Computer simulation of energy use, greenhouse gas emissions, and costs for alternative methods of processing fluid milk.

Computer simulation is a useful tool for benchmarking electrical and fuel energy consumption and water use in a fluid milk plant. In this study, a computer simulation model of the fluid milk process based on high temperature, short time (HTST) pasteurization was extended to include models for processes for shelf-stable milk and extended shelf-life milk that may help prevent the loss or waste of milk that leads to increases in the greenhouse gas (GHG) emissions for fluid milk. The models were for UHT processing, crossflow microfiltration (MF) without HTST pasteurization, crossflow MF followed by HTST pasteurization (MF/HTST), crossflow MF/HTST with partial homogenization, and pulsed electric field (PEF) processing, and were incorporated into the existing model for the fluid milk process. Simulation trials were conducted assuming a production rate for the plants of 113.6 million liters of milk per year to produce only whole milk (3.25%) and 40% cream. Results showed that GHG emissions in the form of process-related CO2 emissions, defined as CO2 equivalents (e)/kg of raw milk processed (RMP), and specific energy consumptions (SEC) for electricity and natural gas use for the HTST process alone were 37.6g of CO2e/kg of RMP, 0.14 MJ/kg of RMP, and 0.13 MJ/kg of RMP, respectively. Emissions of CO2 and SEC for electricity and natural gas use were highest for the PEF process, with values of 99.1g of CO2e/kg of RMP, 0.44 MJ/kg of RMP, and 0.10 MJ/kg of RMP, respectively, and lowest for the UHT process at 31.4 g of CO2e/kg of RMP, 0.10 MJ/kg of RMP, and 0.17 MJ/kg of RMP. Estimated unit production costs associated with the various processes were lowest for the HTST process and MF/HTST with partial homogenization at $0.507/L and highest for the UHT process at $0.60/L. The increase in shelf life associated with the UHT and MF processes may eliminate some of the supply chain product and consumer losses and waste of milk and compensate for the small increases in GHG emissions or total SEC noted for these processes compared with HTST pasteurization alone. The water use calculated for the HTST and PEF processes were both 0.245 kg of water/kg of RMP. The highest water use was associated with the MF/HTST process, which required 0.333 kg of water/kg of RMP, with the additional water required for membrane cleaning. The simulation model is a benchmarking framework for current plant operations and a tool for evaluating the costs of process upgrades and new technologies that improve energy efficiency and water savings.

Computer simulation of energy use, greenhouse gas emissions, and process economics of the fluid milk process.

Energy-savings measures have been implemented in fluid milk plants to lower energy costs and the energy-related carbon dioxide (CO2) emissions. Although these measures have resulted in reductions in steam, electricity, compressed air, and refrigeration use of up to 30%, a benchmarking framework is necessary to examine the implementation of process-specific measures that would lower energy use, costs, and CO2 emissions even further. In this study, using information provided by the dairy industry and equipment vendors, a customizable model of the fluid milk process was developed for use in process design software to benchmark the electrical and fuel energy consumption and CO2 emissions of current processes. It may also be used to test the feasibility of new processing concepts to lower energy and CO2 emissions with calculation of new capital and operating costs. The accuracy of the model in predicting total energy usage of the entire fluid milk process and the pasteurization step was validated using available literature and industry energy data. Computer simulation of small (40.0 million L/yr), medium (113.6 million L/yr), and large (227.1 million L/yr) processing plants predicted the carbon footprint of milk, defined as grams of CO2 equivalents (CO2e) per kilogram of packaged milk, to within 5% of the value of 96 g of CO 2e/kg of packaged milk obtained in an industry-conducted life cycle assessment and also showed, in agreement with the same study, that plant size had no effect on the carbon footprint of milk but that larger plants were more cost effective in producing milk. Analysis of the pasteurization step showed that increasing the percentage regeneration of the pasteurizer from 90 to 96% would lower its thermal energy use by almost 60% and that implementation of partial homogenization would lower electrical energy use and CO2e emissions of homogenization by 82 and 5.4%, respectively. It was also demonstrated that implementation of steps to lower non-process-related electrical energy in the plant would be more effective in lowering energy use and CO2e emissions than fuel-related energy reductions. The model also predicts process-related water usage, but this portion of the model was not validated due to a lack of data. The simulator model can serve as a benchmarking framework for current plant operations and a tool to test cost-effective process upgrades or evaluate new technologies that improve the energy efficiency and lower the carbon footprint of milk processing plants.

