PROJECT TITLE
Familial indifference to pain characterization in a large swedish family.
PROJECT DESCRIPTION
A study of familial indifference to pain or Hereditary Sensory and Autonomic Neuropathy in the Lahti
and Kemi relations originating from Vittangi in the Norrbotten county Sweden. The project shall in
PHASE 1 determine diagnoses for patients with both advanced and mild diseases. This will be done
through clinical neurological and orthopedic examinations, x-ray examinations, neurophysiological
examinations, nerve morphology and quantifying of biopsy material from the sural nerve. Additionally,
muscle, skeleton, bone membrane and skin biopsies and synovia biopsies are of interest. Comprehensive
genetic studies of both healthy and affected persons in the relationship will also be performed in
cooperation with Umangenomic AB in Umeå.
The project is a cooperative project between the Gällivare Hospital Orthopedic Clinic, the Institution for
orthopedics and sports medicine NUS, the clinical genetics institution NUS, neurocenter NUS and the
Institution for clinical neurophysiology NUS. We are also cooperating with the Huddinge University
Hospital,departments of Neuropathology and Neurology for review of the sural biopsies. Due to
suspected neuropeptide disorders in both the central and peripheral nervous systems, a cooperation has
been initiated with the Andris Kreichsberg’s neuropeptide lab at the Karolinska University Hospital and
Biocity in Turku Academy Pertti Panula. Additionally, contact has been made with Professor Felicia
Axelrod at the Dysautonomia center in New York and her colleague Professor Max Hilz, Erlangen,
Germany, who has many years of research in this very rare disease.
BACKGROUND
Familial indifference to pain is an uncommon type of peripheral neuropathy. The illness has been
documented among a number of families throughout the world.( 1,2,3,4,6,7,8 ) Since the 1970's a few
cases have been known in the Norrbotten and in the late 1980's additional cases were found in a specific
kindship in the Vittangi area in Norrbotten with origin from the family name Hindersson Kyrö from the
1600's. According to local history, a similar disease has existed in earlier generations among persons in
Vittangi and the surrounding area primarily in the present day Lahti and Kemi kindships. Dislocated and
deformed bones were common along with various types of neuropathic symptoms. The now known living
and deceased persons with various degrees of indifference to pain have been shown by genealogical
studies to be related. The early generation is the founder of Vittangi village from the 1600's, Hindrich
Hindersson-Kyrö who in turn most likely stems from Österbotten area in Finland from an earlier
immigrant Anund Anundsson Tulkkila. He was a juryman in Pello at the Finnish border and it is known
that he died in 1549. Hence, the family most probably stems from Finland Isokyrö in Österbotten. In Pello
on the Swedish side there have been royal merchants since the 1400's. It is likely the disease followed the
immigrants who settled in the lower Torneå valley and in later generations moved to Vittangi village.
The more severe cases have a marked indifference to pain primarily in the legs which prevents the patient
from feeling pain from bone fractures. Further, deformed bones develop at an early age, finally leading to
fulminant Charcot joints. Other milder cases have also been observed with Charcot changes developing
progressively in adult age. However, no definite autonomic deficit such as impaired the sweat function
has been found in our cases. The first examined patient is a woman 80 years of age with severe Charcot
changes in both knee joints, the ankles and the right shoulder. The second examined patient, the woman's
son, had pronounced Charcot changes in both ankles. In a family study in 1987 an additional sister of the
first patient was found. She was under treatment for the diagnosis polyarthritis and had roentgenological
pronounced Charcot joint in the left hip with caput necrosis and in the right knee which was operated with
arthrodesis but never healed. The two sisters are now deceased but x-ray images and madical files remain.
