Biochemical and molecular analysis of mucopolysaccharidoses in Turkey

The mucopolysaccharidoses (MPSs) are a family of heritable disorders caused by deficiency of lysosomal enzymes needed to degrade glycosaminoglycans (GAGs). The undegraded or partially degraded GAGs are stored in lysosomes and/or excreted in urine. In our study, 118 patients seen over the past 20 years and suspected to have lysosomal storage disorders (LSDs) were subjected to clinical and biochemical analysis at Hacettepe University Children's Hospital. We analyzed urine and blood samples from 42 patients given a clinical MPS diagnosis. Using urine screening technique, we were able to show that 34 of the 42 patients had MPS condition. Further analysis of eight patients with normal urine MPS patterns revealed four patients as likely to have alpha-mannosidosis, fucosidosis, sialidosis, and aspartylglucosaminuria (one each). Four patients had normal oligosaccharide patterns. We were able to clearly identify 4 MPS I, 2 MPS II, 5 MPS IIIA, 8 MPS IIIB, 11 MPS IVA, 3 MPS VI, and 1 MPS IIIC patients. These results provided biochemical diagnosis for these 34 patients, and clearly show that Turkey has a higher incidence of MPS IVA, IIIB, and IIIA than of previously suspected MPS types. Molecular analysis of four MPS I patients revealed three polymorphisms which have been previously reported (A314, T388, and A461T). In MPS II patients, mutation analysis identified one previously detected (R172X) and one novel mutation (W109C).     

Early diagnosis and management of cardiac manifestations in mucopolysaccharidoses: a practical guide for paediatric and adult cardiologists

Mucopolysaccharidoses (MPS) are a group of hereditary disorders caused by lysosomal storage of glycosaminoglycans (GAGs) and characterized by a wide variability of phenotypes from severe fetal-neonatal forms to attenuated diseases diagnosed in adult individuals. The clinical picture generally worsens with age due to progressive storage involving mucosal tissue, upper airways and lungs, bones and joints, central and peripheral nervous system, heart, liver, eye, and ear. Cardiac storage of GAGs involves valves, heart muscle, and vessels (particularly the coronary arteries), and can be specific in relation to different MPS types and enzyme defects. MPS I, II, and VI are those with the most severe cardiac involvement. The cardiologist is a key figure in MPS, and their role is expanding from cardiac-specific management to early diagnosis when the mild disease phenotypes have not yet been recognized by other specialists. Familial and personal history, electrocardiography, imaging, and laboratory findings represent important steps in the clinical investigation of these patients. New treatments have led to an increased need for cardiologists to be on the lookout for MPS patients since they can significantly improve the lives of people with MPS if they suspect the diagnosis and refer them for enzyme replacement therapy or bone marrow transplantation.     

Development and testing of new screening method for keratan sulfate in mucopolysaccharidosis IVA

Mucopolysaccharidosis IVA (MPS IVA), a progressive lysosomal storage disease, causes skeletal dysplasia through excessive storage of keratan sulfate (KS). We developed an ELISA-sandwich assay that used a MAb specific to KS. Forty-five blood and 59 urine specimens from MPS IVA patients (ages 1-65 y) were analyzed to determine whether KS concentration is a suitable marker for early diagnosis and longitudinal assessment of disease severity. Blood specimens were obtained from patients categorized as phenotypically severe (n = 36) and milder (n = 9). Urine specimens were also analyzed from patients categorized as severe (n = 56) and milder (n = 12), respectively. Blood KS levels (101-1525 ng/mL) in MPS IVA patients were two to eight times higher than those in age-matched controls (15-323 ng/mL). It was found that blood KS level varied with age and clinical severity. Blood KS levels in both MPS IVA and controls peaked between 5 and 10 y of age (mean, 776 versus 234 ng/mL, respectively). Blood levels in severe MPS IVA were 1.5 times higher than in the milder form. In contrast to blood, urine KS levels in both MPS IVA and controls peaked between 1 and 5 y (15.3 versus 0.26 mg/g creatinine), and thereafter declined with age. Urine KS level also varied with age and clinical severity, and the severe MPS IVA phenotype was associated with 6.7 times greater urine KS excretion than the milder one. These findings indicate that the new assay for blood or urine KS may be suitable for early diagnosis and longitudinal assessment of disease severity in MPS IVA.     