Recurrent and founder mutations in the Netherlands: the cardiac phenotype of DES founder mutations p.S13F and p.N342D.

BACKGROUND: Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES). We describe new families carrying the p.S13F or p.N342D DES mutations, the cardiac phenotype of all carriers, and the founder effects. METHODS: We collected the clinical details of all carriers of p.S13F or p.N342D. The founder effects were studied using genealogy and haplotype analysis. RESULTS: We identified three new index patients carrying the p.S13F mutation and two new families carrying the p.N342D mutation. In total, we summarised the clinical details of 39 p.S13F carriers (eight index patients) and of 21 p.N342D carriers (three index patients). The cardiac phenotype of p.S13F carriers is fully penetrant and severe, characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement. Although muscle weakness is a prominent and presenting symptom in p.N342D carriers, their cardiac phenotype is similar to that of p.S13F carriers. The founder effects of p.S13F and p.N342D were demonstrated by genealogy and haplotype analysis. CONCLUSION: DRM may occur as an apparently isolated cardiological disorder. The cardiac phenotypes of the DES founder mutations p.S13F and p.N342D are characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement.

Correction of dystrophia myotonica type 1 pre-mRNA transcripts by artificial trans-splicing.

Dystrophia myotonica type 1 (DM1), the most common muscular dystrophy in adults, results from expansion of a CTG repeat in the 3'-untranslated region of the dystrophia myotonica protein kinase gene (DMPK). Correction of the mutant DMPK transcript is a potential therapeutic strategy in DM1. We investigated the efficacy of artificial trans-splicing molecules (ATMs) to target and correct DMPK transcripts. ATMs designed to target intron 14 of DMPK pre-mRNA transcripts were tested for their ability to trans-splice the transcripts of a DMPK mini-gene construct and the endogenous DMPK transcripts of human myosarcoma cells (CCL-136). On agarose gel electrophoresis analysis, six of eight ATMs showed trans-splicing efficacy when applied to DMPK mini-gene construct transcripts, of which three were able to trans-splice endogenous DMPK pre-mRNA transcripts in myosarcoma cells, with trans-splicing efficiency ranging from 1.81 to 7.41%. These findings confirm that artificial trans-splicing can repair DMPK pre-mRNA and provide proof-of-principle evidence for this approach as potential therapeutic strategy for DM1.

Improved neuronal transgene expression from an AAV-2 vector with a hybrid CMV enhancer/PDGF-beta promoter.

BACKGROUND: Adeno-associated virus type 2 (AAV-2) vectors are highly promising tools for gene therapy of neurological disorders. After accommodating a cellular promoter, AAV-2 vectors are able to drive sustained expression of transgene in the brain. This study aimed to develop AAV-2 vectors that also facilitate a high level of neuronal expression by enhancing the strength of a neuron-specific promoter, the human platelet-derived growth factor beta-chain (PDGF) promoter. METHODS AND RESULTS: A hybrid promoter approach was adopted to fuse the enhancer of human cytomegalovirus immediately early (CMV) promoter to the PDGF promoter. In cultured cortex neurons, AAV-2 vectors containing the hybrid promoter augmented transgene expression up to 20-fold over that mediated by titer-matched AAV-2 vectors with the PDGF promoter alone and 4-fold over the CMV enhancer/promoter. Injection of AAV-2 vectors with the hybrid promoter into the rat striatum resulted in neuron-specific transgene expression, the level of which was about 10-fold higher than those provided by the two control AAV-2 expression cassettes at 4 weeks post-injection and maintained for at least 12 weeks. Gene expression in the substantia nigra through possible retrograde transport of the AAV-2 vectors injected into the striatum was not obvious. After direct injection of AAV-2 vectors into the substantia nigra, transgene expression driven by the hybrid promoter was observed specifically in dopaminergic neurons and its level was about 3 and 17 times higher than that provided by the PDGF promoter alone and the CMV enhancer/promoter, respectively. CONCLUSIONS: Enhanced transgene capacity plus neuron-specificity of the AAV-2 vectors developed in this study might prove valuable for gene therapy of Parkinson's disease.

Serum antibodies to heparan sulfate glycosaminoglycans in Guillain-Barré syndrome and other demyelinating polyneuropathies.

