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  • 1.
    Axelson, Hans W
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Microdialysis and electromyography of experimental muscle fatigue in healthy volunteers and patients with mitochondrial myopathy2002In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 26, no 4, p. 520-526Article in journal (Refereed)
    Abstract [en]

    Consecutive 60-min microdialysis samples were taken from the tibial anterior muscle in 11 healthy subjects and 4 patients with mitochondrial myopathy before (2-3 samples) and after (3-4 samples, 2 controls and 1 patient excluded) sustained isometric foot dorsiflexions. Before exercise, mean concentrations of lactate, pyruvate, hypoxanthine, urate, aspartate, and glutamate did not significantly differ between controls and patients. After exercise, the controls showed significantly increased concentrations of lactate, pyruvate, and urate, decreased hypoxanthine, and no change in aspartate and glutamate. Similar findings were observed in the patients. Plasma lactate was unchanged. Exercise-induced increase in integrated electromyogram amplitude and rated subjective fatigue were correlated to increased post-exercise lactate concentrations, with no obvious difference between the groups. Microdialysis of skeletal muscle allows the detection and monitoring of biochemical changes in the interstitial space. With the exercise protocol used, however, it was not possible to demonstrate any biochemical difference between healthy controls and patients with mitochondrial myopathy.

  • 2.
    Berntsson, Shala G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Gauffin, Helena
    Univ Linkoping, Med Fac, Dept Clin & Expt Med, Neurol, Linkoping, Sweden.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Holtz, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology. Univ Linkoping, Med Fac, Dept Clin & Expt Med, Neurol, Linkoping, Sweden.
    Inherited Ataxia and Intrathecal Baclofen for the Treatment of Spasticity and Painful Spasms2019In: Stereotactic and Functional Neurosurgery, ISSN 1011-6125, E-ISSN 1423-0372, Vol. 97, no 1, p. 18-23Article in journal (Refereed)
    Abstract [en]

    Background: Intrathecal baclofen (ITB) treatment is considered a powerful tool in the management of severe spasticity in neurological conditions such as multiple sclerosis, cerebral palsy, and traumatic spinal cord and brain injury.

    Objectives: The objective of this study was to assess the effectiveness of the ITB in patients with inherited ataxia suffering from severe painful spasms and/or spasticity.

    Method: A total of 5 patients with spinocerebellar ataxia 3 or 7 or Friedreich's ataxia were included in this observational multicenter study. The patients were interviewed and completed outcome measures assessing pain (The Brief Pain Inventory), fatigue (Fatigue Severity Scale), and life satisfaction (LiSAT-9) before and 1 year after the treatment. Spasticity (Modified Ashworth Scale) and spasm frequency (SPFS) were measured objectively for each patient.

    Results: The mean treatment time was 1.9 years. Evaluation of established standard forms revealed symptomatic relief from spasticity, spasms, pain, and fatigue in addition to improved body posture, sleep, and life satisfaction after ITB treatment.

    Conclusions: We report the potential beneficial effects of ITB treatment in patients with inherited ataxia who also suffer from spasticity/spasms. ITB treatment indication in neurological disorders allows for extension to the treatment of spasticity/spasms in patients with hereditary ataxia.

  • 3.
    Berntsson, Shala Ghaderi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Holtz, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Does intrathecal baclofen have a place in the treatment of painful spasms in friedreich ataxia2013In: Case Reports in Neurology, ISSN 1662-680X, E-ISSN 1662-680X, Vol. 5, no 3, p. 201-203Article in journal (Refereed)
    Abstract [en]

    We present the case of a 50-year-old female patient with Friedreich ataxia (FA) who was treated successfully with an intrathecal baclofen (ITB)-delivering pump for painful spasms. To our knowledge, this is the second reported case of FA where ITB relieved painful and disabling spasms. We suggest that ITB should be considered in the treatment of disabling spasms in patients with FA.

  • 4.
    Feresiadou, Amalia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Eriksson, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
    Larsen, Hans-Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Nygren, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Recurrence of Susac Syndrome following 23 Years of Remission2014In: Case Reports in Neurology, ISSN 1662-680X, E-ISSN 1662-680X, Vol. 6, no 2, p. 171-175Article in journal (Refereed)
    Abstract [en]

    Susac syndrome is an autoimmune microangiopathy affecting the brain, retina and inner ear (cochlea and semicircular canals), leading to encephalopathy, branch retinal artery occlusions (BRAOs) and asymmetric neurosensory hearing loss, respectively. The natural history and long-term prognosis are variable as the disease has been shown to be monophasic and self-limiting, polycyclic or chronic continuous. We describe a 35-year-old woman who presented with a sudden hearing loss in the left ear in the 37th week of her second pregnancy. She subsequently developed BRAO in the right eye 2.5 months after having given birth. MRI findings included round lesions in the corpus callosum which are pathognomonic for Susac syndrome. Previous patient records documented encephalopathy, sudden deafness of the right ear and visual field defects in the left eye at the age of 12, followed by permanent hearing and visual defects. We expand on the variability in the course of Susac syndrome as recurrence may occur after as long as 23 years. Cases of monophasic self-limiting Susac syndrome may in fact turn polycyclic with an interval of more than 2 decades between the bouts of the disease. In these cases, suspecting the development of exacerbation early is important in order to start the treatment promptly.

