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Norrbottnian congenital insensitivity to pain

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The document summarizes research on congenital insensitivity to pain in Norrbotten, Sweden. It describes: - A family in Vittangi with a mutation in the nerve growth factor beta gene causing insensitivity to pain. Homozygous individuals have no deep pain sensation. - Affected individuals experience fractures and joint deformities without pain. They develop Charcot joints in knees and feet from an early age. - The condition was traced back to a family that immigrated to the area in the 1600s, resulting in consanguinity that concentrated the genetic mutation.

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CONGENITAL INSENSITIVITY TO PAIN NORRBOTTNIAN TYPE (Ärftlig smärtokänslighet) Jan Minde MD, PhD jan.minde@nll.se Gällivare hospital, Sweden
CONGENITAL INSENSITIVITY TO PAIN NORRBOTTNIAN TYPE
1600 century PELLO 1700-century Pello Vittangi 1600 century 1700 century Tornio River in the middle and arrows shove Kyrö ancestor moved from South Finland to Pello and later to Vittangi along the river. Green = Homestead for Homozygot; Red= Homestead for Heterozygotes Version 2006
Ìý
ARJEPLOG SJUKAN Arjeplogssjukan Porphyri 1935 Einar Wallqvist Skellefteåsjukan Familjär Amyloidos 1976 Rune Andersson Kostmanns sjukdom Agranulocytos 1956 Rolf Kostmann Familjär smärtokänslighet 2006 Vittangi sjukan Common Hereditary disease in North Sweden (NORRLANDS SJUKDOMAR) Mb Gaucher Norrbottnian typ III 1986 Anders Eriksson
Nociceptive pain are important and common symptom for a orthopedic surgeon. is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm Insensitivity to pain is it a dream condition ?
Pain How to ask about pain to a Norrbottnian patient Who never felt pure pain ! Insensitivity to pain gives a risk Skin injury, joint deformity
Pain function The ability to experience pain is essential for protection from injury, and recognition of the presence of injury. Pain is considered as highly subjective
Pain definition Ìý Pain is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage".
Ìý
Pain classification Nociceptive pain is pain in which normal nerves transmit information to the central nervous system about trauma to tissues (nocere = to injure, Latin). Neuropathic pain is pain in which there are structural and/or functional nervous system adaptations secondary to injury, that take place either centrally or peripherally (Jensen, 1996). Much of what has previously been considered psychogenic pain is now better understood as neuropathic pain of central origin. The IASP defines central pain as "pain initiated or caused by a primary lesion or dysfunction in the central nervous system" (Merskey, and Bogduk, 1994). "Neuropathic" should not be confused with "neurogenic", a term used to describe pain resulting from injury to a peripheral nerve but without necessarily implying any "neuropathy". Ref [email_address] 2008/08/12
Ìý
Congenital insensitivity to pain Norrbottnian type PROJECT TITLE Localization and identification of the causes of familial insensitivity to pain in Norrbotten and characterization of various types of the disease.
Congenital insensitivity to pain Norrbottnian type Since the 1960’s a few isolated cases have been known in Norrbotten. In the late 1980’s a few additional cases were discovered in a certain family in the Vittangi area in Norrbotten.
Congenital insensitivity to pain Norrbottnian type The study was initiated when I met two adult patients, a mother and her son both with Charcot joints in the knee and ankle without an explanatory diagnosis. Shortly thereafter, a young boy was admitted to the orthopedic floor of Gällivare hospital with painless foot fractures, noted by his mother as a swollen foot. The correct diagnosis escaped us for a long time, until another patient with a similar clinical presentation turned up.
Congenital insensitivity to pain Norrbottnian type The affected family resides in the Vittangi area of Norrbotten. The family emanated from southern Finland and immigrated in the 1600s. The earliest immigrant was a juryman in the small village of Pello along Tornio River at the Finnish border, who died in 1549. The index person was the founder of Vittangi village in the 1600s. He stemmed from the immigrant family in Pello. As in other isolated remote communities, consanguinity was common. It is likely that the disorder followed the migrants settling in Tornio valley.
Congenital insensitivity to pain Norrbottnian type The patients with Norrbottnian hereditary sensory and autonomic neuropathy their homestead are around the Tornio River valley, which is characterized by large rivers flowing from the mountains of northern Sweden into the Gulf of Bothnia Settlements were strictly concentrated along the rivers from south to north.
