A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia.

BACKGROUND AND PURPOSE: Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous monogenic disorders. To date, nearly 70 genes are known to be causative. The aim of this project was to identify the genetic cause of autosomal dominantly inherited pure HSP in two large, unrelated non-consanguineous families. METHODS: The two families were characterized clinically and selected members underwent whole exome sequencing. Potentially disease-causing variants were confirmed by Sanger sequencing and their functional consequences on protein function were predicted by bioinformatic prediction tools. RESULTS: The patients presented with pure spastic paraplegia with age of onset between 9 and 46 years. In both families, a novel heterozygous missense variant in ERLIN2, c.386G>C; p.Ser129Thr, was the only potentially pathogenic variant identified that segregated with the disease. CONCLUSIONS: Biallelic variants in ERLIN2 are known to cause recessive HSP type SPG18. Here, the first two families with an autosomal dominant, pure form of HSP caused by a novel ERLIN2 heterozygous missense variant are described. These findings expand the mutational and inheritance spectrum of SPG18. ERLIN2 variants should also be considered in the diagnostic evaluation of patients with autosomal dominant HSP.

Homocarnosinosis: A historical update and findings in the SPG11 gene.

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.

A founder mutation p.H701P identified as a major cause of SPG7 in Norway.

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.

An up-date on health-related quality of life in myasthenia gravis -results from population based cohorts.

UNLABELLED: Current available therapies control Myasthenia gravis (MG) reasonably well, but Health Related Quality of life (HRQOL) remains lower than expected. The aim was provide insights in how HRQOL in MG stands across borders and time, compare the scores to general population controls and other chronic disorders and assess the impact of potential predictors for quality of life such as a) clinical characteristics b) antibodies c) thymoma and d) treatment in a population-based cohort. METHODS: We designed a population-based cross-sectional study including 858 patients, 373 from Norway and 485 from the Netherlands. The Short Form Health Survey 36 (SF-36) and a cross-cultural validated questionnaire were used. Data were in addition compared to the general population, other chronic diseases and previous studies. RESULTS: Mean physical composite score was 59.4 and mental composite score 69.0 with no differences between the countries. The mean HRQOL score was lower in patients with bulbar and generalized symptoms (p < 0.001) compared to sex and age adjusted healthy controls, but not in patients with ocular symptoms or patients in remission. Multivariate analysis revealed that female gender, generalized symptoms and use of secondary immunosuppressive drugs at the time of testing were risk factors for reduced HRQOL. CONCLUSIONS: Remission and absence of generalized symptoms were favorable factors for HRQOL in MG patients. Historically, the HRQOL levels have not changed since 2001 and no new clinical predictors could be detected in this exhaustive population-based study. Further studies should explore the impact of non clinical factors like ethnic variations, socio-economic and hormonal factors on HRQOL.

A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis.

Double-seronegative myasthenia gravis (dSN-MG, without detectable AChR and MuSK antibodies) presents a serious gap in MG diagnosis and understanding. Recently, autoantibodies against the low-density lipoprotein receptor-related protein 4 (LRP4) have been identified in several dSN-MG sera, but with dramatic frequency variation (∼2-50%). We have developed a cell based assay (CBA) based on human LRP4 expressing HEK293 cells, for the reliable and efficient detection of LRP4 antibodies. We have screened about 800 MG patient sera from 10 countries for LRP4 antibodies. The overall frequency of LRP4-MG in the dSN-MG group (635 patients) was 18.7% but with variations among different populations (range 7-32.7%). Interestingly, we also identified double positive sera: 8/107 anti-AChR positive and 10/67 anti-MuSK positive sera also had detectable LRP4 antibodies, predominantly originating from only two of the participating groups. No LRP4 antibodies were identified in sera from 56 healthy controls tested, while 4/110 from patients with other neuroimmune diseases were positive. The clinical data, when available, for the LRP4-MG patients were then studied. At disease onset symptoms were mild (81% had MGFA grade I or II), with some identified thymic changes (32% hyperplasia, none with thymoma). On the other hand, double positive patients (AChR/LRP4-MG and MuSK/LRP4-MG) had more severe symptoms at onset compared with any single positive MG subgroup. Contrary to MuSK-MG, 27% of ocular dSN-MG patients were LRP4 antibody positive. Similarly, contrary to MuSK antibodies, which are predominantly of the IgG4 subtype, LRP4 antibodies were predominantly of the IgG1 and IgG2 subtypes. The prevalence was higher in women than in men (female/male ratio 2.5/1), with an average disease onset at ages 33.4 for females and 41.9 for males. Overall, the response of LRP4-MG patients to treatment was similar to published responses of AChR-MG rather than to MuSK-MG patients.

