Mucopolysaccharidosis (MPS) represents a group of rare inherited metabolic disorders characterized by abnormal accumulation of glycosaminoglycans (GAGs) due to deficiencies of lysosomal enzymes. Mucopolysaccharidosis type I (MPS I) is caused by biallelic pathogenic variants in the IDUA gene and is inherited in an autosomal recessive pattern. The IDUA gene is located on chromosome 4p16.3 and encodes the lysosomal enzyme α-L-iduronidase, which plays a critical role in the degradation of GAGs, particularly dermatan sulfate and heparan sulfate. Reduced or absent IDUA enzymatic activity leads to the progressive accumulation of undegraded substrates within lysosomes, resulting in multisystem organ involvement. Based on clinical severity, MPS I is traditionally classified into three phenotypic subtypes: the severe form (Hurler syndrome), the intermediate form (Hurler-Scheie syndrome), and the attenuated form (Scheie syndrome, MPS I-S). This report describes a 13-year-old female patient in whom compound heterozygous pathogenic variants in the IDUA gene were identified by genetic testing, and whose clinical manifestations were consistent with the MPS I-S. In addition to typical skeletal and joint abnormalities, the patient also presented with uterine developmental abnormality. Currently, there is no definitive evidence supporting a direct causal relationship between MPS I and uterine developmental abnormalities; however, this case suggests a potential association between MPS I and reproductive system developmental abnormalities. This case may help further expand the phenotypic spectrum of MPS I and enhance clinical awareness of its multisystem involvement.

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease caused by mutations in the IDUA gene, resulting in decreased activity of the lysosomal enzyme α-l-iduronidase (IDUA) and consequent accumulation of glycosaminoglycans in the lysosomes. There are more than 300 disease-causing variants reported in the IDUA gene, and the mutational profile varies considerably worldwide. In this study, we performed molecular analysis on 119 MPS I patients, representing the largest Brazilian cohort studied so far. Forty-seven different mutations were identified in our sample, and 13 of them are newly described: c.48delG, c.78delC, c.159-23_159-1del23, p.Gln125Ter, p.Trp175Ter, c.590-6ins4G, c.763delC, c.973-1G>A, p.Asp349Glu, p.Asn350Lys, p.Lys384Asn, c.1403-12_1403-4del9, and p.Lys546Ter. In silico analysis of novel variants suggests they are possibly pathogenic, supporting previous biochemical and clinical diagnoses. Among recurrent mutations, p.Trp402Ter and p.Pro533Arg are the most frequent in Brazil, found in 42.4% and 16% of the alleles, respectively. These results reveal the great allelic heterogeneity of IDUA variants in Brazilian patients. Unraveling the genetic profile of MPS I patients may improve the diagnosis and management of this rare disease.

Scheie syndrome is the attenuated phenotype of mucopolysaccharidosis type I (MPS I), a lysosomal storage disorder resulting from partial deficiency of α-L-iduronidase. The attenuated clinical spectrum and absence of cognitive impairment often delay recognition. Early manifestations may mimic common pediatric conditions, leading to repeated evaluations without a definitive diagnosis. We describe a 12-year-old girl who presented with slowly progressive bilateral hand stiffness, weak grip strength, and intermittent sensory symptoms over one year. Her initial investigations-including laboratory studies, electrophysiology, imaging, and multispecialty evaluations-were unremarkable. The gradual progression of symptoms involving joints, motor function, and vision prompted metabolic testing. Whole exome sequencing revealed a homozygous IDUA variant, and enzymatic testing confirmed markedly reduced α-L-iduronidase activity, establishing the diagnosis of Scheie syndrome. Early initiation of enzyme replacement therapy was pursued. This case emphasizes that children with unexplained musculoskeletal and sensory symptoms should be evaluated for attenuated MPS I, especially when routine studies are inconclusive. Heightened clinical suspicion can reduce diagnostic delay and improve long-term outcomes.