We tested for serum antibodies to glycosaminoglycans (GAGs), including heparan sulfate, in patients with Guillain-Barré syndrome (GBS) and other disorders. We used ELISA methods that optimize immunoglobulin binding to carbohydrate antigens to measure serum antibodies to heparan sulfate GAGs in GBS, and control neuromuscular and immune disorders. We found serum IgM or IgG antibodies to heparan sulfate GAGs in 34% of patients with GBS. Serum IgM binding to heparan sulfate GAGs was also found in some chronic demyelinating polyneuropathies, with the highest frequency (33%) in patients with IgM anti-MAG M-proteins. Antibodies to heparan sulfate GAGs were rare (1%) in control serums from patients with other disorders. This result is the first demonstration of high titer serum antibodies to a specific antigen in a substantial group of, and with some specificity for, patients with the classically described GBS syndrome of acute-onset, motor-sensory polyneuropathy with demyelinating features.

N lines in a myopathy with myosin loss.

N lines can be seen by electron microscopy within the I band of skeletal muscle, but are poorly visualized in conventional preparations. We present a case of acute quadriplegic myopathy with myosin loss and prominent N lines. The only other reported cases of N lines were also seen in patients with myosin loss from diverse etiologies. Myosin loss and the subsequent detachment of titin from myosin may result in the formation of prominent N lines.

Polyneuropathies associated with high titre antisulphatide antibodies: characteristics of patients with and without serum monoclonal proteins.

OBJECTIVES: Previous studies of small numbers of patients have shown that antisulphatide autoantibodies are associated with polyneuropathies having a prominent sensory component. However, clinical and electrodiagnostic features are variable. The range of clinical and electrodiagnostic findings in 19 patients with polyneuropathies and high titre (> 4500) serum IgM antisulphatide antibodies is described, together with testing for serum monoclonal (M) proteins. METHODS: About 20000 serum samples that were referred to the clinical laboratory from 1990 to the end of 1994 were screened by enzyme linked immunosorbent assay (ELISA) for specific high titre antisulphatide antibodies. The clinical and electrodiagnostic data in 23 patients with positive results were reviewed. IgM binding to peripheral nerve structures was also evaluated in these patients. RESULTS: Nineteen patients had predominantly distal, symmetric pansensory loss. Patients with IgM antisulphatide antibodies and no serum M protein usually had clinical syndromes that included: (1) neuropathic pain or dysaesthesiae, (2) no functionally significant weakness, and (3) an axonal neuropathy on electrodiagnostic testing. On immunocytochemical studies serum IgM from the patients without M proteins usually (nine of 10; 90%) bound to peripheral nerve axons, but never to myelin. Patients with antisulphatide antibodies and a serum M protein, usually IgM, were more likely than patients without a serum M protein, to have syndromes with: (1) no pain or dysaesthesiae, (2) motor abnormalities, and (3) a demyelinating polyneuropathy by electrodiagnostic criteria. In immunocytochemical studies serum IgM most often bound to either peripheral nerve myelin or endoneurial structures. CONCLUSION: Patients with polyneuropathy and high titre serum IgM antisulphatide antibodies can be classified into subgroups according to the presence or absence of a serum M protein. Patients without an M protein are more likely to have pure sensory syndromes, pain, an axonal neuropathy, and serum IgM binding to axons. Patients with a serum M protein commonly had syndromes with prominent motor involvement, no pain, and a demyelinating neuropathy.

Hereditary motor and sensory neuropathy IIB: clinical and electrodiagnostic characteristics.

Axonal forms of autosomal dominant hereditary motor and sensory neuropathies (HMSNs) represent a heterogeneous group of disorders based on genetic linkage studies. We recently identified one large family with axonal HMSN exhibiting linkage to chromosome 3q, designated HMSN IIB, and report here the clinical and electrodiagnostic features. We clinically evaluated 10 individuals with HMSN IIB and performed detailed electrophysiologic studies in 5 of these patients. HMSN IIB is characterized clinically by the presence of distal symmetric motor weakness and prominent sensory loss affecting the lower extremities with preserved ankle reflexes. Symptomatic age at onset is in the second or early third decade of life. Six patients with HMSN IIB had distal trophic ulcerations in the feet, leading to eventual toe amputations in four cases. Electrodiagnostic studies confirmed a distal sensorimotor axonopathy involving the lower limbs with normal motor conduction velocities. Tibial H-reflexes were preserved in HMSN IIB, despite the uniform loss of sural nerve potentials. Overall, individuals with HMSN IIB demonstrated a consistent clinical and electrodiagnostic phenotype that had no overlap with genetically unaffected family members. The identification of specific clinical and electrodiagnostic features of HMSN IIB may prove useful in the diagnosis and differentiation between various subtypes of HMSN II.

