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Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (, Dietmar Hopp Stiftung (DE); Medical Faculty of the University of Heidelberg.

International audience; Spastic paraplegia type 5 (SPG5/HSP-CYP7B1) is an autosomal recessive hereditary spastic paraplegia (HSP) caused by biallelic variants in the CYP7B1 gene, resulting in dysfunction of the enzyme oxysterol-7-α-hydroxylase. The consequent accumulation of hydroxycholesterols in plasma seems to be pathognomonic for SPG5, and represent a possible target for treatment. We aimed to characterize Norwegian patients with SPG5, including clinical examinations, genetic analyses, measurements of hydroxycholesterols, electrophysiological investigations and brain imaging. Five unrelated patients carried presumed disease-causing variants in CYP7B1, three of the variants were novel. Four patients presented with pure HSP, one with complex HSP. The three tested patients all had markedly increased levels of 25- and 27-hydroxycholesterol in plasma. Our results suggest that the clinical examination is still the best approach to classify disease severity in patients with SPG5. Plasma hydroxycholesterols were elevated, thus presenting as potentially valuable diagnostic biomarkers, in particular in patients where genetic analyses are inconclusive.

Affective disorders are overrepresented in epilepsy, and people with epilepsy may be at risk of dropping out from school. The aim of the present study was to assess factors influencing high school dropout, anxiety, and depression in genetic generalized epilepsy (GGE). One hundred and ten people with GGE aged 19‐40 years underwent a clinical interview, including the Hospital Anxiety and Depression Scale (HADS) questionnaire. Potential predictors of high school dropout were analyzed with logistic regression, and factors influencing total HADS score were analyzed with linear regression. Having felt excluded because of epilepsy was significantly associated with high school dropout (odds ratio 7.80, P = .009), as was total HADS score (odds ratio 1.22, P = .005). If a participant was currently employed or undergoing education, previous high school dropout was less likely (odds ratio 0.07, P = .005). High school dropout was associated with increased current anxiety and depression (β = 0.32, P = .005). Epilepsy severity (current drug resistance, current polytherapy, and active generalized tonic‐clonic seizures) was not associated with high school dropout, nor with total HADS score. The issue of stigma in epilepsy must be thoroughly addressed in comprehensive care and may be as important as seizure control when it comes to education and quality of life.

DYT-TOR1A dystonia is caused by dominant mutations in the TOR1A gene, most frequently a heterozygous in-frame deletion in exon 5 (c.904_906delGAG; p.302/303delE).1 The most frequent phenotype has childhood onset in a limb, spreading to generalized dystonia within a few years. However, also mild focal forms and onset in the cervical and even cranial region have been described. Age at onset varies from 3 to 64 years,2 and penetrance is only 30%. Other in-frame deletions and point mutations in TOR1A have been associated with dystonia in a limited number of patients.3,4 Here, we report 2 new patients with missense mutations in TOR1A .

Background and purpose Patients with juvenile myoclonus epilepsy (JME) may experience uncontrolled seizures and challenges regarding adherence. Implementation of therapeutic drug monitoring (TDM) may contribute to individualization of the therapy with antiepileptic drugs (AEDs). The purpose of this study was to investigate how the treatment of patients with JME is monitored and to demonstrate pharmacokinetic variability within and between patients with a long-term TDM approach. Method Retrospective data from patients with JME from the TDM-database at Drammen Hospital and the National Center for Epilepsy in Norway (2007–2018) were included. Results Data from 80 of 90 patients with JME using AEDs with TDM measurements was included (88%, 49/31 women/men aged 14–39). One third (27, 33%) was seizure free, 19 (24%) had generalized tonic-clonic seizures, and 53 (66%) myoclonic seizures during the last year. The most common AEDs measured included lamotrigine, valproate, and levetiracetam. Long-term TDM demonstrated variability over time expressed as intra-patient median values and inter-patient ranges of 19% (7–47) for valproate, 43% (10–83) for lamotrigine and 35% (6–111) for levetiracetam. Fifteen pecent (83/563) of serum concentrations were below the reference ranges and clould be due to variable adherence. Comedication with valproate for lamotrigine and pregnancy contributed to variability. The applicability is illustrated in a case of 10 years’ follow-up in a young woman. Conclusion There was extensive pharmacokinetic variability of AEDs in and between patients with JME. A long-term TDM approach may contribute to closer monitoring of patients with JME and be used as a practical tool during clinical consultations.