  • 5.
    Finnsson, Johannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Savitcheva, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fällmar, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Glucose metabolism in the brain in LMNB1-related autosomal dominant leukodystrophy.2019In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 139, no 2, p. 135-142Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: LMNB1-related autosomal dominant leukodystrophy is caused by an overexpression of the protein lamin B1, usually due to a duplication of the LMNB1 gene. Symptoms start in 5th to 6th decade. This slowly progressive disease terminates with death. We studied brain glucose metabolism in this disease using 18 F-fluorodeoxyglucose positron emission tomography (PET).

    METHODS: We examined 8 patients, aged 48-64 years, in varying stages of clinical symptomatology. Two patients were investigated with quantitative PET on clinical indications after which six more patients were recruited. Absolute glucose metabolism was analyzed with the PVElab software in 6 patients and 18 healthy controls. A semiquantitative analysis using the CortexID software was performed in seven investigations, relating local metabolism levels to global glucose metabolism.

    RESULTS: The clinical quantitative PET revealed low global glucose metabolism, with the most marked reduction in the cerebellum. In the PVElab analysis, patients presented low mean glucose metabolism in the cerebellum, brainstem and global grey matter. In the semiquantitative analysis, 2 patients showed a decreased metabolism in the cerebellum and 4 patients a relatively higher metabolism in parts of the temporal lobes. Since none of the patients showed an increased metabolism in the quantitative analysis, we interpret these increases as "pseudo-increases" related to a globally reduced metabolism.

    CONCLUSIONS: Global reduction of grey matter glucose metabolism in this white matter disease most likely depends on a combination of cortical afferent dysfunction and, in later stages, neuronal loss. The lowest metabolism in the cerebellum is consistent with histopathological findings and prominent cerebellar symptoms.

  • 6.
    Finnsson, Johannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    1H-MR spectroscopy of adult-onset autosomal dominant leukodystrophy with autonomic symptoms2013In: Neuroradiology, ISSN 0028-3940, E-ISSN 1432-1920, Vol. 55, no 8, p. 933-939Article in journal (Refereed)
    Abstract [en]

    Adult-onset ADLD with autonomic symptoms is a rare disease with a clinical course somewhat similar to chronic progressive MS but with different imaging findings consisting of extensive white matter changes in the cerebrum and cerebellar peduncles. Patients usually present in the fourth to sixth decade with autonomic symptoms, manifesting later symptoms from the pyramidal tracts and ataxia. Here, we present magnetic resonance spectroscopy (MRS) findings in this disease. Fourteen subjects, from two non-related families, with genetic linkage to the disease were studied with magnetic resonance imaging and single-voxel MRS. Clinically, they ranged from asymptomatic to wheelchair-using. Their results were compared to those of age- and sex-matched healthy controls. One MRS was excluded due to suboptimal quality. The remaining 13 subjects manifested characteristic evidence of pathology on MRI, 11 of them exhibited extensive changes. The metabolite concentrations of total Cr, total Cho, and total NAA measured in millimolars, using internal water as a reference, were significantly lower in these 11 subjects compared to controls, and we found linear correlations between all these metabolite levels. When total Cr was used as a reference, we found no difference between subjects and controls. No lactate was detected. The decreased metabolite concentrations measured using internal water as a reference are most likely due to increased water content in the tissues, diluting all metabolites to a similar degree. This is also in agreement with the high signal intensity exhibited in the white matter on T2-weighted MR images and with the reported histopathological findings of vacuolated myelin.

  • 7.
    Finnsson, Johannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    1H-MR spectroscopy only shows elevated water content in adult onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no S1, p. 401-401Article in journal (Other academic)
  • 8.
    Finnsson, Johannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    MRI and clinical  follow-up in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms2012In: Neuroradiology, ISSN 0028-3940, E-ISSN 1432-1920, Vol. 54, no Suppl1, p. S61-, article id O1A-3.7Article in journal (Refereed)
  • 9.
    Finnsson, Johannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Proton MR spectroscopy of supraventricular white matter in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms2011In: Neuroradiology, ISSN 0028-3940, E-ISSN 1432-1920, Vol. 53, no Suppl 1, p. S50-S51Article in journal (Refereed)
  • 10.
    Finnsson, Johannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Savitcheva, I
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Glucose metabolism in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms2013In: Neuroradiology, ISSN 0028-3940, E-ISSN 1432-1920, Vol. 55, no Suppl1, p. S36-, article id S.18.06Article in journal (Refereed)
  • 11.
    Finnsson, Johannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sundblom, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course2015In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 78, no 3, p. 412-25Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia. Magnetic resonance imaging (MRI) of the brain reveals characteristic findings. This is the first longitudinal study on this disease. Our objective is to describe the natural clinical and radiological course of LMNB1-related ADLD.

