Jan Minde

Familial insensitivity to pain (HSAN V) and a mutation in the NGFB gene. A neurophysiological and pathological study.

We have studied a large Swedish family with a mutation in the nerve growth factor beta (NGFB) gene causing insensitivity to deep pain without anhidrosis (hereditary sensory and autonomic neuropathy, type V; HSAN V). Painfree joint destruction and fractures were common. Peripheral nerve conduction was normal, but temperature thresholds were increased. Sural nerve biopsies showed a moderate loss of Aδ fibers and a severe reduction of C fibers. The three most severely affected cases were all born to consanguineous parents, and were homozygotes for the causal genetic mutation. Treatment of these patients is discussed. Muscle Nerve, 2004

Orthopedic aspects of familial insensitivity to pain due to a novel nerve growth factor beta mutation.

Background Congenital insensitivity to pain is a rare hereditary sensory neuropathy Patients We present 6 patients from a family with a mutation in the nerve growth factor beta gene (NGFB) Results 3 patients were homozygous with a mutilating arthropathy starting early in life, and 3 patients were presumably heterozygous with a milder course starting in adulthood. All patients had normal mental abilities. In addition to absence of deep pain, the patients had impaired temperature sensation, but no autonomic deficiency. Sural nerve biopsies showed a moderate loss of A-δfibres and a severe reduction in C fibers. Clinically, the disorder most often affected the lower extremities, with an insidious progressive joint swelling or a painless fracture, but the spine could also be involved with gross and unstable spondylolisthesis. Fracture healing was uneventful, but the arthropathy was progressive, eventually resulting in gross deformity and instability. When treating patients with congenital disorders such as this one, it is important to consider the slowly progressive nature of the disorder, and the orthopedic operations should therefore be planned from a long-term standpoint. Arthrodesis, limb lengthening and spinal decompression or fusion are the only elective procedures that seem reasonable. Fitting of orthosis for joint protection is also demanding. To delay the development of neuropathic arthropathy, patient education is essential but difficult in the very young Interpretation The different expression between homo- and heterozygous subjects and the central role of nerve growth factor make this disease an interesting model system for studies of disease mechanisms and the molecular background to pain.

A novel NGFB point mutation, a phenotype study of heterozygous patients

Objective: A family with neurological findings similar to hereditary sensory and autonomic neuropathy type V having a point mutation in the nerve growth factor beta (NGFB) gene was recently described. The homozygous genotype gives disabling symptoms. The purpose of the present study was to evaluate the symptoms in heterozygous patients. Methods: 26 patients heterozygous for the NGFB mutation (12 men, mean age 50 (13–90) years) were examined clinically and answered a health status questionnaire, including the Michigan Neuropathy Screening Instrument (MNSI). 28 relatives (15 men, mean age 44 (15–86) years) without the mutation served as controls in the clinical examination part. 23 of the heterozygotes were examined neurophysiologically and six heterozygous patients underwent a sural nerve biopsy. Results: The heterozygous phenotype ranged from eight patients with Charcot arthropathy starting in adult age and associated with variable symptoms of neuropathy but without complete insensitivity to pain, anhidrosis or mental retardation, to 10 symptom free patients. There was no difference in MNSI between the young heterozygous cases (<55 years old) and the controls. Six of 23 heterozygous patients had impaired cutaneous thermal perception and 11 of 23 had signs of carpal tunnel syndrome. Sural nerve biopsies showed a moderate reduction of both small myelinated (Aδ) and unmyelinated (C) fibres. No apparent correlation of small fibre reduction to symptoms was found. Conclusions: The NGFB mutation in its heterozygous form results in a milder disease than in homozygotes, with a variable clinical picture, ranging from asymptomatic cases to those with Charcot arthropathy appearing in adult age. Particularly age, but perhaps lifestyle factors also, may influence the development of clinical polyneuropathy.