Enzyme replacement therapy: from concept to clinical practice

In the early 1960s, the first lysosomal storage disease was identified. Since then over 40 such diseases have been reported. The common feature is that enzyme deficiency leads to accumulation of undegraded macromolecules and lysosomal engorgement, resulting in organ dysfunction. Enzyme replacement therapy (ERT) is being developed for many of these disorders. The present paper summarizes the history of the development of ERT, with particular reference to the mucopolysaccharidoses, and specifically, to mucopolysaccharidosis type VII (MPS VII). The rarity of MPS VII has meant that ERT is not yet available for the small number of affected patients, although the study of MPS VII and murine models of the disease have played an important part in the development of treatment for related disorders, including Gaucher disease.
Conclusion : Much progress has been made in our understanding of lysosomal storage diseases over the past 40 years. This has led to the development of effective ERT for some of the more common storage diseases, such as Fabry disease and Gaucher disease. Treatment is still awaited, however, for many of the other rare disorders in this area, such as MPS VII.     

Enzyme replacement therapy: from concept to clinical practice

In the early 1960s, the first lysosomal storage disease was identified. Since then over 40 such diseases have been reported. The common feature is that enzyme deficiency leads to accumulation of undegraded macromolecules and lysosomal engorgement, resulting in organ dysfunction. Enzyme replacement therapy (ERT) is being developed for many of these disorders. The present paper summarizes the history of the development of ERT, with particular reference to the mucopolysaccharidoses, and specifically, to mucopolysaccharidosis type VII (MPS VII). The rarity of MPS VII has meant that ERT is not yet available for the small number of affected patients, although the study of MPS VII and murine models of the disease have played an important part in the development of treatment for related disorders, including Gaucher disease. CONCLUSION: Much progress has been made in our understanding of lysosomal storage diseases over the past 40 years. This has led to the development of effective ERT for some of the more common storage diseases, such as Fabry disease and Gaucher disease. Treatment is still awaited, however, for many of the other rare disorders in this area, such as MPS VII.     

Early Onset of Lysosomal Storage Disease in a Murine Model of Mucopolysaccharidosis Type VII: Undegraded Substrate Accumulates in Many Tissues in the Fetus and Very Young MPS VII Mouse

Lysosomal storage diseases (LSDs), due to deficiency of a lysosomal enzyme, are inherited, progressive disorders that are often fatal during childhood. The mucopolysaccharidoses (MPS) are LSDs caused by deficiency of a lysosomal enzyme needed for the stepwise degradation of glycosaminoglycans. A murine model of MPS VII shares many clinical, biochemical, and pathologic features with human MPS and has proved valuable for the study of the pathophysiology of MPS and for evaluation of therapies for LSDs. Early therapy of MPS VII mice, initiated in the first weeks of life, is much more effective in decreasing clinical and morphologic evidence of disease than treatment begun in mature animals. Whether such early therapy decreases existing storage or prevents its accumulation is incompletely investigated. We performed an analysis of storage in very young MPS VII mice to define the extent of disease at and before the time of initiation of early treatments. MPS VII pups from 12 days postcoitus (dpc) to 31 days postnatal (dpn) were studied. Storage accumulated in fixed tissue macrophages in the liver and cartilage as soon as 12 dpc and was present in central nervous system glia, leptomeninges, and perivascular cells by 15 dpc. Osteoblast and primitive neocortical cell storage was apparent at 18 to 19 dpc. At 2 dpn, lysosomal distention appeared in circulating leukocytes. Abundant lysosomal storage was present in many sites by 14 dpn. Secondary accumulation of β-hexosaminidase paralleled increasing glycosaminoglycan storage. These results confirm the presence of widespread storage even in utero and in the very young MPS VII mouse and highlight the importance of early treatment to prevent storage accumulation.     