Background CAPOS (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss) syndrome is caused by the heterozygous mutation, c.2452G > A, in the ATP1A3 gene. Other mutations in this gene can cause a spectrum of overlapping phenotypes including alternating hemiplegia of childhood, rapid onset dystonia parkinsonism, early infantile epileptic encephalopathy and fever induced paroxysmal weakness and encephalopathy. The phenotype is still mistaken for mitochondrial/metabolic disorders and follow up studies are scare. Case presentation We report a 20 year old Norwegian male with ataxia, sensorineural deafness and visual loss. Before the age of five he experienced three fever related episodes of acute neurological deterioration when he temporarily lost his acquired motor skills and developed persistent gait and limb ataxia. In childhood, he developed bilateral optic atrophy and bilateral sensorineural hearing loss. Motor skills improved and at age 20 the patient showed a mild ataxia, hearing loss and reduced vision. A c.2452G > A mutation in the ATP1A3 gene was identified and CAPOS syndrome was confirmed. Conclusions This is the first Norwegian patient reported with CAPOS syndrome. Our patient had a de novo, previously identified ATP1A3 mutation. The combination of recurrent episodes of fever related ataxia, loss of motor skills in early childhood, and early onset hearing and vision loss is typical of CAPOS syndrome. Previous reports suggest a gradual progression of the disease after the initial episodes, while this patient showed a good outcome with improvement of motor skills from adolescence long after the last deterioration episode. Electronic supplementary material The online version of this article (10.1186/s40673-019-0096-3) contains supplementary material, which is available to authorized users.

Background Patients with juvenile myoclonic epilepsy (JME) may have uncontrolled seizures. The purpose of this study was to investigate the use and challenges with antiepileptic drugs (AEDs) and the patients' view of these challenges. Method A questionnaire about the use of AEDs, adherence to therapy, and quality of life was given to patients with JME recruited from Drammen Hospital. Data regarding AEDs were confirmed from medical records at Drammen Hospital, Norway (2007–2018). Additional clinical interviews were performed, and a mixed method approach was applied. Results Ninety patients with defined JME diagnosis, 54/36 women/men aged 14–39 (mean: 25) years, were included. Only 29 (33%) were seizure-free. Within the last year, 21% experienced generalized tonic–clonic seizures (GTCS), and 68% had myoclonic jerks. Seventy-six (84%) used AEDs, 78% in monotherapy. A total of 10 AEDs were used;: most commonly valproate (n = 33), lamotrigine (n = 27), and levetiracetam (n = 21). Two-thirds of valproate users were men while all other AEDs were used more in females than in men. Valproate and levetiracetam displayed better efficacy against GTCS than lamotrigine. One-third often/sometimes forgot their medication nonintentionally while 14% had intentional poor adherence. The majority reported good quality of life (76%). No significant correlations between the use of AEDs, use of valproate, poor adherence, quality of life score, and seizure freedom were demonstrated. Half of the patients had serum concentrations measured every year, and two-thirds thought this was important. Qualitative interviews elucidated treatment challenges in JME;, adverse effect burden, adherence, and activities of daily life. Conclusion Despite the use of AEDs in the majority of patients, only one-third were seizure-free. Other challenges included polypharmacy, the use of valproate in women, and variable adherence. This points to a need for closer follow-up in patients with JME.

Doparesponsiv dystoni er en gruppe sykdommer som gir endrede nivåer av nevrotransmittere. Dette kan behandles med god effekt. Økt innsikt i patofysiologiske årsaksforhold har bedret forståelsen av sykdommene.Artikkelen bygger på 39 artikler fra et systematisk søk i databasen Medline, to nettsteder og en lærebok.Doparesponsiv dystoni debuterer som oftest i barne- eller ungdomsårene og gir motoriske, kognitive, psykiatriske og/eller autonome symptomer og funn. Disse kan være uspesifikke og lett mistolkes som annen nevrologisk sykdom. Sykdommen skyldes feilkoding i ett enkelt gen og arves autosomalt recessivt eller dominant. Sykdomsgivende varianter er beskrevet fra tre ulike gener: guanosintrifosfat (GTP)-syklohydrolase-1-genet, sepiapterinreduktase-genet og tyrosinhydroksylase-genet. De sykdomsgivende variantene fører til enzymdefekt og gir tidlig debuterende dystoni, som responderer godt på levodopa. Nivåbestemmelse av pteriner, biogene monoaminer og deres metabolitter i spinalvæsken samt genetiske undersøkelser gir den eksakte diagnosen.Dagens kunnskap baserer seg på kasuistikker og mindre pasientmaterialer. Her fremgår det at pasientgruppen har stor nytte av levodopa. Diagnostikken har blitt enklere de siste årene med nyere biokjemiske og molekylærgenetiske analysemetoder. Basert på dagens litteratur er det grunn til å tro at vi har udiagnostiserte pasienter i Norge med doparesponsiv dystoni.

