Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2.

A gene mutated in Charcot-Marie-Tooth disease type 4B (CMT4B), an autosomal recessive demyelinating neuropathy with myelin outfoldings, has been mapped on chromosome 11q22. Using a positional-cloning strategy, we identified in unrelated CMT4B patients mutations occurring in the gene MTMR2, encoding myotubularin-related protein-2, a dual specificity phosphatase (DSP).

Transplantation of pancreatic islets with immunoexclusion membranes.

The above studies strongly emphasize that transplantation of islets using immunoisolation with hollow fiber semipermeable immunoexclusion membranes is possible. Experiments in diabetic dogs have demonstrated that both the intravascular perfusion configured device and the intraperitoneal diffusion device could be applied clinically. Future experiments must be directed toward increasing device output, extending islet viability, and utilizing islet xenografts in both perfusion and diffusion devices in large animals prior to clinical trials.

Use of Dacron cuffed silicone catheters as long-term hemodialysis access.

Sixty-five Dacron cuffed, dual lumen, silicone central venous dialysis catheters (Quinton PermCath, Seattle, WA) were inserted in 51 patients as the sole form of permanent access for chronic hemodialysis. Six and 12 month actuarial survival rates of patients for all catheters were 53% and 35%, respectively. When calculations included revisions, 6 and 12 month actuarial catheter survival rates were 61% and 43%, respectively. The major limiting factors in survival using long-term catheters remain infection and thrombosis. Dacron cuffed, dual lumen, central venous, dialysis catheters can provide long-term vascular access for hemodialysis in high risk patients.

Evaluation of the hybrid artificial pancreas in diabetic dogs.

Immunoisolation of nonsyngeneic tissue using a selectively permeable membrane is designed to facilitate transplantation without the use of immunosuppression. The authors' studies have evaluated a hybrid artificial pancreas device that is implanted as an arteriovenous vascular shunt. Devices containing allogeneic or xenogeneic islets were implanted in diabetic dogs who had undergone pancreatectomies, and the devices eliminated the requirement for exogenous insulin for control of fasting glycemia in 11 animals for periods ranging from 1 to 8 months. Furthermore, unseeded devices in normal dogs have been shown to remain patent for over 2 years with low doses of aspirin as the only anticoagulant. These results indicate that this approach has potential as a therapy for diabetes.

Islet transplantation using an immunoprotective membrane in dogs that have undergone a pancreatectomy.

The use of a selectively permeable membrane to transplant nonsyngeneic tissue without accompanying immunosuppressive therapy has been investigated using two approaches. The first hybrid artificial pancreas is implanted as a vascular shunt in which blood circulates through the lumen of a tubular membrane. The islet tissue is distributed within a chamber surrounding the membrane enclosed by an acrylic housing. Studies with diabetic dogs that have had pancreatectomies have demonstrated that these devices could replace exogenous insulin therapy for at least 6 months in five animals. This report presents data on two of these dogs, demonstrating viability and function of the transplanted tissue after 1 year. As an alternative to the vascular device, islets sealed within cylindrical permselective membrane chambers have been implanted in the peritoneum. Preliminary data from three dogs indicate that the nonvascular implants can also regulate fasting glucose levels in the diabetic dog model.

Denaturing high-performance liquid chromatography of the myotubularin-related 2 gene (MTMR2) in unrelated patients with Charcot-Marie-Tooth disease suggests a low frequency of mutation in inherited neuropathy.

Charcot-Marie-Tooth type 4B (CMT4B), an autosomal recessive demyelinating neuropathy characterized by focally folded myelin sheaths in the peripheral nerve, has been associated with mutations in the gene encoding myotubularin-related protein 2, MTMR2, on chromosome 11q22. To investigate whether mutations in MTMR2 may also cause different forms of CMT, we screened 183 unrelated patients with a broad spectrum of CMT and related neuropathies using denaturing high-performance liquid chromatography. We identified four frequent and three rare exonic variants; two of the rare variants were identified in two unrelated patients with congenital hypomyelinating neuropathy and not in the normal controls. Our results suggest that loss-of-function mutations in MTMR2 are preferentially associated with the CMT4B phenotype.

X linked Charcot-Marie-Tooth disease (CMTX1): a study of 15 families with 12 highly informative polymorphisms.

X linked dominant Charcot-Marie-Tooth disease (CMTX1) has previously been localised to Xq13-21. Fifteen families were studied using 12 highly informative polymorphisms in the pericentric region of the X chromosome. Phase known recombinations in these families localise the X linked dominant CMT gene to the region distal to DXS106 (Xq11.2-12) and proximal to DXS559 (Xq13.1). These markers flank approximately 2 to 3 Mb of DNA to which GJB1 and CCG1 have already been mapped. A recent report of mutations in the GJB1 gene in subjects with CMTX1 makes this a strong candidate gene.

Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1)

X-linked dominant Charcot-Marie-Tooth disease (CMTX1) is a peripheral neuropathy which maps to Xq13 and is flanked by the loci DXS106 (Xq11.2-q12) and DXS559 (Xq13.1). Contained within this interval of approximately 2-3Mb of DNA is the gene, connexin 32 (locus designation GJ beta 1). This gene encodes a gap junction protein which is expressed in large quantities within the liver and throughout a range of other mammalian tissues. We have sequenced the coding region of exon 2 of this gene from affected individuals in nine families with CMTX 1 and have found mutations which segregate with the disease in eight of these families. The mutations detected include missense point mutations at codons 15, 60, 63, 208, and 215, a nonsense point mutation at codon 220, deletions of one base in codon 72/3 producing a stop codon 12 codons down stream and a three base pair deletion which can be predicted to result in the loss of a single amino acid. These findings are consistent with the disease CMTX1 being the result of mutations affecting the gene connexin 32 (Cx32).

Genetic refinement and physical mapping of the CMT4B gene on chromosome 11q22.

Charcot-Marie-Tooth disease type 4B (CMT4B) is a demyelinating autosomal recessive motor and sensory neuropathy characterized by focally folded myelin sheaths in the peripheral nerve. We recently mapped the CMT4B gene to a 5-cM interval on chromosome 11q22, using homozygosity mapping and haplotype sharing analysis on a large inbred pedigree. In the present study, we report the construction of a YAC-based transcript map across the 5-cM critical region, including 26 YACs, 35 STSs, and 52 ESTs. Furthermore, using 15 additional physically ordered microsatellite markers from the 11q22 region on the original inbred family, we were able to narrow the critical interval for the gene to 2 Mb, which is now flanked by markers D11S1757 and CHLC-GATA3B05. Finally, after computer analysis of the 33 ESTs assigned to the 2-Mb interval, we demonstrated that 21 different transcripts as well as 3 known genes might represent potential candidates for the disease.