Shunji Tomatsu

Epidemiology of mucopolysaccharidoses

The aim of this study was to obtain data about the epidemiology of the different types of mucopolysaccharidoses in Japan and Switzerland and to compare with similar data from other countries. Data for Japan was collected between 1982 and 2009, and 467 cases with MPS were identified. The combined birth prevalence was 1.53 per 100,000 live births. The highest birth prevalence was 0.84 for MPS II, accounting for 55% of all MPS. MPS I, III, and IV accounted for 15, 16, and 10%, respectively. MPS VI and VII were more rare and accounted for 1.7 and 1.3%, respectively. A retrospective epidemiological data collection was performed in Switzerland between 1975 and 2008 (34years), and 41 living MPS patients were identified. The combined birth prevalence was 1.56 per 100,000 live births. The highest birth prevalence was 0.46 for MPS II, accounting for 29% of all MPS. MPS I, III, and IV accounted for 12, 24, and 24%, respectively. As seen in the Japanese population, MPS VI and VII were more rare and accounted for 7.3 and 2.4%, respectively. The high birth prevalence of MPS II in Japan was comparable to that seen in other East Asian countries where this MPS accounted for approximately 50% of all forms of MPS. Birth prevalence was also similar in some European countries (Germany, Northern Ireland, Portugal and the Netherlands) although the prevalence of other forms of MPS is also reported to be higher in these countries. Birth prevalence of MPS II in Switzerland and other European countries is comparatively lower. The birth prevalence of MPS III and IV in Switzerland is higher than in Japan but comparable to that in most other European countries. Moreover, the birth prevalence of MPS VI and VII was very low in both, Switzerland and Japan. Overall, the frequency of MPS varies for each population due to differences in ethnic backgrounds and/or founder effects that affect the birth prevalence of each type of MPS, as seen for other rare genetic diseases. Methods for identification of MPS patients are not uniform across all countries, and consequently, if patients are not identified, recorded prevalence rates will be aberrantly low.

Mucopolysaccharidosis IVA and glycosaminoglycans

Mucopolysaccharidosis IVA (MPS IVA; Morquio A: OMIM 253000) is a lysosomal storage disease with an autosomal recessive trait caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to accumulation of specific glycosaminoglycans (GAGs): chondroitin-6-sulfate (C6S) and keratan sulfate (KS). C6S and KS are mainly produced in the cartilage. Therefore, the undegraded substrates are stored primarily in cartilage and in its extracellular matrix (ECM), leading to a direct impact on cartilage and bone development, and successive systemic skeletal dysplasia. Chondrogenesis, the earliest phase of skeletal formation, is maintained by cellular interactions with the ECM, growth and differentiation factors, signaling pathways, and transcription factors in a temporal-spatial manner. In patients with MPS IVA, the cartilage is disrupted at birth as a consequence of abnormal chondrogenesis and/or endochondral ossification. The unique skeletal features are distinguished by a disproportional short stature, odontoid hypoplasia, spinal cord compression, tracheal obstruction, pectus carinatum, kyphoscoliosis, platyspondyly, coxa valga, genu valgum, waddling gait, and laxity of joints. In spite of many descriptions of these unique clinical features, delay of diagnosis still happens. The pathogenesis and treatment of systemic skeletal dysplasia in MPS IVA remains an unmet challenge. In this review article, we comprehensively describe historical aspect, property of GAGs, diagnosis, screening, pathogenesis, and current and future therapies of MPS IVA.

Bone mineral density in MPS IV A (Morquio syndrome type A).

Mucopolysaccharidosis IV A (MPS IV A), Morquio A, is caused by deficiency in lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which is responsible for the catabolism of the glycosaminoglycans (GAGs) keratan sulfate (KS) and chondroitin 6-sulfate (C6S). Accumulation of GAGs results in disrupted cartilage formation and skeletal dysplasia. In this prospective cross-sectional study, bone mineral density (BMD) of the whole body (WB), lumbar spine (LS), and lateral distal femur (LDF) was acquired by dual-energy X-ray absorptiometry (DXA) on patients with MPS IV A. Functional abilities, medical history, Tanner score, and laboratory results were reviewed. Age and sex-matched norms were used to calculate Z-scores. Participants included 18 patients (13 females; 16 were unrelated) with a mean age of 21.4years (3.3 to 40.8years). While every patient was able to bear weight, 9 were full-time ambulators. Whole-body DXA could be obtained on only 6 patients (5 full-time ambulators) because of respiratory compromise caused by the position, presence of hardware, or positioning difficulties. Mean WB Z-score was -2.0 (range-0.3 to -4.1). Technical issues invalidating LS DXA in 8 patients included kyphosis at the thoracolumbar junction resulting in overlap of vertebrae in the posterior-anterior view. Mean LS BMD Z-score in full-time ambulators was -3.4 (range-1.6 to -5.0) and in the non-/partial ambulator was -4.0 (-3.7 to -4.2). Lateral distal femur BMD was acquired on every patient, and average Z-scores were -2 or less at all sites; full-time ambulators exhibited higher BMD. In conclusion, the LDF proved to be the most feasible site to measure in patients with MPS IV A. The higher LDF values in ambulators suggest this should be a consideration in promoting bone health for this group.