The disease has principally affected knees and ankles although other joints also have been affected. Other
individuals are afflicted with poor ”Kemi legs.” Presently, a younger man 35 years old is known with
onset of the disease already at 7 years of age with bone changes in the knees without symptoms that later
proved to be Charcot changes and later charcot changes in the lower back also appeared. Also, a 10 year
old boy with a more advanced disease with onset already at 3 years of age with pain free multiple
fractures in the foot and lower legs quickly developed Charcot joints in the right ankle. This patient has
also been shown to have complete insensitivity to pain in the lower extremities. Additionally, a 19 year
old woman has the same disease since birth affecting the right ankle and right knee. These three patients
are today seriously handicapped and have been multiply operated with arthrodesis (fusion operation) in
one or multiple joints. Today there is a total 6 known cases of whom 2 have died. We also have a few
patients with milder symtoms where it is not yet clear whether they have the same disease. All of the
mentioned patients are related to each other and married cousins among the parents is noted. Today the
disease is in its 8th to 10th filial generation from the ancestor.
The disease varies somewhat but it can be assumed to be hereditary and similar to the HSAN (Hereditary
Sensory Autonomic Neuropathy) disease, classified by Peter Dyck and Ohta, described in the article ”Not
indifference to pain but varieties of Hereditary sensory and Autonomic neuropathy” ( 1 ) and later the
classification was modified by PK Thomas ( 8 ) In Scandinavia a more severe case of the disease is also
described in Norway by Örbeck et al ”Familial Dysautonomia in a non-jewish child ” ( 10 ) A case has
been reported from Denmark of congenital indifference to pain by Anna Jörgensen ”Medfödt mangel på
smerteseans” ( 5 ) In Sweden there are only few cases described Westerberg and Nordborg in 1981, ”A
new type of non-progressive sensory neuropathy in children” ( 9 )The disease is extremely rare in the
world and the classification has progressively been revised.
GOALS AND OBJECTIVES
The project concerns a Norrland-specific disease (HSAN) in the Kemi and Lahti relationships with origin
from Vittangi in the Norrbotten county. The goal of the study is to describe and analyze of the so-called
Kemi sickness. The project shall in PHASE 1 establish the diagnoses of interest in the family and classify
the presently known forms of the disease. Further, comprehensive clinical genetic studies of the
relationship will be performed. In PHASE 2 we will study of the defect at a cellular level and study
various forms of neuropeptides, and their receptors and hopefully find methods of treating the disease.
METHOD
Patients having the disease have undergone x-ray examinations of the affected joints and patients
suspected of having the disease or who have unspecified joint problems will be screened with a primary
clinical examination and x-ray examination of the joints of interest at their home communities.
Additionally, the pedigree will be further mapped to possibly diagnose more undiscovered cases of
indifference to pain. A genealogy part with the purpose of complementing pedigree with searches in the
family tree and if possible trace cases from other parts of the Scandinavian Shield since relatives have
emigrated to both Finland and Norway during the 1800’s and the ancestors have been assumed to have
immigrated in the late 1500’s from Österbotten, Finland.
PHASE 1 Comprises 5 patients during the spring of 2001. Some of these patients have during the autumn
of 2000 undergone neurological examination including liquor sampling. Further examinations with
EMG/neurography, EEG, SEP, thermography. The remainder will be examined in spring 2001. Further,
all patients will undergo genetic screening for Charcot-Marie-Tooth (Hereditary motor sensory
neuropathy) since one of the family branches is affected by the disease for several generations.
The next phase will be during April 2001, a calling of the patients to Gällivare hospital for renewed x-ray
checkups and examinations. Further the patients will be examined with invasive diagnosing and taking of
tissue specimens. The diagnosing includes arthroscopy (endoscope examination of the joint) of the ankles
and knee joints with simultaneous taking of biopsies from the synovium and joint fluid samples. Bone-
periost biopsies will be taken for neuropeptide analysis at the Neuropeptide lab KS in Stockholm. Skin
biopsies from the forearm and lower leg for neuropeptide FF measurement at Biocity in Turku and for
nerve diagnosis of skin nerves. Finally muscle biopsies to the muscle lab in Umeå.
Additionally biopsies of the sural nerve at the ankle level will be taken in the same seans by Göran
Solders and be handled by Inger Nennesmo for preparation and freezing. Studies will be made for
quantitative nerve histology, electron microscopy with typing of nerve fibers and quantifying them.
Various forms of neuropeptides and opoids (the body’s own endorphins) will be analyzed in the tissue
segments and in liquor from earlier taking of samples in Umeå.
Additionally 3 patients may be examined during the autumn of 2001 with the same procedure.
