Norrbottnian congenital insensitivity to pain
description
Transcript of Norrbottnian congenital insensitivity to pain
CONGENITAL INSENSITIVITY TO PAINNORRBOTTNIAN TYPE
(Ärftlig smärtokänslighet)
Jan Minde MD, PhD [email protected] Gällivare hospital, Sweden
CONGENITAL INSENSITIVITY TO PAINNORRBOTTNIAN 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
ARJEPLOG SJUKAN
Arjeplogssjukan Porphyri 1935 Einar Wallqvist
Skellefteåsjukan Familjär Amyloidos1976 Rune Andersson
Kostmanns sjukdom Agranulocytos1956 Rolf Kostmann
Familjär smärtokänslighet 2006 Vittangi sjukan
Common Hereditary disease in North Sweden (NORRLANDS SJUKDOMAR)
Mb Gaucher Norrbottnian typ III1986 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 painis it a dream condition ?
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
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".
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 protected] 2008/08/12
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 mutation26 patient mild adult formNo 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 formTyp III familjär dysautonomi (Report 3 case 1981 ,Nordborg et al i Sverige)Typ IV och V Insensitivity to painTyp IV with anhidrosis, 1 spontanfall i SverigeTyp V utan anhidrosis
CONGENITAL INSENSITIVITY TO PAINNORRBOTTNIAN 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
HSAN Type
Transmission
Gene Locus Onset Reference
I AD SPTLCI/ 9q22.1-22.3 Adult Bejaoui et al. 2001
I B AD 3p22-p24 Adult Kok et al. 2001
II AR HSN2/12p13.3 Early Lafreniere et al. 2004
III AR IKBKAP/ 9q31-q33 Birth Slaugenhaupt et al. 2001
IV AR TRKA/NGF/1q21-22 Birth Indo et al. 1996
V AR 1q21-22 Early Houlden et al. 2001
VI eller V-b AR NGFB/1p11.2- p13.2 Early Minde et al. 2004
Insensitivity to pain Genetic classification Minde et al 2006
HSAN type
Age
ons
et
Mut
atio
n
Con
sang
uine
ous
pare
nts
Ons
et s
ympt
om
Inse
nsit
ivit
y to
pai
n
Men
tal r
etar
dati
on
Tem
pera
ture
sen
sati
on
Anh
idro
sis
Aut
onom
sym
ptom
Fra
ctur
e
Mul
tipl
e in
fect
ion
or
ulce
r
Aut
oam
puta
tion
Cha
rcot
join
t
Ner
vebi
opsy
CT
S
EN
eG
ReferensTRKA
HomozygousCongenital TRKA Y A/ F Y Y N Y Y Y Y Y Y Aα N
Aδ ↓↓ C ↓
N NP Mardy et al. 2001, Shatzky et al. 2000
NGFB Homozygous
Child hood NGFB Y A/ F Y N Y/N N Y/N Y Y N Y Aα N Aδ ↓ C ↓↓
N NP Minde et al. 2004
TRKA compound
heterozygous
Adult TRKA Y A Y N Y N Y Y ? ? Y Aα N Aδ ↓↓
C ↓
? ? Yotsumoto et al. 1999
NGFB Heterozygous
symtom
Adult NGFB Y/N A N N Y/N N Y/N N N N Y Aα N Aδ ↓ C ↓
Y N/NP Minde et al. 2006
NGFB Heterozygous
carrier
All age NGFB Y/N N N N Y N N N N N N Aα N Aδ ↓ C ↓
N N 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.
GENETIKHAPLOTYPE 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
Patienternas symtom är mer likt ett stycke absurd teater eller en märklig dokussåpa ?
Kommentar om sjukdomen iSVD ledare 2006
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 caseWoman 80 years oldVarus deformity both knees.No pain!Instability in the shoulder
Knee
Schoulder
Andra fallet
60 years-old, son to case 1Tidigare helt friskDeformity ankel joints No pain
Ankle
Diagnose many patients with severe deformity knees with discrete pain
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
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
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
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-L1Fusionerad frånTh11-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