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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 (C9 pos ). Further, we compared C9 pos and C9 neg 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 C9 pos , with half being sporadic ALS cases. The proportion of C9 pos cases differed between regions, ranging from 17.9% in the Northern region to 1.9% in the Western region. The majority of C9 pos patients had non-Finnish European descent and were not closely related. C9 pos patients exhibited a significantly shorter mean survival time, had a higher frequency of relatives with ALS or dementia, and were more often unmarried/single and childless than C9 neg patients., Conclusion: C9 pos patients constitute a large portion of the Norwegian ALS population. Ancestry and relatedness do not adequately explain regional differences. Relying on clinical information to identify C9 pos patients has proven to be challenging. Half of C9 pos patients were reported as having sporadic ALS, underlining the importance of carefully assessing family history and the need for genetic testing.

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 CNS manifestations. Clinical and neurophysiological evaluations revealed a predominant sensory axonal polyneuropathy with slight to moderate motor components. In all 10 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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Competing Interests: Competing interests: None declared.

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., (© 2022. The Author(s).)

Background: Arthrogryposis multiplex congenita (AMC) is a descriptive term that encompasses a group of congenital, aetiologically heterogeneous conditions characterised by multiple joint contractions., Case Presentation: As a teenager, the index patient was told she had AMC, as did one of her parents. Subsequently, she wondered how her condition might evolve over time, since her affected parent had become wheelchair- dependent. Her history and clinical findings led to genetic testing which identified a causative variant in the COL6A2 gene, revealing an underlying diagnosis of Bethlem myopathy., Interpretation: Adults who have rare monogenic disorders may lack an aetiological diagnosis because of limited access to genetic laboratory testing in the past. Advances in genetic laboratory diagnostics during the last 10−15 years have made testing more widely available. As exemplified by this case, molecular genetic diagnosis may provide benefits such as information concerning prognosis and treatment options.

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 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 the 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 by 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., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder., Methods: Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays., Results: We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype., Conclusions: Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.

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.

Objective: To test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years., Methods: We recruited patients, collected clinical data, and conducted whole-exome sequencing (WES; n = 126) and MME single-gene sequencing (n = 104). We further queried WES repositories for MME variants and measured blood levels of the MME -encoded protein neprilysin., Results: In the WES cohort, the overall detection rate for assumed disease-causing variants in genes for CMT or other conditions associated with neuropathies was 18.3% (familial cases 26.4%, apparently sporadic cases 12.3%). MME was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of MME for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independent patient sample, preponderance of MME variants among patients compared to population frequencies, retrieval of additional late-onset neuropathy patients with MME variants from WES repositories, and low neprilysin levels in patients' blood samples. Transmission of MME variants was often consistent with an incompletely penetrant autosomal-dominant trait and less frequently with autosomal-recessive inheritance., Conclusions: A detectable fraction of unexplained late-onset axonal neuropathies is genetically determined, by variants in either CMT genes or genes involved in other conditions that affect the peripheral nerves and can mimic a CMT phenotype. MME variants can act as completely penetrant recessive alleles but also confer dominantly inherited susceptibility to axonal neuropathies in an aging population., (© 2020 American Academy of Neurology.)

