Clinical and biochemical effects of the E139K missense mutation in the TIMP3 gene, associated with Sorsby fundus dystrophy.

PURPOSE: To determine the phenotypic and biochemical characteristics of the p.E139K missense variant in tissue inhibitor of metalloproteinase 3 (TIMP3) associated with Sorsby fundus dystrophy (SFD). METHODS: The coding regions and adjacent intronic sequence of TIMP3 were amplified by polymerase chain reaction and then analyzed by bidirectional sequencing. Allele-specific PCR was used to determine the minimum allele frequency of the mutant allele in ethnically matched controls. Clinical examination and imaging of affected individuals with color fundus photography, scanning laser ophthalmoscope (fundal autofluorescence), and optical coherence tomography was performed. A mutant construct of the TIMP3 protein was created and expressed in human retinal pigment epithelium (ARPE19) cells, which were then assayed for oligomerization and intrinsic matrix metalloproteinase (MMP) inhibitory activity. RESULTS: Three affected individuals from a family of Welsh origin each harbored one allele of the TIMP3 missense variant c.415 G>A, (p.E139K), which was not identified in 534 ethnically matched control chromosomes and thus presumed pathogenic. The mutant protein was shown to dimerize in culture cells and retain its MMP inhibitory activity. Retinal examination was variable between eyes of affected individuals and between family members. Drusen-like deposits were common to all three affected individuals and yellow subretinal deposits, exudative maculopathy, and geographic atrophy were also observed. Optical coherence tomography (OCT) images of affected individuals demonstrated hyperreflectivity of the RPE-photoreceptor-choroid complex. CONCLUSIONS: The TIMP3 p.E139K mutation is another cause of SFD. It is the second TIMP3 sequence variant reported that does not affect the number of cysteine residues in the mutant protein yet dimerizes in vitro. The clinical presentation of this family is in keeping with previous clinical reports of this disorder.

Mapping recombination hotspots in human phosphoglucomutase (PGM1).

Human phosphoglucomutase (PGM1) is a highly poly-morphic protein. Three mutations and four intragenic recombination events between the three mutation sites generate eight protein variants including the four universally common alleles, 1+, 1 -, 2+ and 2 -, and four others that are polymorphic in some Oriental populations, 3+, 3-, 7+ and 7-. The mutations 3/7, 2/1 and +/-are in exons 1A, 4 and 8, and are 40 and 18 kb apart, respectively. Using 12 polymorphic markers, including 2/1 and +/-, we have now obtained direct evidence for a high rate of intragenic recombination across this 58 kb region. From segregation analysis of PGM1 haplotypes in CEPH families, the recombination frequency was estimated to be 1.7%. We have also used a population genetics approach to map the patterns of linkage disequilibrium across the PGM1 gene in three diverse population samples (Caucasian, Chinese and Vietnamese). This has allowed us to compare indirect estimates of intragenic recombination with the meiotic data from family studies. Comprehensive pairwise allelic association analysis of the markers indicated the presence of two recombi-nation 'hotspots': one between exons 1A and 4 and the other in the region of exon 7. These locations are in keeping with the meiotic data and with the original hypothesis of intragenic recombination based on PGM1 isozyme analysis.

Resection arthroplasty for septic arthritis of the hip in ambulatory and nonambulatory adult patients.

Twenty-three patients who required resection arthroplasty because of pyogenic infection of a hip joint were reviewed. Nine of the patients were ambulatory, and the others were either paraplegic or bed-ridden because of chronic neurologic disease. The average duration of symptoms was more than two months. The only consistently abnormal laboratory test was the erythrocyte sedimentation rate (ESR). Joint-space narrowing and bone erosion due to osteomyelitis were the most common roentgenographic findings. Different microorganisms were isolated from the different cases, but Staphylococcus aureus was documented in eight hips. Femoral head dislocation of subluxation was documented in 11 of 24 hips. Osteoarthrosis or osteonecrosis was a preexisting condition in only four hips, all in ambulatory patients. Pathologic findings included loss of articular cartilage by surface erosion and by subchondral bone resorption, resulting in the separation of the cartilage from the underlying bone, bone erosion, osteomyelitis, and segmental osteonecrosis.

Natural history of atlanto-axial subluxation in rheumatoid arthritis.

In 1969 the authors started their prospective study to determine the natural history of atlanto-axial subluxation in patients suffering from rheumatoid arthritis. Between January 1969 and July 1971 they accumulated 41 cases of atlanto-axial subluxation. These patients were studied clinically and radiologically, and the initial findings were published in the Journal of Bone and Joint Surgery, Volume 55B, August 1973. All of these patients were followed clinically and radiologically until 1981 or until their demise. Roentgenographically, 61% have remained unchanged, 27% have shown progression of the atlanto-axial subluxation, and 12% showed decrease in the amount of atlanto-axial subluxation, including one following surgery. During this 10-year period, 12 patients with atlanto-axial subluxation have died, two with historical evidence of neurologic damage. The remaining 10 patients have died from unrelated causes. Only 3 patients underwent surgical stabilization. This study concluded that the atlanto-axial subluxation is compatible with life, but some patients require surgical intervention.

Long-term follow-up of prosthetic joint replacement in hemophilia.