Congenital insensitivity to pain Norrbottnian type We recently reported on a Swedish family, clinically best described as HSAN type V, having a point mutation in the nerve growth factor beta (NGFb) gene on chromosome 1p11.2-p13.2 No earlier cases described in Sweden Reported ca 90 cases HSAN Type IV 20 cases HSAN type V (2009)
Congenital insensitivity to pain Norrbottnian type today Homozygote NGFB mutation 3 cases with severe congenital disease Insensitivity to deep pain + Temperature disturbance+ Small fiber neuropathy +Symtomless fractures + Charcot joint + Skin ulcus Heterozygota NGFB mutation 26 patient mild adult form No typical insensitivity to pain +Charcot joint adult (30-70 år) + CTS 26 patient är symtomless .
Congenital insensitivity to pain Norrbottnian type Hereditär Sensorisk och Autonom Neuropati som blev primärt klassifierad av P J Dyck 1983 HSAN five types Typ I dominant form Typ III familjär dysautonomi (Report 3 case 1981 , Nordborg et al i Sverige) Typ IV och V Insensitivity to pain Typ IV with anhidrosis, 1 spontanfall i Sverige Typ V utan anhidrosis
CONGENITAL INSENSITIVITY TO PAIN NORRBOTTNIAN TYPE Peter J Dyck discussed about Norrbottnian congenital insensitivity to Pain as a new type VI (Visit Dyck lab Mayo clinic 2007)
HSAN Genetic classification Reviere et al 2004 Minde et al. 2004 Early NGFB/1p11.2- p13.2 AR VI eller V-b Houlden et al. 2001 Early 1q21-22 AR V Indo et al. 1996 Birth TRKA/NGF/1q21-22 AR IV Slaugenhaupt et al. 2001 Birth IKBKAP/ 9q31-q33 AR III Lafreniere et al. 2004 Early HSN2/12p13.3 AR II Kok et al. 2001 Adult 3p22-p24 AD I B Bejaoui et al. 2001 Adult SPTLCI/ 9q22.1-22.3 AD I Reference Onset Gene Locus Trans mission HSAN Type
Insensitivity to pain Genetic classification Minde et al 2006
Genealogi Genealogical information was obtained from relatives, genealogists and church records. We used a genealogy program (Min Släkt version 3.1, Dannberg Data, Sweden) to register data for the pedigree. The genetic program used was Cyrillic Pedigree Editor for Windows 3.1.
Genealogi: 16-generations family tree with komplex consanginity.
INSENSITIVITY TO PAIN Haplotype analysis of chromosome 1p11.2-13.2. Pedigree of the family with loss of pain perception, showing a common haplotype on chromosome 1p11.2-p13.2 for which the affected individuals, number 4, 8 and 11, are homozygous.
GENETIK HAPLOTYPE ANALYSIS Haplotype analysis of chromosome 1p11.2-13.2. Pedigree of the family with loss of pain perception showing a common haplotype on chromosome 1p11.2-p13.2 for which the affected individuals, number 4, 8 and 11, are homozygous. Squares=males; circles=females; filled symbols=individuals affected with the severe form of pain insensitivity; Dots= obligate carriers. Filled bars indicate the disease haplotype. The disease critical region is restricted by SNP markers rs2490334 and rs2275607.
GENETIK Mutation analysis Structure of the NGFB protein, adapted from Rydén and Ibánez with the alternative amino acid in position 100 of the mature protein, highlighted.
GENETIK Mutation analysis Electropherogram showing part of exon 3 of the NGFB gene sequence containing the NGFB mutation associated with the disease phenotype. The arrow indicates the mutation at position 661 changing a basic arginine to a non- polar tryptophan. The affected individual (8, Fig. 1) is homozygous for the mutation, his unaffected parent (6, Fig. 1) heterozygous and an unaffected relative (3, Fig. 1) homozygous for the wt allele. Mutation analysis
GENETIK Mutation analysis Sequence alignment of part of the NGFB protein sequence from different species as well as of human neurotrophins showing the conservation of the mutated amino acid in position 100 of the mature NGFB protein (boxed).