De novo variants represent a significant cause of neurodevelopmental delay and intellectual disability. A genetic basis can be identified in only half of individuals who have neurodevelopmental disorders (NDDs); this indicates that additional causes need to be elucidated. We compared the frequency of de novo variants in patient-parent trios with (n = 2,030) versus without (n = 2,755) NDDs. We identified de novo variants in TAOK1 (thousand and one [TAO] amino acid kinase 1), which encodes the serine/threonine-protein kinase TAO1, in three individuals with NDDs but not in persons who did not have NDDs. Through further screening and the use of GeneMatcher, five additional individuals with NDDs were found to have de novo variants. All eight variants were absent from gnomAD (Genome Aggregation Database). The variant carriers shared a non-specific phenotype of developmental delay, and six individuals had additional muscular hypotonia. We established a fibroblast line of one mutation carrier, and we demonstrated that reduced mRNA levels of TAOK1 could be increased upon cycloheximide treatment. These results indicate nonsense-mediated mRNA decay. Further, there was neither detectable phosphorylated TAO1 kinase nor phosphorylated tau in these cells, and mitochondrial morphology was altered. Knockdown of the ortholog gene Tao1 (Tao, CG14217) in Drosophila resulted in delayed early development. The majority of the Tao1-knockdown flies did not survive beyond the third instar larval stage. When compared to control flies, Tao1 knockdown flies revealed changed morphology of the ventral nerve cord and the neuromuscular junctions as well as a decreased number of endings (boutons). Furthermore, mitochondria in mutant flies showed altered distribution and decreased size in axons of motor neurons. Thus, we provide compelling evidence that de novo variants in TAOK1 cause NDDs., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Autosomal recessive Charcot-Marie-Tooth disease (CMT) is considered rare and phenotypic descriptions are scarce for the different subgroups. Mutations in the SH3TC2 gene, causing recessive demyelinating CMT type 4C have been found in several Norwegian CMT patients over the last years. We aimed to estimate a minimum prevalence and to study the genotypic and phenotypic variability of CMT4C in Norway. Patients were selected from diagnostic registries in medical genetic centers in Norway for cases of CMT4C. All patients were invited to complete a questionnaire and give medical consent to the use of clinical data from medical hospital records. A total of 35 patients from 31 families were found with CMT4C, which gives a minimum prevalence of 0.7/100,000 in Norway. Six new mutations were identified. Most patients had debut in the first decade with foot deformities, distal limb paresis, sensory ataxia and scoliosis. Proximal lower limb paresis and cranial nerve involvement was seen in about half of the patients. CMT4C is the most common recessive CMT in Norway. In addition to the classic distal limb affection, early debut, scoliosis, proximal paresis, cranial nerve affection and sensory ataxia are the most prominent features of CMT4C., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Introduction: Charcot-Marie-Tooth disease (CMT) is a heterogeneous inherited neuropathy. The number of known CMT genes is rapidly increasing mainly due to next-generation sequencing technology, at present more than 70 CMT-associated genes are known. We investigated whether variants in the DCTN2 could cause CMT., Material and Methods: Fifty-nine Norwegian CMT families from the general population with unknown genotype were tested by targeted next-generation sequencing (NGS) for variants in DCTN2 along with 32 CMT genes and 19 other genes causing other inherited neuropathies or neuronopathies, due to phenotypic overlap. In the family with the DCTN2 variant, exome sequencing was then carried out on all available eight family members to rule out the presence of more potential variants., Results: Targeted NGS identified in one family a variant of DCTN2, c.337C>T, segregating with the phenotype in five affected members, while it was not present in the three unaffected members. The DCTN2 variant c.337C>T; p.(His113Tyr) was neither found in in-house controls nor in SNP databases. Exome sequencing revealed a singular heterozygous shared haplotype containing four genes, DCTN2, DNAH10, LRIG3, and MYO1A, with novel sequence variants. The haplotype was shared by all the affected members, while the unaffected members did not have it., Conclusions: This is the first time a haplotype on chromosome 12 containing sequence variants in the genes DCTN2, DNAH10, LRIG3, and MYO1A has been linked to an inherited neuropathy in humans., (© 2015 The Authors. Acta Neurologica Scandinavica Published by John Wiley & Sons Ltd.)

Background: Next-generation sequencing (NGS) is a genetic technique used to determine the order of nucleotides in DNA. The technique has proved to be more efficient than the traditional method, Sanger sequencing, for sequencing multiple genes. NGS is now being used to diagnose disorders in which multiple genes are involved. This study has examined whether next-generation sequencing produces a greater number of positive diagnoses than its traditional counterpart in patients with suspected hereditary peripheral neuropathy., Material and Method: This study is a retrospective review of samples from 103 patients investigated for hereditary peripheral neuropathy, received by Telemark Hospital in the period 2012-14. After exclusion of duplication/deletion of PMP22, 96 samples were analysed by NGS with physical enrichment of 52 hereditary peripheral neuropathy genes., Results: A genetic cause was identified in 35 patients (34%) with peripheral neuropathy, of which 28 (27%) were point mutations identified by NGS., Interpretation: Of the pathogenic point mutations identified in this study, 12 were in genes that would previously have been analysed by Sanger sequencing in our department, whereas 16 were in genes that would not previously have been tested.