Mucopolysaccharidosis type I (MPS I), is an autosomal recessive disorder caused by a deficiency in the enzyme α-L-iduronidase (IDUA), leading to the accumulation of glycosaminoglycans (GAGs) in tissues. Early diagnosis and treatment [i.e., bone marrow transplantation and/or enzyme replacement therapy (ERT) with laronidase] are essential to prevent irreversible damage. The long-term effectiveness of exclusive ERT has been primarily described in attenuated phenotypes, while only a few cases have been reported in severe phenotypes. This study is a retrospective analysis summarising the collective experience of disease progression in 48 patients with severe and attenuated MPS I who were treated exclusively with laronidase over a median of 10 years at the Lyon Reference Centre for Hereditary Metabolic Diseases in France. Patients were categorised by genotype and further stratified by age at treatment initiation. The study assessed the evolution of urinary excretion of GAGs, pulmonary function, cardiac involvement and evolution, height, cognitive impairment, functional status, orthopaedic and ear-nose-throat (ENT) procedures, sleep apnoea, and carpal tunnel syndrome. Descriptive statistical analysis methods were used. ERT reduced the GAGus levels by 88% in severe MPS I and by 71% in attenuated MPS I, of which 47% and 65% patients, respectively achieved normal age-related GAG levels at the last follow-up. ERT provided stable or consistent improvement in forced vital capacity, slowed progression of adverse cardiac course and improved auditory transmission in majority of the severe and attenuated patients. At the last follow-up, 84% attenuated patients had normal cognitive development. In alive Hurler patients, cognitive development was very heterogenous; however, 73% patients had a developmental quotient (DQ) ≥ 70. Laronidase was effective in improving statural growth of attenuated patients treated before 9 years of age. Early ERT and regular multidisciplinary management are effective in slowing disease progression in severe and attenuated patients with MPS I and helping to maintain autonomy in patients with attenuated MPS I, ensuring a better quality of life. Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap. Affected individuals are best described as having either a phenotype consistent with either severe (Hurler syndrome) or attenuated MPS I, a distinction that influences therapeutic options. Severe MPS I: Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year. Gibbus deformity of the lower spine is common and often noted within the first year. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal, as is progressive arthropathy involving most joints. By age three years, linear growth decreases. Intellectual disability is progressive and profound but may not be readily apparent in the first year of life. Progressive cardiorespiratory involvement, hearing loss, and corneal clouding are common. Without treatment, death (typically from cardiorespiratory failure) usually occurs within the first ten years of life. Attenuated MPS I: Clinical onset is usually between ages three and ten years. The severity and rate of disease progression range from serious life-threatening complications leading to death in the second to third decade, to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. While some individuals have no neurologic involvement and psychomotor development may be normal in early childhood, learning disabilities and psychiatric manifestations can be present later in life. Hearing loss, cardiac valvular disease, respiratory involvement, and corneal clouding are common. The diagnosis of MPS I is established in a proband with suggestive clinical and laboratory findings by: detection of deficient activity of the lysosomal enzyme α-L-iduronidase (IDUA) in combination with elevation of glycosaminoglycan levels; and/or identification of biallelic pathogenic variants in IDUA on molecular genetic testing. Identification of the causative IDUA variants plays an important role in the determination of phenotype. Treatment of manifestations: An essential component of management is the determination of whether the proband has severe or attenuated MPS I. This requires detailed clinical and laboratory assessment and can be challenging in very young individuals. Targeted therapies: Hematopoietic stem cell transplantation (HSCT) is considered the standard of care for children with severe MPS I. Outcome is significantly influenced by disease burden at the time of diagnosis (and thus, by the age of the individual). HSCT can improve cognitive outcomes, increase survival, improve growth, reduce facial coarseness and hepatosplenomegaly, improve hearing, prevent