VITTANGI Historik
Primary Neuropathies with Charcot artropati HSAN hereditary sensory autonomic neuropathy HMSN hereditary motor sensory neuropathy Charcot-Marie-Tooth FAMILIAL AMYLOIDOS Skellefteå sjukan
NGFB mutation Patent since 2003, world wide Vi har konstatera att vårt muterade NGFB stör utsöndring av Pro-NGF från cellerna  NGF ↓ som påverkar nervfiber utveckling men troligen också smärtmedieringen. Ref: Ej publicerats Norberg, Minde, Holmberg et al 2007 odling av PC12 phaechromocytom celler
NGFB molekylen visar en punkt mutation på aminosyra 100 Rydén and Ibánez
2 NGFB molekyler bildar NGF dimer
Ìý
Ìý
Patienternas symtom är mer likt ett stycke absurd teater eller en märklig dokussåpa ? Kommentar om sjukdomen i SVD ledare 2006
Ìý
Ìý
Norrbottnisk Ärftlig smärtokänslighet The most frequent orthopedic manifestations in HSAN patients are multiple fractures, Charcot joints, avascular necrosis with possible leg length discrepancy, osteomyelitis, septic arthritis, dislocations, auto-amputations, self-mutilations and self-inflicted soft-tissue injuries.
First case Woman 80 years old Varus deformity both knees. No pain! Instability in the shoulder
Knee
Schoulder
Andra fallet 60 years-old, son to case 1 Tidigare helt frisk Deformity ankel joints No pain
Ankle
Ìý
Diagnose many patients with severe deformity knees with discrete pain
Ìý
Congenital Neuropatisk artropati !
Charcot artropati Destruktiv joint disease More instability then pain Common causes are diabetes mellitus Other : Syfilis, myelomeningocele Syringomyeli, Leprosy CMT Skellefteå sjukan Alkoholism, spinalcord tumor CIPA JM Charcot
Första unga patienten Pojke 4 år söker med mamman pga. fotsvullnad av oklar genes Pojken hade hoppat ut året innan från 2a vån utan att smärta eller skada. Inga smärtor i foten, Inget säker trauma Mamman noterat att pojken har en hög smärt tröskel ? När han började krypa slog skallen i väggar utan symtom, tvingad använda hjälm.
Svullnaden fot var smärtlösa multipla frakturer med riklig callus
5 år symtomfri tibia fraktur. Skrämde Ssk med att lyfta benet som vek sig onaturligt
6 år börjar han utveckla Charcot artropatier i fotleder, talus destruktion
Utvecklar grav hydrops knäleder  ostechondriter  kompletta Charcot leder knän utan smärta vid 14 års ålder, sitter i rullstol. Vi planerar artrodes höger knä, osteotomi vänster knä
Ìý
Andra unga patienten Tjej idag 23 år Behandlats i Umeå för bilat knä och fotleds charcot på 80-talet, symtomdebut 7 år I skolan hoppade från ribbstolar ned på knäna för det roliga ploppande ljudet. Ingen smärta 13 år Artrodes knä och fotled
Ìý
2005 Charcot utveckling i höger höft
Tredje unga patienten 31 år data ingenjör Debuterar 7 år med Hydrops hö-knä och en symtomlös tibia fraktur. Succesiv progress av knä charcot. Opererad artrodes vä knä och Osteotomi höger knä
Ìý
20 år sällsynt recidiverande Spinal charcot artropati utveckling, debuterar med instabil L5-S1 opererad bakre fusion.
22 år recidiv i nivån L2-L3 med parapares, refusionerad och slutligen samma utvecklig efter 3 år i nivån Th12-L1
Ytterligare Recidiv Th12-L1 Fusionerad från Th11-S1
Pat (5e fallet) åttonde Charcot led ! vänster armbåge utvecklats nu i sommar
Normal Sural nerve biopsi
Sural nerve biopsi från en homozygot patient visar kraftig reduktion av Aδ myeliniserade fibrer och normal large-diameter myeliniserade fibrer.
