that CMT in patients with p.His123Arg in GDAP1 is relatively mild and slow in progression.

Molecular epidemiology of hereditary ataxia in Finland.

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.

Recurrent traumatic brain injury is predicted by the index injury occurring under the influence of alcohol.

BACKGROUND: Little is known of the role of alcohol intoxication as a risk factor for recurrent traumatic brain injuries (TBI). This study was a population-based longitudinal study to investigate this problem. METHODS: The record linkage technique was used and data gathered from the Finnish Hospital Discharge Register, hospital records and by a questionnaire of family characteristics regarding the 12 058 subjects forming the Northern Finland Birth Cohort of 1966. Excluded were TBI subjects injured before the age of 12 years. RESULTS: Of the 236 patients who had survived their first (mainly mild) TBI, 21 had had a recurrent TBI and three of them two recurrent TBIs during the follow-up period (from 1978-2000). An alcohol-related first injury (RR 4.41, 95% CI 1.53-12.70) and urban place of birth (RR 4.39, 95% CI 1.68-11.48) were significant independent predictors of recurrent TBI. A significant positive correlation between the first and recurrent TBIs with respect to alcohol involvement (rs = 0.61, p = 0.003) was observed. CONCLUSIONS: A first TBI related to alcohol drinking is predictive of recurrent TBI, which will often similarly be alcohol-related. The risk of recurrent injury seems to extend over several years after the first TBI. To prevent recurrence, efforts should be made to identify those with an alcohol-related first TBI. A brief intervention focused on drinking habits is needed as an immediate preventive measure.

Traumatic brain injuries in children and young adults: a birth cohort study from northern Finland.

AIMS: Incidence and mortality rates of traumatic brain injury (TBI) were investigated by using the Northern Finland Birth Cohort. This cohort provides a valuable source of data from the population born in 1966 (n = 12,058) in the 2 northernmost provinces of Finland. METHODS: The cohort was followed for 34 years, and data were gathered from the Finnish Hospital Discharge Register and the Registry for Causes of Death by Statistics Finland. RESULTS: The annual incidence of and mortality from TBI were 118 and 14/100,000, respectively. Case fatality was 12%. An estimated prevalence of TBI at the age of 34 years was 269/100,000. Peak occurrences were observed at the age of 6-7 years in both genders and at the age of 18-23 years in men. The proportion of TBI mortality out of total mortality was 12%. Young men aged 16-34 years had 10-fold proportionate mortality from TBI compared to boys aged