p.L18P: a novel IDUA mutation that causes a distinct attenuated phenotype in mucopolysaccharidosis type I patients

Mucopolysaccharidosis type Iis a rare autosomal recessive disorder caused by deficiency of α-l- iduronidase(IDUA) which leads to a wide spectrum of clinical severity. Here, we describe the case of four male patients who present the previously undescribed p.L18P mutation. Patient 1 (p.L18P/p.L18P) presents, despite multiple joint contractures, an attenuated phenotype. Patient 2 (p.L18P/p.W402X) was diagnosed at 4 years of age with bone dysplasia, coarse facies, limited mobility, clawhands and underwent bilateral carpal tunnel surgeryat 6 years of age. Patients 3 and 4 (both p.L18P/p.L18P) are brothers. Patient 3 was diagnosed at 4 years of age, when presented clawhands, lower limb and shoulder pain, restricted articular movement and bilateral carpal tunnel syndrome. Patient 4 was diagnosed at 17 months of age when presented lower limb pain at night, respiratory allergyand repeated upper airways infections. Bioinformatics analysis indicates that p.L18P mutation reduces the signal peptideto 25 amino acids and alters its secondary structure. In conclusion, we report a new IDUA variant that alters the structure of the signal peptide, which likely impairs transport to lysosomes. Moreover, it leads to a distinct attenuated phenotype with mainly bone and cartilage symptoms, without visceromegalies, heart disease, or cognitive impairment.