Molecular diagnosis of patients affected by mucopolysaccharidosis: a multicenter study

Abstract

Mucopolysaccharidoses (MPS) are a subgroup of 11 monogenic lysosomal storage disorders due to the deficit of activity of the lysosomal hydrolases deputed to the degradation of mucopolysaccharides. Although individually rare, all together they account for at least 1:25,000 live births. In this study, we present the genetic analysis of a population of 71 MPS patients enrolled in a multicenter Italian study. We re-annotated all variants, according to the latest recommendations, and re-classified them as suggested by the American College of Medical Genetics and Genomics. Variant distribution per type was mainly represented by missense mutations. Overall, 10 patients had received no molecular diagnosis, although 6 of them had undergone either HSCT or ERT, based on clinical and enzymatic evaluations. Moreover, nine novel variants are reported. Conclusions : Our analysis underlines the need to complete the molecular diagnosis in patients previously diagnosed only on a biochemical basis, suggests a periodical re-annotation of the variants and solicits their deposition in public databases freely available to clinicians and researchers. We strongly recommend a molecular diagnosis based on the analysis of the “trio” instead of the sole proband. These recommendations will help to obtain a complete and correct diagnosis of mucopolysaccharidosis, rendering also possible genetic counseling. What is known • MPS are a group of 11 metabolic genetic disorders due to deficits of enzymes involved in the mucopolysaccharides degradation. • Molecular analysis is commonly performed to confirm enzymatic assays. What is new • Eighty-six percent of the 71 patients we collected received a molecular diagnosis; among them, 9 novel variants were reported. • We stress the importance of molecular diagnosis in biochemically diagnosed patients, encourage a periodical re-annotation of variants according to the recent nomenclature and their publication in open databases. Electronic supplementary material The online version of this article (10.1007/s00431-019-03341-8) contains supplementary material, which is available to authorized users.

Analysis of long-term observations of the large group of Russian patients with Hunter syndrome (mucopolysaccharidosis type II)

“…The protein changes p.Aspn63Asp (three patients; two families), p.Ala79Glu, (two patients; one family), p.Ala85Thr, p.Leu102Arg (two patients; one family), p.Asp198Gly, p.Gly412Term, p.Pro197Leu (four patients; one family), p.Gly340Asp, p.Ala346Val (three patients; one family), p.Arg443Term, the small deletion without frame shift and site-splicing substitution IVS2-9 c->g led to the development of less severe cases with later symptom manifestations, milder symptoms and higher IQ scores. Our data are consistent with the studies of other researchers who analyzed the influence of amino acid substitution on the IDS structure [ 20 , 21 ].…”

Mucopolysaccharidosis type I - Clinical and genetic characteristics of Romanian patients

“…Biochemical assays already described for these variants showed essentially no activity in homozygotes (13), concord-ant with Hurler phenotype, in our patients being observed a very low activity for the enzyme, the clinical phenotype being also Hurler syndrome. The incidence of p.Q70* (c.208C>T) mutation, 3/8 alleles of pathological variants of IDUA gene alleles identified in our group is according to results reported by other studies (5,(14)(15)(16)(17)(18)(19). In F4, compound heterozygous p.Q70*(c.208C>T), the second variant is a deletion located on exon 1 (p.S16_A19del, 46_57delTCGCTCCTGGCC), described by Bunge in 1994, as a mutation that induces a severe phenotype (3,20).…”

Identification and Functional Characterization of IDS Gene Mutations Underlying Taiwanese Hunter Syndrome (Mucopolysaccharidosis Type II)

“…Of these cases, 66 had missense mutations, 3 had nonsense mutations, 4 had silent mutations, 106 had splicing mutations, 5 had small deletions, 3 had gross deletions, and 4 had complex rearrangements (IDS inversion). Twelve missense mutations including c.137A>C, c.189T>G, c.262C>T, c.413A>G, c.454A>C, c.998C>T, c.1039A>G, c.1402C>T, c.1403G>A, c.1454T>G, c.1466G>A, and c.1478G>C have been reported to cause the severe phenotype [13,14,[16][17][18]22,23,[26][27][28][29] according to clinical manifestations of neuronopathic with intellectual disabilities and cognitive decline with hyperactive and aggressive behavior, as well as in vitro expression studies [23,43]. Of these mutations, only one missense mutation, c.454A>C, was a novel variant that showed 0.0% IDS activity of the wild type (extremely significance, p < 0.001).…”

“…Kosuga et al previously verified that the disease phenotype of the missense mutation c.851C>T (p.P284L) is the attenuated form [24]. Another missense mutation c.1400C>T (p.P467L) has been reported to be pathogenic to cause severe MPS manifestations [27,28]. The infant and another highly suspected infant with the novel missense mutation c.311A>T (p.D104V) who did not have pre-symptoms received Enzyme Replacement Therapy (ERT) (idursulfase) or ERT plus hematopoietic stem cell transplantation (HSCT) at the ages of 1.11 and 0.55 years old, respectively, due to definite evidence of a family history.…”