We evaluated the outcome of seven severe hemophilic patients who underwent four total hip and four total knee arthroplasties since 1976. These patients have been followed at regular intervals over a period of 2.5-9.5 years (mean 5.8). Of the four total hip replacements, one had to be removed because of loosening and secondary infection 3 years after the initial surgery but was salvaged by pseudoarthrosis; the other three are pain-free and radiologically stable and have an excellent range of motion 2.5, 5, and 7 years postoperatively. Of the four total knee replacements, one had to be removed because of infection but was successfully salvaged by arthrodesis; one patient has loose components, but the prosthesis is still functional; and the final patient with bilateral knee prostheses is pain-free with limited but functional range of motion. Clotting-factor replacement therapy was effective in controlling intraoperative bleeding, even in a patient with an inhibitor, and only one procedure was complicated by hematoma formation. We conclude that prosthetic joint replacement may be safely performed in hemophilic patients but should be reserved for those who have limited function because of severe pain, joint destruction, and deformity. Total hip arthroplasty is as successful in these patients as in nonhemophiliacs. Total knee arthroplasty provides relief of pain, reduces the frequency of hemarthroses, and corrects most of the deformity, but it is usually associated with a limited range of motion.

Arthrography after total hip arthroplasty: a modified technique used in the diagnosis of pain.

The results of plain film radiography and arthrography in diagnosing loosening of a prosthetic component after total hip arthroplasty were correlated with surgical findings in 31 patients who required surgery because of hip pain. The accuracy of arthrography in diagnosing component loosening using 5 ml of contrast material was 51%, and the accuracy of plain radiography was 69%. An accuracy of 92% was achieved using a modified arthrographic technique in which the pressure in the joint was recorded after injection of contrast material and while the patient walked to ensure that it was comparable with the pressure that caused the patient's pain prior to the study. Three per cent of the arthrographic studies using this technique were false negative and 5% were false positive.

Juvenile rheumatoid arthritis of the foot.

Rheumatoid arthritis occurring in children under 16 years of age is defined as juvenile rheumatoid arthritis. It is more common in females and the peak incidence is between 1 and 3 years of age. It can present in different forms. Mono- and pauciarticular type is complicated by iridocyclitis in 20%. Growth disturbances are common. Any conceivable combination of foot deformities can occur. Some of the secondary deformities can be prevented with conservative care. Principals of soft tissue and bony surgery have been outlined.

Pathologic evaluation of the failed cup arthroplasty: a review of 32 cases.

Thirty-one specimens of femoral heads from failed arthroplasty operations were analyzed. One hip joint from autopsy was also reviewed. Cup arthroplasty does not lead to the formation of hyaline cartilage and sometimes not even fibrocartilage. Fibrous tissue rather than fibrocartilage lined the interspace between femoral head and cup in the majority of cases. There was frequent resorption of subchondral bone, and avascular necrosis of the bone inside the cup. Osteoarthritis and progressive femoral head degenerative bone changes generally continued despite surgical reaming and removal of all articular cartilage.

Hemophilic bleeding evaluated by blood pool scanning.

The technique of blood pool scanning was used to examine 15 hemophilic subjects. Employing an in vivo method for erythrocyte labeling with Technetium-99 m, a dynamic perfusion sequence is obtained using a scintillation camera positioned over the area to be examined. This demonstrates the vascularity of the tissue. Subsequently, equilibrium blood pool images of the area are obtained and analyzed with a densitometer to assess relative regional blood volume. In patients who were not bleeding but had chronic arthropathy, vascularity was not increased, and the blood volume of comparable joints was similar. By contrast, marked increases in vascularity and image density were observed in studies of acutely bleeding joints. Chronic hemarthroses were associated with persistent, but less marked increases in joint perfusion. Transient increases in joint vascularity were demonstrated after insertion of knee prostheses. In a patient with a thigh hematoma, the dimensions of the hemorrhage were clearly delineated. Since only a tracer dose of nuclide is infused intravenously, there are no allergic reactions or other side effects of the procedure. Blood pool scanning is a safe, non-invasive technique that augments clinical and radiographic evaluations, and provides a new dimension in the assessment of the hemophilic patient.

Complications of posterolateral dislocation of the knee: case report and literature review.

A 49-year-old man incurred a posterolateral dislocation of the knee, a rare type of knee injury. The injury was associated with a significant skin slough as a result of internal pressure from the displaced medial femoral condyle. The dislocation also was associated with a rupture of the quadriceps tendon. The mechanism of injury was a forcible abduction of the flexed knee, coupled with medial rotation of the tibia upon the femur. This type of knee dislocation cannot be reduced closed and therefore immediate open reduction with primary ligamentous repair is the treatment of choice.

Excision of the head of the radius in rheumatoid arthritis.

The results of excision of the head of the radius in forty-four elbows affected by rheumatoid arthritis are presented. Relief of pain was obtained in 90 per cent and an increase in the range of flexion and extension was seen in 70 per cent. Involvement of the humero-ulnar joint seen radiologically is no contra-indication to the operation; simple excision of the radial head often gives gratifying results; In our experience the relief of pain and increased range of movement have greatly reduced the need for total replacement arthroplasty.