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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: 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.

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.