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Lysosomal Storage Disorders and Enzyme Replacement Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
MPS II is also named Hunter syndrome as it has been first described by Major Charles Hunter in an article entitled A Rare Disease in TWo Brothers published in 1917 (Hunter). The reason is a deficiency of the lysosomal enzyme iduronate-2-sulfatase due to mutations in the IDS gene. The functional enzyme initiates the degradation of dermatan sulfate and heparan sulfate by cleaving O-linked sulfate moieties from these GAGs. Although the Hunter syndrome is inherited in an X-linked recessive condition the disease has also been reported to affect females (Tuschl et al., 2005); this is possible in case of mutations in both copies of the gene which is rather unlikely so that males are affected by X-linked recessive disorders much more frequently.
When sex matters: a complete model of X-linked diseases
Published in International Journal of General Systems, 2018
C. Del Vecchio, F. Verrilli, L. Glielmo
A genetic disorder is defined as an illness caused by abnormalities within the DNA sequence of human genes. Although genetic diseases are very rare, it has been estimated that millions of people are affected worldwide (Word Health Organisation 2015). X-linked recessive diseases include the severe diseases haemophilia A, Duchenne/Becker muscular dystrophy, and Lesch–Nyhan syndrome as well as common and less serious conditions such as male pattern baldness and red-green colour blindness. The incidence of an X-linked recessive disease depends on the disorder's severity: it ranges from 1 in 3000 newborn males for Duchanne muscular dystrophy to 1 in 20 for the red and green colour blindness. Despite such relevance, only a few mathematical models have been specifically developed to study the dynamics and spread of X-linked recessive diseases in a population (Yeghiazarian 1999; Del Vecchio, Glielmo, and Corless 2014; Verrilli et al. 2017). The Hardy–Weinberg (HW) law is a cornerstone for these studies. Under specific assumptions – i.e. infinite population size, random mating, no selection, no migration, no mutation, and equal initial genotype frequencies in the two sexes – the HW law allows one to predict the genotype frequencies in the next generations. However, the stringent hypotheses of the law limit its applicability in epidemiological studies. Other genetic population models have been subsequently developed, relaxing some of the HW principle's assumption. Related studies analysed the inheritance mechanism of any gene – not necessarily responsible for a genetic disease – placed on the X chromosome (Lange 1982; Lange and Redelings 2002); they belong to the field of population genetics. Even in more generic scenarios (i.e. not specifically designed for X-linked recessive diseases), contributions seldom examine the combined effects of selection and mutation on population's dynamics and equilibrium (see Nagylaki 1977; Szucs 1991).