Tack för mig Tack för mig

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Norrbottnian congenital insensitivity to pain

  • 1. CONGENITAL INSENSITIVITY TO PAIN NORRBOTTNIAN TYPE (Ärftlig smärtokänslighet) Jan Minde MD, PhD jan.minde@nll.se Gällivare hospital, Sweden
  • 2. CONGENITAL INSENSITIVITY TO PAIN NORRBOTTNIAN TYPE
  • 3. 1600 century PELLO 1700-century Pello Vittangi 1600 century 1700 century Tornio River in the middle and arrows shove Kyrö ancestor moved from South Finland to Pello and later to Vittangi along the river. Green = Homestead for Homozygot; Red= Homestead for Heterozygotes Version 2006
  • 5. ARJEPLOG SJUKAN Arjeplogssjukan Porphyri 1935 Einar Wallqvist SkellefteÃ¥sjukan Familjär Amyloidos 1976 Rune Andersson Kostmanns sjukdom Agranulocytos 1956 Rolf Kostmann Familjär smärtokänslighet 2006 Vittangi sjukan Common Hereditary disease in North Sweden (NORRLANDS SJUKDOMAR) Mb Gaucher Norrbottnian typ III 1986 Anders Eriksson
  • 6. Nociceptive pain are important and common symptom for a orthopedic surgeon. is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm Insensitivity to pain is it a dream condition ?
  • 7. Pain How to ask about pain to a Norrbottnian patient Who never felt pure pain ! Insensitivity to pain gives a risk Skin injury, joint deformity
  • 8. Pain function The ability to experience pain is essential for protection from injury, and recognition of the presence of injury. Pain is considered as highly subjective
  • 9. Pain definition Ìý Pain is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage".
  • 10. Ìý
  • 11. Pain classification Nociceptive pain is pain in which normal nerves transmit information to the central nervous system about trauma to tissues (nocere = to injure, Latin). Neuropathic pain is pain in which there are structural and/or functional nervous system adaptations secondary to injury, that take place either centrally or peripherally (Jensen, 1996). Much of what has previously been considered psychogenic pain is now better understood as neuropathic pain of central origin. The IASP defines central pain as "pain initiated or caused by a primary lesion or dysfunction in the central nervous system" (Merskey, and Bogduk, 1994). "Neuropathic" should not be confused with "neurogenic", a term used to describe pain resulting from injury to a peripheral nerve but without necessarily implying any "neuropathy". Ref [email_address] 2008/08/12
  • 12. Ìý
  • 13. Congenital insensitivity to pain Norrbottnian type PROJECT TITLE Localization and identification of the causes of familial insensitivity to pain in Norrbotten and characterization of various types of the disease.
  • 14. Congenital insensitivity to pain Norrbottnian type Since the 1960’s a few isolated cases have been known in Norrbotten. In the late 1980’s a few additional cases were discovered in a certain family in the Vittangi area in Norrbotten.
  • 15. Congenital insensitivity to pain Norrbottnian type The study was initiated when I met two adult patients, a mother and her son both with Charcot joints in the knee and ankle without an explanatory diagnosis. Shortly thereafter, a young boy was admitted to the orthopedic floor of Gällivare hospital with painless foot fractures, noted by his mother as a swollen foot. The correct diagnosis escaped us for a long time, until another patient with a similar clinical presentation turned up.
  • 16. Congenital insensitivity to pain Norrbottnian type The affected family resides in the Vittangi area of Norrbotten. The family emanated from southern Finland and immigrated in the 1600s. The earliest immigrant was a juryman in the small village of Pello along Tornio River at the Finnish border, who died in 1549. The index person was the founder of Vittangi village in the 1600s. He stemmed from the immigrant family in Pello. As in other isolated remote communities, consanguinity was common. It is likely that the disorder followed the migrants settling in Tornio valley.
  • 17. Congenital insensitivity to pain Norrbottnian type The patients with Norrbottnian hereditary sensory and autonomic neuropathy their homestead are around the Tornio River valley, which is characterized by large rivers flowing from the mountains of northern Sweden into the Gulf of Bothnia Settlements were strictly concentrated along the rivers from south to north.
  • 18. Congenital insensitivity to pain Norrbottnian type We recently reported on a Swedish family, clinically best described as HSAN type V, having a point mutation in the nerve growth factor beta (NGFb) gene on chromosome 1p11.2-p13.2 No earlier cases described in Sweden Reported ca 90 cases HSAN Type IV 20 cases HSAN type V (2009)
  • 19. Congenital insensitivity to pain Norrbottnian type today Homozygote NGFB mutation 3 cases with severe congenital disease Insensitivity to deep pain + Temperature disturbance+ Small fiber neuropathy +Symtomless fractures + Charcot joint + Skin ulcus Heterozygota NGFB mutation 26 patient mild adult form No typical insensitivity to pain +Charcot joint adult (30-70 Ã¥r) + CTS 26 patient är symtomless .
