Attenuated Mucopolysaccharidosis Type Research Articles

Natural history of cardiac findings in mucopolysaccharidosis type I: report from an international registry.

Mucopolysaccharidosis type I is an inborn error of glycosaminoglycan catabolism with phenotypes ranging from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes). Cardiovascular involvement is common and contributes significantly to morbidity and mortality. We conducted a retrospective analysis of the prevalence and natural history of cardiac abnormalities in treatment-naïve individuals enrolled in the international Mucopolysaccharidosis Type I Registry. Interrogation of echocardiography data (presence of cardiac valve regurgitation and/or stenosis; measurements of left ventricular chamber dimensions in diastole and systole, diastolic left ventricular posterior wall and interventricular septal thicknesses and ventricular systolic function (shortening fraction)) showed that mitral regurgitation was the most common and earliest finding for individuals with both severe (58.3%, median age 1.2 years) and attenuated (74.2%, median age 8.0 years) disease. Left-sided valve stenosis was also common in individuals with attenuated disease (mitral 30.3%; aortic 25%). Abnormal ventricular wall and septal thickness (Z-scores ≥2) were observed early in both phenotypes. Z-scores for diastolic left ventricular posterior wall and interventricular septal thicknesses increased with age in the severe phenotype (annualised slopes of 0.2777 [p = 0.037] and 0.3831 [p = 0.001], respectively); a similar correlation was not observed in the attenuated phenotype (annualised slopes of -0.0401 [p = 0.069] and -0.0029 [p = 0.875], respectively). Decreased cardiac ventricular systolic function (defined as shortening fraction <28%) was uncommon but, when noted, was more frequent in infants with the severe phenotype. While cardiac abnormalities occur early in both severe and attenuated mucopolysaccharidosis type I, the pattern of valve dysfunction and progression of ventricular abnormalities vary by phenotype.

Growth in individuals with attenuated mucopolysaccharidosis type I during untreated and treated periods: Data from the MPS I registry.

Mucopolysaccharidosis Type I (MPS I) is caused by deficiency of α‐L‐iduronidase. Short stature and growth deceleration are common in individuals with the attenuated MPS I phenotype. Study objectives were to assess growth in individuals with attenuated MPS I enrolled in The MPS I Registry while untreated and after initiation of enzyme replacement therapy (ERT) with laronidase (recombinant human iduronidase). Individuals in the MPS I Registry with at least one observation for height and assigned attenuated MPS I phenotype as of September 2020 were included. The cohort included 142 males and 153 females 2–18 years of age. Age and sex adjusted standardized height‐for‐age z‐scores during the natural history and ERT‐treatment periods were assessed using linear mixed model repeated measures analyses. Growth curves were estimated during both periods and compared to standard growth charts from the Center for Disease Control (CDC). There was a significantly slower decline in height z‐scores with age during the ERT‐treated period compared to the natural history period. Estimated average height z‐scores in the ERT‐treatment versus the natural history period at age 10 were −2.4 versus −3.3 in females and −1.4 versus −2.9 in males (females first treated 3 year; males <4.1 year). While median height remained below CDC standards during both the natural history and ERT‐treated periods for individuals with attenuated MPS I, laronidase ERT was associated with slower declines in height z‐scores.

Evaluation of Two Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Severe and Attenuated Mucopolysaccharidosis Type II.

