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- Sitosterolemia should be considered in patients with unexplained macrothrombocytopenia. - Sitosterolemia should be diagnosed in patients with sitosterol level (>15 μg/mL). - Once an index case is identified, family members should also undergo sterol testing. - Four novel variants may expand the genetic spectrum of sitosterolemia. - Ezetimibe can be a good choice for hematologic abnormalities in sitosterolemia. Sitosterolemia is a rare lipid disorder caused by mutations in adenosine triphosphate-binding cassette genes (ABCG) 5 and 8. To evaluate the phenotypic/genotypic features of sitosterolemia in a group of Turkish patients. Seven probands with unexplained hematologic abnormalities and their 13 relatives were enrolled. Sterol levels were measured by gas chromatography and genetic studies were performed using Sanger sequencing. Individuals were diagnosed with sitosterolemia if they were found to have frankly elevated sitosterol level >15 μg/mL and/or pathogenic variants of the ABCG 5/ ABCG 8. The seven probands and their six relatives were diagnosed with frank sitosterolemia, and all these patients had hematologic abnormalities. The remaining seven relatives were asymptomatic heterozygous carriers. Three novel variants in the ABCG 5 gene (c.161G> A , c.1375C> T , IVS10–1G> T), one novel variant in the ABCG 8 gene (c.1762G> C) and one known variant in the ABCG 5 gene (c.1336 C > T) were identified. No variant was identified in one case. The mean sitosterol level was significantly higher and mean platelet count was significantly lower in patients with homozygous variants compared to heterozygous variants (p <0.05, for all). Diets low in plant sterols were recommended for 13 symptomatic cases. Four homozygotes received ezetimibe, and their splenomegaly, anemia, and thrombocytopenia completely resolved except one. The five pathogenic variants identified in this study indicate the genetic heterogeneity of sitosterolemia in Turkish population. Patients with unexplained hematologic abnormalities (specifically macrothrombocytopenia) should have their sterol level measured as initial testing. Ezetimibe can be a good choice for sitosterolemia. [ABSTRACT FROM AUTHOR]

Background Glutaric aciduria type 1 (GA-1) is an organic acidemia with potentially severe neurological sequelae. In Taiwan, newborn screening (NBS) for GA-1 began in 2001, but large-scale reporting is lacking. This study describes Taiwan's largest newborn screening population to date. Methods Between 2001 and 2015, 1,490,636 newborns were screened for GA-1. Confirmatory examinations included the carnitine loading test. Confirmed patients were treated with a low lysine diet, carnitine, and high-energy intake during illness. Clinical, laboratory, and neuroimaging data were analyzed. Results Fourteen newborns were diagnosed with GA-1 (incidence: 1/106,474). C5DC concentration was clearly increased after carnitine loading in the affected newborns, but not in false-positive newborns ( p = 0.004), indicating that this test is useful as an adjuvant diagnostic method. Eleven patients followed in our hospital were enrolled, namely nine NBS patients and two patients diagnosed clinically. IVS10-2A>C was the most common mutation. Two novel mutations (T36fs and N291K) were identified. Pendular nystagmus was found in two pediatric GA-1 patients. The corresponding pathology was optic atrophy in one patient, but remained undetermined in the other patient. The frequency of encephalopathic crisis decreased substantially following NBS. Among patients diagnosed by NBS, cognitive functioning was better among patients with good compliance than patients with poor compliance ( p = 0.03). Abnormalities were detected by brain MRI including diffusion-weighted imaging and apparent diffusion coefficient maps; these affected various brain regions at different stages of the disease. Basal ganglion injuries occurred after an encephalopathic crisis. White matter disease was prevalent among older patients, either with or without an encephalopathic crisis. Conclusion Early diagnosis by newborn screening followed by full compliance with treatment guidelines is important to a good outcome. [ABSTRACT FROM AUTHOR]

