• Journal of mucopolysaccharidosis and rare diseases
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• 제2권1호
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• pp.5-7
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• 2016

Mucolipidoses II and III alpha/beta (ML II and ML III) are lysosomal disorders in which the essential mannose-6-phosphate recognition marker is not synthesized onto lysosomal hydrolases and other glycoproteins. The disorders are caused by mutations in GNPTAB, which encodes two of three subunits of the heterohexameric enzyme, N-acetylglucosamine-1-phosphotransferase ML II, recognizable at birth, often causes intrauterine growth impairment and sometimes the prenatal "Pacman" dysplasia. The main postnatal manifestations of ML II include gradual coarsening of neonatally evident craniofacial features, early cessation of statural growth and neuromotor development, dysostosis multiplex and major morbidity by hardening of soft connective tissue about the joints and in the cardiac valves. Fatal outcome occurs often before or in early childhood. ML III with clinical onset rarely detectable before three years of age, progresses slowly with gradual coarsening of the facial features, growth deficiency, dysostosis multiplex, restriction of movement in all joints before or from adolescence, painful gait impairment by prominent hip disease. Cognitive handicap remains minor or absent even in the adult, often wheelchair-bound patient with variable though significantly reduced life expectancy. As yet, there is no cure for individuals affected by these diseases. So, clinical manifestations and conservative treatment is important. This review aimed to highlight the extra-skeletal clinical problems in ML II and III.

• Journal of mucopolysaccharidosis and rare diseases
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• 제2권1호
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• pp.13-16
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• 2016

Mucolipidosis (ML) II/III are autosomal recessive diseases caused by deficiency of post-translational modification of lysosomal enzymes. The mannose-6-phosphate (M6P) residue in lysosomal enzymes synthesized by N-acetylglucosamine 1-phosphotransferase (GlcNAc-phosphotransferase) serves as recognition marker for trafficking in lysosomes. GlcNAc-phosphotransferase is encoded by GNPTAB and GNPTG. Mutations in GNPTAB cause severe ML II alpha/beta and the attenuated ML III alpha/beta. Whereas mutations in GNPTG cause the ML III gamma, the attenuated type of ML III variant. For the diagnostic approaches, increased urinary oligosaccharides excretion could be a screening test in clinically suspicious patients. To confirm the diagnosis, instead of measuring the activity of GlcNAc phosphotransferase, measuring the enzymatic activities of different lysosomal hydrolases are useful for diagnosis. The activities of several lysosomal hydrolases are decreased in fibroblasts but increased in serum of the patients. In addition, the sequence analysis of causative gene is warranted. Therefore, the confirmatory diagnosis requires a combination of clinical evaluation, biochemical and molecular genetic testing. ML II/III show complex disease manifestations with lysosomal storage as the prime cellular defect that initiates consequential organic dysfunctions. As there are no specific therapy for ML to date, understanding the molecular pathogenesis can contribute to develop new therapeutic approaches ultimately.

• Journal of mucopolysaccharidosis and rare diseases
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• 제2권2호
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• pp.50-51
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• 2016

Combining basal insulin therapy with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) has clear clinical advantages, and is supported by the latest EASD/ADA position statement (1). IDegLira is a once-daily combination of the basal insulin, degludec, and the GLP-1RA, liraglutide, in one pen. The DUAL phase 3 clinical trial program provides important evidence about the efficacy and safety of IDegLira in three different populations of patients with type 2 diabetes (T2D): insulin naïve subjects uncontrolled on oral antidiabetic drugs (OADs), subjects uncontrolled on OAD(s) and a GLP-1 RA, and subjects uncontrolled on OAD(s) and basal insulin. Treatment with IDegLira reduced mean HbA1c to below the EASD/ADA treatment target of 7.0% in all five trials. The mean reduction of HbA1c from baseline ranged from 1.3% and 1.9%. IDegLira resulted in weight loss for subjects uncontrolled on basal insulin, was weight neutral for subjects on OADs and weight gain was minimal (2 kg) for subjects previously treated with a GLP-1 RA. Rates of hypoglycaemia were low across all the trials, particularly considering the level of glycaemic control achieved.

• Journal of mucopolysaccharidosis and rare diseases
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• 제2권2호
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• pp.35-37
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• 2016

Prader-Willi syndrome (PWS) often develops type 2 diabetes mellitus (T2DM) related to severe obesity. The prevalence of T2DM in adults with PWS (7-20%) exceeds greatly the prevalence in the general population (5-7%). It is uncommon for pre-pubertal children with PWS to develop overt diabetes or glucose intolerance. GH therapy and genotype did not influence the development of altered glucose metabolism. It has been assumed that T2DM in PWS develops as a consequence of morbid obesity and concomitant insulin resistance. However recent studies suggest the relationship between morbid obesity and T2DM development is more complex and appears to differ in PWS subjects compared to non-PWS subjects. PWS patients had relatively lower fasting insulin levels and increased adiponectin levels compared with BMI-matched obese control despite of similar levels of leptin. So PWS children may be protected to some extent form of obesity-associated insulin resistance. Although there's no data, it seems logical to approach diabetes management including weight loss and increased exercise, using similar pharmacological agents as with non-PWS obesity-related diabetes such as metformin or thiazolidinedione, with the introduction of insulin as required. On the other hand, several recent T2DM in PWS case reports suggest favorable outcomes using Glucagon-like peptide 1 (GLP-1) analog with regard to ghrelin reduction, control of glucose and appetite, weight loss and pre-prandial insulin secretion. The role of GLP-1 agonist therapy is promising, but has not yet been fully elucidated.