Smoking and socio-economic status may affect myasthenia gravis.

BACKGROUND AND PURPOSE: The influence of environmental factors in myasthenia gravis (MG) is unknown. The aim of this cross-sectional population-based study was to investigate if smoking and socio-economic status (SES) were associated with MG in the Norwegian population. METHODS: Subjects were 491 MG patients identified in Norway at the time of the study (point prevalence 12.7/100 000). A questionnaire covering smoking habits and markers of SES (education and occupation) was mailed to all patients. Population data were obtained from Statistics Norway. RESULTS: A total of 375 (76.6%) patients completed the questionnaire (236 women, mean age 59 ± 18 years), of which 193 reported to be early onset MG (EOMG, onset ≤40 years, 155 women). Compared with the general population, current smoking was more prevalent amongst MG patients [risk ratio (RR) 1.5; 95% confidence interval (CI) 1.1-1.9], most of whom had EOMG. Female MG patients had higher education compared with the general population (RR 4.5; 95% CI 3.2-6.2). Male MG patients were similar to the general population regarding both education and occupation, except for a subset of late onset MG who had shorter education (RR 1.9; 95% CI 1.1-3.2) and had worked in crafts and related trades. About half of working age MG patients received disability pension, a finding significantly related to low educational level and a more severe disease course (P < 0.001). CONCLUSION: This is the first report indicating that smoking and SES may affect MG. Further studies investigating their role as potential risk factors are warranted.

SCA14 in Norway, two families with autosomal dominant cerebellar ataxia and a novel mutation in the PRKCG gene.

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%.

EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders.

OBJECTIVES: These EFNS guidelines on the molecular diagnosis of motoneuron disorders, neuropathies and myopathies are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. SEARCH STRATEGY: To collect data about planning, conditions and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers and guideline recommendations reviewed. RESULTS: The best level of evidence for genetic testing recommendation (B) can be found for the disorders with specific presentations, including familial amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, Charcot-Marie-Tooth 1A, myotonic dystrophy and Duchenne muscular dystrophy. For a number of less common disorders, a precise description of the phenotype, including the use of immunologic methods in the case of myopathies, is considered as good clinical practice to guide molecular genetic testing. CONCLUSION: These guidelines are provisional and the future availability of molecular-genetic epidemiological data about the neurogenetic disorders under discussion in this article will allow improved recommendation with an increased level of evidence.

Multi-system neurological disease is common in patients with OPA1 mutations.

Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal 'dominant optic atrophy plus' variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.

Development and validation of a self-administered questionnaire for myasthenia gravis patients.

BACKGROUND: To date, the investigation of the epidemiological profile of myasthenia gravis (MG) is sparse, and the influence of environmental and lifestyle factors on the occurrence of the disease remains thus unknown. The main aim of this study, which is part of a European collaborative project (EuroMyasthenia), was to develop a self-administered questionnaire to investigate these potential predisposing factors for MG. No instrument for investigating these particular factors has previously been designed for MG patients. MATERIAL AND METHODS: The questionnaire was developed in 3 stages: (1) devising a draft questionnaire based on questions derived from previously validated questionnaires and self-designed questions on MG characteristics; (2) testing the questionnaire on Norwegian MG patients (n = 57), and (3) assessing the content and criterion validity, and test-retest reliability, of the final questionnaire. RESULTS: The questionnaire was easy to use and showed good feasibility for MG patients. Psychometric evaluation established the validity and reliability of the self-designed questions on MG characteristics. CONCLUSION: This is the first validated instrument developed to identify self-assessed environmental factors and potential predisposing factors for MG, and suitable for use in large-scale epidemiological studies.

EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias.

OBJECTIVES: These EFNS guidelines on the molecular diagnosis of channelopathies, including epilepsy and migraine, as well as stroke, and dementia are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. SEARCH STRATEGY: To collect data about planning, conditions, and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. RESULTS: The best level of evidence for genetic testing recommendation (B) can be found for a small number of syndromes, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, severe myoclonic epilepsy of infancy, familial recurrent hemorrhages, familial Alzheimer's disease, and frontotemporal lobar degeneration. Good practice points can be formulated for a number of other disorders. CONCLUSION: These guidelines are provisional, and the future availability of molecular genetic epidemiological data about the neurogenetic disorders under discussion in our article will allow improved recommendation with an increased level of evidence.

EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.

BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of two particularly complex groups of disorders, the ataxias and spastic paraplegias. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.

Parental SCN1A mutation mosaicism in familial Dravet syndrome.