Blood samples have and will be collected from both healthy and ill patients in the relationship both during
the examinations and by sending referrals for blood tests to the patients. Depending on the results of the
primary diagnosing and CMT screening, a contract may possibly made be with Umangenomic AB in
Umeå during the spring of 2001. If there are too few definite cases to begin a genetic study, the group will
continue to plan for expanded tissue research. From this follows the early stage expanded neuropeptide
sampling from absolutely definite cases of 4 patients with HSAN.
The geneticists will make preparations of DNA from the blood tests. When the diagnosis is established,
the inheritance pattern in the relationship will be determined. Chromosomal localization of the gene will
then be determined with molecular genetic methodology. When the gene has been localized it will be
isolated with the aid of known chromosome localization and the error that causes the illness will be
determined. Gene localization for HSAN type II and V is today unknown.
PROJECT MEMBERS
PHASE 1 of the project is a cooperation between Head Physician Jan Minde at the Orthopedic clinic,
Gällivare Hospital, Docent Göran Tolanen at the Institution for Orthopedics NUS, professor Olle
Svensson at the Institutionen for Orthopedics NUS, professor A Kreichberg at the orthopedic clinic,
Karolinska Institution, professor Gösta Holmgren at the clinical genetics department, NUS, doctoral
candidate Anna Carlssonat the Institutionen for Microbiology, Umeå Universitet, professor Lars Forsgren
Neurocentrum NUS, professor Rolf Libelius neurophysiological department NUS, Ass professor Inger
Nennesmo Huddinge University hospital, Ass professor Göran Solders at the Neurological clinic,
Huddinge University Hospital, Professor Pertti Panula at Biocity Turku Academy University. Further, the
genetic part is in cooperation with Umangenomics AB Umeå, a company owned largely by landstinget,
with Ph.D. Monica Holmberg having the head responsibility.
We will gather knowledge and suggestions for expanded research on the group of patients in PHASE 2
from Professor Felicia Axelrod, Dysautonomia Center, New York, and her partner in Europé, Professor
Max Hilz, Erlangen Germany. We will then possibly expand the number of patients with two known
patients in Sweden with HSAN , living in Luleå and Värmland without known relation to the Vittangi
cases and one patient from Narvik, Norway with ancestors from Norrbotten.
EXPECTED SIGNIFICANCE
The project is important in understanding the etiology of the disease and thereby to increase the
possibility of improving the medical treatment. Further, the results may also contribute to increased
knowledge of pain and how neuropathic pain can be alleviated. There is currently no known treatment of
the disease.
References
1
Not indifference to pain but varieties of
Hereditary sensory and Autonomic neuropathy
Dyck P et al
Brain 106 373-390 1983
2
Congenital Sensory Neuropathy with Selective
Loss of Small Myelinated Fibers
3
Hereditary sensory neuropathy with neurotrophic Donaghy et al
keratitis
Brain 110:563-583 1987
4
Nonprogressiv Type II Hereditary sensory and
autonomic neuropathy: A Homogeneous
Clinicopathologic Entity
Medfödt mangel på smertesans
Ferriere Gerard, Guzzetta
Francesco
Journal of child Neurology Vol
7. Oct 1992
Jörgensen
Ugeeskr laeger 144/51
Hereditary sensory neuropathy type II. Clinical,
electrophysiologic, histologic and biochemical
studies of a Quebec kinship
Two brothers with a variant of hereditary sensory
neuropathy
Hereditary Sensory Neuropathies
Ohta M, Ellefson RD,
Lambert EH, Dyck PJ
Arch Neurol 29: 23-37 1973.
Pavone et al
Neuropediatrics 23 (1992)92-95
Thomas PK
Brain Pathology 3:157-163 1993
9
A new type of non-progressive sensory
neuropatrhy in children with atypical
dysautonomia
Westerberg, Nordborg et al
Acta neuropathologica 1981
55:135-141
10
Familial Dysautonomia in a non-jewish child
Örbeck, Oftedal
Acta Pediatr Scand 66:777-781
1977
5
6
7
8
Low, Burke, McLeod et al
Annuals of Neurology Vol 3 No
2 1978