    METHODS: Twenty-three subjects in two families with LMNB1 duplications were studied over two decades with clinical assessment and MRI of the brain and spinal cord. They were 29 to 70 years old at their first MRI. Repeated MRIs were performed in 14 subjects over a time period of up to 17 years.

    RESULTS: Pathological MRI findings were found in the brain and spinal cord in all examinations (i.e., even preceding clinical symptoms). MRI changes and clinical symptoms progressed in a definite order. Autonomic dysfunction appeared in the fifth to sixth decade, preceding or together with gait and coordination difficulties. Motor signs developed ascending from spastic paraplegia to tetraplegia and pseudobulbar palsy in the seventh decade. There were clinical, radiological, and neurophysiological signs of myelopathy. Survival lasted more than two decades after clinical onset.

    INTERPRETATION: LMNB1-related ADLD is a slowly progressive neurological disease. MRI abnormalities of the brain and spinal cord can precede clinical symptoms by more than a decade and are extensive in all symptomatic patients. Spinal cord involvement is a likely contributing factor to early autonomic symptoms and spastic paraplegia. Ann Neurol 2015;78:412-425.

  • 12.
    Finnsson, Johannes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Sundblom, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    O151-Longitudinal MRI Study of the Spinal Cord in Lamin B1 Autosomal Dominant Leukodystrophy: Do the first symptoms come from the spinal cord?2014In: Neuroradiology, ISSN 0028-3940, E-ISSN 1432-1920, Vol. 56, no Suppl 1, p. S246-Article in journal (Refereed)
  • 13. Giorgio, Elisa
    et al.
    Rolyan, Harshvardhan
    Kropp, Laura
    Chakka, Anish Baswanth
    Yatsenko, Svetlana
    Gregorio, Eleonora Di
    Lacerenza, Daniela
    Vaula, Giovanna
    Talarico, Flavia
    Mandich, Paola
    Toro, Camilo
    Pierre, Eleonore Eymard
    Labauge, Pierre
    Capellari, Sabina
    Cortelli, Pietro
    Vairo, Filippo Pinto
    Miguel, Diego
    Stubbolo, Danielle
    Marques, Lourenco Charles
    Gahl, William
    Boespflug-Tanguy, Odile
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Hassin-Baer, Sharon
    Cohen, Oren S
    Pjontek, Rastislav
    Grau, Armin
    Klopstock, Thomas
    Fogel, Brent
    Meijer, Inge
    Rouleau, Guy
    Bouchard, Jean-Pierre L
    Ganapathiraju, Madhavi
    Vanderver, Adeline
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Hobson, Grace
    Brusco, Alfredo
    Brussino, Alessandro
    Padiath, Quasar Saleem
    Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele-Specific Expression2013In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 34, no 8, p. 1160-1171Article in journal (Refereed)
    Abstract [en]

    Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication-based mechanisms such fork stalling and template switching or microhomology-mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients' fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele-specific LMNB1 expression levels.

  • 14. Hedberg, C.
    et al.
    Ohlsson, M.
    Bradvik, B.
    Lindberg, C.
    Tajsharghi, H.
    Danielsson, O.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Udd, B.
    Martinsson, T.
    Oldfors, A.
    Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin2012In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 22, no 9-10, p. 873-873Article in journal (Other academic)
    Abstract [en]

    Hereditary myopathy with early respiratory failure (HMERF) and extensive myofibrillar lesions have been described in sporadic and familial cases and linked to various chromosomal regions. We describe the clinical manifestations, muscle histopathology and genetics in eight individuals from three apparently unrelated families with clinical and pathological features of HMERF. All patients had muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375, T>C; p.Cys30071Arg, in the titin gene, TTN. The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 699 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry of this novel and first disease-causing mutation in A-band titin associated with HMERF.

  • 15. Hedberg, Carola
    et al.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Dahlbom, Kathe
    Oldfors, Anders
    Hereditary myopathy with early respiratory failure is caused by mutations in the titin FN3 119 domain2014In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 137, no 4, p. e270-Article in journal (Refereed)
  • 16. Hedberg, Carola
    et al.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Kuhl, Angelika
    Jenne, Dieter
    Oldfors, Anders
    Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation2012In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 20, no 9, p. 984-985Article in journal (Refereed)
    Abstract [en]

    Using exome sequencing we searched for the genetic cause of autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy (ARVC) in a Swedish family. A heterozygous C-to-T transition, c.1255C>T, p.Pro419Ser in the desmin gene on chromosome 2q35, was identified. Previous studies had demonstrated linkage to chromosome 10q22.3, but no causative mutation had been found in that region. Sanger sequencing of DNA from 17 family members confirmed the heterozygous c.1255C>T desmin mutation in seven out of ten family members that had been classified as affected in the previous study. Our new results demonstrate the usefulness of next-generation sequencing, and the diagnostic difficulties with some forms of dominantly inherited muscle diseases as they can display a wide clinical and morphological variability even within a given family.