  • 20. Congenital insensitivity to pain Norrbottnian type Hereditär Sensorisk och Autonom Neuropati som blev primärt klassifierad av P J Dyck 1983 HSAN five types Typ I dominant form Typ III familjär dysautonomi (Report 3 case 1981 , Nordborg et al i Sverige) Typ IV och V Insensitivity to pain Typ IV with anhidrosis, 1 spontanfall i Sverige Typ V utan anhidrosis
  • 21. CONGENITAL INSENSITIVITY TO PAIN NORRBOTTNIAN TYPE Peter J Dyck discussed about Norrbottnian congenital insensitivity to Pain as a new type VI (Visit Dyck lab Mayo clinic 2007)
  • 22. HSAN Genetic classification Reviere et al 2004 Minde et al. 2004 Early NGFB/1p11.2- p13.2 AR VI eller V-b Houlden et al. 2001 Early 1q21-22 AR V Indo et al. 1996 Birth TRKA/NGF/1q21-22 AR IV Slaugenhaupt et al. 2001 Birth IKBKAP/ 9q31-q33 AR III Lafreniere et al. 2004 Early HSN2/12p13.3 AR II Kok et al. 2001 Adult 3p22-p24 AD I B Bejaoui et al. 2001 Adult SPTLCI/ 9q22.1-22.3 AD I Reference Onset Gene Locus Trans mission HSAN Type
  • 23. Insensitivity to pain Genetic classification Minde et al 2006
  • 24. Genealogi Genealogical information was obtained from relatives, genealogists and church records. We used a genealogy program (Min Släkt version 3.1, Dannberg Data, Sweden) to register data for the pedigree. The genetic program used was Cyrillic Pedigree Editor for Windows 3.1.
  • 25. Genealogi: 16-generations family tree with komplex consanginity.
  • 26. INSENSITIVITY TO PAIN Haplotype analysis of chromosome 1p11.2-13.2. Pedigree of the family with loss of pain perception, showing a common haplotype on chromosome 1p11.2-p13.2 for which the affected individuals, number 4, 8 and 11, are homozygous.
  • 27. GENETIK HAPLOTYPE ANALYSIS Haplotype analysis of chromosome 1p11.2-13.2. Pedigree of the family with loss of pain perception showing a common haplotype on chromosome 1p11.2-p13.2 for which the affected individuals, number 4, 8 and 11, are homozygous. Squares=males; circles=females; filled symbols=individuals affected with the severe form of pain insensitivity; Dots= obligate carriers. Filled bars indicate the disease haplotype. The disease critical region is restricted by SNP markers rs2490334 and rs2275607.
  • 28. GENETIK Mutation analysis Structure of the NGFB protein, adapted from Rydén and Ibánez with the alternative amino acid in position 100 of the mature protein, highlighted.
  • 29. GENETIK Mutation analysis Electropherogram showing part of exon 3 of the NGFB gene sequence containing the NGFB mutation associated with the disease phenotype. The arrow indicates the mutation at position 661 changing a basic arginine to a non- polar tryptophan. The affected individual (8, Fig. 1) is homozygous for the mutation, his unaffected parent (6, Fig. 1) heterozygous and an unaffected relative (3, Fig. 1) homozygous for the wt allele. Mutation analysis
  • 30. GENETIK Mutation analysis Sequence alignment of part of the NGFB protein sequence from different species as well as of human neurotrophins showing the conservation of the mutated amino acid in position 100 of the mature NGFB protein (boxed).
