Histopathological Findings in a male with Late-Onset Ornithine Transcarbamylase Deficiency

Late onset of symptoms in a 12 1/2-year-old male with ornithine transcarbamylase (OTC) deficiency were associated with unusual histological features in the liver. The patient presented with an acute onset of hyperammonemia and altered mental status after a 2-day prodrome of vomiting and lethargy. Physical examination showed a combative and disoriented male with icteric sclerae but with no fever or hepatomegaly. The plasma ammonia level was 282 μM. Enzyme assays of liver tissue obtained by percutaneous needle biopsy showed OTC activity of approximately 3% of normal; carbamyl phosphate synthetase was normal. Histopathological findings included severe microvesicular centrilobular steatosis. Hepatic architecture and reticulin framework were well preserved. Many hepatocyte nuclei were filled with glycogen. Electron microscopy showed mitochondria that were rounded and expanded with cristae at the edge of the mitochondrial membrane. In contrast to other reports, only slight variations in size and shape were seen. Megamitochondria and intramatrical paracrystalline inclusions were not identified. The cytoplasm contained scattered fat globules, peroxisomes, and dilated smooth endoplasmic reticulum. The prominent mitochondrial abnormalities commonly found in OTC deficiency were notably absent.     

The use of partially HLA-mismatched donors for allogeneic transplantation in patients with mucopolysaccharidosis-I

Allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling appears to improve survival and diminish some of the physiologic derangements seen in children with mucopolysaccharidosis (MPS)-I (Hurler Syndrome), an inherited metabolic storage disease resulting from the lack of alpha-L-iduronidase enzyme activity. Death is usually expected in the first decade of life. Unfortunately, most patients lack an HLA-matched sibling donor and alternative donors have been identified for transplant. This study reports on a five-year median follow-up (range: 985-2,355 days) in 11 Hurler Syndrome patients who underwent allogeneic BMT from partially mismatched related donors (PMRDs). The median age was 20 months (range: 11-44 months). The overall survival rate was 64% (95% CI 34-94%). The overall graft failure rate (36%) was higher than reported with matched sibling BMT. All patients with sustained engraftment experienced improvement in physical manifestations, such as corneal opacity, gum and tongue hypertrophy, hepatosplenomegaly and joint mobility. Skeletal abnormalities, such as dysostosis-multiplex, were stabilized but not reversed. Some patients have continued to show decline in neuropsychometric testing, while others appear to stabilize and one has demonstrated improvement. Until better methods for replacing enzyme activity are developed, BMT from a matched sibling of alternative donors can be considered a viable intervention for Hurler Syndrome patients to achieve partial improvement or stabilization from the deterioration caused by substrate storage, particularly in minimally affected patients early in life.     

Cardiac functional and histopathologic findings in humans and mice with mucopolysaccharidosis type I: implications for assessment of therapeutic interventions in hurler syndrome

Hurler syndrome (mucopolysaccharidosis type I [MPS I]) is a uniformly lethal autosomal recessive storage disease caused by absence of the enzyme alpha-l-iduronidase (IDUA), which is involved in lysosomal degradation of sulfated glycosaminoglycans (GAGs). Cardiomyopathy and valvar insufficiency occur as GAGs accumulate in the myocardium, spongiosa of cardiac valves, and myointima of coronary arteries. Here we report the functional, biochemical, and morphologic cardiac findings in the MPS I mouse. We compare the cardiac functional and histopathological findings in the mouse to human MPS I. In MPS I mice, we have noted aortic insufficiency, increased left ventricular size, and decreased ventricular function. Aortic and mitral valves are thickened and the aortic root is dilated. However, murine MPS I is not identical to human MPS I. Myointimal proliferation of epicardial coronary arteries is unique to human MPS I, whereas dilation of aortic root appears unique to murine MPS I. Despite the differences between murine and human MPS I, the murine model provides reliable in vivo outcome parameters, such as thickened and insufficient aortic valves and depressed cardiac function that can be followed to assess the impact of therapeutic interventions in preclinical studies in Hurler syndrome.     

Hurler syndrome with severe complication in post-bone marrow transplantation course: Life threatening interstitial pneumonitis and hypertension

Bone marrow transplantation (BMT) was performed in a 3 year old patient with Hurler syndrome. The post-BMT course was complicated by interstitial pneumonitis and severe hypertension, which were life threatening. The patient responded well to therapy and recovered. BMT in this patient resulted in significant clinical improvement in the signs and symptoms of Hurler syndrome. Biochemical improvement, including elevated α-l -iduronidase activity in white blood cells and decreased urinary glycosaminoglycan excretion was significant. However, skeletal and neurological impairment were not improved. We conclude that BMT for Hurler syndrome should be performed at an earlier stage, before severe neuronal damage has occurred. Moreover, BMT is a high risk procedure and there will always be a possibility that life threatening complications will occur, as in our case.     