Background: New DNA-sequencing technology is revolutionising medical diagnostics. Through the use of exome sequencing, it is now possible to sequence all human genes in parallel. This technology has been widely used in research over the last few years and is now also being applied to diagnostics. The aim of this study was to systematically examine initial experiences with diagnostic exome sequencing in Norway., Material and Method: This is a retrospective observational study of the results of all exome sequencing performed by the Section of Medical Genetics at Telemark Hospital between December 2012 and October 2014, and includes 125 persons in 46 families. The majority of these families were being investigated for a syndrome (n = 35, 76%) or neurological disease (n = 9, 20%)., Results: Exome sequencing detected pathogenic sequence variants in 15 of 46 probands, and variants of unknown significance in 12 probands. Of the 100 patients who stated their wishes regarding feedback of any incidental findings, six indicated that they did not wish to receive such information. There were no incidental findings in this study, but neither were such sequence variants actively looked for., Interpretation: Exome sequencing can enable more patients with syndromes or neurological diseases to receive a causal diagnosis, and to receive this diagnosis at an earlier stage. However, the patients in this study were quite highly selected, and the results must therefore be interpreted with caution.

Copy number variations (CNVs) are important in relation to diversity and evolution but can sometimes cause disease. The most common genetic cause of the inherited peripheral neuropathy Charcot-Marie-Tooth disease is the PMP22 duplication; otherwise, CNVs have been considered rare. We investigated CNVs in a population-based sample of Charcot-Marie-Tooth (CMT) families. The 81 CMT families had previously been screened for the PMP22 duplication and point mutations in 51 peripheral neuropathy genes, and a genetic cause was identified in 37 CMT families (46%). Index patients from the 44 CMT families with an unknown genetic diagnosis were analysed by whole-genome array comparative genomic hybridization to investigate the entire genome for larger CNVs and multiplex ligation-dependent probe amplification to detect smaller intragenomic CNVs in MFN2 and MPZ. One patient had the pathogenic PMP22 duplication not detected by previous methods. Three patients had potentially pathogenic CNVs in the CNTNAP2, LAMA2, or SEMA5A, that is, genes related to neuromuscular or neurodevelopmental disease. Genotype and phenotype correlation indicated likely pathogenicity for the LAMA2 CNV, whereas the CNTNAP2 and SEMA5A CNVs remained potentially pathogenic. Except the PMP22 duplication, disease causing CNVs are rare but may cause CMT in about 1% (95% CI 0-7%) of the Norwegian CMT families.

Survival after invasive bladder cancer has improved less than that of other common non-skin cancers. In many types of malignancy, treatment failure has been attributed to therapy-resistant stem-like cancer cells. Our aim was therefore to determine identities of stem cell marker-positive cells in bladder cancer tissue and to investigate possible associations between these cells and different forms of bladder neoplasia. We investigated tissue from 52 patients with bladder neoplasia and 18 patients with benign bladder conditions, from a cohort that had been previously described with regard to diagnosis and outcome. The samples were analysed immunohistologically for the stem cell markers aldehyde dehydrogenase 1 A1 (ALDH1) and CD44, and markers of cell differentiation. The majority of stem cell marker-positive cells were located in connective tissue, and a smaller fraction in epithelial tissue. Stem cell marker-positive cells exhibiting possible stem cell characteristics included cells in deeper locations of benign and malignant epithelium, and sub-endothelial cells in patients with or without neoplasia. Stem cell marker-positive cells with non-stem cell character included stellate cells, mast cells, endothelial cells, foamy histiocytes, and neurons. Significantly, ALDH1+ stellate cells and ALDH1+ mast cells were reduced in number in stroma of benign-appearing mucosa of bladder cancer patients. The stem cell markers ALDH1 and CD44 label several types of differentiated cells in bladder tissue. ALDH1+ stellate cells and mast cells appear to be reduced in stroma of normal-appearing mucosa of bladder cancer patients, and may be part of a "field effect" in cancer-near areas.

Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identified. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. Thus, more efficient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identified in 22 families; the remaining 59 families were analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classified into five pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classified certainly or likely pathogenic, were identified in 37 (46%) of the 81 families. Point mutations in known CMT genes were identified in 21 families (26%), whereas four families (5%) had point mutations in other neuropathy genes, ARHGEF10, POLG, SETX, and SOD1. Eleven families (14%) carried the PMP22 duplication and one family carried a MPZ duplication (1%). Most mutations were identified not only in known CMT genes but also in other neuropathy genes, emphasising that genetic analysis should not be restricted to CMT genes only. Next-generation sequencing is a cost-effective tool in diagnosis of CMT improving diagnostic precision and time efficiency.

Background: Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. The frequency of different CMT genotypes has been estimated in clinic populations, but prevalence data from the general population is lacking. Point mutations in the mitofusin 2 (MFN2) gene has been identified exclusively in Charcot-Marie-Tooth disease type 2 (CMT2), and in a single family with intermediate CMT. MFN2 point mutations are probably the most common cause of CMT2. The CMT phenotype caused by mutation in the myelin protein zero (MPZ) gene varies considerably, from early onset and severe forms to late onset and milder forms. The mechanism is not well understood. The myelin protein zero (P(0) ) mediates adhesion in the spiral wraps of the Schwann cell's myelin sheath. X-linked Charcot-Marie Tooth disease (CMTX) is caused by mutations in the connexin32 (cx32) gene that encodes a polypeptide which is arranged in hexameric array and form gap junctions., Aims: Estimate prevalence of CMT. Estimate frequency of Peripheral Myelin Protein 22 (PMP22) duplication and point mutations, insertions and deletions in Cx32, Early growth response 2 (EGR2), MFN2, MPZ, PMP22 and Small integral membrane protein of lysosome/late endosome (SIMPLE) genes. Description of novel mutations in Cx32, MFN2 and MPZ. Description of de novo mutations in MFN2., Material and Methods: Our population based genetic epidemiological survey included persons with CMT residing in eastern Akershus County, Norway. The participants were interviewed and examined by one geneticist/neurologist, and classified clinically, neurophysiologically and genetically. Two-hundred and thirty-two consecutive unselected and unrelated CMT families with available DNA from all regions in Norway were included in the MFN2 study. We screened for point mutations in the MFN2 gene. We describe four novel mutations, two in the connexin32 gene and two in the MPZ gene., Results: A total of 245 affected from 116 CMT families from the general population of eastern Akershus county were included in the genetic epidemiological survey. In the general population 1 per 1214 persons (95% CI 1062-1366) has CMT. Charcot-Marie-Tooth disease type 1 (CMT1), CMT2 and intermediate CMT were found in 48.2%, 49.4% and 2.4% of the families, respectively. A mutation in the investigated genes was found in 27.2% of the CMT families and in 28.6% of the affected. The prevalence of the PMP22 duplication and mutations in the Cx32, MPZ and MFN2 genes was found in 13.6%, 6.2%, 1.2%, 6.2% of the families, and in 19.6%, 4.8%, 1.1%, 3.2% of the affected, respectively. None of the families had point mutations, insertions or deletions in the EGR2, PMP22 or SIMPLE genes. Four known and three novel mitofusin 2 (MFN2) point mutations in 8 unrelated Norwegian CMT families were identified. The novel point mutations were not found in 100 healthy controls. This corresponds to 3.4% (8/232) of CMT families having point mutations in MFN2. The phenotypes were compatible with CMT1 in two families, CMT2 in four families, intermediate CMT in one family and distal hereditary motor neuronopathy (dHMN) in one family. A point mutation in the MFN2 gene was found in 2.3% of CMT1, 5.5% of CMT2, 12.5% of intermediate CMT and 6.7% of dHMN families. Two novel missense mutations in the MPZ gene were identified. Family 1 had a c.368G>A (Gly123Asp) transition while family 2 and 3 had a c.103G>A (Asp35Asn) transition. The affected in family 1 had early onset and severe symptoms compatible with Dejerine-Sottas syndrome (DSS), while affected in family 2 and 3 had late onset, milder symptoms and axonal neuropathy compatible with CMT2. Two novel connexin32 mutations that cause early onset X-linked CMT were identified. Family 1 had a deletion c.225delG (R75fsX83) which causes a frameshift and premature stop codon at position 247 while family 2 had a c.536G>A (Cys179Tyr) transition which causes a change of the highly conserved cysteine residue, i.e. disruption of at least one of three disulfide bridges. The mean age at onset was in the first decade and the nerve conduction velocities were in the intermediate range., Discussion: Charcot-Marie-Tooth disease is the most common inherited neuropathy. At present 47 hereditary neuropathy genes are known, and an examination of all known genes would probably only identify mutations in approximately 50% of those with CMT. Thus, it is likely that at least 30-50 CMT genes are yet to be identified. 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. The phenotypic variation caused by different missense mutations in the MPZ gene is likely caused by different conformational changes of the MPZ protein which affects the functional tetramers. Severe changes of the MPZ protein cause dysfunctional tetramers and predominantly uncompacted myelin, i.e. the severe phenotypes congenital hypomyelinating neuropathy and DSS, while milder changes cause the phenotypes CMT1 and CMT2. The two novel mutations in the connexin32 gene are more severe than the majority of previously described mutations possibly due to the severe structural change of the gap junction they encode., Conclusion: Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system with an estimated prevalence of 1 in 1214. CMT1 and CMT2 are equally frequent in the general population. The prevalence of PMP22 duplication and of mutations in Cx32, MPZ and MFN2 is 19.6%, 4.8%, 1.1% and 3.2%, respectively. The ratio of probable de novo mutations in CMT families was estimated to be 22.7%. Genotype- phenotype correlations for seven novel mutations in the genes Cx32 (2), MFN2 (3) and MPZ (2) are described. Two novel phenotypes were ascribed to the MFN2 gene, however further studies are needed to confirm that MFN2 mutations can cause CMT1 and dHMN., (© 2012 John Wiley & Sons A/S.)