Serum IgM monoclonal autoantibody binding to the 301 to 314 amino acid epitope of beta-tubulin: clinical association with slowly progressive demyelinating polyneuropathy.

We identified five patients with IgM monoclonal autoantibodies that bound to human brain tubulin. In a companion study, we found that IgM in these sera selectively recognized one of three epitopes on tubulin. IgM from three patients bound selectively to a small epitope on human beta-tubulin comprising amino acids 301 to 314. The other two sera recognized tubulin amino acids 215 to 235 and 315 to 336. In this study, we compared the clinical syndromes in these patients with the tubulin epitope recognized by their serum IgM. The three patients with IgM binding to tubulin amino acids 301 to 314 all had chronic inflammatory demyelinating polyneuropathy (CIDP) syndromes with slowly progressive weakness, hyporeflexia, and electrophysiologic studies consistent with demyelination. Two of these patients had significant asymmetry to their weakness. The two other patients had diagnoses of polyradiculopathy and amyotrophic lateral sclerosis with no evidence of peripheral nerve demyelination. We conclude that IgM monoclonal anti-tubulin antibodies have some association with demyelinating polyneuropathy syndromes, but may occur in patients with other clinical syndromes as well. A stronger association with demyelinating polyneuropathies may occur if the anti-tubulin antibodies recognize the 301 to 314 amino acid epitope on tubulin. This tubulin epitope, or a similar one on another molecule, could play an important antigenic role in the development of demyelinating polyneuropathies with features of CIDP.

Characterization of the gene encoding human sarcolipin (SLN), a proteolipid associated with SERCA1: absence of structural mutations in five patients with Brody disease.

Sarcolipin (SLN) is a low-molecular-weight protein that copurifies with the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase (SERCA1). Genomic DNA and cDNA encoding human sarcolipin (SLN) were isolated and characterized and the SLN gene was mapped to chromosome 11q22-q23. Human, rabbit, and mouse cDNAs encode a protein of 31 amino acids. Homology of SLN with phospholamban (PLN) suggests that the first 7 hydrophilic amino acids are cytoplasmic, the next 19 hydrophobic amino acids form a single transmembrane helix, and the last 5 hydrophilic amino acids are lumenal. The cytoplasmic and transmembrane sequences are not well conserved among the three species, but the lumenal sequence is highly conserved. Like SERCA1, SLN is highly expressed in rabbit fast-twitch skeletal muscle, but it is expressed to a lower extent in slow-twitch muscle and to an even lower extent in cardiac muscle, where SERCA2a and PLN are highly expressed. It is expressed in only trace amounts in pancreas and prostate. SLN and PLN genes resemble each other in having two small exons, with their entire coding sequences lying in exon 2 and a large intron separating the two segments. Brody disease is an inherited disorder of skeletal muscle function, characterized by exercise-induced impairment of muscle relaxation. Mutations in the ATP2A1 gene encoding SERCA1 have been associated with the autosomal recessive inheritance of Brody disease in three families, but not with autosomal dominant inheritance of the disease. A search for mutations in the SLN gene in five Brody families, four of which were not linked to ATP2A1, did not reveal any alterations in coding, splice junction or promoter sequences. The homozygous deletion of C438 in the coding sequence of ATP2A1 in Brody disease family 3, leading to a frameshift and truncation following Pro147 in SERCA1, is the fourth ATP2A1 mutation to be associated with autosomal recessive Brody disease.

Childhood chronic inflammatory demyelinating neuropathies: clinical course and long-term follow-up.