SummaryObjective Despite juvenile myoclonic epilepsy (JME) being considered one of the most common epilepsies, population-based prevalence studies of JME are lacking. Our aim was to estimate the prevalence of JME in a Norwegian county, using updated diagnostic criteria. Methods This was a cross-sectional study, based on reviews of the medical records of all patients with a diagnosis of epilepsy at Drammen Hospital in the period 1999–2013. The study population consisted of 98,152 people

Background Juvenile myoclonic epilepsy (JME) is a common subtype of genetic generalized epilepsy (GGE) arising in adolescence and is often associated with executive function (EF) deficits. Some EF components like response inhibition have been extensively evaluated in JME, but few studies have focused upon trait impulsivity or compared between GGE subtypes. The aim of the present study was to compare the association of trait impulsivity in JME with other GGE subtypes. Methods Patients with GGE aged between 14 and 40 years (n = 137) were divided into those with JME (n = 92) and those with other GGEs (n = 45: 8 childhood absence epilepsy (CAE), 22 juvenile absence epilepsy (JAE), and 15 epilepsy with generalized tonic–clonic seizures only (EGTCS)). The study participants were recruited through medical records of the general population of Buskerud County and the neighboring municipalities, covering 477,000 people or 9.1% of Norway's total population. All participants underwent a clinical interview including the Barratt Impulsiveness Scale (BIS), an established measure of trait impulsivity. We controlled for other potential predictors of BIS score using analysis of covariance (ANCOVA). Results There were no differences between JME and other types of GGE for BIS scores, but the presence of myoclonic seizures within the last year, irrespective of GGE subtype, was independently associated with significantly increased behavioral impulsivity. Conclusions This study demonstrates that trait impulsivity in GGE is most strongly related to the recent occurrence of myoclonic seizures rather than GGE subtype.

Summary The causes of epilepsy are age related, but confirmative data from population‐based studies are scarce. Our aim was to describe the typical causes of epilepsy in the different age groups of a defined population. The study was cross‐sectional, based on a review of all medical files containing a diagnostic code for epilepsy at Drammen Hospital from 1999‐2013. Drammen Hospital serves the population of Buskerud County, with 272 228 residents (as of January 1, 2014), including 1771 people with active epilepsy. This group of persons with active epilepsy was divided into different age groups with the causes of epilepsy mapped in each group. The proportion with unknown etiology ranged from 27% (age 5‐9) to 41% (age 10‐19). Structural‐metabolic epilepsy and perinatal insults were the leading causes of epilepsy in the age group 5‐9 (46%), whereas disturbances of brain development dominated in the youngest (23% in patients ≤4 years old). In the group comprising persons with epilepsy ≥60 years old, stroke was the most common cause of epilepsy (44%). Despite recent advances in research and technology, a large number of patients in all age groups (including the youngest) still have an unknown cause of epilepsy. We conclude that an effort must be made to improve the diagnostics for and understanding of the causes of epilepsy across all ages.