Abnormalities in the hair morphology of patients with some but not all types of mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are a group of inherited, progressive, metabolic diseases, caused by the deficiency of one of the enzymes involved in the degradation of glycosaminoglycans (GAGs). The disease is usually fatal, with the life span of most untreated MPS patients being between one and two decades. In this report, on the basis of scanning electron microscopy (SEM) studies, we demonstrate that, besides the many other symptoms of MPS, there are characteristic abnormalities in the hair morphology of patients suffering from some types of this disease (MPS I, MPS II, MPS IIIA, MPS IIIB), but not from other types (MPS IVA, MPS IVB, MPS VI), where the changes are minor, if any. Different GAGs accumulate in the tissues of patients suffering from the various MPS types, and analysis of the disease types in which severe hair abnormalities occur or not could suggest that the accumulation of heparan sulfate, rather than dermatan sulfate or keratan sufate, may be responsible for the major changes in hair morphology. Considerable abnormalities in hair morphology occur in patients suffering from MPS I, MPS II, MPS IIIA, and MPS IIIB, but not in patients suffering from MPS IVA, MPS IVB, and MPS VI; this feature might potentially be used as an additional test for the assessment of the efficacy of treatments for MPS patients (types I, II, IIIA, and IIIB).     

Mucopolysaccharidosis type VII in the developing mouse fetus

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a deficiency of beta-glucuronidase (1). MPS VII is a fatal, progressive degenerative disorder, and a number of patients die of hydrops fetalis. Thus an approach to treating this disease may be by transplantation or gene therapy in utero. A mouse model of MPS VII has been studied extensively but the disease in affected fetal mice has not been characterized, which is essential for evaluation of therapeutic efficacy. Fetal and newborn mice affected with MPS VII were examined for lysosomal enzyme activities and for the presence of typical storage lesions in comparison to normal and carrier littermates. No beta-glucuronidase enzymatic activity was detected in any of the tissues of affected mice, indicating that transplacental transfer of beta-glucuronidase from the dam did not occur. Lesions were not detected in affected fetuses of 13.5 d gestational age on light or electron microscopy. Vacuolation in cells, typical of lysosomal accumulation of substrate, was first seen in a small number of cells of the reticulo-endothelial system in 15.5 d gestational age livers and in 18.5 d gestational age brains. Storage lesions were not seen consistently in endothelial and Kupffer cells of fetal livers until 18.5 d gestational age and in brains until birth. The results suggest that treatment of affected mice performed at 13.5 d gestational age may be effective in forestalling disease manifestations.     

Neurobehavioral phenotypes of neuronopathic mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are a group of lysosomal multisystemic, chronic, and progressive diseases characterized by the storage of glycosaminoglycans (GAGs) that may affect the central nervous system. Neuronopathic MPS such as MPS IH, MPS II, MPS IIIA–D, and MPS VII are characterized by neurocognitive regression. In severe MPS I (MPS IH, or Hurler syndrome) initial developmental trajectory is usually unremarkable but cognitive development shows a plateau by 2 to 4 years of age and then progressively regresses with aging. Patients with neuronopathic MPS II have a plateau of cognitive and adaptive development on average by 4 to 4.5 years of age, although there is significant variability, followed by progressive neurocognitive decline. In patients with classic MPS III, developmental trajectory reaches a plateau around 3 years of age, followed by regression. Sleep disturbances and behavioral problems occur early in MPS II and III with features of externalizing disorders. Acquired autism-like behavior is often observed in children with MPS III after 4–6 years of age. Impaired social and communication abilities do occur, but MPS III children do not have restricted and repetitive interests such as in autism spectrum disorder. MPS type VII is an ultra-rare neuronopathic MPS with a wide clinical spectrum from very severe with early mortality to milder phenotypes with longer survival into adolescence and adulthood. Most patients with MPS VII have intellectual disability and severely delayed speech development, usually associated with hearing impairment. Cognitive regression in neuronopathic MPS runs parallel to a significant decrease in brain tissue volume. Assessment of the developmental profile is challenging because of low cognitive abilities, physical impairment, and behavioral disturbances. Early diagnosis is crucial as different promising treatment approaches have been extensively studied in animal MPS models and are currently being applied in clinical trials.     