  • 17. Hedberg, Carola
    et al.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Kuhl, Angelika
    Jenne, Dieter
    Oldfors, Anders
    Functional characterization of desmin mutant p.P419S Reply2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 6, p. 590-590Article in journal (Refereed)
  • 18.
    Klar, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sobol, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Mäbert, Katrin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Johansson, Anna C V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Feuk, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Entesarian, Miriam
    Örlén, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Welander Distal Myopathy Caused by an Ancient Founder Mutation in TIA1 Associated with Perturbed Splicing.2013In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 34, no 4, p. 572-577Article in journal (Refereed)
    Abstract [en]

    Welander distal myopathy (WDM) is an adult onset autosomal dominant disorder characterized by distal limb weakness which progresses slowly from the fifth decade. All WDM patients are of Swedish or Finnish descent and share a rare chromosome 2p13 haplotype. We restricted the WDM associated haplotype followed by whole exome sequencing. Within the conserved haplotype we identified a single heterozygous mutation c.1150G>A (p.E384K) in TIA1 in all WDM patients investigated (n = 43). The TIA1 protein regulates splicing and translation through direct interaction with mRNA and the p.E384K mutation is located in the C-terminal Q-rich domain that interacts with the U1-C splicing factor. TIA1 has been shown to prevent skipping of SMN2 exon 7 and we show that WDM patients have increased levels of spliced SMN2 in skeletal muscle cells when compared to controls. Immunostaining of WDM muscle biopsies showed accumulation of TIA1 and stress granulae proteins adjacent to intracellular inclusions, a typical finding in WDM. The combined findings strongly suggest that the TIA1 mutation causes perturbed RNA splicing and cellular stress resulting in WDM. The selection against the mutation is likely to be negligible and the age of the TIA1 founder mutation was calculated to approximately 1050 years, which coincides with the epoch of early seafaring across the Baltic Sea.

  • 19. Kollberg, Gittan
    et al.
    Jansson, Monica
    Pérez-Bercoff, Åsa
    Melberg, Atle
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Neurologi.
    Lindberg, Christopher
    Holme, Elisabeth
    Moslemi, Ali-Reza
    Oldfors, Anders
    Low frequency of mtDNA point mutations in patients with PEO associated with POLG1 mutations2005In: Eur J Human Genetics, Vol. 13, p. 463-469Article in journal (Refereed)
  • 20. Kollberg, Gittan
    et al.
    Moslemi, Ali-Reza
    Darin, Niklas
    Nennesmo, Inger
    Bjarnadottir, Ingibjörg
    Uverant, Paul
    Holme, Elisabeth
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Tulinius, Már
    Oldfors, Anders
    POLG1 mutations associated with progressive encephalopathy in childhood2006In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 65, no 8, p. 758-768Article in journal (Refereed)
    Abstract [en]

    We have identified compound heterozygous missense mutations in POLG1, encoding the mitochondrial DNA polymerase gamma (Pol gamma), in 7 children with progressive encephalopathy from 5 unrelated families. The clinical features in 6 of the children included psychomotor regression, refractory seizures, stroke-like episodes, hepatopathy, and ataxia compatible with Alpers-Huttenlocher syndrome. Three families harbored a previously reported A467T substitution, which was found in compound with the earlier described G848S or the W748S substitution or a novel R574W substitution. Two families harbored the W748S change in compound with either of 2 novel mutations predicted to give an R232H or M1163R substitution. Muscle morphology showed mitochondrial myopathy with cytochrome c oxidase (COX)-deficient fibers in 4 patients. mtDNA analyses in muscle tissue revealed mtDNA depletion in 3 of the children and mtDNA deletions in the 2 sibling pairs. Neuropathologic investigation in 3 children revealed widespread cortical degeneration with gliosis and subcortical neuronal loss, especially in the thalamus, whereas there were only subcortical neurodegenerative findings in another child. The results support the concept that deletions as well as depletion of mtDNA are involved in the pathogenesis of Alpers-Huttenlocher syndrome and add 3 new POLG1 mutations associated with an early-onset neurodegenerative disease.