Objectives A family with homocarnosinosis was reported in the literature in 1976. Three affected siblings had spastic paraplegia, retinitis pigmentosa, mental retardation, and cerebrospinal fluid (CSF) homocarnosine concentrations 20 times higher than in controls. Based on the clinical findings and new genetic techniques, we have been able to establish a precise genetic diagnosis. Method The medical records were re-evaluated, and genetic analyses were performed post-mortem in this original family. SNP array-based whole genome homozygosity mapping and Sanger sequencing of the SPG11 gene were performed. Seven additional Norwegian SPG11 patients and their disease-causing variants and clinical findings were evaluated. Homocarnosine levels in CSF were measured in four of these seven patients. Results A homozygous pathogenic splice-site variant in the SPG11 gene, c.2316 + 1G>A, was found. The clinical findings in the original family correlate with the heterogeneous SPG11 phenotype. The same variant was found in seven other Norwegian SPG11 patients, unrelated to the original family, either as homozygous or compound heterozygous constellation. Normal homocarnosine levels were found in the CSF of all unrelated SPG11 patients. Conclusions A re-evaluation of the clinical symptoms and findings in the original family correlates with the SPG11 phenotype. The increased levels of homocarnosine do not seem to be a biomarker for SPG11 in our patients. Homocarnosinosis is still a biochemical aberration with unknown clinical significance.

Background Updated knowledge on the prevalence of epilepsy is valuable for planning of health services to this large and complex patient group. Comprehensive epidemiological research on epilepsy has been undertaken, but because of variations in methodology, the results are difficult to compare. The objective of this article is to present evidence-based estimates of the prevalence and incidence of epilepsy in the Nordic countries. Method The article is based on a search in PubMed with the search terms epilepsy and epidemiology, combined with each of the Nordic countries separately. Results Altogether 38 original articles reported incidence and/or prevalence rates of epilepsy in a Nordic country. Four studies had investigated the prevalence of active epilepsy in all age groups, with results ranging from 3.4 to 7.6 per 1,000 inhabitants. Only two studies had investigated the incidence of epilepsy in a prospective material that included all age groups. The reported incidence amounted to 33 and 34 per 100,000 person-years respectively. A prospective study that only included adults reported an incidence of 56 per 100,000 person-years. Interpretation We estimate that approximately 0.6% of the population of the Nordic countries have active epilepsy, i.e. approximately 30,000 persons in Norway. Epilepsy is thus one of the most common neurological disorders. The incidence data are more uncertain, but we may reasonably assume that 30-60 new cases occur per 100,000 person-years.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a hereditary neurodegenerative disorder caused by a mutation on the X chromosome. The major signs and symptoms are tremor, ataxia and parkinsonism. Up to one in 2 000 persons over 50 years of age will develop the syndrome. There is reason to believe that too few individuals in Norway undergo testing for this condition.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a hereditary neurodegenerative disorder caused by a mutation on the X chromosome. The major signs and symptoms are tremor, ataxia and parkinsonism. Up to one in 2 000 persons over 50 years of age will develop the syndrome. There is reason to believe that too few individuals in Norway undergo testing for this condition.

Hereditary ataxia and spastic paraplegia are heterogeneous monogenic neurodegenerative disorders. To date, a large number of individuals with such disorders remain undiagnosed. Here, we have assessed molecular diagnosis by gene panel sequencing in 105 early and late-onset hereditary ataxia and spastic paraplegia probands, in whom extensive previous investigations had failed to identify the genetic cause of disease. Pathogenic and likely-pathogenic variants were identified in 20 probands (19%) and variants of uncertain significance in ten probands (10%). Together these accounted for 30 probands (29%) and involved 18 different genes. Among several interesting findings, dominantly inherited KIF1A variants, p.(Val8Met) and p.(Ile27Thr) segregated in two independent families, both presenting with a pure spastic paraplegia phenotype. Two homozygous missense variants, p.(Gly4230Ser) and p.(Leu4221Val) were found in SACS in one consanguineous family, presenting with spastic ataxia and isolated cerebellar atrophy. The average disease duration in probands with pathogenic and likely-pathogenic variants was 31 years, ranging from 4 to 51 years. In conclusion, this study confirmed and expanded the clinical phenotypes associated with known disease genes. The results demonstrate that gene panel sequencing and similar sequencing approaches can serve as efficient diagnostic tools for different heterogeneous disorders. Early use of such strategies may help to reduce both costs and time of the diagnostic process.