Gene therapy for Mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders (LSDs) caused by a deficiency of lysosomal enzymes, leading to a wide range of various clinical symptoms depending upon the type of MPS or its severity. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), substrate reduction therapy (SRT), and various surgical procedures are currently available for patients with MPS. However, there is no curative treatment for this group of disorders. Gene therapy should be a one-time permanent therapy, repairing the cause of enzyme deficiency. Preclinical studies of gene therapy for MPS have been developed over the past three decades. Currently, clinical trials of gene therapy for some types of MPS are ongoing in the United States, some European countries, and Australia. Here, in this review, we summarize the development of gene therapy for MPS in preclinical and clinical trials.

Natural history of Morquio A patient with tracheal obstruction from birth to death

Morquio A syndrome (mucopolysaccharidosis IVA, MPS IVA) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase, resulting in systemic accumulation of the partially degraded glycosaminoglycans (GAGs), keratan sulfate and chondroitin-6-sulfate. The accumulation of these GAGs leads to distinguishing features as skeletal dysplasia with disproportionate dwarfism, short neck, kyphoscoliosis, pectus carinatum, tracheal obstruction, coxa valga, genu valgum, and joint laxity. In the absence of autopsied cases and systemic analysis of multiple tissues, the pathological mechanism of the characteristic skeletal dysplasia associated with the disease largely remains a question. Here we report an autopsied case of a 23-year-old male with MPS IVA, who developed characteristic skeletal abnormalities by 4 months of age and died of severe tracheal obstruction and hypoventilation originating from respiratory muscle weakness from neurological cord deficit due to cord myelopathy at the age of 23. We analyzed postmortem tissues pathohistologically, including the thyroid, lung, lung bronchus, trachea, heart, aorta, liver, spleen, kidney, testes, humerus, knee cartilage, and knee ligament. Examination of the tissues demonstrated systemic storage materials in multiple tissues, as well as severely ballooned and vacuolated chondrocytes in the trachea, humerus, knee cartilage, and lung bronchus. This autopsied case with MPS IVA addresses the importance of tracheal obstruction for morbidity and mortality of the disease, and the pathological findings contribute to a further understanding of the pathogenesis of MPS IVA and the development of novel therapies.

Growth impairment in mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders that affect regulation of glycosaminoglycan (GAG) processing. In MPS, the lysosomes cannot efficiently break down GAGs, and the specific GAGs accumulated depend on the type of MPS. The level of impairment of breakdown varies between patients, making this one of the many factors that lead to a range of clinical presentations even in the same type of MPS. These clinical presentations usually involve skeletal dysplasia, in which the most common feature is bone growth impairment and successive short stature. Growth impairment occurs due to the deposition and retention of GAGs in bone and cartilage. The accumulation of GAGs in these tissues leads to progressive damage in cartilage that in turn reduces bone growth by destruction of the growth plate, incomplete ossification, and imbalance of growth. Imbalance of growth leads to various skeletal abnormalities including disproportionate dwarfism with short neck and trunk, prominent forehead, rigidity of joints, tracheal obstruction, kyphoscoliosis, pectus carinatum, platyspondyly, round-shaped vertebral bodies or beaking sign, underdeveloped acetabula, wide flared iliac, coxa valgus, flattered capital femoral epiphyses, and genu valgum. If left untreated, skeletal abnormalities including growth impairment result in a significant impact on these patients quality of life and activity of daily living, leading to high morbidity and severe handicap. This review focuses on growth impairment in untreated patients with MPS. We comprehensively describe the growth abnormalities through height, weight, growth velocity, and BMI in each type of MPS and compare the status of growth with healthy age-matched controls. The timing, the degree, and the difference in growth impairment of each MPS are highlighted to understand the natural course of growth and to evaluate future therapeutic efficacy.

