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Norrbottnian congenital insensitivity to pain
Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Umeå: Kirurgisk och perioperativ vetenskap , 2006. , 32 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1020
Keyword [en]
Pain insensitivity, HSAN
National Category
Surgery
Identifiers
URN: urn:nbn:se:umu:diva-746ISBN: 91-7264-057-X (print)OAI: oai:DiVA.org:umu-746DiVA: diva2:144411
Public defence
2006-04-28, Betula, 6M, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2010-01-18Bibliographically approved
List of papers
1. Familial insensitivity to pain (HSAN V) and a mutation in the NGFB gene. A neurophysiological and pathological study.
Open this publication in new window or tab >>Familial insensitivity to pain (HSAN V) and a mutation in the NGFB gene. A neurophysiological and pathological study.
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2004 (English)In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 30, no 6, 752-760 p.Article in journal (Refereed) Published
Keyword
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
Identifiers
urn:nbn:se:umu:diva-14113 (URN)10.1002/mus.20172 (DOI)15468048 (PubMedID)
Available from: 2007-05-23 Created: 2007-05-23 Last updated: 2017-12-14Bibliographically approved
2. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.
Open this publication in new window or tab >>A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.
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2004 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 13, no 8, 799-805 p.Article in journal (Refereed) 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.

Keyword
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
Identifiers
urn:nbn:se:umu:diva-14121 (URN)10.1093/hmg/ddh096 (DOI)14976160 (PubMedID)
Available from: 2007-09-13 Created: 2007-09-13 Last updated: 2017-12-14Bibliographically approved
3. Orthopedic aspects of familial insensitivity to pain due to a novel nerve growth factor beta mutation.
Open this publication in new window or tab >>Orthopedic aspects of familial insensitivity to pain due to a novel nerve growth factor beta mutation.
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2006 (English)In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 77, no 2, 198-202 p.Article in journal (Refereed) Published
Keyword
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
Identifiers
urn:nbn:se:umu:diva-14306 (URN)10.1080/17453670610045911 (DOI)16752279 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
4. HSAN V, a phenotype study of patients heterozygous for the NGFß-mutation
Open this publication in new window or tab >>HSAN V, a phenotype study of patients heterozygous for the NGFß-mutation
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-5055 (URN)
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2010-10-14Bibliographically approved
5. Skin innervation in congenital insensitivity to pain, HSAN V
Open this publication in new window or tab >>Skin innervation in congenital insensitivity to pain, HSAN V
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-5056 (URN)
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2010-01-13Bibliographically approved

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CiteExportLink to record
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Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
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  • Other style
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  • de-DE
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  • Other locale
More languages
Output format
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