Chronic inflammatory demyelinating neuropathy (CIDP) is a rare disease in childhood. We reviewed the clinical characteristics, response to therapy, and long-term prognosis in 13 children (1.5 to 16 years of age) diagnosed with CIDP at Washington University Medical Center, St. Louis, and the Royal Children's Hospital, Melbourne, Australia, between 1979 and 1994. The most common presenting symptom (in 11/13 [85%]) was lower extremity weakness associated with difficulty in walking. Preceding events within 1 months of onset, mostly intercurrent infections or vaccinations, occurred in seven children (54%). The disease was monophasic in three children (23%). One relapse occurred in four (30%) and multiple relapses in six (46%). All patients had at least short-term response to steroids. Three children (23%) recovered completely during the first year. Ten children (77%) had residual weakness after an average follow-up of 6 years. There seems to be two populations of children with CIDP. One subgroup, with a favorable prognosis, progressed to peak disability over less than 3 months; these children often have a monophasic course with complete resolution of symptoms and signs and withdrawal from all medications by 1 year after onset. A second subgroup progressed for 3 months or longer; these children all required substantial does of prednisone for prolonged periods and had considerable long-term morbidity with persistent weakness.

Characterization of cDNA and genomic DNA encoding SERCA1, the Ca(2+)-ATPase of human fast-twitch skeletal muscle sarcoplasmic reticulum, and its elimination as a candidate gene for Brody disease.

Genomic DNA and cDNA encoding human SERCA1, the Ca(2+)-ATPase of fast-twitch skeletal muscle sarcoplasmic reticulum (the ATP2A1 gene on chromosome 16p12), were isolated and characterized. The cDNA encodes 994 amino acids. The genomic DNA is 26 kb long and contains 23 exons, one of which can be alternatively spliced. The locations of each of the exon/intron boundaries are the same as those previously identified in the rabbit ATP2A1 gene. Brody disease is an inherited disorder of skeletal muscle, characterized by exercise-induced impairment of muscle relaxation. It has been postulated to result from a deficiency in SERCA1. In a search for the genetic basis of Brody disease, the coding sequence of the ATP2A1 gene in one Brody patient and the full-length sequences of two SERCA1 cDNAs in two other, unrelated Brody patients were compared with normal ATP2A1 sequences. In all three cases, the coding and splice junction sequences were normal, indicating that the forms of Brody disease manifested in these three patients are not caused by mutations in the coding or splice junction regions of the ATP2A1 gene.

Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q.

Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy. The neuronal form of this disorder is referred to as Charcot-Marie-Tooth type II disease (CMT2). CMT2 is usually inherited as an autosomal dominant trait with a variable age at onset of symptoms associated with progressive axonal neuropathy. In some families, the locus that predisposes to CMT2 has been demonstrated to map to the distal portion of the short arm of chromosome 1. Other families with CMT2 do not show linkage with 1p markers, suggesting genetic heterogeneity in CMT2. We investigated linkage in a single large kindred with autosomal dominant CMT2. The gene responsible for CMT2 in this kindred (CMT2B) was mapped to the interval between the microsatellite markers D3S1769 and D3S1744 in the 3q13-22 region. Study of additional CMT2 kindreds should serve to further refine the disease gene region and may ultimately lead to the identification of a gene defect that underlies the CMT2 phenotype.

Myopathy and paraproteinemia with serum IgM binding to a high-molecular-weight muscle fiber surface protein.

We evaluated a 69-year-old man with Waldenström's macroglobulinemia (IgM-kappa M-protein) and progressive weakness over 2 to 3 years. The neurological examination showed symmetrical, predominantly proximal weakness. Electrophysiological testing revealed small brief motor unit potentials with fibrillations and positive sharp waves consistent with an irritative myopathy. The muscle biopsy specimen showed myopathic changes including variation in fiber size and increased connective tissue but no inflammation. IgM-kappa but not IgM-lambda was deposited along the surface of muscle fiber membranes. Serum IgM-kappa but not IgM-lambda from the patient stained the surface of normal human muscle fibers but not other regions of muscle fibers or other tissues. The serum IgM-kappa at dilutions up to 1:512,000 bound to a high-molecular-weight muscle protein by Western and dot blot studies. By enzyme-linked immunosorbent assay and Western blot analysis, serum IgM-kappa bound specifically to the muscle protein and not to other muscle or neural antigens, including GM1 ganglioside, myelin-associated glycoprotein, and sulfatide. We conclude that the myopathy in our patient is probably related to the presence of serum IgM-kappa antibodies directed against a muscle surface antigen. Characterization of the target antigen, a high-molecular-weight protein located specifically in muscle, should further elucidate the pathogenesis of this presumably humorally mediated immune myopathy.

