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Norrbottnian congenital insensitivity to pain
Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap.
2006 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Congenital insensitivity to pain is a rare hereditary neuropathy. We present patients from a large family in Norrbotten, Sweden with a mutation in the nerve growth factor β gene (NGFß). Using a model of recessive inheritance, we identified an 8.3-Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of candidate genes in the disease-critical region revealed a mutation in the coding region of the NGFß gene specific for the disease haplotype. All three severely affected individuals were homozygous for the mutation. The disease haplotype was also observed in both unaffected and mildly affected family members, but in heterozygote form. We have identified 43 patients, 3 homozygous and 40 heterozygous. The homozygous patients have a severe congenital form with onset of symptoms at an early age, most often affecting the lower extremities with insidious progressive joint swellings or painless fractures. Fracture healing was normal, but the arthropathy was progressive, resulting in disabling Charcot joints with gross deformity and instability. These patients lacked deep pain perception in bones and joints and had no protective reflexes, leading to gross bone and joint complications. They also had abnormal temperature perception but normal ability to sweat. There was no mental retardation. Clinically, they fit best into the group HSAN type V. Sural nerve biopsies showed a moderate loss of thin myelinated fibers (Ad-fibers) and a severe reduction of unmyelinated fibers (C-fibers). 14 of the 40 heterozygous adult patients had mild or moderate problems with joint deformities, usually with only slight discomfort. Treatment was conservative with (if needed) different kinds of orthosis and in some cases joint replacement. Three patients had only neuropathy, and 16 patients had no symptoms.

In congenital disorders like these, it is important to evaluate the age and also the slowly progressive nature, when considering treatment. There is an increased risk of growth disturbances in the very young. The orthopedic operations should therefore be planned from a long-term point of view, but patient education and orthosis are cornerstones in the treatment—to delay the development of neuropathic arthropathy. Arthrodesis, limb lengthening and spinal decompression with fusions are the only elective procedures that seem reasonable.

This Norrbottnian disease is also interesting as a model system for the study of pain.

sted, utgiver, år, opplag, sider
Umeå: Kirurgisk och perioperativ vetenskap , 2006. , s. 32
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1020
Emneord [en]
Pain insensitivity, HSAN
HSV kategori
Identifikatorer
URN: urn:nbn:se:umu:diva-746ISBN: 91-7264-057-X (tryckt)OAI: oai:DiVA.org:umu-746DiVA, id: diva2:144411
Disputas
2006-04-28, Betula, 6M, Norrlands universitetssjukhus, Umeå, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2006-04-07 Laget: 2006-04-07 Sist oppdatert: 2010-01-18bibliografisk kontrollert
Delarbeid
1. Familial insensitivity to pain (HSAN V) and a mutation in the NGFB gene. A neurophysiological and pathological study.
Åpne denne publikasjonen i ny fane eller vindu >>Familial insensitivity to pain (HSAN V) and a mutation in the NGFB gene. A neurophysiological and pathological study.
Vise andre…
2004 (engelsk)Inngår i: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 30, nr 6, s. 752-760Artikkel i tidsskrift (Fagfellevurdert) Published
Emneord
Adult, Aged, Aged; 80 and over, Child, Female, Hereditary Sensory and Autonomic Neuropathies/*genetics/*physiopathology/radiography, Humans, Male, Mutation, Nerve Growth Factor/*genetics, Pedigree, Sural Nerve/pathology
Identifikatorer
urn:nbn:se:umu:diva-14113 (URN)10.1002/mus.20172 (DOI)15468048 (PubMedID)
Tilgjengelig fra: 2007-05-23 Laget: 2007-05-23 Sist oppdatert: 2018-06-09bibliografisk kontrollert
2. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.
Åpne denne publikasjonen i ny fane eller vindu >>A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.
Vise andre…
2004 (engelsk)Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 13, nr 8, s. 799-805Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Identification of genes associated with pain insensitivity syndromes can increase the understanding of the pathways involved in pain and contribute to the understanding of how sensory pathways relate to other neurological functions. In this report we describe the mapping and identification of the gene responsible for loss of deep pain perception in a large family from northern Sweden. The loss of pain perception in this family is characterized by impairment in the sensing of deep pain and temperature but with normal mental abilities and with most other neurological responses intact. A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients. Thus the cases in this study fall into the class of patients with loss of pain perception with underlying peripheral neuropathy. Clinically they best fit into HSAN V. Using a model of recessive inheritance we identified an 8.3 Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of functional candidate genes in the disease critical region revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype. This NGF mutation seems to separate the effects of NGF involved in development of central nervous system functions such as mental abilities, from those involved in peripheral pain pathways. This mutation could therefore potentially provide an important tool to study different roles of NGF, and of pain control.

Emneord
Adolescent, Adult, Animals, Cattle, Child, Child; Preschool, DNA Mutational Analysis, Female, Guinea Pigs, Humans, Male, Mice, Nerve Growth Factor/*genetics, Pain/*genetics, Pain Insensitivity; Congenital/*genetics, Pedigree, Protein Structure; Secondary, Rats
Identifikatorer
urn:nbn:se:umu:diva-14121 (URN)10.1093/hmg/ddh096 (DOI)14976160 (PubMedID)
Tilgjengelig fra: 2007-09-13 Laget: 2007-09-13 Sist oppdatert: 2018-06-09bibliografisk kontrollert
3. Orthopedic aspects of familial insensitivity to pain due to a novel nerve growth factor beta mutation.
Åpne denne publikasjonen i ny fane eller vindu >>Orthopedic aspects of familial insensitivity to pain due to a novel nerve growth factor beta mutation.
Vise andre…
2006 (engelsk)Inngår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 77, nr 2, s. 198-202Artikkel i tidsskrift (Fagfellevurdert) Published
Emneord
Adolescent, Adult, Child, Child; Preschool, Consanguinity, Female, Fractures; Bone/genetics/radiography/surgery, Heterozygote, Homozygote, Humans, Joint Diseases/genetics/radiography/surgery, Male, Mutation, Nerve Growth Factor/*genetics, Orthopedic Procedures/methods, Orthotic Devices, Pain Insensitivity; Congenital/complications/*genetics/surgery, Pedigree, Wound Healing
Identifikatorer
urn:nbn:se:umu:diva-14306 (URN)10.1080/17453670610045911 (DOI)16752279 (PubMedID)
Tilgjengelig fra: 2008-01-11 Laget: 2008-01-11 Sist oppdatert: 2018-06-09bibliografisk kontrollert
4. HSAN V, a phenotype study of patients heterozygous for the NGFß-mutation
Åpne denne publikasjonen i ny fane eller vindu >>HSAN V, a phenotype study of patients heterozygous for the NGFß-mutation
Vise andre…
(engelsk)Manuskript (Annet vitenskapelig)
Identifikatorer
urn:nbn:se:umu:diva-5055 (URN)
Tilgjengelig fra: 2006-04-07 Laget: 2006-04-07 Sist oppdatert: 2018-06-09bibliografisk kontrollert
5. Skin innervation in congenital insensitivity to pain, HSAN V
Åpne denne publikasjonen i ny fane eller vindu >>Skin innervation in congenital insensitivity to pain, HSAN V
Vise andre…
Manuskript (Annet vitenskapelig)
Identifikatorer
urn:nbn:se:umu:diva-5056 (URN)
Tilgjengelig fra: 2006-04-07 Laget: 2006-04-07 Sist oppdatert: 2010-01-13bibliografisk kontrollert

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