CONGENITAL INSENSITIVITY TO PAINNORRBOTTNIAN TYPE

(Ärftlig smärtokänslighet)

Jan Minde MD, PhD jan.minde@nll.se 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 ranney@hsfx.ca 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.

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Tack för mig