Neurophysiology of hearing in patients with mucopolysaccharidosis type IV

BACKGROUNDnHearing impairment is a common problem in patients with mucopolysaccharidosis IV (MPS IV) throughout their life. Many of the adult patients with MPS IV exhibit permanent or severe hearing loss. However, there has been no systematic review of detailed audiological test results in MPS IV.nnnMATERIALS AND METHODSnFourteen individuals with MPS IV (13 MPS IVA and 1 MPS IVB; aged between 12 and 38u202fyears old) participated in the current study. We obtained auditory neurophysiological responses (auditory brainstem responses and otoacoustic emissions test) in addition to pure-tone audiometry and middle ear function tests (tympanometry and acoustic reflexes).nnnRESULTSnThe results indicated various levels and types of hearing loss with abnormal neurophysiological responses even in those patients with MPS IVA with normal pure tone thresholds. We also found a strong relationship between height (short stature is an indicator of skeletal severity) and hearing sensitivity as well as a strong relationship between height and outer hair cell function in the inner ear (measured by otoacoustic emissions) among MPS IVA patients.nnnCONCLUSIONnThe strong correlation between reduced height and hearing loss indicates that patients with severe skeletal dysplasia may be at higher risk of developing more severe hearing loss. More importantly, the spectrum of hearing disorders indicates that MPS IV patients should have annual neurophysiological hearing tests in addition to audiometric testing from an early age regardless of their skeletal severity to more carefully monitor disease progression.

Elevation of glycosaminoglycans in the amniotic fluid of a fetus with mucopolysaccharidosis VII

The aim of this study was to quantify glycosaminoglycans (GAGs) in amniotic fluid (AF) from an MPS VII fetus compared with age‐matched fetuses obtained from normal pregnancies.

Bone mineral density in mucopolysaccharidosis IVB.

To date, the only published reports of bone mineral density (BMD) in MPS IV involve patients with MPS IVA; no reports exist describing BMD for MPS IVB. In this prospective study of BMD in three patients with MPS IVB, BMD was acquired by dual-energy X-ray absorptiometry (DXA) at whole body (WB), lumbar spine (LS), and lateral distal femur (LDF). Functional abilities, ambulatory status, medical history, and height z-score were evaluated. Three patients with MPS IVB (two females), aged 17.7, 31.4 and 31.7 years, were evaluated. Every patient was ambulatory and one sustained two fractures caused by trauma. Whole body and hip DXA scans were technically invalid in every patient due to the presence of prosthetic hip hardware. Lumbar spine was valid in only 1 patient due skeletal abnormalities, and was normal (Z-score of − 0.8). The LDF was valid in every patient and was low at all three regions of interest: average LDF z-scores were − 3.1 (range, − 2.9 to − 3.6), − 2.3 (range, − 2.0 to − 2.5), and − 2.1 (range, − 2.0 to − 2.3) for region 1–region 3, respectively. Patients with MPS IVB have low BMD of the lower extremities even with full-time ambulation. Routine body sites to measure by DXA were problematic; hip and WB were invalid due to artifact, and LS had limited utility. The LDF was the only body site consistently available on all patients. Patients did not experience low-energy fractures despite low BMD.

Shutdown of ER-associated degradation pathway rescues functions of mutant iduronate 2-sulfatase linked to mucopolysaccharidosis type II

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a devastating progressive disease caused by mutations in the iduronate 2-sulfatase (IDS) gene. IDS is one of the sulfatase enzymes required for lysosomal degradation of glycosaminoglycans. Mutant proteins linked to diseases are often prone to misfolding. These misfolded proteins accumulate in the endoplasmic reticulum (ER) and are degraded by the ubiquitin–proteasome pathway (ER-associated degradation (ERAD)). The decreased enzyme activities of IDS mutants may be due to accelerated degradation by ERAD. However, intracellular dynamics including degradation of IDS mutants is unexplored. In this report, we examined biochemical and biological characteristics of wild-type (WT) IDS and IDS mutants expressed in HeLa cells. IDS was shown to be glycosylated in the ER and Golgi apparatus and proteolytically cleaved to generate the mature forms in the Golgi apparatus. The mature WT IDS was translocated to the lysosome. In contrast, all IDS mutants we examined were found to accumulate in the ER and could not efficiently translocate to the lysosome. Accumulated IDS mutants in the ER were ubiquitinated by ERAD-related ubiquitin E3 ligase HRD1 followed by degradation via ERAD. Suppressed degradation of ‘attenuated’ mutant A85T IDS (the late-onset form of MPS II) by inhibiting ERAD components improved translocation to the lysosome and its activities. Our novel findings provide alternative targets to current principal therapies for MPS II. These perspectives provide a potenti al framework to develop fundamental therapeutic strategies and agents.