Lumbar gibbus in storage diseases and bone dysplasias

Objective. The objective of this study was to review the problem of lumbar gibbus in children with storage diseases and bone dysplasias utilizing plain films and MR imaging. Materials and methods. Clinical histories and radiographic images in five patients with storage diseases [four mucopolysaccharidosis (MPS) and one mucolipidosis] and two with achondroplasia were reviewed. The International Skeletal Dysplasia Registry (Los Angeles, Calif.), surveyed for all patients with lumbar gibbus and skeletal dysplasias, provided 12 additional cases. Results. All patients had localized gibbus of the upper lumbar spine, characterized by anterior wedging and posterior displacement of the vertebrae at the apex of the curve, producing a beaked appearance. The curve, exaggerated in the sitting or standing position, was most severe in the two patients with MPS-IV (one of whom died). Both developed severe neurologic signs and symptoms requiring surgical intervention. In four patients, MR images demonstrated the apex of the curve to be at or below the conus. Two patients demonstrated anterior herniation of the intervertebral discs at the apex of the curve, though the signal intensity of the intervertebral discs was normal. Conclusion. Lumbar gibbus has important neurologic and orthopedic implications, and is most severe in patients with MPS. The etiology of the gibbus with vertebral beaking is multifactorial and includes poor truncal muscle tone, weight-bearing forces, growth disturbance and anterior disc herniation. The curve is generally at or below the conus. Neurologic complications are unusual, although orthopedic problems can arise. Due to their longer survival, patients with achondroplasia or Morquio's disease are more vulnerable to eventual gibbus-related musculoskeletal complications. Received: 15 May 1996 Accepted: 3 July 1996     

Update of the spectrum of mucopolysaccharidoses type III in Tunisia: identification of three novel mutations and <Emphasis Type="Italic">in silico</Emphasis> structural analysis of the missense mutations

Background:Mucopolysaccharidoses type Ⅲ (MPS Ⅲ) are a group of autosomai recessive lysosomal storage diseases,caused by mutations in genes that code for enzymes involved in the lysosomal degradation of heparan sulphate:heparan sulfate sulfamidase (SGSH),a-N-acetylglucosaminidase (NAGLU),heparan sulfate acetyl-CoA:a-glucosaminide N-acetyltransferase (HGSNAT),and N-acetylglucosamine-6-sulfatase (GNS).Methods:In this study,we have performed the molecular analysis of the SGSH,NAGLU and HGSNAT genes in 10 patients from 6 different MPS Ⅲ Tunisian families.Results:In the SGSH gene,two mutations were identified:one novel (p.D477N) and one already described (p.Q365X).In the NAGLU gene,two novel mutations were discovered (p.L550P and p.E153X).For the novel missense mutations found in these two genes we performed an in silico structural analysis and the results were consistent with the clinical course of the patients harboring those mutations.Finally,in HGSNAT gene,we found the splicesite mutation c.234+1G＞A that had already been reported as relatively frequent in MPS ⅢC patients from countries surrounding the basin of the Mediterranean sea.Its presence in two Tunisian MPS ⅢC families points to the hypothesis of its peri Mediterranean origin.With the exception of the c.234+1G＞A mutation,that was identified in two unrelated MPS ⅢC families,the other identified mutations were family-specific and were always found in homozygosity in the patients studied,thus reflecting the existence of consanguinity in MPS Ⅲ Tunisian families.Conclusions:Three novel mutations are reported here,further contributing to the knowledge of the molecular basis of these diseases.The results of this study will allow carrier detection in affected families and prenatal molecular diagnosis,leading to an improvement in genetic counseling.     