All newborn screening (NBS) for mucopolysaccharidosis-I and -II (MPS-I and MPS-II) is carried out via the measurement of α-iduronidase (IDUA) and iduronate-2-sulfatase (IDS) enzymatic activity, respectively, in dried blood spots (DBS). The majority of low enzyme results are due to pseudodeficiencies, and data from recent MPS-II population screenings and studies from the Mayo Clinic show that the false positive rate can be dramatically reduced by the inclusion of a second-tier analysis of glycosaminoglycans (GAGs) in DBS as part of NBS. In the present study, which focused on MPS-II, we obtained newborn DBS from 17 patients with severe MPS-II, 1 with attenuated MPS-II, and 6 patients with various IDS pseudodeficiencies. These samples were submitted to two different GAG mass spectrometry analyses in a comparative study: (1) internal disaccharide biomarkers and (2) endogenous biomarkers. For both of these methods, the biomarker levels in six patients with pseudodeficiencies were below the range measured in MPS-II patients. One patient with attenuated MPS-II was not distinguishable from severe disease patients, but all MPS-II patients were distinguishable from the reference range using both methods. The minimal differential factor (lowest GAG marker level in MPS-II samples divided by highest level in the reference range of 60 random newborns) was 3.01-fold for the internal disaccharide method. The endogenous biomarker method demonstrated an improved minimum differential of 5.41-fold. The minimum differential factors between MPS-II patients and patients with pseudodeficiencies for the internal disaccharide and endogenous biomarker methods were 3.77-fold and 2.06-fold, respectively. This study supports use of the second-tier GAG analysis of newborn DBS, especially the endogenous disaccharide method, as part of NBS to reduce the false positive rate.

Proposal of an Algorithm to Early Detect Attenuated Type I Mucopolysaccharidosis (MPS Ia) among Children with Growth Abnormalities.

Background and Objectives: Diagnostic delay is common in attenuated Mucopolysaccharidosis Type I (MPS Ia) due to the rarity of the disease and the variability of clinical presentation. Short stature and impaired growth velocity are frequent findings in MPS Ia, but they rarely raise suspicion as paediatric endocrinologists are generally poorly trained to detect earlier and milder clinical signs of this condition. Materials and Methods: Following a consensus-based methodology, a multidisciplinary panel including paediatric endocrinologists, paediatricians with expertise in metabolic disorders, radiologists, and rheumatologists shared their experience on a possible clinical approach to the diagnosis of MPS Ia in children with short stature or stunted growth. Results: The result was the formation of an algorithm that illustrates how to raise the suspicion of MPS Ia in a patient older than 5 years with short stature and suggestive clinical signs. Conclusion: The proposed algorithm may represent a useful tool to improve the awareness of paediatric endocrinologists and reduce the diagnostic delay for patients with MPS Ia.

Angle-closure glaucoma with attenuated mucopolysaccharidosis type I in a Chinese family.

Angle-closure glaucoma with attenuated mucopolysaccharidosis type I in a Chinese family.

Evidence of problems with “processing efficiency” in attenuated mucopolysaccharidosis type I

Evidence of problems with “processing efficiency” in attenuated mucopolysaccharidosis type I

Short stature as a presenting symptom of attenuated Mucopolysaccharidosis type I: case report and clinical insights

BackgroundMucopolysaccharidosis type I (MPS I) results in significant disease burden and early treatment is important for optimal outcomes. Recognition of short stature and growth failure as symptoms of MPS I among pediatric endocrinologists may lead to earlier diagnosis and treatment.Case presentationA male patient first began experiencing hip pain at 5 years of age and was referred to an endocrinologist for short stature at age 7. Clinical history included recurrent respiratory infections, sleep apnea, moderate joint contractures, mild facial dysmorphic features, scoliosis, and umbilical hernia. Height was more than − 2 SD below the median at all time points. Growth velocity was below the 3rd percentile. Treatment for short stature included leuprolide acetate and recombinant human growth hormone. The patient was diagnosed with MPS I and began enzyme replacement therapy with laronidase at age 18.ConclusionsThe case study patient had many symptoms of MPS I yet remained undiagnosed for 11 years after presenting with short stature. The appropriate path to MPS I diagnosis when patients present with short stature and/or growth failure plus one or more of the common signs of attenuated disease is described. Improved awareness regarding association of short stature and growth failure with attenuated MPS I is needed since early identification and treatment significantly decreases disease burden.