Introduction: Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. The majority has a duplication of the peripheral myelin protein 22. CMT is otherwise caused by point mutations or small insertions/deletions in one of the 44 known CMT genes., Methods and Results: Conventional sequencing of six CMT genes were followed by Multiplex Ligation-dependent Probe Amplification (MLPA), array Comparative Genomic Hybridization (aCGH) and breakpoint analysis in a large Norwegian CMT pedigree. Affected had an extra copy of the myelin protein zero (MPZ) gene., Conclusion: To our knowledge this is the first non-peripheral myelin protein 22 copy number variation to cause Charcot-Marie-Tooth disease., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Objective: To determine interobserver variation in histopathologic diagnosis of carcinoma in situ (CIS) and dysplasia (collectively intraurothelial neoplasia [IUN]) of the bladder and identify histomorphologic features important for diagnosis., Study Design: A total of 272 consecutive bladder tissue samples were re-evaluated blindly by two general pathologists and one uropathologist for IUN. Discrepancies were resolved jointly. Fifteen histopathologic attributes were evaluated for prediction of diagnosis. Followup revealed recurrence and progression rates for each diagnostic category., Results: Thirty-six percent of specimens contained no evaluable flat mucosa; 51% percent of specimens from papillary urothelial neoplasia (PUN) cases showed CIS. General pathologists detected 56-69% of CIS and 8-42% of dysplasia. Histopathologic features most predictive for CIS were nuclear size, variation in nuclear shape, loss of maturation, loss of polarity, and architectural disorder. None of these individually or in combination exceeded general pathologists' diagnostic accuracy. IUN was not predictive of recurrence or progress., Conclusion: Using material mostly consisting of flat mucosa gratuitously provided in PUN resection specimens, IUN carries no prognostic value. General histopathologists detect IUN poorly to moderately, and the five most discriminatory histomorphologic features are insufficient for diagnosis. Interobserver agreement for dysplasia is dismal. Absent flat mucosa in PUN resections predicts recurrence.