Abnormal fatty acid metabolism in spinal muscular atrophy may predispose to perioperative risks

A 15 year old boy with SMA type II underwent spinal fusion and suffered a mitochondrial Reye-like catabolic crisis 4 days postop with hypoketotic hypoglycemia, lactic acidaemia, hyperammonemia and liver failure, with 90% coagulative necrosis and diffuse macro- and microvesicular steatosis, requiring orthotopic liver transplantation. This crisis responded in part to mitochondrial therapy and anabolic rescue. He made a dramatic sustained neurological recovery, though his post-transplant liver biopsies revealed micro- and macrosteatosis. We hypothesize that a combination of surgical stress-catecholamine induced lipolysis, prolonged general anaesthesia with propofol and sevoflurane, and perioperative fasting on a background of decreased β-oxidation were potential risk factors for the mitochondrial decompensation.     

Incidence and prevalence of mucopolysaccharidosis type 1 in the Irish republic

Mucopolysaccharidosis type 1 (MPS1) is an autosomal recessive disorder with severe, moderate and mild phenotypes: Hurler, Hurler-Scheie and Scheie syndromes. We estimated incidence (2001-2006) and prevalence (2002 census) of MPS1 in the Irish Republic (ROI) using population data, database and chart review of all live MPS1 patients attending two specialised centres. Patient genotypes, ethnicity, province of origin, age at diagnosis and presenting features were recorded. Thirty-one patients (14 females, 17 males) were alive, 27 of whom were <15 years. Twenty-six patients had Hurler syndrome, four had Hurler-Scheie and one had Scheie syndrome. The birth incidence was 1 in 26 206 births with a carrier frequency of 1 in 81. Of note, 19/26 (73%) Hurler patients were Irish Travellers. Amongst Irish Travellers the incidence was 1 in 371 with a carrier frequency of 1 in 10. This is the highest recorded incidence worldwide. Given the morbidity and mortality associated with delayed treatment we recommend targeted newborn screening for this population.     

Enzyme replacement therapy in mucopolysaccharidosis type I

Mucopolysaccharidosis (MPS) type I is a lysosomal storage disorder caused by deficiency of the enzyme alpha-L-iduronidase (IDUA), which presents with a wide spectrum of phenotypes. Recently, enzyme replacement therapy (ERT) became available for patients with MPS I and has been demonstrated to be safe and effective in patients with the milder Hurler-Scheie and Scheie phenotypes. Treatment for 26 weeks with recombinant human IDUA (laronidase) has been shown to significantly increase the percentage of predicted normal forced vital capacity and the distance walked in the 6-minute walk test. There was also a clear reduction in the volume of the liver and the levels of urinary glycosaminoglycan excretion. The drug was generally well tolerated. There were no drug-related severe adverse events, and although the majority of patients developed IgG antibodies, these declined by the end of the study. Conclusion: ERT seems to be a very promising new therapeutic regimen for patients with MPS I, especially for those with the less severe variants. However, as laronidase does not cross the blood-brain barrier it will probably not influence the central nervous manifestations in the most severely affected patients with the Hurler phenotype, although it may improve general lung and heart function, making bone marrow transplantation easier to tolerate.     

Combined enzyme replacement and haematopoietic stem cell transplantation in Hurler syndrome

We report the long-term follow-up of successful treatment of mucopolysaccharidosis type I H (MPS IH, Hurler syndrome) with combined enzyme replacement therapy and haematopoietic progenitor stem cell transplant.     