Outcomes of Long-Term Treatment with Laronidase in Patients with Mucopolysaccharidosis Type I

To evaluate long-term outcomes of laronidase enzyme replacement therapy in patients with attenuated mucopolysaccharidosis type I. Retrospective analyses of case notes, laboratory results, and data from clinical trials were used to evaluate urinary glycosaminoglycans, forced vital capacity (FVC), 6-minute walk test (6MWT), height-for-age Z score, cardiac valve function, corneal clouding, and visual acuity in 35 patients with attenuated mucopolysaccharidosis type I (Hurler-Scheie and Scheie syndromes) for up to 10 years following the initiation of laronidase therapy. Statistically significant (P < .001) reductions in mean urinary glycosaminoglycan levels relative to baseline were observed 6 months after treatment initiation and were sustained throughout follow-up. Disease remained stable after treatment initiation with no statistically significant changes in mean FVC, 6MWT, or height-for-age Z score. At last assessments, mitral and aortic valve function remained stable in 65% (22/34) of patients; corneal clouding remained stable in 78% (18/23); visual acuity remained stable in 33% (8/24) and improved in 42% (10/24) of patients. Younger patients (<10 years at treatment initiation) maintained disease measures closer to norms for age for FVC, 6MWT, and height and showed fewer deteriorations in mitral and aortic valve disease and corneal clouding compared with patients aged ≥10 years at treatment initiation. Laronidase treatment resulted in disease stabilization in the majority of patients with a mean follow-up of 6.1 years. Data suggest that early treatment may result in better outcomes.

A longitudinal study of emotional adjustment, quality of life and adaptive function in attenuated MPS II

ObjectivesThe behavioral, adaptive and quality of life characteristics of attenuated mucopolysaccharidosis type II (MPS II) have not been well studied. Understanding changes over time in the attenuated phenotype may assist in helping achieve better outcomes in long-term function. This longitudinal study investigates these outcomes in relation to age, somatic disease burden, and IQ. Specifically, somatic disease burden is a major challenge for these patients, even with treatment with enzyme replacement therapy. Methods15 patients, 10 between ages 6 and <12 and 5 between ages ≥12 and 18, were selected who had at least 2 yearly visits. The occurrence of physical signs, the Physical Symptom Score, and IQ in these two groups was studied as well as the longitudinal association of age with standardized measures of quality of life, adaptive function, and behavioral symptoms as rated by parents and the child's self-report. Slopes by age across and within patients were calculated for these measures. ResultsAll but one child had hearing loss, most had joint contractures and short stature. Somatic disease burden increased with age. IQ, although normal for most, also improved with age in those under 12years of age. Physical quality of life decreased while psychosocial quality of life increased with age. Although other adaptive skills were in the broad average range, daily living skills were low at baseline relative to normative data and decreased over time. Behavior ratings indicated improvement in attention and hyperactivity over time. No patient had severe psychopathology, but older children reported an increasing sense of inadequacy and low self-esteem on self-report, presumably due to increasing awareness of differences from peers over time. ConclusionsAttenuated MPS II patients have increasing somatic disease burden and poor physical quality of life as they develop as well as decreasing self-esteem and sense of adequacy. Psychosocial quality of life, adaptive skills, and attention improve. Recognition of and intervention around these issues will be beneficial to MPS II attenuated patients who have the resources to use such assistance to improve their long-term outcomes.

Mucopolysaccharridosis type 1 and the challenges in managing this rare genetic disorder in the resource poor setting

This case report is about a six-year-old Nigerian boy with a rare genetic disorder of attenuated mucopolysaccharidosis type 1 and the challenges that the clinicians face in managing these patients in resource poor settings. This patient presented with short stature with skeletal deformities, poor speech and intellectual impairment. He also had features such as coarse facial features with macroglossia, lichenified, dry thick skin and hepatosplenomegaly. Delay in the diagnosis is a common problem with this rare genetic disorder. Confirmation of the diagnosis and providing the recommended disease-specific therapeutic options such as of enzyme replacement therapy and haematopoeitic stem cell transplantation are the challenges that we face in managing these patients in the resource poor settings.