Objective: To determine whether a reduced set of the histopathologic features used in internationally accepted classifications is capable of accurately grading papillary urothelial neoplasms (PUN)., Study Design: All surgical specimens from urinary bladders received during a 2-year period were reexamined by an expert uropathologist for assessing the accuracy of original nonexpert PUN grading and staging. Thirteen histopathologic features entailing 32 attributes were evaluated with regard to prediction of expert grade. Patients were followed for 35-59 months (mean, 47)., Results: A total of 88 PUN specimens could be analyzed completely including follow-up specimens. Agreement between original and expert grade was 71% for low-grade and 87% for high-grade PUN, with overall kappa = 0.53. The histomorphologic features most predictive of expert grade were architectural disorder, variability of nuclear enlargement, and absence of umbrella cells. Neither individual histomorphologic attributes nor their combinations were as predictive of expert pathologist grade as original diagnoses., Conclusion: Improvements in PUN grading and prognostication are not likely to be accomplished by only reducing the number of histomorphologic features currently recommended by the World Health Organization and International Society of Urological Pathology.

Background and Purpose: the frequency of different Charcot-Marie-Tooth (CMT) genotypes has been estimated in clinic populations, but prevalence data from the general population are lacking., Methods: our population-based genetic epidemiological survey included persons with CMT residing in eastern Akershus County, Norway. The participants were interviewed and examined by one geneticist/neurologist and classified clinically, neurophysiologically and genetically., Results: two hundred and forty-five persons from 116 families had CMT. This corresponds to 1 per 1214 persons (95% CI 1062-1366) have CMT in the general population. CMT1 (motor conduction velocity (MCV) <38 m/s), CMT2 (MCV >38 m/s) and CMT intermediate (MCV 25-45 m/s) were found in 48.2%, 49.4% and 2.4% of the families. A total of 27.2% of the families and 28.6% of the affected had a mutation in the investigated CMT genes. The prevalence of the peripheral myelin protein 22 (PMP22) duplication and point mutation in the connexin32 (Cx32), myelin protein zero (MPZ) and mitofusin2 (MFN2) genes was found in 13.6%, 6.2%, 1.2%, 6.2% of the families, and in 19.6%, 4.8%, 1.1%, 3.2% of the affected, respectively. None of the families had point mutations in the early growth response 2 (EGR2), PMP22 or small integral membrane protein of lysosome/late endosome (SIMPLE) genes., Conclusions: CMT is the most common inherited neuropathy. At present, 43 CMT genes are known, and an examination of all known genes would probably only identify mutations in approximately 50% of those with CMT. Thus, it is probable that at least 30-50 CMT genes are yet to be identified.

Background: The Charcot-Marie-Tooth (CMT) phenotype caused by mutation in the myelin protein zero (MPZ) gene varies considerably, from early onset and severe forms to late onset and milder forms. The mechanism is not well understood. The myelin protein zero (P0) mediates adhesion in the spiral wraps of the Schwann cell's myelin sheath. The crystalline structure of the extracellular domain of the myelin protein zero (P0ex) is known, while the transmembrane and intracellular structure is unknown., Findings: One novel missense mutation caused a milder late onset CMT type 2, while the second missense mutation caused a severe early onset phenotype compatible with Déjérine-Sottas syndrome., Conclusions: The phenotypic variation caused by different missense mutations in the MPZ gene is likely caused by different conformational changes of the MPZ protein which affects the functional tetramers. Severe changes of the MPZ protein cause dysfunctional tetramers and predominantly uncompacted myelin, i.e. the severe phenotypes congenital hypomyelinating neuropathy and Déjérine-Sottas syndrome, while milder changes cause the phenotypes CMT type 1 and 2.

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.