Summary Background & aims Many studies have reported that serum total homocysteine (tHcy) levels in cystathionine-beta-synthase (CBS) carriers are usually normal and only elevated after a methionine load. However, the amount of methionine required for a loading test is non-physiological and is never reached with regular feeding. Therefore, CBS carriers do not seem to be at an increased risk of cardiovascular diseases. However, the risk of cardiovascular diseases of CBS carriers with folate deficiency has not been studied. We recently found an extraordinarily high carrier rate (1/7.78) of a novel CBS mutation (p.D47E, c.T141A) in an Austronesian Taiwanese Tao tribe who live in a geographic area with folate deficiency. We evaluated if the CBS carriers tend to have higher fasting serum tHcy concentrations than non-carriers in presence of folate deficiency. Methods The serum tHcy and folate levels before and after folate replacement were measured in 48 adult Tao carriers, 40 age-matched Tao non-carriers and 40 age-matched Han Taiwanese controls. Results The serum tHcy level of the Tao CBS carriers (17.9 ± 3.8 μmol/l) was significantly higher than in Tao non-carriers (15.7 ± 3.5 μmol/l; p < 0.008) and Taiwanese controls (11.8 ± 2.9 μmol/l; p < 0.001). Furthermore, a high prevalence of folate deficiency in the Tao compared with the Taiwanese controls (4.9 ± 1.8 ng/ml vs. 10.6 ± 5.5 ng/ml; p < 0.001) was also noted. Of note, the difference in tHcy levels between the carriers and non-carriers was eliminated by folate supplementation. (carriers:13.65 ± 2.13 μmol/l; non-carriers:12.39 ± 3.25 μmol/l, p = 0.321). Conclusions CBS carriers tend to have a higher tHcy level in the presence of folate deficiency than non-carriers. Although many reports have indicated that CBS carriers are not associated with cardiovascular disease, the risk for CBS carriers with folate deficiency has not been well studied. Owing to a significantly elevated level of fasting tHcy without methionine loading, it is important to evaluate the risk of cardiovascular disease in CBS carriers with folate deficiency. [ABSTRACT FROM AUTHOR]

Background Clinical observation and treatment of children with homozygous familial hypercholesterolemia (HoFH) has rarely been reported. We report clinical observations and treatment of 10 ethnic Chinese children with HoFH due to low-density lipoprotein receptor (LDLR) defect. Objectives In children with HoFH, we evaluated the response to conventional cholesterol-lowering drug therapy and performed LDLR gene analysis. Methods A retrospective review of lipid profile changes in pediatric patients diagnosed with HoFH seen in our pediatric endocrinology outpatient clinic was performed. HoFH was diagnosed by molecular study of these patients and their parents. Results One novel (c.64del G) and 12 known mutations were found in the LDLR gene. Mutation of p.C308Y was the most common and was found in 26% of the studied alleles.Seven patients had fair responses to conventional drug therapy (high-dose statin with ezetimibe) with a reduction of 50% or more of the total cholesterol levels. The low-density lipoprotein–cholesterol levels of three patients decreased to lower than 160 mg/dL. One who had a good response to conventional drug therapy developed significant atheromatous plaques (largest plaque: 7.4 × 2.7 cm) in the extracranial carotid arteries and myocardial ischemia changes at 11 years old. Conclusion The results suggest that despite aggressive therapy, many patients are not well controlled; atherosclerosis may progress, and novel therapies are required. [ABSTRACT FROM AUTHOR]

The authors present a case of citrullinemia with a genotype of argininosuccinate synthetase (ASS1), c.380 G>A (p.R127Q)/c.380 G>A (p.R127Q), in two alleles. A 3-day-old female infant presented with status epilepticus and coma. Laboratory data showed hyperammonemia and marked lactic acidosis in the blood and cerebrospinal fluid; electroencephalography showed severely suppressed cerebral activity and focal paroxysmal volleys of slow and sharp waves (< 1 Hz) over the left hemisphere. Real-time transcranial Doppler ultrasonography showed a brain edema and high peaked systolic and low diastolic flows in basal, anterior, and middle cerebral arteries; however, immediately after a blood exchange transfusion, systolic flows were lower and diastolic flows were higher. The resistance indices were significantly different (means: 0.58 vs. 0.37; p = 0.01). The patient was placed on diet therapy. After six blood exchange transfusions and peritoneal dialysis, her neurologic examination results and serum ammonia and lactate values were normal. The authors found that electroencephalography and transcranial Doppler ultrasonography were useful for the diagnosis and follow-up treatment of neonatal citrullinemia. [ABSTRACT FROM AUTHOR]

Glutaric aciduria type 1 (GA1) is a rare, inherited mitochondrial disorder that results from deficiency of mitochondrial glutaryl-CoA dehydrogenase. Most patients develop neurological dysfunction early in life, which leads to severe disabilities. We present a 37-month-old girl with GA1 manifested as macrocephaly and hypotonia who received comprehensive dental restoration surgery under general anesthesia with sevoflurane. She was placed on specialized fluid management during a preoperative fasting period and anesthesia was administered without complications. All the physiological parameters, including glucose and lactate blood levels and arterial blood gas were carefully monitored and maintained within normal range perioperatively. Strategies for anesthetic management should include prevention of pulmonary aspiration, dehydration, hyperthermia and catabolic state, adequate analgesia to minimize surgical stress, and avoidance of prolonged neuromuscular blockade. We administered general anesthesia with sevoflurane uneventfully, which was well tolerated by our patient with GA1. Additionally, communication with a pediatric geneticist and surgeons should be undertaken to formulate a comprehensive anesthetic strategy in these patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: Fabry disease is an X-linked inherited lysosomal storage disease that can be treated with the enzymes of agalsidase beta (Fabrazyme) and agalsidase alfa (Replagal). Since June 2009, viral contamination of Genzyme's production facility has resulted in a worldwide shortage of agalsidase beta, leading to the switch to agalsidase alfa for patients with Fabry disease in Taiwan. Methods: The medical records were retrospectively reviewed for nine male patients with Fabry disease from the start of agalsidase beta treatment until the switch to agalsidase alfa for at least 1 year. Results: After 12–112 months of enzyme replacement therapy (ERT), decreased plasma globotriaosylsphingosine (lyso-Gb3) was found in five out of seven patients, indicating improvement in disease severity. Among the six patients with available echocardiographic data at baseline and after ERT, all six experienced reductions of left ventricular mass index. Renal function, including microalbuminuria and estimated glomerular filtration rate, showed stability after ERT. Mainz Severity Score Index scores revealed that all nine patients remained stable at 12 months after switching to agalsidase alfa. ERT improved or stabilized cardiac status and stabilized renal function, while reducing plasma lyso-Gb3. ERT was well tolerated, even among the three patients who had hypersensitivity reactions. Conclusion: The switch of ERT from agalsidase beta to agalsidase alfa appears to be safe after 1 year of follow-up for Taiwanese patients with Fabry disease. [Copyright &y& Elsevier]