Age and developmental change in adaptive behavior in severe and attenuated mucopolysaccharidosis type 1

Age and developmental change in adaptive behavior in severe and attenuated mucopolysaccharidosis type 1

Unexpected coronary artery findings in mucopolysaccharidosis. Report of four cases and literature review

The mucopolysaccharidosis syndromes are a group of lethal inherited disorders affecting multiple organ systems by the progressive deposition of glycosaminoglycan. Advances in treatment such as enzyme replacement and hematopoietic stem cell transplantation have significantly improved the outcome of these disorders. An in-depth understanding of the pathophysiology of heart disease in these disorders is essential since death from cardiac causes continues to be common. Epicardial coronary artery luminal narrowing from myointimal proliferation and glycosaminoglycan deposition is well described in severe mucopolysaccharidosis type I [Hurler syndrome, mucopolysaccharide IH] but poorly understood in other "non-Hurler" phenotypes of these disorders. Given the rarity of these conditions, autopsy specimens are uncommon. Tissue from epicardial coronary arteries from autopsies of four patients with non-Hurler mucopolysaccharidosis (attenuated type I, type IIIA, type IIIC, and type VI) who had died after hematopoietic cell transplantation (within 1 month in three cases; after 5 years in the fourth) was examined by light microscopy. Unexpectedly, near-normal coronary arteries were observed in the patient with attenuated mucopolysaccharidosis type I, while the coronaries from patients with type IIIA, IIIC, and VI demonstrated classic histologic features of glycosaminoglycan deposition. The most severe findings were found in the MPS IIIC patient who had 5 years of full donor engraftment after transplantation. Our current understanding of the cardiac manifestations of the mucopolysaccharidoses fails to explain why near-normal coronary arteries may be observed when abnormalities would be most likely to be expected and, conversely, why significant histopathology is present when it would be least expected. Identification of downstream effects of glycosaminoglycan deposition may identify other metabolites or metabolic pathways that are important in the clinicopathologic manifestations of these diseases. The mucopolysaccharidosis diseases are a group of inherited disorders affecting multiple organ systems by the progressive deposition of glycosaminoglycan. Severe coronary artery disease is well recognized in severe type I mucopolysaccharidosis (Hurler syndrome), but unexpected coronary artery disease occurs in other, "non-Hurler" mucopolysaccharidoses. Factors responsible for the development of coronary pathology in the mucopolysaccharidoses remain elusive.

Neuropsychological function and brain abnormalities in Children with attenuated Mucopolysaccharidosis type II

Neuropsychological function and brain abnormalities in Children with attenuated Mucopolysaccharidosis type II

Attenuated mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) due to homozygosity for the p.Y210C mutation in the ARSB gene

We describe the case of a boy recently diagnosed with an attenuated form of mucopolysacchararidosis VI (MPS VI, Maroteaux-Lamy syndrome). The Y210C mutation has not been described previously in the homozygous state, although this is a common ARSB mutation. His phenotype is essentially musculoskeletal. Urine screening tests based on measuring total GAG may miss this presentation as total GAGs were not elevated in the patient (although the electrophoresis pattern was clearly abnormal). In this phenotype the benefit of ERT remains to be established.

Mutation analysis of 11 Chinese patients with attenuated mucopolysaccharidosis type

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease resulting from the deficiency in the lysosomal enzyme alpha-L-iduronidase (IDUA). The present study was conducted to identify IDUA gene mutations in attenuated (MPS I H/S and MPS I S) patients with MPS I in northern China. Fourteen exons with adjacent intronic sequences of the IDUA gene in 11 MPS I patients were amplified by polymerase chain reaction (PCR), and the PCR products were sequenced directly and origin analysis was conducted. Seven mutations were detected in the 11 MPS I patients, i.e., c.236 C to T (p. A79V), c.266 G to A (p.R89Q), c.265 C to T (p.R89W), c.532G to A (p.E178K), c.589G to A (p.G197S), c.1037T to G (p.L346R), and c.1877 G to A (p.W626X). All of them were known mutations. Six patients were homozygotes and 1 was heterozygote with nonsense mutation. In addition, 9 reported single nucleotide polymorphism (SNP) were detected, i.e., p.A8, p.A20, p.H33Q, p.R105Q, p.A314, p. A361T, p.T388, p.T410 and p.V454I. The mutation spectrum of the IDUA gene in attenuated MPS I Chinese patients may be different from that in patients from other countries.