Objective: To validate Down syndrome registration in the Medical Birth Registry of Norway (MBRN), 2001-2005, and study time trends and geographical differences in Down syndrome prevalence,1967-2005., Design/setting: Population-based cohort study, Norway., Population: 2.3 million pregnancies and births registered in the MBRN, 1967-2005., Methods: We linked data from the MBRN during 2001-2005 with data from Norway's four laboratories of medical genetics. We calculated sensitivity and positive predictive values (PPV) of the MBRN registration overall, and by background variables. Prevalence rates from 1967 to 2005, overall and regional, were presented graphically as smoothed lowess estimates, crude and standardized for maternal age. Time trends were evaluated, adjusting for maternal age by logistic regression., Main Outcome Measures: Sensitivity, PPV, and prevalence rates., Results: Five hundred and seventy-six verified cases of Down syndrome gave a prevalence of 2.0 per 1,000 among 288,213 births and terminations in the MBRN during 2001-2005. Of verified cases, 470 (81.6%) were registered with Down syndrome in the MBRN, while 470 (90.2%) of 521 MBRN-registered cases were verified. Sensitivity was higher in the Northern (93.1%; p=0.005) and Middle (90.6%; p=0.02) region relative the Southern (76.3%), higher for mothers > or =35 years (92.9%) than younger ones (86.1%; p=0.01), and higher for live births (88.8%) relative stillbirths (55.6%; p<0.001). When adjusting for maternal age, there were no significant time trends in prevalence rates from 1967 to 2005. Regional differences over time were found, probably representing reporting differences., Conclusions: Validity of registration in the MBRN was satisfactory during 2001-2005. Increasing prevalence rates over time were explained by increasing maternal age.

Background: X-linked Charcot-Marie Tooth (CMT) is caused by mutations in the connexin32 gene that encodes a polypeptide which is arranged in hexameric array and form gap junctions., Methods: We describe two novel mutations in the connexin32 gene in two Norwegian families., Results: Family 1 had a c.225delG (R75fsX83) which causes a frameshift and premature stop codon at position 247. This probably results in a shorter non-functional protein structure. Affected individuals had an early age at onset usually in the first decade. The symptoms were more severe in men than women. All had severe muscle weakness in the legs. Several abortions were observed in this family. Family 2 had a c.536 G>A (C179Y) transition which causes a change of the highly conserved cysteine residue, i.e. disruption of at least one of three disulfide bridges. The mean age at onset was in the first decade. Muscle wasting was severe and correlated with muscle weakness in legs. The men and one woman also had symptom from their hands. The neuropathy is demyelinating and the nerve conduction velocities were in the intermediate range (25-49 m/s). Affected individuals had symmetrical clinical findings, while the neurophysiology revealed minor asymmetrical findings in nerve conduction velocity in 6 of 10 affected individuals., Conclusion: The two novel mutations in the connexin32 gene are more severe than the majority of previously described mutations possibly due to the severe structural change of the gap junction they encode.

Background: A pair of monozygotic twin brothers were referred due to hereditary peripheral neuropathy resembling late onset Charcot-Marie-Tooth (CMT)., Aim of the Study: Diagnostic classification of the twin pair., Method: Clinical, neurological, genetical and neurophysiological examination, and molecular genetic testing., Results: The clinic and neurophysiology was compatible with CMT disease with late onset. Molecular genetic analysis excluded mutations in PMP22, connexin32, MPZ, LITAF and MFNZ genes, as well as duplication and deletion of PMP22., Conclusions: The twins were employed in PVC production and developed symptoms after 14 years of massive exposure. We think that the heavy exposure to various neurotoxic compounds caused symptoms that mimic late-onset CMT. However, the twins had distal dysesthesia which is unusual in inherited neuropathies. This illustrates the importance of an occupational history even in the molecular genetic era.