Nerve growth factor R221W responsible for insensitivity to pain is defectively processed and accumulates as proNGF.

We have previously identified a homozygous missense (R221W) mutation in the NGFB gene in patients with loss of deep pain perception. NGF is important not only for the survival of sensory neurons but also for the sympathetic neurons and cholinergic neurons of the basal forebrain; however, it is the sensory neurons that are mainly affected in patients with mutant NGFB. In this report, we describe the effects of the mutation on the function of NGF protein and the molecular mechanisms that may underlie the pain insensitivity phenotype in these patients. We show that the mutant NGF has lost its ability to mediate differentiation of PC12 cells into a neuron-like phenotype. We also show that the inability of PC12 cells to differentiate is due to a markedly reduced secretion of mature R221W NGF. The R221W NGF is found mainly as proNGF, in contrast to wild-type NGF which is predominantly in the mature form in both undifferentiated and differentiated PC12 cells. The reduction in numbers of sensory fibers observed in the patients is therefore probably due to loss of trophic support as a result of drastically reduced secretion of NGF from the target organs. Taken together, these data show a clear decrease in the availability of mutant mature NGF and also an accumulation of proNGF in both neuronal and non-neuronal cells. The differential loss of NGF-dependent neurons in these patients, mainly affecting sensory neurons, may depend on differences in the roles of mature NGF and proNGF in different cells and tissues.

Norrbottnian congenital insensitivity to pain

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 beta gene (NGFbeta). 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 NGFbeta 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 (Adelta-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 three cases joint replacement. Nine patients had neuropathy, and nine 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.

Socket wall addition device in the treatment of recurrent hip prosthesis dislocation : Good outcome in 12 patients followed for 4.5 (1–9) years

Background Recurrent dislocation in total hip replacement is difficult to treat and causes severe morbidity. Patients and methods 12 patients suffering dislocations were reoperated with a socket wall addition device (anti-luxation ring) for the Lubinus SPII prosthesis, and were followed up after a mean of 4.5 (1–9) years with regard to redislocation, function and radiographic loos-ening. Results 1 of the patients suffered a redislocation after almost 7 years of use. There was no loosening during the follow-up time. A Harris hip score of 87 (60–100), a health-related quality of life (EQ-5D) index of 0.8 (0.6–1.0) and total range of motion of 145° (125–165) indicate that the patients had a level of function comparable to that of age-matched hip surgery patients with no com-plications. Interpretation The anti-luxation ring shows promising mid-term results and seems to provide an alternative to more extensive revision surgery for selected patients. ▪

Rare human nerve growth factor-β mutation reveals relationship between C-afferent density and acute pain evaluation

The rare nerve growth factor-β (NGFB) mutation R221W causes a selective loss of thinly myelinated fibers and especially unmyelinated C-fibers. Carriers of this mutation show altered pain sensation. A subset presents with arthropathic symptoms, with the homozygous most severely affected. The aim of the present study was to investigate the relationship between peripheral afferent loss and pain evaluation by performing a quantification of small-fiber density in the cornea of the carriers, relating density to pain evaluation measures. In vivo corneal confocal microscopy (CCM) was used to quantify C-fiber loss in the cornea of 19 R221W mutation carriers (3 homozygous) and 19 age-matched healthy control subjects. Pain evaluation data via the Situational Pain Questionnaire (SPQ) and the severity of neuropathy based on the Neuropathy Disability Score (NDS) were assessed. Homozygotes, heterozygotes, and control groups differed significantly in corneal C-nerve fiber density, with the homozygotes showing a significant afferent reduction. Importantly, peripheral C-fiber loss correlated negatively with pain evaluation, as revealed by SPQ scores. This study is the first to investigate the contribution of small-fiber density to the perceptual evaluation of pain. It demonstrates that the lower the peripheral small-fiber density, the lower the degree of reported pain intensity, indicating a functional relationship between small-fiber density and higher level pain experience.