The Child with a Syndrome
John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed in Paediatrics, The Ear, Skull Base, 2018
The mucopolysaccharoidoses (MPS) comprise a group of conditions that result from the deficiency of lysosomal enzymes causing the accumulation of glycosamino-glycans in tissues. Head and neck structures are frequently involved early and the otolaryngologist may see children before the onset of systemic disease.14 Features commonly include recurrent otitis media, mixed hearing loss, upper airway obstruction +/– obstructive sleep apnoea and coarse facial features. Due to the non-specific clinical features, diagnosis is frequently delayed but early diagnosis is essential, particularly in Hunter syndrome, where enzyme replacement therapy is now available.15 MPS is also associated with intubation difficulties and may pose a significant anaesthetic risk. OSA is extremely common, with a prevalence of up to 90%, and patients may benefit from adenotonsillectomy.16 Suspicion of MPS should prompt specialist referral, and confirmation is with urinary glycosaminoglycan measurement and enzyme assays.14
Digital microfluidics comes of age: high-throughput screening to bedside diagnostic testing for genetic disorders in newborns
Published in Expert Review of Molecular Diagnostics, 2018
David Millington, Scott Norton, Raj Singh, Rama Sista, Vijay Srinivasan, Vamsee Pamula
Hunter Syndrome is one of the LSDs that has been treated successfully in early infancy [43] and is being considered as a potential target for NBS. The use of 4-methylumbelliferyl-α-L-iduronide-2-sulfate as a fluorescence substrate to measure the activity of IDS requires the sequential action of a second enzyme, α-iduronidase, to convert the product of the sulfatase, 4-methylumbelliferyl-α-L-iduronic acid, into iduronic acid and the fluorescent end-product, 4-methylumbelliferone (4-MU). Previous fluorometric assays for IDS used partially purified iduronidase from rabbit liver or bovine testis and sequentially performed the two reactions over a 24 h incubation period to accommodate the difference in pH optima for the 2 enzymes [44]. An improved homogeneous assay for IDS was accomplished on the DMF platform by combining both the enzymes in a single reaction mix using sulfatase (from the DBS sample) and pure, recombinant iduronidase with a 1 h incubation time [45]. This novel assay was able to completely differentiate DBS samples from known affected patients with Hunter (n = 6) from unaffected controls (n = 105), and represented an important step toward the validation of DMF assays for LSDs [46].
The CRISPR revolution and its potential impact on global health security
Published in Pathogens and Global Health, 2021
Kyle E. Watters, Jesse Kirkpatrick, Megan J. Palmer, Gregory D. Koblentz
The first human recipient of ZFNs to treat Hunter Syndrome began a new period of genome editing in humans, and was followed shortly by a wave of clinical trials using CRISPR-Cas genome editors [87]. Additional work on curing a variety of genetic diseases with CRISPR, such as muscular dystrophy [88], is underway [89]. This progress on treating genetic diseases can feed back to impact global health security efforts. For example, retroviruses like HIV can be removed from the population by excising the viral DNA from the genome, which has already been tested in mice [90]. There is more work to be done, however, as concerns have been raised about the possibility of escape mutations driving further evolution of the virus [91]. Alternatively, viral infections could be combated by editing the human genome to resist viral infections altogether. For example, genome editing could be used to truncate the CCR5 receptor to mimic the CCR5-Δ32 mutation that provides innate immunity to the virus [92].
Recent advances in molecular testing to improve early diagnosis in children with mucopolysaccharidoses
Published in Expert Review of Molecular Diagnostics, 2018
Ana Carolina Brusius-Facchin, Diana Rojas Malaga, Sandra Leistner-Segal, Roberto Giugliani
The mucopolysaccharidoses (MPS) represent the second most prevalent group of LSD, after the sphingolipidoses [2]. Including the recently described MPSPS (mucopolysaccharidosis-plus syndrome) [3,4], it consists of 12 different types and subtypes of monogenic disorders (Table 1), with a combined birth prevalence ranging from 2.2 per 100 000 in British Columbia to 5.2 per 100 000 live births in the United Arab Emirates [5–11]. However, preliminary data from newborn screening programs indicate that the prevalence could be considerably higher [12]. All MPS have autosomal recessive inheritance, with the exception of Hunter syndrome (MPS II), which is X-linked recessive.
Related Knowledge Centers
- Dermatan Sulfate
- Enzyme
- Glycosaminoglycan
- Mucopolysaccharidosis
- Syndrome
- Lysosome
- Lysosomal Storage Disease
- Iduronate-2-Sulfatase
- Heparan Sulfate
- X-Linked Recessive Inheritance