  • 21. Kors, E. E.
    et al.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Vanmolkot, K. R.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Haan, Jan
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ginjaar, H.B.
    Frants, R.R.
    Ferrari, M.D.
    van den Maagdenberg, A. M.
    Childhood, epilepsy, familial hemiplegic migraine, cerebellar ataxia, and a new CACNA1A mutation2004In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 63, no 6, p. 1136-1137Article in journal (Refereed)
  • 22. Kuhl, Angelika
    et al.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Meinl, Edgar
    Nürnberg, Gudrun
    Nürnberg, Peter
    Kehrer-Sawatzki, Hildegard
    Jenne, Dieter
    Myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7: corroboration and narrowing of the critical region on 10q22.32008In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 16, no 3, p. 367-373Article in journal (Refereed)
    Abstract [en]

    Several years ago, autosomal dominant myofibrillar myopathy (MFM) in combination with arrhythmogenic right ventricular cardiomyopathy (ARVC7) was tentatively mapped to a 10.6-Mbp (million base pairs) region on chromosome 10q22.3 between D10S605 (78.9 Mbp) and D10S215 (89.5 Mbp) in a Swedish family assuming that ARVC7 was allelic with cardiomyopathy, dilated 1C (CMD1C). To date, neither the genetic defect in ARVC7 nor CMD1C has been reported. In a comprehensive follow-up study were-examined and confirmed the previous linkage data for ARVC7 using a high-density single nucleotide polymorphism marker panel from Affymetrix (Human Mapping 10K Array). No other regions with significant evidence for linkage were discovered. The critical interval was narrowed down to 4.27 Mbp between D10S1645 and D10S1786. This reduced the total number of candidate genes to 18 of which 17 (RAI17, PPIF, C100RF56, SFTPA1, SFTPA2, SFTPA1B, SFTPA2B, SFTPD, C100RF57, PLAC9, ANXA11, MAT1A, DYDC1, DYDC2, C100RF58, TSPAN14 and SH2D4B) are shared with the CMD1C region. No disease-causing mutation was found in their coding regions. Moreover, metavinculin (VCL) and ZASP/cypher (LDB3) proximal and distal to this linked region were excluded by sequence analysis. To search for submicroscopic and intragenic deletions by PCR, we generated hybrid cell lines carrying only the affected or normal chromosome 10 homolog. All sequence tagged sites and exons were present on both homologs. We speculate that regulatory mutations in 1 of the 18 genes from 10q22.3 are responsible for a heterogenous spectrum of clinically distinct myodegenerative disorders, affecting both skeletal and cardiac muscles to variable degrees.

  • 23. Luoma, Petri
    et al.
    Melberg, Atle
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Neurologi.
    Rinne, Juha
    Kaukonen, Jyrki
    Nupponen, Nina
    Chalmers, Richard
    Oldfors, Anders
    Rautakorpi, Ilkka
    Peltonen, Leena
    Majamaa, Kari
    Somer, Hannu
    Suomalainen, Anu
    Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study2004In: Lancet, Vol. 364, p. 875-882Article in journal (Refereed)
  • 24.
    Marklund, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Melin, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Adult-onset autosomal dominant leukodystrophy with autonomic symptoms restricted to 1.5 Mbp on chromosome 5q232006In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, ISSN 1552-4841, Vol. 141B, no 6, p. 608-614Article in journal (Refereed)
    Abstract [en]

    Autosomal dominant leukodystrophy (ADLD) with autonomic symptoms is a slowly progressive leukodystrophy with an onset in the 4th to 6th decade of life. Early symptoms are derived from the autonomic nervous system with bladder dysfunction in the majority of patients. The disease progresses slowly with loss of fine motor skills, ataxia, and affected individuals may survive for two decades after onset of symptoms. The molecular basis behind ADLD remains unknown but the causative locus was previously mapped to a 4 cM region on chromosome 5. We have recently identified a large family of Swedish origin with this type of ADLD. Linkage analysis on samples from family members confirmed linkage to 5q23 and supports genetic homogeneity for the disease. We fine mapped and localized the ADLD gene to a 0.96 cM region between D5S1495 and CTT/CCT15. A maximum parametric multipoint location score of 9.45 was obtained for a position at the marker CTT55. From our results we conclude that the ADLD gene locus is restricted to a 1.47 Mbp interval containing 13 known or putative genes.