OBJECTIVES: Sepiapterin reductase deficiency is a rare, but treatable inherited disorder of tetrahydrobiopterin and neurotransmitter metabolism. This disorder is most probably underdiagnosed. To date, only 44 cases have been described in the literature. We present the clinical and genetic investigations in a family with a complex movement disorder. MATERIALS AND METHODS: We examined two affected sisters and three healthy family members. The cerebrospinal fluid was analyzed for neurotransmitter and pterins, and the sepiapterin reductase gene (SPR) was sequenced. RESULTS: The sisters had a complex movement disorders with dystonia and diurnal fluctuations. Both had oculogyric crises, and the older sister also hypersomnia. Both sisters had raised prolactin levels twice above the reference level. One sister had a dramatic response to levodopa, the other responded, but developed dyskinesia despite low doses. Both patients improved dramatically over time with levodopa (2.3 and 1.5 mg/kg/day). Very low levels of homovanillic acid and 5-hydroxyindoleacetic acid and increased levels of sepiapterin and dihydrobiopterin were measured in the cerebrospinal fluid before treatment. DNA analyses revealed a novel homozygous mutation in exon 2 in the SPR gene, c.364A>G/p.(Tyr123Cys), located in a highly conserved region in the gene. Both parents and the healthy sister were carriers for the same mutation. CONCLUSIONS: A new homozygous mutation in the SPR gene was found in two sisters with dopa-responsive dystonia. This important and treatable neurotransmitter disorder must be considered in patients with a complex movement disorder with diurnal fluctuations with or without intellectual impairment. Patients with these symptoms should undergo levodopa trial, cerebrospinal fluid investigations, and genetic analyses.

Background Benign hereditary chorea is a rare disorder which is characterized by early onset, non-progressive choreic movement disturbance, with other hyperkinetic movements and unsteadiness also commonly seen. Hypothyroidism and lung disease are frequent additional features. The disorder is caused by mutations of the NKX2-1 gene on chromosome 14. Case presentation A Norwegian four-generation family with eight affected was identified. All family members had an early onset movement disorder, starting before one year of age with motor delay and chorea. Learning difficulties were commonly reported from early school years. The family presented with choreic movements at rest, but other movements were seen; myoclonus, dystonia, ataxia, stuttering and tics-like movements. All patients reported unsteadiness and ataxic gait was observed in two patients. Videos are provided in the supplementary material. Most affected family members had asthma and a subclinical or clinical hypothyroidism. Sequencing revealed a mutation in the NKX2-1 gene in all eight affected family members. Conclusions This is the first Norwegian family with benign hereditary chorea due to a mutation in the NKX2-1 gene, c.671 T > G (p.Leu224Arg). This family demonstrates well the wide phenotype, including dystonia, myoclonus and ataxia. Electronic supplementary material The online version of this article (doi:10.1186/s40673-016-0041-7) contains supplementary material, which is available to authorized users.

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly,80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22GA), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22GA demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22GA variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

Background Benign hereditary chorea (BHC) is a rare autosomal dominant disorder characterised by childhood onset that tends to improve in adulthood. The associated gene, NKX2-1 (previously called TITF1 ), is essential for organogenesis of the basal ganglia, thyroid and lungs. The aim of the study was to refine the movement disorders phenotype. We also studied disease course and response to therapy in a large series of genetically proven patients. Methods We analysed clinical, genetic findings and follow-up data in 28 NKX2-1 mutated BHC patients from 13 families. Results All patients had private mutations, including seven new mutations, three previously reported mutations and three sporadic deletions encompassing the NKX2-1 gene. Hypotonia and chorea were present in early infancy, with delayed walking ability (25/28); dystonia, myoclonus and tics were often associated. Attention deficit hyperactivity disorder (ADHD) was present in seven. Among the 14 patients followed-up until adulthood, nine had persistent mild chorea, two had near total resolution of chorea but persistent disabling prominent myoclonus and three recovered completely. Learning difficulties were observed in 20/28 patients, and three had mental retardation. Various combinations of BHC, thyroid (67%) and lung (46%) features were noted. We found no genotype–phenotype correlation. A rapid and sustained beneficial effect on chorea was obtained in 5/8 patients treated with tetrabenazine. Conclusion Early onset chorea preceded by hypotonia is suggestive of BHC. Associated thyroid or respiratory disorders further support the diagnosis and call for genetic studies. Tetrabenazine may be an interesting option to treat disabling chorea.