• Journal of mucopolysaccharidosis and rare diseases
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• 제3권2호
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• pp.41-43
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• 2017

Prader-Willi syndrome (PWS) is a genetic disorder that is considered, especially on child, to cause poor feeding, hypotonia, failure to thrive, developmental delay and hypogonadism which is known to affect between 1 in 10,000 and 30,000 people. The children with PWS are viewed as affected by growth hormone (GH) insufficiency, although the exact mechanisms of GH deficiency are not fully understood. However, the benefits of GH treatment in children with PWS are well established. Myers, et al. (2006), Grugni, et al. (2016) indicated its positive effects on linear growth, body composition, motor function, respiratory function and psychomotor development. Despite of its effectiveness and advantages had been well known and proven in many other studies, there is only one recombinant GH product that is approved for PWS in Korea, $Genotropin^{(R)}$, till now. A phase III clinical study of GH treatment with $Eutropin^{TM}$, in 34 Korean PWS children is in progress, which is expected to have comparable effects and safety profile with the active control by assessing auxological changes such as height standard deviation score, body composition changes such as lean body mass and percent body fat, motor and cognitive development using Bayley scale, and safety profiles.

• Journal of mucopolysaccharidosis and rare diseases
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• 제4권2호
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• pp.42-44
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• 2018

Prader-Willi syndrome (PWS) is a multisystemic complex disorder characterized by hyperphagia and impaired satiety which lead to severe and early obesity. In infancy, hypotonia and poor suck are main problems, and a child goes through Failure-to-thrive. During childhood, clinical manifestations change to food seeking as well as excessive weight gain, short stature, developmental delay, cognitive disability and behavioral problems. Also, growth hormone insufficiency is frequent. Most patients receive the recombinant growth hormone (rGH) therapy that provides improvement in growth, body composition, and physical attributes. The clinical care guideline for rGH therapy in PWS had been noticed in 2013. The rGH therapy helps in body fat, lean body mass, height SDS and head circumference. Also, the rGH therapy helps motor function, psychomotor development and cognition and behavioral issues.In Samsung medical center, there are clinical care guidelines for rGH therapy in PWS and an useful application for the patients. 'Living with PWS', the name of an moblie application for PWS patients, was introduced in the lecture. The application revised to version 2. It was made more convenient to users than in version 1. It helps caregivers to schedule the rGH therapy and to monitor height and weight.

• Journal of mucopolysaccharidosis and rare diseases
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• 제5권1호
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• pp.29-33
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• 2021

Prader-Willi Syndrome (PWS) is a neurodevelopmental genomic imprinting disorder involving a lack of gene expression from the paternal chromosome 15q11-q13 region. This is typically due to paternal 15q11-q13 deletions (in approximately 60% of cases), maternal uniparental disomy 15, or when both 15s are from the mother (about 35% of cases). An imprinting center controls the expression of imprinted genes in the chromosome 15q11-q13 region. PWS is a neurodevelopmental disorder characterized by mental retardation and distinct physical, behavioral, and psychiatric features. Characteristic behavioral disturbances in PWS include excessive interest in food, skin picking, difficulty with a change in routine, temper tantrums, obsessive and compulsive behaviors, and mood fluctuations. Individuals with PWS typically have intellectual disabilities (borderline to mild/moderate mental retardation) and exhibit a higher overall level of behavior disturbances compared to individuals with similar intellectual disabilities. This condition severely limits social adaptations and quality of life. Different factors have been linked to the intensity and form of these behavioral disturbances, but there is no consensus regarding the cause. Consequently, there is still controversy surrounding management strategies and there is a need for new data. PWS is a multisystem disorder. Family members, caregivers, physicians, dieticians, and speech-language pathologists all play an important role in the management and treatment of symptoms in an individual with PWS. Here we analyze behavioral problems in children and adults with PWS by age and review appropriate management and treatment strategies for these symptoms.