黏多糖贮积症Ⅲ型的鉴别诊断与产前诊断

目的 建立以人工合成荧光底物测定乙酰肝素N-硫酸酯酶(SGSH),α-N-乙酰葡萄糖苷酶(NAGLU)活性的方法,应用这两种方法对黏多糖贮积症Ⅲ型中的A、B亚型(MPSⅢA和ⅢB)病例进行鉴别诊断,并对MPSⅢB高危妊娠的孕妇进行了产前诊断,同时从分子遗传学方面对MPSⅢA患儿进行了SGSH基因分析.方法 采用人工合成的荧光底物(4-甲基伞形酮-α-D-N-硫酸葡萄糖苷4-methylumbelliferyl-α-D-N-sulphoglucosaminide.Na,4-甲基伞形酮-N-乙酰-α-葡萄糖苷4-methylumbelliferyl-α-N-acetylglucosaminide)测定疑似患儿白细胞和血浆中SGSH及NAGLU活性,在收集的12例患儿中,女4例,男8例,年龄3~10岁.来自10个无相关的家庭.用MPSⅢA的患儿外周血白细胞DNA进行SGSH基因的外显子PCR扩增,并通过的序列测定确定突变位置.用绒毛或经培养的羊水细胞为检材,对MPSⅢB高危妊娠的孕妇进行产前诊断.结果 获得中国正常人白细胞中SGSH活性正常值4.4～8.1 nmot/(17 h·mg蛋白),各种组织中NAGLU活性正常值:血浆中为33.3～62.4 nmoL/(4 h·ml),绒毛组织为44.9~91.7 nmol/(17 h ·mg蛋白),经培养的羊水细胞为53.2-82.2 nmol/(17 h·mg蛋白);在12例疑似患儿中确诊了7例MPSⅢA(其中两例为同胞),5例MPS ⅢB患者(其中2例为同胞),SGSH基因分析发现6种突变类型,已知突变5种(G191R,D235N,R377C,E447K和R233X),插入突变1种(D219Wfs264X),此插入突变为新生突变.3例MPSⅢB产前诊断中,2例胎儿正常,1例胎儿受累.结论 应用荧光法测定SGSH和NAGLU酶活性是敏感、可靠、快速的方法,可用于MPSⅢA和ⅢB病例的鉴别诊断及产前诊断;SGSH基因分析方法成本低,突变检出率高,可用于MPSⅢA的诊断和产前诊断.     

Enzyme replacement therapy improves reproductive performance in mucopolysaccharidosis type VII mice but does not prevent postnatal losses

Mice with mucopolysaccharidosis type VII (MPS VII) are devoid of beta-glucuronidase and accumulate glycosaminoglycans in lysosomes resulting in bone dysplasia, learning disabilities, and decreased mobility. MPS VII males do not breed and, while MPS VII females occasionally mate with heterozygous males, they do not maintain their young postnatally. Heterozygous matings produce less than 25% MPS VII offspring, but until now it was unclear whether this results from prenatal or postnatal losses. The administration of recombinant beta-glucuronidase from birth significantly reduces glycosaminoglycan storage in most tissues, increases life span, and improves the animal's cognitive ability and mobility. To determine whether reproductive failure is corrected by such therapy, male and female MPS VII mice were injected with enzyme at weekly intervals from birth to 5 wk of age (6xinj). Enzyme-replaced MPS VII mice bred when mated together. The 6xinj MPS VII males mated repeatedly until they were killed 135 d postinjection. All mated 6xinj MPS VII females gave birth to two litters, but maintained few of their young. Selective loss of MPS VII offspring was observed in matings between heterozygotes. Analysis of 379 preterm fetuses from heterozygous matings showed a frequency of 24.6% MPS VII pups, indicating that the decreased number of MPS VII pups produced by mating heterozygotes results from postnatal losses. The ovaries of young adult MPS VII mice have follicles and corpora lutea, and the testes generate sperm. Results suggest that the reproductive failure in MPS VII mice is related to impaired mobility and/or impaired cognitive function, and enzyme replacement restores mating capacity.     

