RESUMO
Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe, rare autosomal recessive disorder caused by variants in the heparan-α-glucosaminide N-acetyltransferase (HGSNAT) gene which result in lysosomal accumulation of heparan sulfate. We analyzed clinical presentation, molecular defects and their haplotype context in 78 (27 novel) MPSIIIC cases from 22 countries, the largest group studied so far. We describe for the first time disease-causing variants in the patients from Brazil, Algeria, Azerbaijan, and Iran, and extend their spectrum within Canada, Colombia, Turkey, and the USA. Six variants are novel: two missense, c.773A>T/p.N258I and c.1267G>T/p.G423W, a nonsense c.164T>A/p.L55*, a splice-site mutation c.494-1G>A/p.[P165_L187delinsQSCYVTQAGVRWHHLGSLQALPPGFTPFSYLSLLSSWNC,P165fs], a deletion c.1348delG/p.(D450fs) and an insertion c.1479dupA/p.(Leu494fs). The missense HGSNAT variants lacked lysosomal targeting, enzymatic activity, and likely the correct folding. The haplotype analysis identified founder mutations, p.N258I, c.525dupT, and p.L55* in the Brazilian state of Paraiba, c.493+1G>A in Eastern Canada/Quebec, p.A489E in the USA, p.R384* in Poland, p.R344C and p.S518F in the Netherlands and suggested that variants c.525dupT, c.372-2G>A, and c.234+1G>A present in cis with c.564-98T>C and c.710C>A rare single-nucleotide polymorphisms, have been introduced by Portuguese settlers in Brazil. Altogether, our results provide insights into the origin, migration roots and founder effects of HGSNAT disease-causing variants, and reveal the evolutionary history of MPSIIIC.
Assuntos
Acetiltransferases/genética , Mucopolissacaridose III/genética , Mutação , Acetiltransferases/química , Argélia , Animais , Azerbaijão , Brasil , Células COS , Canadá , Chlorocebus aethiops , Colômbia , Evolução Molecular , Feminino , Efeito Fundador , Haplótipos , Humanos , Irã (Geográfico) , Masculino , Países Baixos , Linhagem , Filogeografia , Polônia , Dobramento de ProteínaRESUMO
OBJECTIVE: To determine whether children with chronic fatigue syndrome (CFS) have a higher prevalence of joint hypermobility than gender-matched controls. STUDY DESIGN: Matched case-control study comparing the Beighton joint hypermobility scores in 58 consecutive children with CFS (incident cases) with 58 otherwise healthy controls referred to a dermatology clinic for evaluation of common skin problems. A second group of 58 patients previously diagnosed with CFS (prevalent cases) was matched by gender to the incident cases to evaluate temporal changes in referral patterns. RESULTS: Of the 58 patients in each group, 71% were female. The median Beighton scores were higher in incident CFS cases than in healthy controls (4 vs 1, P <.001). More incident CFS cases had Beighton scores >/=4 (consistent with joint hypermobility), 60% versus 24%, P <.0001. Incident and prevalent CFS cases had similar Beighton scores. The odds ratio for hypermobility in all patients with CFS versus healthy controls was 3.5 (P <.001; 95% CI, 1.6-7.5). CONCLUSIONS: Joint hypermobility is more common in patients with CFS than in otherwise healthy children with common skin disorders. The etiologic significance of the observed association remains to be defined.