Narrow trachea in mucopolysaccharidoses

Nine of 56 patients with mucopolysaccharidoses (MPS) showed small tracheal diameters on their frontal chest radiographs. Autopsy of an MPS I-H (Hurler disease) patient demonstrated that the small calibre was secondary to deposition of glycosaminoglycan (mucopolysaccharide). Autopsies of two patients with other storage diseases, one with geleophysic dysplasia and one with mucolipidosis II, also exhibited compromise of their airways because of storage material accumulation. Paper presented at the European Pediatric Radiology Society Meeting in Paris, France, 5 May 1983     

Cholesteryl ester storage disease in a young child presenting as isolated hepatomegaly treated with simvastatin

Cholesteryl ester storage disease (CESD) is an autosomal recessive disorder resulting from lysosomal acid lipase deficiency and is usually characterized by hepatomegaly and hyperlipidemia. This paper reports a two-year-old boy who had hepatosplenomegaly, hyperlipidemia and hypertransaminasemia determined incidentally. The liver biopsy sample was orange-yellow in appearance. Microscopically, microvesicular steatosis and birefringent crystals were seen in liver biopsy. The diagnosis of CESD was confirmed by the reduced human acid lipase activity in peripheral leukocytes. Simvastatin therapy was given and tolerated without side effects. Our patient is the youngest reported case in the literature treated with 3-hydroxy 3-methyl glutaryl (HMG) CoA reductase inhibitor.     

Acute encephalopathy and recurrent hepatic steatosis with normal long and medium chain fatty acyl-CoA-dehydrogenase activity

A boy suffering from recurrent episodes of acute encephalopathy and hepatic steatosis died at 40 months of age. The symptoms started when he was 13 months old and he appeared completely normal in the intervals. Pertinent biologic findings were as follows: slight labile hypoglycemia and hyperammonemia having no direct correlation with neurologic derangement, no elevation of ammonia levels in loading tests, complete failure to generate ketones and the absence of organic aciduria during a fast, normal plasma carnitine levels and normal activity of long and medium chain acyl-CoA-dehydrogenase in skin fibroblasts. Pertinent autopsy findings were marked steatosis of liver and renal tubular cells with many foamy histiocytes in bone marrow. An error in metabolic pathways, particularly a derangement in lipid metabolism, was considered.     

Potentiation of the toxic effects of acetaminophen in mice by concurrent infection with influenza B virus: a possible mechanism for human Reye's syndrome?

Using weanling mice of two different genetic strains we demonstrated a potentiation of the toxic effects of acetaminophen by prior infection with influenza B virus. The C57BL/6N (B6) strain of mice is genetically predisposed to increased toxicity from acetaminophen when the hepatic cytochrome P-450 mixed function oxidase system is preinduced. When B6 animals are pretreated with influenza B virus and an mixed function oxidase system inducing agent before administering acetaminophen, we observed a significant incidence of atypical "fatty" liver pathology on light microscopy similar to the microvesicular steatosis seen in human Reye's syndrome. Electron microscopic changes in the liver of these animals resemble those published to date in human Reye's syndrome.     

Hematopoietic stem cell transplantation effects on spinal cord compression in Hurler

Hurler syndrome type 1 (MPS‐1) is an autosomal recessive lysosomal disorder due to the deficiency of the enzyme alpha‐L‐iduronidase which is necessary for the degradation of dermatan and heparan sulfate. It is characterized by deposit of glycosaminoglycans in tissues, progressive multisystem dysfunction, and early death. HSCT for children with MPS‐I is effective, resulting in increased life expectancy and improvement of clinical parameters. The spinal MRI performed on a female 10 yr old undergoing HSCT at the age of 18 months and receiving ERT revealed a considerable decrease in soft tissue around the tip of odontoid causing a significant reduction in spinal cord compression. In light of this result, we suppose that combined ERT and HSCT are successful in Hurler I disease.     

Idiopathic hyperammonemia after hematopoietic stem cell transplantation: A case report

IHA is characterized by a sudden increase in plasma ammonia levels in the absence of any identifiable causes, which mostly results in intractable coma and high mortality. It has been reported in some patients after receiving intensive chemotherapy for hematological malignancy or HSCT. We describe a case of a patient with FA that developed acute idiopathic hyperammonemia after the preparative regimen for HSCT.     

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.     

Enzyme replacement therapy in mucopolysaccharidosis type I

Mucopolysaccharidosis (MPS) type I is a lysosomal storage disorder caused by deficiency of the enzyme α- l -iduronidase (IDUA), which presents with a wide spectrum of phenotypes. Recently, enzyme replacement therapy (ERT) became available for patients with MPS I and has been demonstrated to be safe and effective in patients with the milder Hurler–Scheie and Scheie phenotypes. Treatment for 26 weeks with recombinant human IDUA (laronidase) has been shown to significantly increase the percentage of predicted normal forced vital capacity and the distance walked in the 6-minute walk test. There was also a clear reduction in the volume of the liver and the levels of urinary glycosaminoglycan excretion. The drug was generally well tolerated. There were no drug-related severe adverse events, and although the majority of patients developed IgG antibodies, these declined by the end of the study.
Conclusion: ERT seems to be a very promising new therapeutic regimen for patients with MPS I, especially for those with the less severe variants. However, as laronidase does not cross the blood–brain barrier it will probably not influence the central nervous manifestations in the most severely affected patients with the Hurler phenotype, although it may improve general lung and heart function, making bone marrow transplantation easier to tolerate.     