  • 25.
    Melberg, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Oldfors, A
    Blomström-Lundqvist, C
    Department of Medical Sciences.
    Stålberg, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Carlsson, B
    Larsson, E
    Department of Genetics and Pathology.
    Lidell, C
    Eeg-Olofsson, K E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Wikström, G
    Henriksson, G
    Dahl, N
    Department of Genetics and Pathology.
    Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q.1999In: Ann Neurol, ISSN 0364-5134, Vol. 46, no 5, p. 684-92Article in journal (Refereed)
  • 26.
    Melberg, Atle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hallberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    MR characteristics and neuropathology in adult-onset autosomal dominant leukodystrophy with autonomic symptoms2006In: American Journal of Neuroradiology, ISSN 0195-6108, E-ISSN 1936-959X, Vol. 27, no 4, p. 904-11Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Three families with adult-onset autosomal dominant leukodystrophy (ADLD) presenting autonomic dysfunction as the first symptom are reported. We describe detailed MR appearances of the brain in 2 new families and neuropathology in 2 patients and compare the findings with those in other adult-onset leukodystrophies. METHODS: Twenty subjects (12 women and 8 men; age range, 29-70 years) from 2 unrelated families with ADLD were examined with MR. Six subjects were asymptomatic. Fourteen had autonomic dysfunction. Eleven of them also had pyramidal signs and ataxia. The brains of 2 autopsied patients were examined histopathologically. RESULTS: Two subjects manifested no neurologic symptoms, signs, or MR pathology. Eighteen subjects displayed radiologic abnormalities ranging from subtle T2 high-signal-intensity changes in the upper corticospinal tract to extensive confluent white matter changes, predominantly in a frontoparietal distribution, along the corticospinal tracts down to the medulla oblongata and in the upper and middle cerebellar peduncles. Periventricular white matter was spared or less affected than the adjacent white matter. Histopathology revealed marked loss of cerebral and cerebellar myelin without signs of inflammation. Oligodendrocytes were relatively spared, the number of axons not markedly decreased, and reactive gliosis was modest. The number of Purkinje cells in the cerebellum was reduced. CONCLUSIONS: Two families with adult-onset ADLD with the disease entity originally reported by Eldridge et al. (N Engl J Med 1984;311:948-53) were described. We propose naming the disease "adult-onset ADLD with autonomic symptoms." The characteristic radiologic findings, combined with the clinical symptoms and mode of inheritance, enable the diagnosis.

  • 27.
    Melberg, Atle
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. neurologi.
    Nennesmo, Inger
    Moslemi, Ali-Reza
    Kollberg, Gittan
    Luoma, Petri
    Suomalainen, Anu
    Holme, Elisabeeth
    Oldfors, Anders
    Alzheimer pathology associated with POLG1 mutation, multiple mtDNA deletions, and APOE4/4: premature ageing or just coicidence2005In: Acta Neuropathol, Vol. 110, p. 315-316Article in journal (Refereed)
  • 28. Ohlsson, Monica
    et al.
    Hedberg, Carola
    Brådvik, Björn
    Lindberg, Christopher
    Tajsharghi, Homa
    Danielsson, Olof
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Udd, Bjarne
    Martinsson, Tommy
    Oldfors, Anders
    Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin2012In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 135, no 6, p. 1682-1694Article in journal (Refereed)
    Abstract [en]

    Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T>C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.

  • 29. Pedroso, José Luiz
    et al.
    Povoas Barsottini, Orlando Graziani
    Lin, Ling
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Oliveira, Acary S B
    Mignot, Emmanuel
    A Novel de novo Exon 21 DNMT1 Mutation Causes Cerebellar Ataxia, Deafness, and Narcolepsy in a Brazilian Patient2013In: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 36, no 8, p. 1257-1259Article in journal (Refereed)
    Abstract [en]

    STUDY OBJECTIVES: Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is caused by DNMT1 mutations. Diagnosing the syndrome can be difficult, as all clinical features may not be present at onset, HLA-DQB1*06:02 is often negative, and sporadic cases occur. We report on clinical and genetic findings in a 31-year-old woman with cerebellar ataxia, deafness, and narcolepsy, and discuss diagnostic challenges.

    DESIGN: Clinical and genetic investigation in a patient and family members.

    SETTING: Ataxia clinic, São Paulo, Brazil.

    PATIENTS OR PARTICIPANTS: One patient and her family members.

    INTERVENTIONS: N/A.

    MEASUREMENTS AND RESULTS: Narcolepsy was supported by polysomnographic and multiple sleep latency testing. HLA-DQB1*06:02 was positive. CSF hypocretin-1 was 191 pg/mL (normal values > 200 pg/mL). Mild brain atrophy was observed on MRI, with cerebellar involvement. The patient, her asymptomatic mother, and 3 siblings gave blood samples for genetic analysis. DNMT1 exons 20 and 21 were sequenced. Haplotyping of polymorphic markers surrounding the mutation was performed. The proband had a novel DNMT1 mutation in exon 21, p.Cys596Arg, c.1786T > C. All 4 parental haplotypes could be characterized in asymptomatic siblings without the mutation, indicating that the mutation is de novo in the patient.

    CONCLUSIONS: The Brazilian patient reported here further adds to the worldwide distribution of ADCA-DN. The mutation is novel, and illustrates a sporadic case with de novo mutation. We believe that many more cases with this syndrome are likely to be diagnosed in the near future, mandating knowledge of this condition and consideration of the diagnosis.