  • 32. Primary Neuropathies with Charcot artropati HSAN hereditary sensory autonomic neuropathy HMSN hereditary motor sensory neuropathy Charcot-Marie-Tooth FAMILIAL AMYLOIDOS SkellefteÃ¥ sjukan
  • 33. NGFB mutation Patent since 2003, world wide Vi har konstatera att vÃ¥rt muterade NGFB stör utsöndring av Pro-NGF frÃ¥n cellerna  NGF ↓ som pÃ¥verkar nervfiber utveckling men troligen ocksÃ¥ smärtmedieringen. Ref: Ej publicerats Norberg, Minde, Holmberg et al 2007 odling av PC12 phaechromocytom celler
  • 34. NGFB molekylen visar en punkt mutation pÃ¥ aminosyra 100 Rydén and Ibánez
  • 35. 2 NGFB molekyler bildar NGF dimer
  • 36. Ìý
  • 37. Ìý
  • 38. Patienternas symtom är mer likt ett stycke absurd teater eller en märklig dokussÃ¥pa ? Kommentar om sjukdomen i SVD ledare 2006
  • 39. Ìý
  • 40. Ìý
  • 41. Norrbottnisk Ärftlig smärtokänslighet The most frequent orthopedic manifestations in HSAN patients are multiple fractures, Charcot joints, avascular necrosis with possible leg length discrepancy, osteomyelitis, septic arthritis, dislocations, auto-amputations, self-mutilations and self-inflicted soft-tissue injuries.
  • 42. First case Woman 80 years old Varus deformity both knees. No pain! Instability in the shoulder
  • 43. Knee
  • 45. Andra fallet 60 years-old, son to case 1 Tidigare helt frisk Deformity ankel joints No pain
  • 46. Ankle
  • 47. Ìý
  • 48. Diagnose many patients with severe deformity knees with discrete pain
  • 49. Ìý
  • 51. Charcot artropati Destruktiv joint disease More instability then pain Common causes are diabetes mellitus Other : Syfilis, myelomeningocele Syringomyeli, Leprosy CMT SkellefteÃ¥ sjukan Alkoholism, spinalcord tumor CIPA JM Charcot
  • 52. Första unga patienten Pojke 4 Ã¥r söker med mamman pga. fotsvullnad av oklar genes Pojken hade hoppat ut Ã¥ret innan frÃ¥n 2a vÃ¥n utan att smärta eller skada. Inga smärtor i foten, Inget säker trauma Mamman noterat att pojken har en hög smärt tröskel ? När han började krypa slog skallen i väggar utan symtom, tvingad använda hjälm.
  • 53. Svullnaden fot var smärtlösa multipla frakturer med riklig callus
  • 54. 5 Ã¥r symtomfri tibia fraktur. Skrämde Ssk med att lyfta benet som vek sig onaturligt
  • 55. 6 Ã¥r börjar han utveckla Charcot artropatier i fotleder, talus destruktion
  • 56. Utvecklar grav hydrops knäleder  ostechondriter  kompletta Charcot leder knän utan smärta vid 14 Ã¥rs Ã¥lder, sitter i rullstol. Vi planerar artrodes höger knä, osteotomi vänster knä
  • 57. Ìý
  • 58. Andra unga patienten Tjej idag 23 Ã¥r Behandlats i UmeÃ¥ för bilat knä och fotleds charcot pÃ¥ 80-talet, symtomdebut 7 Ã¥r I skolan hoppade frÃ¥n ribbstolar ned pÃ¥ knäna för det roliga ploppande ljudet. Ingen smärta 13 Ã¥r Artrodes knä och fotled
  • 59. Ìý
  • 60. 2005 Charcot utveckling i höger höft
  • 61. Tredje unga patienten 31 Ã¥r data ingenjör Debuterar 7 Ã¥r med Hydrops hö-knä och en symtomlös tibia fraktur. Succesiv progress av knä charcot. Opererad artrodes vä knä och Osteotomi höger knä
  • 62. Ìý
  • 63. 20 Ã¥r sällsynt recidiverande Spinal charcot artropati utveckling, debuterar med instabil L5-S1 opererad bakre fusion.
  • 64. 22 Ã¥r recidiv i nivÃ¥n L2-L3 med parapares, refusionerad och slutligen samma utvecklig efter 3 Ã¥r i nivÃ¥n Th12-L1
  • 65. Ytterligare Recidiv Th12-L1 Fusionerad frÃ¥n Th11-S1
  • 66. Pat (5e fallet) Ã¥ttonde Charcot led ! vänster armbÃ¥ge utvecklats nu i sommar
  • 67. Normal Sural nerve biopsi
  • 68. Sural nerve biopsi frÃ¥n en homozygot patient visar kraftig reduktion av Aδ myeliniserade fibrer och normal large-diameter myeliniserade fibrer.
  • 69. Tack för mig Tack för mig