Different SCN1A mutations are known to cause a variety of phenotypes, such as generalized epilepsy with febrile seizures plus (GEFS+), Dravet syndrome and familial hemiplegic migraine (FHM). In Dravet syndrome, most mutations are de novo and familial cases are rare. In this study, Dravet syndrome is observed in two maternal half sisters. They have healthy fathers and their common mother has never experienced seizures, but has a lifelong history of migraine. Direct sequencing of DNA extracted from blood revealed a heterozygous SCN1A nonsense mutation c.3985C>T in the sisters, but not in the mother. The mutation induces a premature stop codon and probably leads to a non-functional protein. Further examination of the mother's DNA showed that she has a mosaicism of the mutation. This report of parental SCN1A nonsense mutation mosaicism in familial Dravet syndrome suggests that mosaicism might be more common than previously suspected and emphasizes the importance of taking mosaicism into account in genetic counselling of Dravet syndrome and SCN1A mutations. Furthermore, whether the migraine of the mother could be influenced by her SCN1A mutation mosaicism is not known, but increased awareness of migraine in future studies of SCN1A related epilepsies could clarify this intriguing link between migraine and epilepsy.

Miglustat therapy in juvenile Sandhoff disease.

GM(2)-gangliosidosis is a rare and heterogeneous inherited metabolic disorder caused by autosomal recessive mutations in genes encoding the lysosomal enzyme ß-hexosaminidase, resulting in the accumulation of ganglioside GM(2) in various tissues, particularly the central nervous system. It is characterized by progressive neurological deterioration that mainly affects motor and spinocerebellar function. Several forms of GM(2)-gangliosidosis exist, including the Sandhoff variant. Currently there is no treatment for these conditions, except for palliative care. Miglustat (Zavesca) is a reversible inhibitor of glucosylceramide synthase, which catalyses the first committed step in the synthesis of glucose-based glycolipids. Miglustat has pharmacokinetic properties that allow it to cross the blood-brain barrier, and preclinical data suggest that it may benefit neuronopathic lysosomal storage diseases. Here we present a case report of a Norwegian patient with Sandhoff disease treated with miglustat at our centre in Norway. The patient initially presented with ataxia and dysarthria at 2-3 years of age, which progressed slowly during childhood. At age 14, he experienced episodes of depression and apathy, leading to weight loss. He was diagnosed with Sandhoff disease at age 16. Following 2.5 years of treatment with miglustat, his body weight was stabilized and disease progression appeared to have slowed, as evidenced by the lack of progressive brain atrophy. His depressive symptoms were managed using electroconvulsive treatment (ECT), which improved general functioning. These findings suggest that miglustat may provide beneficial effects in patients with juvenile Sandhoff disease, and that ECT may alleviate depressive symptoms.

Proton magnetic resonance spectroscopy and cognition in patients with spastin mutations.

The hereditary spastic paraplegias (HSP) are heterogeneous neurodegenerative disorders characterized by progressive spasticity and weakness in the lower limbs. Axonal loss in the long corticospinal tracts has been shown. Supraspinal symptoms and findings in the most common dominant HSP type, SPG4, support the theory that the disease also causes cerebral neuronal damage in specific parts of the brain. To investigate whether SPG4-HSP is associated with neuronal biochemical changes detectable on MR spectroscopy (MRS), single-voxel proton MRS of the brain was performed in eight subjects from four families with genetically confirmed SPG4-type HSP and eight healthy age-matched controls. Volumes of interest (VOI) were located in the frontal white matter and motor cortex. N-acetyl-aspartate-to-creatine ratio (NAA/Cr), N-acetyl-aspartate-to-choline (NAA/Cho), cholin to creatin (Cho/Cr) and myo-inositol-to-creatine (Ins/Cr) ratios were calculated for both locations. Neuropsychological tests were performed to support the neuroradiological findings. The Cho/Cr ratio in motor cortex (MC) of SPG4-HSP subjects was significantly lower than in controls. This reduction of the Cho/Cr ratio in SPG4 subjects was significantly associated with age-related verbal learning- and memory (CVLT) reduction. Our findings support involvement of motor cortex in SPG4-HSP. Proton MRS could be a useful tool for detecting metabolite abnormalities in areas of brain that appear normal on MRI. Cho/Cr ratio may be a marker of neurodegenerative process in SPG4-HSP.

EFNS guidelines on the molecular diagnosis of mitochondrial disorders.

OBJECTIVES: These European Federation of Neurological Sciences (EFNS) guidelines are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics for diagnosing mitochondrial disorders (MIDs), which gain increasing attention and are more frequently diagnosed due to improved diagnostic tools. BACKGROUND: Since the publication of the first EFNS guidelines on the molecular diagnosis of inherited neurological diseases in 2001, rapid progress has been made in this field, necessitating the creation of an updated version. SEARCH STRATEGY: To collect data about the molecular diagnosis of MIDs search for literature in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST or Embase, were carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. RESULTS: The guidelines summarise the possibilities and limitations of molecular genetic diagnosis of MIDs and provide practical recommendations and diagnostic criteria in accordance with the EFNS Scientific Committee to guide the molecular diagnostic work-up of MIDs. RECOMMENDATIONS: The proposed guidelines suggest an approach to the molecular diagnosis of MIDs in a manner accessible to general neurologists.