  • 30.
    Schuster, Jens
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundblom, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hassin-Baer, Sharon
    Klopstock, Thomas
    Dichgans, Martin
    Cohen, Oren S.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms2011In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 12, no 1, p. 65-72Article in journal (Refereed)
    Abstract [en]

    Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms features micturition urgency, constipation, erectile dysfunction, and orthostatic hypotension, usually followed by pyramidal signs and ataxia. Peripheral nerve conduction is normal. The disease is often mistaken for multiple sclerosis in the initial phase. There is a characteristic pattern of white matter changes in the brain and spinal cord on magnetic resonance imaging (MRI), mild atrophy of the brain, and a more marked atrophy of the spinal cord. ADLD is associated with duplications of the lamin B1 (LMNB1) gene but the mechanism by which the rearrangement conveys the phenotype is not fully defined. We analyzed four unrelated families segregating ADLD with autonomic symptoms for duplications of the LMNB1 gene. A single nucleotide polymorphism (SNP) array analysis revealed novel duplications spanning the entire LMNB1 gene in probands from each of the four families. We then analyzed the expression of lamin B1 in peripheral leukocytes by Western blot analysis in five patients from two available families. The protein levels of lamin B1 were found significantly increased. These results indicate that the ADLD phenotype associated with LMNB1 duplications is mediated by increased levels of the lamin B1 protein. Furthermore, we show that a molecular diagnosis for ADLD with autonomic symptoms can be obtained by a direct analysis of lamin B1 in peripheral leukocytes.

  • 31.
    Sundblom, Jimmy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    MR imaging characteristics and neuropathology of the spinal cord in adult-onset autosomal dominant leukodystrophy with autonomic symptoms2009In: American Journal of Neuroradiology, ISSN 0195-6108, E-ISSN 1936-959X, Vol. 30, no 2, p. 328-335Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE:

    MR imaging findings in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms have been described in the brain, but no descriptions of MR imaging findings in the spinal cord have been published. Here, we describe MR imaging findings in the spinal cord in adult-onset ADLD with autonomic symptoms and histopathologic investigations of the spinal cord.

    MATERIALS AND METHODS:

    Twelve subjects from 2 families with adult-onset ADLD with autonomic symptoms identified by clinical investigation underwent MR imaging examination of the spinal cord. Sagittal and transverse sections were obtained. MR imaging examination of the brain was performed in 11 patients. One of the patients underwent postmortem examination, and the spinal cord was subjected to histopathologic analysis.

    RESULTS:

    In all family members with adult-onset ADLD with autonomic symptoms, even in the asymptomatic person, the spinal cord was thin. All examined family members also had a slight general white matter signal intensity (SI) increase in the whole spinal cord, mainly visible in T2-weighted transverse images. The pathologic examination revealed a discrete demyelination in the spinal cord. Brain MR imaging also showed increased T2 SI in the white matter.

    CONCLUSIONS:

    The spinal cord is affected in adult-onset ADLD with autonomic symptoms. Findings consist of atrophy and a diffuse T2 SI increase in the white matter. Transverse images are needed to assess these findings. The typical SI changes of the spinal cord are also present in subjects without clinical symptoms of the disease and with very limited changes in the brain.

  • 32.
    Sundblom, Jimmy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Rücker, Franz
    Department of Medicine, Visby Hospital.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Islander, Gunilla
    MH Unit, Department of Intensive- and perioperative care, Lund University Hospital.
    A family with discordance between Malignant hyperthermia susceptibility and Rippling muscle disease2013In: Journal of Anesthesia, ISSN 0913-8668, E-ISSN 1438-8359, Vol. 27, no 1, p. 128-131Article in journal (Refereed)
    Abstract [en]

    Rippling muscle disease (RMD) is a benign disorder affecting striated muscle.Malignant hyperthermia (MH) susceptibility is a potentially lethal disorder in which otherwise healthy individuals can develop an extreme hypermetabolism and muscle rigidity/rhabdomyolysis during anesthesia with potent inhalational agents and/or succinylcholine. Disturbed calcium homeostasis has been suggested as the cause of RMD symptoms. Uncontrolled increase in intracellular calcium concentration starts a MH reaction.

    Purpose

    To investigate if there is a relation between RMD and MH susceptibility in a family with both RMD and MH susceptibility.

    Materials and methods

    Ten members of a family segregating RMD had, prior to RMD diagnosis, been investigated for MH susceptibility. Results from MH and RMD investigations and anesthesia outcomes were cross-referenced and evaluated to find connections or phenotype variations predicted by in vitro contracture test results.

    Results

    There was no relation between RMD and MH susceptibility. There were no adverse anesthesia reactions recorded in this family.

    Conclusions

    RMD and MH susceptibility did not co-segregate. RMD patients should probably not be considered at risk for MH reactions.

  • 33.
    Sundblom, Jimmy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Österdahl, Maria
    Rücker, Franz
    Montelius, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Nennesmo, Inger
    Islander, Gunilla
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bedside diagnosis of rippling muscle disease in CAV3 p.A46T mutation carriers2010In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 41, no 6, p. 751-757Article in journal (Refereed)
    Abstract [en]

    Thirty-nine members, ages 1 to 67 years, of a Swedish family with rippling muscle disease (RMD) were investigated to assess genotype-phenotype correlations. Clinical, neurophysiological, and muscle morphological examinations were performed. Genetic analysis was performed in 38 individuals. Twenty-three patients had percussion-induced muscle mounding (PIMM) and percussion-induced rapid contractions (PIRC). Rippling and hyperCKemia were not found in all patients. Weakness was minor or absent. The electromyogram showed absence of electrical activity in ripples and PIMM, and muscle biopsy specimens confirmed caveolin-3 deficiency and absence of caveolae. Genetic analysis revealed a CAV3 c.G136A transition resulting in a p.A46T missense mutation in affected family members. The phenotype in these 23 cases of RMD with this mutation appears to be homogenous, benign, and nonprogressive. The presence of PIMM and PIRC seems to be diagnostic at all ages, whereas the absence of hyperCKemia and rippling does not exclude the diagnosis.