干细胞肝内移植治疗高氨血症Ⅱ型6例临床疗效观察

为探讨使用CD133+细胞、脐带间充质干细胞肝动脉内移植对高氨血症Ⅱ型患儿的临床治疗效果和可能存在的作用机制,通过采集健康胎儿脐血, 分离得干细胞悬液,或应用重组人粒细胞集落刺激因子动员患儿父亲外周血5?d后采集单个核细胞,从中分离得到CD133+细胞后,再利用导管介入经皮穿刺肝动脉将上述细胞缓慢输入患儿肝脏,观察患儿临床表现及实验室检查指标如血氨、肝功能、精氨酸、瓜氨酸的改善情况。结果显示,6例患儿移植后血氨水平均呈现明显下降,1~2周之后缓慢回升,但始终低于移植前波动的高水平;谷丙转氨酶同血氨水平变化趋势相类似;血瓜氨酸和精氨酸水平移植后明显增加,且瓜氨酸的增幅超过精氨酸。其中1例典型病例经8个月随访,发现患儿体重身高均较术前增长,睡眠改善,夜啼消失;由对逗引淡漠变为主动追视感兴趣物品,产生简单词汇,精细运动由手眼不协调到拇指中指捏取东西等,大运动方式也有很大进步;GESELL法测评该患儿术后各能区进步平均3.82个月。由此可见,高氨血症患儿移植后血氨下降、肝功能稳定改善,血瓜氨酸、精氨酸稳定增高,在运动、语言、环境适应性等方面都呈现进步趋势。推测干细胞肝动脉移植至少部分激活或补充了鸟氨酸氨甲酰转移酶,从而使血瓜氨酸、精氨酸水平增高,尿素循环障碍在一定程度上得到纠正。     

新生儿期高氨血症的临床筛查

目的 探讨新生儿期高氨血症的病因学.方法 选择2010年9月- 2011年2月湖南省妇幼保健院新生儿科病房和儿童康复科门诊收治的458例符合筛查条件的新生儿作为研究对象,采适量静脉血进行血氨分析,对高氨血症患儿经过3d的对因对症治疗后血氨不下降或不降反升者行血气、血生化、尿酮体、尿气相色谱-质谱分析、串联质谱法血液酯酰肉碱谱和血氨基酸谱分析,必要时行肝活检和酶学检测.结果 共检出高氨血症患儿172例,总发生率约为37.5％.其中先天性高氨血症10例(包括鸟氨酸氨甲酰基转移酶缺乏症5例,双羧酸尿症3例,甲基丙二酸血症并同型半胱氨酸尿症2例),新生儿一过性高氨血症162例.结论 新生儿期高氨血症的病因复杂,以新生儿期一过性高氨血症为主,其发病多与早产、低出生体质量、感染、胃肠外营养有关.先天性高氨血症发病率较低.对存在中枢神经系统等相关症状及存在血氨高危因素的新生儿进行血氨检测有积极意义.     

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.     

Mucopolysaccharidosis I presenting with endocardial fibroelastosis of infancy

We describe two female infants with Hurler syndrome (mucopolysaccharidosis I) whose deaths are attributed to cardiac failure with associated, autopsy-confirmed endocardial fibroelastosis. One infant had confirmed alpha-L-iduronidase deficiency in cultured dermal fibroblasts, and the other infant had histologic evidence of tissue mucopolysaccharide accumulation at autopsy and a sibling with confirmed alpha-L-iduronidase deficiency and the Hurler syndrome phenotype. Clear cells ("Hurler" cells) were identified within the myocardium and endocardium of both infants. We propose that the ventricular mural accumulation of mucopolysaccharides induced extensive proliferation of elastic or collagen fibers within the endocardium. Cardiac failure may precede recognition of clinical and roentgenographic features of Hurler syndrome. Our findings and a literature review suggest that certain heritable storage disorders, including mucopolysaccharidosis I, should be considered when infants have clinical electrocardiographic and echocardiographic findings consistent with endocardial fibroelastosis or have autopsy-documented endocardial fibroelastosis.