| 1. |
- Carlsson, G, et al.
(author)
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Central nervous system involvement in severe congenital neutropenia : neurological and neuropsychological abnormalities associated with specific HAX1 mutations
- 2008
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 264:4, s. 388-400
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Journal article (peer-reviewed)abstract
- OBJECTIVES: Homozygous mutations in the HAX1 gene were recently identified in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden. Our observations suggested that these patients also develop neurological and neuropsychological symptoms. METHODS: Detailed clinical studies and mutation analyses were performed in the surviving patients belonging to the Kostmann kindred and in two patients not related to this family, along with studies of HAX1 splice variant expression in normal human tissues. RESULTS: Five of six Kostmann family patients and one other patient from northern Sweden harboured homozygous HAX1 mutations (568C-->T, Q190X) and one carried a heterozygous ELA2 gene mutation. One Swedish patient of Kurdish extraction carried alternative homozygous HAX1 mutations (131G-->A, W44X). All the three patients with Q190X mutations who were alive and available for evaluation developed neurological disease with decreased cognitive function, and three of four patients who reached 10 years developed epilepsy. In contrast, the patients with the ELA2 and W44X HAX1 mutations, respectively, showed no obvious neurological abnormalities. Moreover, two alternative HAX1 splice variants were identified in normal human tissues, including the brain. Both transcripts contained exon 5, harbouring the Q190X mutation, whereas the 5' end of exon 2 containing the W44X mutation was spliced out from the second transcript. CONCLUSIONS: We describe neurological and neuropsychological abnormalities for the first time in Kostmann disease patients. These central nervous system symptoms appear to be associated with specific HAX1 mutations.
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| 2. |
- Helmers, S.B., et al.
(author)
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Limited effects of high-dose intravenous immunoglobulin (IVIG) treatment on molecular expression in muscle tissue of patients with inflammatory myopathies
- 2007
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 66:10, s. 1276-1283
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Journal article (peer-reviewed)abstract
- Objectives: The study was conducted with the aim of achieving an improved understanding of the molecular mechanisms of high-dose intravenous immunoglobulin (IVIG) in inflammatory myopathies by investigating the effects on muscle function and immunological molecules in skeletal muscle of polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM) patients. Methods: Thirteen treatment-resistant patients, 6 PM, 4 DM, 2 IBM and 1 juvenile DM, were treated with 2 g/kg of IVIG, three times at monthly intervals. Functional Index in Myositis and serum creatinine kinase (CK) levels were determined, and muscle biopsies were performed before treatment and after the third IVIG infusion. Immunological molecules were also studied in biopsies taken 24-48 h after the first infusion. Results: Improved muscle function was observed in three patients (1 PM, 1 DM and 1 IBM) and CK levels decreased in five. T cells, macrophages, major histocompatibility complex (MHC) class I antigen on muscle fibres, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression and membranolytic attack complex (MAC) deposits on capillaries were present to an equal degree in biopsies before and after MG treatment. No correlation between the clinical response and molecular changes was found. Conclusions: The clinical effects of high-dose IVIG on muscle function in patients with refractory inflammatory active myositis did not correspond to effects on any of the investigated molecules in our study. T cells, macrophages, phenotypical changes in muscle fibres and endothelial cell activation were still present after treatment. These observations question a role for IVIG as an immune-modulating therapy in patients with inflammatory myopathies.
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| 3. |
- Minde, Jan, et al.
(author)
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A novel NGFB point mutation : a phenotype study of heterozygous patients
- 2009
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In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 80:2, s. 188-195
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Journal article (peer-reviewed)abstract
- OBJECTIVE: A family with neurological findings similar to hereditary sensory and autonomic neuropathy type V having a point mutation in the nerve growth factor beta (NGFB) gene was recently described. The homozygous genotype gives disabling symptoms. The purpose of the present study was to evaluate the symptoms in heterozygous patients. METHODS: 26 patients heterozygous for the NGFB mutation (12 men, mean age 50 (13-90) years) were examined clinically and answered a health status questionnaire, including the Michigan Neuropathy Screening Instrument (MNSI). 28 relatives (15 men, mean age 44 (15-86) years) without the mutation served as controls in the clinical examination part. 23 of the heterozygotes were examined neurophysiologically and six heterozygous patients underwent a sural nerve biopsy. RESULTS: The heterozygous phenotype ranged from eight patients with Charcot arthropathy starting in adult age and associated with variable symptoms of neuropathy but without complete insensitivity to pain, anhidrosis or mental retardation, to 10 symptom free patients. There was no difference in MNSI between the young heterozygous cases (<55 years old) and the controls. Six of 23 heterozygous patients had impaired cutaneous thermal perception and 11 of 23 had signs of carpal tunnel syndrome. Sural nerve biopsies showed a moderate reduction of both small myelinated (Adelta) and unmyelinated (C) fibres. No apparent correlation of small fibre reduction to symptoms was found. CONCLUSIONS: The NGFB mutation in its heterozygous form results in a milder disease than in homozygotes, with a variable clinical picture, ranging from asymptomatic cases to those with Charcot arthropathy appearing in adult age. Particularly age, but perhaps lifestyle factors also, may influence the development of clinical polyneuropathy.
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