ABSTRACT'y-Glutamylamine cyclotransferase, an enzyme that catalyzes the conversion of L-y-glutamylamines to free amines and 5-oxo-L-proline, was found in rab it kidney and in various other tissues. The specificity of this enzyme indicates that it functions in the metabolism of products of transglutaminase action; among its substrates are F4L-'y-yglutamyl}L-lysine a derivative of this peptide in which the a-amino and car xy groups of the lysine moiety are blocked, and L-'y-glutamylpolyamine derivatives.The E-(y-glutamyl)lysine crosslink, formed in proteins by the catalytic action of transglutaminase (reaction 1), -Gin-+ -Lys----
Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease with early childhood onset that presents as a prominent sensorimotor neuropathy and commonly progresses to affect both the peripheral nervous system and central nervous system. The disease is caused by biallelic mutations in the GAN gene located on 16q23.2, leading to loss of functional gigaxonin, a substrate specific ubiquitin ligase adapter protein necessary for the regulation of intermediate filament turnover. Here, we report on cross-sectional data from the first study visit of a prospectively collected natural history study of 45 individuals, age range 3–21 years with genetically confirmed giant axonal neuropathy to describe and cross-correlate baseline clinical and functional cohort characteristics. We review causative variants distributed throughout the GAN gene in this cohort and identify a recurrent founder mutation in individuals with giant axonal neuropathy of Mexican descent as well as cases of recurrent uniparental isodisomy. Through cross correlation analysis of measures of strength, motor function, and electrophysiologic markers of disease severity, we identified the Motor Function Measure 32 (MFM-32) to have the strongest correlation across measures and age in individuals with giant axonal neuropathy. We analysed the Motor Function Measure 32 scores as they correspond to age and ambulatory status. Importantly, we identified and characterized a sub cohort of individuals with a milder form of giant axonal neuropathy and with a presentation similar to Charcot-Marie-Tooth disease. Such a clinical presentation is distinct from the classic presentation of giant axonal neuropathy, and we demonstrate how the two groups diverge in performance on the Motor Function Measure 32 and other functional motor scales. We further present data on the first systematic clinical analysis of autonomic impairment in giant axonal neuropathy as performed on a subset of the natural history cohort. Our cohort of individuals with genetically confirmed giant axonal neuropathy is the largest reported to date and highlights the clinical heterogeneity and the unique phenotypic and functional characteristics of giant axonal neuropathy in relation to disease state. The present work is designed to serve as a foundation for a prospective natural history study and functions in concert with the ongoing gene therapy trial for children with giant axonal neuropathy.
A study of the phenomenon of “induction” of the enzyme dihydrofolate reductase that occurs in leukocytes and erythrocytes after methotrexate administration has been made with the dog as an experimental model as weU as man. The “induction” has been shown to be specific for 4‐amino analogues of folate that are strong inhibitors of dihydrofolate reductase. Attempts to block induction with possible end products of dihydrofolate reductase activity and an inhibitor of protein synthesis, actinomycin D, were unsuccessful. Based upon studies of the enzymeinhibitor interaction as a function of pH, the rise in enzyme activity observed is explained by an accumulation of methotrexate‐bound enzyme that occurs as a result of protection of the enzyme from normal catabolic processes; free enzyme is observed because of the in vitro conditions employed for enzyme assay.
ObjectiveTo accurately categorize the phenotypes of individuals with collagen VI–related dystrophies (COL6-RDs) during the first years of life to predict long-term motor function and pulmonary function, to provide phenotype-specific anticipatory care, and to improve clinical trial readiness.MethodsThis retrospective, multicenter, international study analyzed the relationship of long-term motor and pulmonary function with the initial maximal motor ability achieved in individuals with COL6-RD.ResultsWe studied 119 patients with COL6-RD from Spain (n = 54) and the United States (n = 65). The early maximal motor milestones of ability to rise from the floor unassisted and ability to climb 4 steps without holding onto a railing demonstrated reliability in distinguishing between 3 COL6-RD phenotypic subgroups: (1) Ullrich congenital muscular dystrophy, (2) intermediate COL6-RD, and (3) Bethlem myopathy. Long-term motor function and pulmonary function are strongly correlated with the maximal motor ability achieved during the first years of life. Maximal motor capacity can predict other disease-relevant events such as the age at loss of ambulation and the need for the initiation of nocturnal noninvasive ventilation.ConclusionThis work proposes a prospective phenotypic classification for COL6-RDs that will enable an accurate prediction of a patient's COL6-RD phenotype during the first years of life. The ability to establish a patient's COL6-RD phenotypic classification early will enable a more accurate prognosis of future motor and pulmonary function, thus improving anticipatory clinical care, and it will be instrumental in aiding the design of future clinical trials by allowing early stratification of trial cohorts.
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