Background: Episodic ataxias (EAs) exist in sporadic and familial forms. They have considerable genetic and clinical heterogeneity. Better understanding of the disorders will hopefully improve management., Material and Methods: This review is based on personal experience and recent literature., Results: EAs are rare autosomal dominant paroxysmic disorders. At present, five forms have been identified. EA 1 is caused by mutations in the potassium channel gene KCNA1 on chromosome 12p13, EA 2 by mutations in the calcium channel gene CACNA1A gene on chromosome 19p13, and EA 5 by mutations in the calcium channel gene CACNB4&beta on chromosome 2q22-q23. Neither gene nor linkage has been identified for EA 3 and 4. As the name indicates, EAs are characterized by paroxystic ataxia. Patients with EA 1 also have interictal myokymia. EAs are characterized by both locus and allelic heterogeneity, since different genes can cause an almost similar phenotype and different mutations in a gene can cause different disorders. Beside EA, mutations in the KCNA1 gene can cause partial epilepsy and myokymia alone, mutations in the CACNA1A gene can cause familial hemiplegic migraine 1 and spinocerebellar ataxia 6, while mutations in the CACNB4&beta4 gene can cause generalized epilepsy and juvenile myoclonic epilepsy. EA can often be efficiently treated with acetazolamide., Interpretation: EAs are rare autosomal dominant disorders caused by mutations in ion-channel genes. The disorders are not life threatening but disabling without treatment or when medical treatment is ineffective or not tolerated.

Background: Cerebral cavernous malformations exist in sporadic and familial forms. They have considerable genetic and clinical heterogeneity. Better understanding of these disorders may improve management., Material and Methods: This review is based on personal experience and recent literature., Results: Cerebral cavernous malformations are venous malformations that can be detected with gradient echo MRI of the brain. Approximately 0.5% of the general population have the sporadic form with a single or a few cerebral cavernous malformations which mostly are asymptomatic. Those with the familial form usually have several cavernous malformations caused by an autosomal dominant condition. So far, 3 loci have been identified: CCM1 on chromosome 7q, CCM2 on chromosome 7p, and CCM3 on chromosome 3q, occurring in, respectively, approximately 40%, 20% and 40% of the families. CCM1 is caused by a mutation in the KRIT1 gene and CCM2 is caused by a mutation in the MGC4607 gene, while the gene for CCM3 is not yet identified. Mean age at onset is 20-40, but onset can occur at all ages. The most frequent symptoms are seizures, cerebral haemorrhage, chronic headache and focal neurological deficits. Many carriers are, however, asymptomatic., Interpretation: Sporadic cerebral cavernous malformation is often asymptomatic, while the familial form shows phenotypic and genetic heterogeneity. The symptoms are depending on the location of the malformations as well as whether haemorrhage does occur.

Norwegian law and international guidelines require genetic counselling before, during and after presymptomatic testing for Huntington's disease. The genetic counselling of at-risk persons who considers taking tests, includes explanation of the possible implications of a test result for both participant and relatives. The test is performed only when explicitly requested by the participant and after informed consent. The participant decides if and when the test should be conducted. The participant also has major influence on the timing of the consecutive phases of the testing procedure, in compliance with medical and ethical recommendations. This paper reviews main issues raised during genetic counselling and the preparation period preceding the test and communication of the test result. We illustrate different individual situations and backgrounds for considering presymptomatic testing for Huntington's disease by describing three anonymized cases and associated pedigrees.

Direct DNA testing for the autosomal dominant neurodegenerative disorder, Huntington's disease, may be performed in a diagnostic setting, as a presymptomatic procedure or prenatally. This paper is intended for physicians practising outside departments of medical genetics who are considering diagnostic testing of patients presenting with symptoms or signs compatible with Huntington's disease. It offers a brief overview of practically relevant clinical, epidemiological, molecular and legal aspects of diagnostic genetic testing for Huntington's disease in Norway. We stress the need for adequate information before sampling and after the test has been performed, and for close contact with the genetics centre which offers the test for Huntington's disease and provides genetic counselling. As with other diagnostic tests, the treating physician is responsible for informing the patient about the result of the test and for ensuring adequate follow-up. The physician will often need the assistance of an expert in clinical genetics. A positive DNA test for Huntington's disease in a patient may have a profound impact on family members, who should be offered genetic counselling and support. Since asymptomatic at-risk family members may ask for a presymptomatic test in the future, diagnostic confirmation at the DNA level is warranted in any person examined because of clinical signs of Huntington's disease, even when the clinical diagnosis is considered unquestionable.