Variable disease progression after successful stem cell transplantation: prospective follow-up investigations in eight patients with Hurler syndrome

We report the results of a prospective, standardized follow-up programme of eight children (median age at SCT 1.2 yr) with mucopolysaccharidosis (MPS1H, M. Hurler) transplanted using a fludarabine-based SCT. SCT resulted in stable engraftment without transplant-related mortality. All patients are alive, engrafted and in ambulatory care. During follow-up (median five yr, 1.9-8 yr), six of eight showed developmental delay (two severe, two mild/no), all eight had spinal deformities and one received hip surgery for acetabular dysplasia. Hand surgery for carpal tunnel release and trigger digits was required in five of the patients. The cranio-cervical junction was narrowed in four patients, one child having already received surgery. CC was present in all patients prior to SCT. It remained unchanged in seven and regressed in one child. Severe cardiac dysfunction was present in two of the eight children before SCT. Cardiac pump function was normal in six patients and ameliorated in two, while valve abnormalities could be detected in six patients. Currently, transplantation seems no longer the major obstacle for MPS1H patients, but the variable musculoskeletal disease progression after successful SCT remains a challenge. Patients with Hurler syndrome need specialized follow-up care because of their manifold health problems. The standardized follow-up presented here is a step to optimize care for MPS children and their families after SCT.     

The new frame for Mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are genetic, progressive, lysosomal storage disorders affecting virtually all organs and systems. The first MPS were clinically identified about 100 years ago. Nowadays, the enzyme defects and related genes are known for all 11 different enzyme defects. Treatments are available for many MPS but these have only partial efficacy, especially when started late. The problems to solve are: 1) the need for an earlier diagnosis (neonatal screening? improving the awareness of physicians?); 2) prompt access to therapies; 3) improving the efficacy of the available treatments; 4) finding new treatments; and 5) the availability of specialist experts in MPS who can meet the traditional needs of MPS patients. This introduction to the IJP Supplement on MPS is a brief comment on the different papers accepted for this volume, which are in turn the elaboration of the lectures given at a meeting on the future of mucopolysaccharidoses held in Milan on 8–9 May 2017.     

Enzyme-replacement therapy from birth delays the development of behavior and learning problems in mucopolysaccharidosis type IIIA mice

Mucopolysaccharidosis type IIIA (MPS IIIA; Sanfilippo syndrome) is a lysosomal storage disorder characterized by severe CNS degeneration, resulting in behavioral abnormalities and loss of learned abilities. Early treatment is vital to prevent long-term clinical pathology in lysosomal storage disorders. We have used naturally occurring MPS IIIA mice to assess the effects of long-term enzyme-replacement therapy initiated either at birth or at 6 wk of age. MPS IIIA and normal control mice received weekly i.v. injections of 1 mg/kg recombinant human sulfamidase until 20 wk of age. Sulfamidase is able to enter the brain until the blood-brain barrier completely closes at 10-14 d of age. MPS IIIA mice that were treated from birth demonstrated normal weight, behavioral characteristics, and ability to learn. MPS IIIA mice that were treated from birth performed significantly better in the Morris water maze than MPS IIIA mice that were treated from 6 wk of age or left untreated. A reduction in storage vacuoles in cells of the CNS in MPS IIIA mice that were treated from birth is consistent with the improvements observed. These data suggest that enzyme that enters the brain in the first few weeks of life, before the blood-brain barrier matures, is able to delay the development of behavior and learning difficulties in MPS IIIA mice.     