  • 34.
    Wang, Chen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Weis, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Månsson, J-E
    Göteborgs universitet.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    The earliest MR imaging and proton MR spectroscopy abnormalities in adult-onset Krabbe disease2007In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 116, no 4, p. 268-272Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Adult-onset Krabbe disease is an uncommon form of leukodystrophy. Its magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) manifestations are not well documented. AIM OF THE STUDY: To describe early MR findings in adult-onset Krabbe disease. MATERIALS AND METHODS: A 28-year-old woman who had spastic paraparesis and a 5-year history of gait problems underwent MRI of the brain and cervical spine. Proton MRS was performed at 1.5 T using a short echo time. Metabolites were analyzed in the areas of MR signal abnormalities and normal-appearing brain. Six healthy volunteers were examined as controls. RESULTS: MRI revealed changes in the upper corticospinal tracts, splenium and, minimally, adjacent to the atria of the lateral ventricles. MRS showed decreased creatine, choline, N-acetylaspartate and glutamate and probably elevated lactate in the upper corticospinal tract but not in the normal-appearing frontal lobe. The spinal cord was thin. Laboratory tests verified Krabbe disease. CONCLUSIONS: These results indicate early involvement of the upper corticospinal tract in adult-onset Krabbe disease. The cases reported earlier had imaging changes indicating a more advanced disease or no MR findings. Thinning of the spinal cord is a new finding in Krabbe disease.

  • 35. Winkelmann, J.
    et al.
    Lin, L.
    Schormair, B.
    Kornum, B. R.
    Faraco, J.
    Plazzi, G.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Cornellio, F.
    Pizza, F.
    Mignot, E.
    Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy2012In: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 35, no S, p. A11-A11Article in journal (Other academic)
  • 36. Winkelmann, Juliane
    et al.
    Lin, Ling
    Schormair, Barbara
    Kornum, Birgitte R
    Faraco, Juliette
    Plazzi, Giuseppe
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Cornelio, Ferdinando
    Urban, Alexander E
    Pizza, Fabio
    Poli, Francesca
    Grubert, Fabian
    Wieland, Thomas
    Graf, Elisabeth
    Hallmayer, Joachim
    Strom, Tim M
    Mignot, Emmanuel
    Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy2012In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 10, p. 2205-2210Article in journal (Refereed)
    Abstract [en]

    Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene.

  • 37.
    Örlén, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Entesarian, Miriam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Söderberg, Per
    Department of Ophthalmology, Västerås Hospital.
    Påhlman, Magnus
    Darin, Niklas
    Kyllerman, Mårten
    Holmberg, Eva
    Engler, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    SPG11 mutations cause Kjellin syndrome, a hereditary spastic paraplegia with thin corpus callosum and central retinal degeneration2009In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 150B, no 7, p. 984-992Article in journal (Refereed)
    Abstract [en]

    Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is genetically heterogenous and approximately 35% of patients carry mutations in either of the SPG11 or SPG15 genes. Disease onset is during the first three decades of life with spastic paraplegia and mental impairment. Peripheral neuropathy and amyotrophy may occur. Kjellin syndrome is characterized by central retinal degeneration in addition to ARHSP-TCC and the disease is associated with mutations in the SPG15 gene. We identified five patients in four unrelated kindreds with spastic paraplegia and mental impairment. Magnetic resonance imaging revealed TCC, atrophy elsewhere in the brain and increased T2 signal intensity in the periventricular white matter. Probands from the four kindreds were screened for mutations in the SPG11 gene. All patients were found homozygous or compound heterozygous for truncating SPG11 mutations of which four are reported for the first time. Ophthalmological investigations revealed that the four index cases have central retinal degeneration consistent with Kjellin syndrome. PET examinations with N-[11C-methyl]-L-deuterodeprenyl (DED) and fluor-18 2-fluorodeoxyglucose (FDG) were performed in two patients with Kjellin syndrome. We observed a reduced glucose uptake in the thalami, anterior cingulum, and sensorimotor cortex indicating neuronal loss, and an increased DED binding in the thalami and pons which suggests astrogliosis. From our results we extend the SPG11 associated phenotype to comprise also Kjellin syndrome, previously found to be associated with mutations in the SPG15 gene. We anticipate that degeneration of the central retina is a common and previously unrecognized feature in SPG11 related disease.

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