EFNS guidelines on the molecular diagnosis of neurogenetic disorders: general issues, Huntington's disease, Parkinson's disease and dystonias.

BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. Since the publication of the first two EFNS-guideline papers on the molecular diagnosis of neurological diseases in 2001, rapid progress has been made in this field, necessitating an updated series of guidelines. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of Huntington's disease, Parkinson's disease and dystonias as well as a general introduction to the topic. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.

O-demethylation of codeine to morphine inhibited by low-dose levomepromazine.

PURPOSE: Codeine/paracetamol (C/P) and levomepromazine (L) are frequently co-administered for the treatment of acute back pain, but the efficacy/effectiveness of this combination drug therapy has not been evaluated. The demethylation of codeine to morphine is catalyzed by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6), of which levomepromazine (methotrimeprazine) is a known inhibitor. The aim of this study was to investigate whether low-dose levomepromazine inhibits the formation of morphine from codeine in a patient population of homozygous extensive (EM) and heterozygous extensive (HEM) metabolizers of CYP2D6. METHODS: Our patient cohort consisted of 29 patients hospitalized for acute back pain who were randomized to a 24-h treatment with either C/P (60 mg codeine + 1000 mg paracetamol) four times daily or to L+C/P (levomepromazine 5 + 5 + 5 + 10 mg + C/P) four times daily. After zero-urine sampling (baseline), the treatment was started and urine collected for 24 h. Blood samples were later genotyped for the CYP2D6*3, *4, and *6 polymorphisms by the PCR (LightCycler system) and for the *5 polymorphism using long PCR, to identify EM and HEM and to eliminate CYP2D6 poor metabolizers. Urine samples were analyzed using the CEDIA immunoassay and gas chromatography-mass spectrometry after enzymatic hydrolysis of glucuronide conjugates. O-demethylation ratios of codeine were calculated as hydrolyzed (total) concentrations of morphine/morphine + codeine. RESULTS: Twenty-two of the patients fulfilled the inclusion criteria, of whom ten were EM (five C/P and five L+C/P) and twelve were HEM (six C/P and six L+C/P) for functional CYP2D6 alleles. In the EM group, the median O-demethylation ratio was significantly higher (P = 0.016, Mann-Whitney test) after the C/P treatment (0.092, range 0.041-0.096) than after the L+C/P treatment (0.031, range 0.009-0.042). However, there was no significant difference between these two treatments in either the HEM group [n = 12; 0.024 (range 0.011-0.042) vs. 0.026 (range 0.009-0.041), respectively; P = 1.00] or in the combined EM/HEM group [11 C/P + 11 L+C/P; 0.041 (range 0.011-0.096) vs. 0.030 (range 0.009-0.042), respectively; P = 0.122]. CONCLUSIONS: Our study revealed significant inhibition in the O-demethylation of codeine to morphine in homozygous EM of CYP2D6 treated with low-dose levomepromazine and codeine/paracetamol, compared to treatment with codeine/paracetamol only. No significant difference could be detected in HEM or in the mixed and heterogenous group of EM/HEM. In patients prescribed this drug combination, the amount of morphine generated by the O-demethylation of codeine may be insufficient for effective pain relief. The therapeutic effect of codeine in the treatment of acute back pain should be assessed with and without levomepromazine.

SPG11--the most common type of recessive spastic paraplegia in Norway?

BACKGROUND: Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity with additional neurological symptoms and signs in complicated forms. Among the many autosomal recessive forms, SPG11 appears to be one of the most frequent. OBJECTIVE: Our objective was to select potential SPG11 patients based on phenotypes in our material, identify eventual disease-causing variants with the collaboration of laboratories abroad, estimate the frequency and spectrum of SPG11-mutations and describe their associated phenotypes. MATERIAL AND METHODS: Two isolated cases and two affected members of one family with cognitive impairment and confirmed thin corpus callosum on magnetic resonance imaging were selected from our database for inclusion into a multicenter study. Results - Mutations were found in the two isolated cases but not in the proband of the family. CONCLUSION: We present the first SPG11-HSP in the Norwegian population. SPG11 should be suspected in patients with isolated or recessive HSP, thin corpus callosum and mental retardation.

Cerebellar ataxia in the eastern and southern parts of 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.