Gene therapy for mucopolysaccharidoses: in vivo and ex vivo approaches

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by a deficiency in lysosomal enzymes catalyzing the stepwise degradation of glycosaminoglycans (GAGs). The current therapeutic strategies of enzyme replacement therapy and allogeneic hematopoietic stem cell transplantation have been reported to reduce patient morbidity and to improve their quality of life, but they are associated with persistence of residual disease burden, in particular at the neurocognitive and musculoskeletal levels. This indicates the need for more efficacious treatments capable of effective and rapid enzyme delivery to the affected organs, especially the brain and the skeleton. Gene therapy (GT) strategies aimed at correcting the genetic defect in patient cells could represent a significant improvement for the treatment of MPS when compared with conventional approaches. While in-vivo GT strategies foresee the administration of viral vector particles directly to patients with the aim of providing normal complementary DNA to the affected cells, ex-vivo GT approaches are based on the ex-vivo transduction of patient cells that are subsequently infused back. This review provides insights into the state-of-art accomplishments made with in vivo and ex vivo GT-based approaches in MPS and provide a vision for the future in the medical community.     

Murine Mucopolysaccharidosis VII: Impact of Therapies on the Phenotype, Clinical Course, and Pathology in a Model of a Lysosomal Storage Disease

The mucopolysaccharidoses are a group of lysosomal storage diseases caused by deficiency of an enzyme required for the normal degradation of glycosaminoglycans. Patients with mucopolysaccharidosis typically have widespread lysosomal storage, skeletal and central nervous system disease, and hepatosplenomegaly. Some patients with mucopolysaccharidosis may benefit from enzyme replacement therapy or bone marrow transplantation. Animal models of mucopolysaccharidosis have proven valuable for the evaluation of the effectiveness of potential treatments for patients with lysosomal storage disease. A murine model of MPS VII (Sly syndrome) has proven particularly useful because of its well-defined genetics and its well-characterized clinical, pathologic, and biochemical alterations, which resemble those seen in patients with mucopolysaccharidosis. Correction of these alterations forms the basis for evaluation of the effectiveness of novel treatments. A wide range of therapies have been tested using this model, including enzyme replacement therapy, bone marrow, stem cell, and neural progenitor cell transplantation, and a variety of viral-mediated gene therapies. The inferences drawn from these therapeutic studies using the murine MPS VII model are likely generalizable to other lysosomal storage diseases. Received March 10, 2001; accepted April 5, 2001.     

35例黏多糖贮积症Ⅳ型患儿临床特点及酶学诊断

目的总结中国人黏多糖贮积症(MPS)Ⅳ型的临床特点及酶学诊断,提供MPS鉴别诊断要点。方法对2006年6月至2011年11月因矮小伴有多发骨骼畸形就诊并诊断为MPSⅣ型患儿的临床特点、骨骼影像学、尿黏多糖定性电泳及酶活性检测结果进行回顾分析。结果 35例患儿诊断为MPSⅣ型(ⅣA型34例,ⅣB型1例),所有患儿具有不同程度的MPSⅣ型临床特点,包括矮小、脊柱发育不良、关节畸形,但智能发育正常;脊柱X线显示,胸腰椎椎体前缘鸟嘴样改变及肋骨飘带状等;80%患儿的尿液黏多糖定性阳性,尿液黏多糖电泳显示CS区带;34例MPSⅣA型患儿白细胞半乳糖胺-6-硫酸盐硫酸酯酶(GALNS)活性极低[(0.85±1.33)nmol/(17 h.mg)],1例MPSⅣB型患儿β-半乳糖苷酶(GLB1)酶活性极低[5.03 nmol/(mg.h)]。结论对临床高度怀疑MPS的患儿,可检测尿液黏多糖进行初步筛查,再以酶活性分析来确诊。