hydrocephalus, and alter the natural history of cardiac and respiratory symptomatology. HSCT has lesser effects on the skeletal and joint manifestations, corneal clouding, and cardiac involvement. HSCT alters the course of cognitive decline in children with severe MPS I; cognitive outcome is greatly influenced by the degree of cognitive impairment at the time of transplantation. Due to the morbidity and mortality associated with HSCT, it is currently recommended primarily for children with severe MPS I. Enzyme replacement therapy (ERT) with laronidase (Aldurazyme®), licensed for treatment of the non-CNS manifestations of MPS I, improves liver size, linear growth, and mobility and joint range of motion; slows progression of respiratory disease; and improves sleep apnea in persons with attenuated disease. The age of initiation of ERT influences the outcome. Supportive care: Infant learning programs/special education for developmental delay; physical therapy, orthopedic surgery as needed, joint replacement for progressive arthropathy, atlanto-occipital stabilization; spinal cord decompression for cervical myelopathy; cerebrospinal fluid shunting for hydrocephalus; early median nerve decompression for carpal tunnel syndrome based on nerve conduction studies before clinical manifestations develop; special attention to anesthetic risks; hats with visors/sunglasses to reduce glare, corneal transplantation for ophthalmologic involvement; cardiac valve replacement as needed and bacterial endocarditis prophylaxis for those with cardiac involvement; tonsillectomy and adenoidectomy for eustachian tube dysfunction and/or upper airway obstruction; ventilating tubes; hearing aids as needed; CPAP for sleep apnea; gastrointestinal management for diarrhea and constipation. Surveillance: Annual assessment by a team of physicians with knowledge of the multisystem nature of MPS I. Specialists and assessments: orthopedic surgery including annual assessment of median nerve conduction velocity; ophthalmology, cardiology (including echocardiography), respiratory with assessment of pulmonary function and sleep studies, audiology, and otolaryngology. Assessment for constipation and/or hernias as needed. Early and continuous monitoring of head growth in infants and children with imaging as needed; assessment for evidence of spinal cord compression by neurologic examination; developmental assessment annually; and psycho-educational assessment of children with attenuated disease prior to primary school entry. Evaluation of relatives at risk: Early diagnosis prior to significant disease manifestations is warranted in relatives at risk in order to initiate therapy as early in the course of disease as possible. MPS I is inherited in an autosomal recessive manner. At conception, each child of a couple in which both parents are heterozygous for a IDUA pathogenic variant has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both disease-causing IDUA variants have been identified in the family.

Measurement of enzymatic activity in newborn dried blood spots (DBS) is the preferred first-tier method in newborn screening (NBS) for mucopolysaccharidosis (MPS) disorders. However, false positives are observed due mainly to the presence of pseudodeficiencies. Our previous publications on glycosaminoglycan (GAG) biomarker levels in dried blood spots (DBS) for mucopolysaccharidoses demonstrated that second-tier GAG biomarker analysis can dramatically reduce the false positive rate in NBS. In the present study, we extend this approach to the analysis of a large number of false positives for MPS-I obtained from the Illinois, New York, and Tennessee NBS programs and from Greenwood Genetics Center. Results show that GAG levels measured by the Endogenous-Non-Reducing End method (Endogenous-NRE) are in the normal reference range for all samples. In a second study, we analyzed 166 samples that showed below-cutoff MPS-I enzymatic activity level after testing 384,144 newborns in the Ontario, Canada NBS program. Both genotype and Endogenous-NRE GAG levels were determined for all 166 samples. Newborns at high risk for MPS-I based on genotype also showed elevated GAG levels and were clinically confirmed to be symptomatic for MPS-I. All newborns with pseudodeficiency or carrier status by genotyping all showed normal levels of the appropriate GAG biomarker. Samples found to be inconclusive based on one or more variants of unknown significance (VUS) all showed normal GAG biomarker levels and were found to be clinically normal during follow-up. These studies show that the Endogenous-NRE GAG second-tier NBS method is preferred over second-tier DNA analysis for the NBS of MPS-I with minimal false positives.