Koht J, Stevanin G, Durr A, Mundwiller E, Brice A, Tallaksen CME. SCA14 in Norway, two families with autosomal dominant cerebellar ataxia and a novel mutation in the PRKCG gene. Acta Neurol Scand: 2012: 125: 116–122. © 2011 John Wiley & Sons A/S. Objectives – Despite a similar prevalence of autosomal dominant cerebellar ataxia (ADCA) in Norway compared to other European countries, less than 10% of the families are explained by the CAG trinucleotide expansions. We wanted to find the occurence of SCA14 in the dominant ataxia population and describe the phenotype. Methods – We screened a large dominant cerebellar ataxia cohort for mutations in the PRKCG gene. Patients were evaluated according to a standard clinical protocol for ataxia patients. Results – A novel mutation was found in two families, a C to A transversion altering Histidine to a Glutamine at codon 139, located in a highly concerved region in the gene. It completely co-segregated with the affected family members and was not seen in 576 control chromosomes. Genetic analysis revealed common alleles at three microsatellite markers between these two families suggesting a shared ancestral chromosome. Affected subjects displayed a mild, slowly progressive cerebellar syndrome that included gait and limb ataxia and saccadic pursuit and head tremor in one. Age at onset ranged from 10 to 45 years. Conclusions – These are the first families with SCA14 reported from Scandinavia and a new mutation in the PRKCG gene. The occurrence in the Norwegian dominant ataxia cohort is 3.5%.

Background - Ataxia with vitamin E deficiency (AVED) is a rare cause of hereditary ataxia in north European countries with unknown prevalence. Few cases are reported from these countries. Methods -Through a systematic population based study of hereditary ataxia in southeast Norway subjects were classified and investigated. Aims - To report a subject with ataxia due to vitamin E deficiency in Norway. Results - One patient with AVED was identified. The subject was a 45 years old woman with progressive ataxia from preschool age. When she was 12 years old Friedreich's ataxia was diagnosed after neurological examination. At the age of 45 re-evaluation and re-examination was performed and genetic analysis of the Frataxin gene was negative. At that time she had truncal and extremities ataxia, titubation of the head, pes cavus, inverted plantar response, loss of proprioceptive and vibration sense and a severe sensory neuropathy. Vitamin E in serum was undetectable and genetic analysis detected a compound heterozygous mutation, p.A120T and p.R134X, in the α-tocopherol transport protein gene on chromosome 8q13. Discussion - Vitamin E should always be assessed in progressive ataxia of genetic or unexplained causes and especially with a Friedreich's ataxia-like phenotype since treatment is available. Conclusion - AVED is rare in Norway, but exists, and we here report the first genetically confirmed subject with ataxia due to vitamin E deficiency in Norway.

Introduction - The relative frequencies of different ataxias vary among different ethnic and geographic groups. The aim of this study was to examine patients with cerebellar ataxia and find the occurrence of autosomal dominant and recessive cerebellar ataxias in the population of the southern and eastern parts of Norway and estimate its prevalence. Materials and methods - Probands were systematically tested for spinocerebellar ataxia 1, 2, 3, 6 and Friedreich's ataxia. A total of 94 patients with ataxia were assessed. Results - We registered 60 patients from 39 unrelated families with hereditary ataxias. One family with SCA2 (two patients), one family with Friedreich's ataxia (two patients), two patients heterozygote for Friedreich's ataxia and one metabolic ataxia were identified. Conclusions - We have few Friedreich's ataxia and SCA 1,2,3 and 6 in our population. Prevalence in Oslo County was estimated at 2.2/100,000 for autosomal recessive and 3.0/100,000 for autosomal dominant ataxia, respectively.

Background and purpose SPG7 is one of the most common forms of autosomal recessive hereditary spastic paraplegia. The phenotype has been shown to be heterogeneous, varying from a complex spastic ataxia to pure spastic paraplegia or pure ataxia. The aim of this study was to clinically and genetically characterize patients with SPG7 in Norway. Methods Six Norwegian families with a clinical diagnosis of hereditary spastic paraplegia were diagnosed with SPG7 through Sanger sequencing and whole-exome sequencing. Haplotypes were established to identify a possible founder mutation. All patients were thoroughly examined and the clinical and molecular findings are described. Results The core phenotype was spastic paraparesis with ataxia, bladder disturbances and progressive external ophthalmoplegia. The variant p.H701P was identified in homozygous state in one family and in compound heterozygous state in three families. Haplotype analysis of seven surrounding single nucleotide polymorphisms supports that this variant resides on a founder haplotype. Four of the families were compound heterozygous for the previously well-described p.A510V variant. Conclusion SPG7 is a common subgroup of hereditary spinocerebellar disorders in Norway. The broad phenotype in the Norwegian SPG7 population illustrates the challenges with the traditional dichotomous classification of hereditary spinocerebellar disorders into hereditary spastic paraplegia or hereditary ataxia. A Norwegian founder mutation p.H701P was identified in four out of six families, making it a major cause of SPG7 in Norway.