• Journal of mucopolysaccharidosis and rare diseases
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• 제5권1호
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• pp.1-7
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• 2021

Gaucher disease (GD, OMIM #230800 OMIM#230800) is a rare, autosomal recessive inherited metabolic disorder caused by mutation in GBA1 encoding the lysosomal enzyme, glucocerebrosidase. The deficiency of glucocerebrosidase leads to an accumulation of its substrate, glucosylceramide in macrophages of various tissues. Common clinical manifestations include cytopenia, splenomegaly, hepatomegaly, and bone lesions. The phenotype of GD is classified into three clinical categories: Type 1 (non-neuronopathic) is characterized by involvements on the viscera, whereas types 2 and 3 (neuronopathic) are associated with not only visceral symptoms but also neurological impairment, either severe in type 2 or variable in type 3. A diagnosis of GD can be confirmed by demonstrating the deficiency of acid glucocerebrosidase activity in leukocytes. Mutations in the GBA1 should be identified as they may be of prognostic value in some cases. Biomarkers including Chitotriosidase, CCL18, and glucosylsphingosine (lyso-GL1) are useful in diagnosis and treatment monitoring. Currently available disease-specific treatment in Korea consists of intravenous enzyme replacement therapy and substrate reduction therapy. For enhancing long-term prognosis, the onset of Parkinson's disease and Lewy body dementia, or the occurrence of a blood disease or cancer (hepatocellular carcinoma) should be monitored in older patients. The development of new strategies that can modify the neurological phenotype are expected, especially in Asia including Korea, where the prevalence of neuronopathic GD is relatively higher than that in western countries.

• 대한유전성대사질환학회지
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• 제13권2호
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• pp.111-119
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• 2013

목적: I형 뮤코다당증 (MPS I)은 ${\alpha}$-L-iduronidase 효소의 결핍으로 인하여 발생하는 리소좀 축적 질환으로, 광범위한 양상으로 다기관에 영향을 미친다. 저신장과 성장 속도의 감소는 MPS I의 중요한 특징이다. 본 연구에서는 효소 보충 요법이 MPS I 환자들의 성장에 미치는 효과에 대해 알아보기 위하여 단일 기관의 환자들을 대상으로 분석하였다. 방법: 2세에서 15세 사이에 효소 보충 요법을 시작하여 최소 3년 이상의 치료를 시행 받은 10명의 한국 MPS I 환자들의 키 측정치를 후향적으로 분석하였다. 효소 보충 요법 시작시의 평균 나이는 7년 7개월 이였으며, 남아는 6명, 여아는 4명 이였다. 키는 표준 편차(SDS)로 표현되었다. 효소 보충 요법 전과 후의 연간 성장 속도를 계산하였으며, 구분회귀모델을 이용하여 치료 전과 후의 키 z-score를 분석하였다. 표현형[(중증(Hurler) versus 경증(Hurler-Scheie, Scheie)]이 성장에 미치는 영향에 대해서는 개별 분석을 시행하였다. 결과: 효소 보충 요법 전 1년 동안의 연간 성장은 3.3 cm (z-score=-0.21) 였으며, 효소 보충 요법 후 1년, 2년, 3년에서는 각각 6.2 cm (z-score=0.17), 5.8 cm (z-score=0.07), 3.8 cm (z-score=-0.4)이였다. 회귀분석 결과, 효소 보충 요법 전에 비하여 치료 후 기울기에 유의한 호전을 보였다(기울기 차이=0.04; P=0.022). 중증과 경증 표현형 간의 치료 전(P=0.001)과 후(P<0.0001)의 기울기 차이는 통계적으로 유의하였으나, 표현형에 따라 분석하였을 때 통계적으로 유의한 차이는 보이지 않았다. 결론: MPS I 환자들의 키 성장에 있어 aldurazyme 효소 보충 요법이 긍정적인 효과를 미치는 것으로 보인다.

• Journal of mucopolysaccharidosis and rare diseases
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• 제1권2호
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• pp.54-59
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• 2015

Purpose: Growth hormone (GH) therapy substantially improves several cognitive functions in PWS. However, the molecular mechanisms underlying the beneficial effects of GH on cognition remain unclear in PWS. In this study, we investigated the effects of recombinant human GH on the gene expression of GABAB receptor subunits and GH/insulin-like growth factor (IGF) axis genes in the brain regions of PWS-mimicking mice (Snord116del). Methods: Snord116del mice were injected subcutaneously with 1.0 mg/kg GH or saline, once daily for 7 days. The collected brain tissues were analyzed for mRNA content using quantitative PCR (qPCR) in the cerebellum, hippocampus, and cerebral cortex. Results: GH increased the mRNA expression level of the $GABA_{B1}$ receptor subunit ($GABA_{BR1}$) and IGF-1R in the cerebellum. Furthermore, a significant positive correlation was found between the level of $GABA_{BR1}$ mRNA and the expression of the IGF-1R transcript. GH also induced an increase in the mRNA expression of IGF-2 and IGF-2R in the cerebellum. Conclusion: These data indicate that GH may provide beneficial effects on cognitive function through its influences on the expression of $GABA_{BR1}$ and GH/IGF-1 axis genes in PWS patients.