Distal lower motor neuron syndrome with high-titer serum IgM anti-GM1 antibodies: improvement following immunotherapy with monthly plasma exchange and intravenous cyclophosphamide.

Motor neuropathies associated with electrodiagnostic evidence of motor conduction block often improve after treatment with immunotherapy, but there is less evidence about the responsiveness of lower motor neuron (LMN) syndromes without conduction block. In this study we treated four patients with an asymmetric, predominantly distal LMN syndrome associated with high serum titers of IgM anti-GM1 ganglioside antibodies but without conduction block on electrodiagnostic testing. Treatment courses consisted of five to seven repeated monthly regimens of plasma exchange on 2 consecutive days followed, on day 3, by intravenous cyclophosphamide (1 g/m2). The results of treatment were quantitatively measured using hand-held dynamometry. We found that all four patients showed progressive improvement in strength over the 6 to 24 months following treatment. Improvement was documented by both objective muscle testing and patient reports of increased strength and less fatigability. We conclude that immunotherapy may be followed by useful functional benefit in selected patients with an asymmetric, predominantly distal LMN syndrome associated with high serum titers of IgM anti-GM1 antibodies. Gradual improvement often begins as late as 6 to 9 months after the onset of treatment and may persist for 1 to 2 years, or longer, after immunosuppressive treatment is stopped.

Anti-MAG antibodies: major effects of antigen purity and antibody cross-reactivity on ELISA results and clinical correlation.

There is controversy regarding the relationship of polyneuropathy syndromes to the presence of serum antibody binding to myelin-associated glycoprotein (MAG). Using standard ELISA methodology, we identified 74 sera that appeared to have high titers of IgM binding to MAG and found that only 34% of these sera stained MAG using Western blot methodology. Follow-up studies showed that two factors greatly influence concordance between ELISA and Western blot testing for anti-MAG antibodies. Sera with high titers of binding to both MAG and histone H3 identified by ELISA rarely stain MAG on Western blot. In addition, sera analyzed by ELISA often bind to impurities in the semipure MAG that is frequently used in ELISA assays. Further purifications to separate MAG from other contaminants improved concordance between ELISA and Western blot results to 85% to 90% in a retrospective analysis, as well as in a prospective study of 49 additional sera. Patients with a polyneuropathy and serum IgM binding to MAG preparations by ELISA but not by Western blot methodology had several different clinical syndromes, including gait disorders and asymmetric motor neuropathies. Patients with IgM binding to MAG by both assay methods usually had a distal, sensory-motor, symmetric polyneuropathy with some features of demyelination on electrodiagnostic testing.

Rapidly evolving myopathy with myosin-deficient muscle fibers.

Five patients with rapidly evolving, severe weakness had an unusual myopathy with virtually complete loss of myosin in 5 to 40% of muscle fibers. Three of the 5 patients began to develop weakness 1 to 2 weeks after lung transplantation. The fourth became weak after a febrile illness. The fifth presented with diabetic ketoacidosis and weakness. All patients had received corticosteroid therapy. In all cases the weakness was progressive and led to severe disability, with respiratory failure in 4 patients. Initial diagnostic testing did not localize an underlying cause for the weakness. Creatine kinase was normal or minimally elevated. Electromyography generally showed mildly myopathic or nondiagnostic changes. However, muscle biopsy revealed numerous small angular fibers with no myosin ATPase staining at any pH. Immunocytochemical staining and ultrastructural studies confirmed a severe loss of myosin in many fibers. This rapidly evolving myopathy with myosin-deficient muscle fibers appears to be different clinically and pathologically from previously described syndromes involving rapidly progressive weakness. Slow recovery over a period of months is the most common outcome.

Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy.

Expansion of the trinucleotide repeat (CAG)n in the first exon of the androgen receptor gene is associated with a rare motor neuron disorder, X-linked spinal and bulbar muscular atrophy. We have found that expanded (CAG)n alleles undergo alteration in length when transmitted from parent to offspring. Of 45 meioses examined, 12 (27%) demonstrated a change in CAG repeat number. Both expansions and contractions were observed, although their magnitude was small. There was a greater rate of instability in male meiosis than in female meiosis. We also found evidence for a correlation between disease severity and CAG repeat length, but other factors seem to contribute to the phenotypic variability in this disorder.