SummaryObjective Epilepsy represents a substantial personal and social burden worldwide. When addressing the multifaceted issues of epilepsy care, updated epidemiologic studies using recent guidelines are essential. The aim of this study was to find the prevalence and causes of epilepsy in a representative Norwegian county, implementing the new guidelines and terminology suggested by the International League Against Epilepsy (ILAE). Methods Included in the study were all patients from Buskerud County in Norway with a diagnosis of epilepsy at Drammen Hospital and the National Center for Epilepsy at Oslo University Hospital. The study period was 1999–2014. Patients with active epilepsy were identified through a systematic review of medical records, containing information about case history, electroencephalography (EEG), cerebral magnetic resonance imaging (MRI), genetic tests, blood samples, treatment, and other investigations. Epilepsies were classified according to the revised terminology suggested by the ILAE in 2010. Results In a population of 272,228 inhabitants, 1,771 persons had active epilepsy. Point prevalence on January 1, 2014 was 0.65%. Of the subjects registered with a diagnostic code of epilepsy, 20% did not fulfill the ILAE criteria of the diagnosis. Epilepsy etiology was structural-metabolic in 43%, genetic/presumed genetic in 20%, and unknown in 32%. Due to lack of information, etiology could not be determined in 4%. Significance Epilepsy is a common disorder, affecting 0.65% of the subjects in this cohort. Every fifth subject registered with a diagnosis of epilepsy was misdiagnosed. In those with a reliable epilepsy diagnosis, every third patient had an unknown etiology. Future advances in genetic research will probably lead to an increased identification of genetic and hopefully treatable causes of epilepsy.

Background A subset of hereditary cerebellar ataxias is inherited as autosomal recessive traits (ARCAs). Classification of recessive ataxias due to phenotypic differences in the cerebellum and cerebellar structures is constantly evolving due to new identified disease genes. Recently, reports have linked mutations in genes involved in ubiquitination (RNF216, OTUD4, STUB1) to ARCA with hypogonadism. Methods and results With a combination of homozygozity mapping and exome sequencing, we identified three mutations in STUB1 in two families with ARCA and cognitive impairment; a homozygous missense variant (c.194A > G, p.Asn65Ser) that segregated in three affected siblings, and a missense change (c.82G > A, p.Glu28Lys) which was inherited in trans with a nonsense mutation (c.430A > T, p.Lys144Ter) in another patient. STUB1 encodes CHIP (C-terminus of Heat shock protein 70 – Interacting Protein), a dual function protein with a role in ubiquitination as a co-chaperone with heat shock proteins, and as an E3 ligase. We show that the p.Asn65Ser substitution impairs CHIP’s ability to ubiquitinate HSC70 in vitro, despite being able to self-ubiquitinate. These results are consistent with previous studies highlighting this as a critical residue for the interaction between CHIP and its co-chaperones. Furthermore, we show that the levels of CHIP are strongly reduced in vivo in patients’ fibroblasts compared to controls. Conclusions These results suggest that STUB1 mutations might cause disease by impacting not only the E3 ligase function, but also its protein interaction properties and protein amount. Whether the clinical heterogeneity seen in STUB1 ARCA can be related to the location of the mutations remains to be understood, but interestingly, all siblings with the p.Asn65Ser substitution showed a marked appearance of accelerated aging not previously described in STUB1 related ARCA, none display hormonal aberrations/clinical hypogonadism while some affected family members had diabetes, alopecia, uveitis and ulcerative colitis, further refining the spectrum of STUB1 related disease. Electronic supplementary material The online version of this article (doi:10.1186/s13023-014-0146-0) contains supplementary material, which is available to authorized users.

Spastic paraplegia 7 is an autosomal recessive disorder caused by mutations in the gene encoding paraplegin, a protein located at the inner mitochondrial membrane and involved in the processing of other mitochondrial proteins. The mechanism whereby paraplegin mutations cause disease is unknown. We studied two female and two male adult patients from two Norwegian families with a combination of progressive external ophthalmoplegia and spastic paraplegia. Sequencing of SPG7 revealed a novel missense mutation, c.2102A>C, p.H 701P, which was homozygous in one family and compound heterozygous in trans with a known pathogenic mutation c.1454_1462del in the other. Muscle was examined from an additional, unrelated adult female patient with a similar phenotype caused by a homozygous c.1047insC mutation in SPG7. Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV. Molecular studies in single, microdissected fibres showed multiple mitochondrial DNA deletions segregating at high levels (38–97%) in respiratory deficient fibres. Our findings demonstrate for the first time that paraplegin mutations cause accumulation of mitochondrial DNA damage and multiple respiratory chain deficiencies. While paraplegin is not known to be directly associated with the mitochondrial nucleoid, it is known to process other mitochondrial proteins and it is possible therefore that paraplegin mutations lead to mitochondrial DNA deletions by impairing proteins involved in the homeostasis of the mitochondrial genome. These studies increase our understanding of the molecular pathogenesis of SPG7 mutations and suggest that SPG7 testing should be included in the diagnostic workup of autosomal recessive, progressive external ophthalmoplegia, especially if spasticity is present. publishedVersion

International audience; Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg/l, P = 0.0004; itself higher than the normal level (3.4 microg/l, range from 0.5 to 17.2 microg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels > or =7 microg/l is 46%. Therefore, selection of patients with an AFP level above 7 microg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.

Epilepsy is a common term for different syndromes and diseases, which are all characterized by repeated unprovoked epileptic seizures. Large variations in seizure types, severity and presence of co-morbidity necessitate very diverse rehabilitation efforts.Based on a literature review and the authors' own clinical experience, the rehabilitation approach to epilepsy is discussed.Epilepsy is a complex medical disorder and the rehabilitation process must address many aspects. Although 2/3 of patients achieve a satisfactory seizure control with current antiepileptic drugs, they may still have considerable epilepsy-related problems, such as drug-related side effects or psychosocial difficulties. The remaining 1/3 who continue to have seizures, need regular specialist follow-up, as well as multidisciplinary evaluations to ensure comprehensive, individually tailored rehabilitation programmes. The aim of the rehabilitation is to eliminate or reduce the medical and social consequences of the disease. Counselling and education of patients are important elements. In Norway, the importance of providing adequate medical information has now been acknowledged through legislation. The rehabilitation needs for people with epilepsy are far from covered. A controlled study has recently demonstrated a significant effect of a nurse-led intervention programme on quality of life parameters in patients with uncontrolled epilepsy. We recommend specially assigned epilepsy nurses in all departments treating individuals with epilepsy.

Background: There is an increasing awareness of the role of the cerebellum not only in motor, but also in cognitive and emotional functions. Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant hereditary ataxia characterized by a relatively pure cerebellar phenotype. Cognitive impairment has been reported in studies with phenotype descriptions of SCA14, but previous studies have been small without control groups, and no homogeneous and systematic test panel has been used. The objective of this study was to thoroughly characterize the neuropsychological profile in ten Norwegian SCA14 subjects compared to unaffected family members and population norm data. Methods: Ten SCA14 subjects and ten intrafamilial unaffected age- and education-matched controls from two Norwegian families were included. The unaffected intrafamilial controls included six first degree relatives, two second degree relatives, and two spouses. General intellectual ability, memory, visuoperceptive skills, psychomotor speed, executive functions, depression and anxiety were examined using internationally standardized tests, with minimal need for manual response to avoid motor bias. Results: No significant cognitive deficit was found in SCA14 subjects compared to intrafamilial controls. Verbal IQ, verbal executive function and psychomotor speed tended to be reduced in affected subjects, but previously reported non-verbal executive dysfunction was not confirmed in this study. Conclusion: Only subtle cognitive impairment was found in SCA14 affected subjects. The current findings do not confirm earlier reports of cognitive dysfunction in SCA14, but does shows a mild impairment in specific verbal executive functions. Genotypic differences may partly account for this discrepancy, and further studies on larger materials are needed to verify the findings.