This study investigated the use of bioelectrical impedance analysis (BIA) as a means of assessing body composition in patients with Prader-Willi syndrome (PWS). Segmental, multifrequency BIA was performed on 30 patients with PWS (16 males and 14 females; mean age: 8.1 ± 3.9 years; age range: 2.9–19.6 years) using eight tactile electrodes. No patient had received growth hormone treatment prior to baseline measurements. Standard deviation scores for height, weight, and body mass index were –0.96 ± 1.29, 2.28 ± 2.66, and 3.14 ± 2.74, respectively. Percentages of body fat, total body water, and soft lean mass were 45.9 ± 10.8%, 36.6 ± 7.3%, and 49.9 ± 9.9%, respectively. Body fat percentage was positively correlated with the body mass index standard deviation score (r = 0.665, p < 0.01). Follow-up BIA was also performed on five patients who received growth hormone therapy (duration of treatment: 1.5–4.6 years). All of these patients showed reductions in their body fat percentages after treatment. BIA confirmed a significantly higher percentage of body fat in patients with PWS compared with normal children. These findings and the follow-up data can be used to develop quality care strategies for patients with PWS. [Copyright &y& Elsevier]

Background: The clinical course of methylmalonic aciduria (MMA) is fulminant in neonates and emergency management is necessary to save lives. It is therefore very important to differentiate affected from unaffected neonates immediately when there are abnormal results regarding MMA in newborn screening. Methods: Between January 2002 and December 2008, 598,522 newborns were screened for MMA by 2 neonatal screening centers: the Chinese Foundation of Health and the Taipei Institute of Pathology. A total of 22 newborns were referred to confirmatory medical centers, and 7 were confirmed as having MMA. The initial propionylcarnitine (C3) level, C3/acetylcarnitine (C2) ratio, plasma ammonia, liver function tests, blood pH and bicarbonate were compared between the true-positive and false-positive groups. Results: The C3/C2 ratio and plasma ammonia were markedly higher in the true-positive MMA group (p < 0.0001). Blood gas pH (p = 0.029), bicarbonate (p = 0.019), and aspartate aminotransferase (p = 0.005) also significantly differed between these 2 groups. Conclusion: Referred newborns with elevated plasma C3/C2 ratios > 0.4 or ammonia levels > 200 mg/dL should be highly suspected of having MMA. [Copyright &y& Elsevier]

Giant congenital melanocytic nevi are rare, with an estimated incidence of approximately 1 in 20,000 live births. They increase the lifetime risk for malignant melanoma and neurological deficits, including leptomeningeal melanocytosis and epilepsy. Recently, we encountered two patients in whom giant congenital melanocytic nevi were noted at birth. Case 1 presented with the largest nevus spreading across the posterior scalp, neck, chest wall, shoulder and upper back. At the age of 2 months, magnetic resonance imaging (MRI) was performed and no leptomeningeal melanocytosis was found. Case 2 presented with a huge nevus covering most parts of the lower abdomen, lower back, buttocks and bilateral upper thighs. She also had normal MRI findings in the newborn period. At the age of 7 years, leptomeningeal thickening on the surface of the junction between the pons and midbrain was found on brain MRI although she was neurologically asymptomatic. Here, we describe these two cases with congenital melanocytic nevi and review the literature about its clinical manifestations, outcomes, risks for malignant melanoma and neurocutaneous melanosis, and possible surgical interventions. [Copyright &y& Elsevier]

The article presents a study on the diagnosis of the cardiac variant of the Fabry disease through newborn screening. Disease incidence were ascertained in the Taiwan Chinese population using the newborn screening program based on the assessment of the enzyme activity. Results show that Fabry mutations among newborns were high, highlighting the importance of early detection to allow therapeutic intervention with enzyme replacement therapy.

Rhabdomyolysis is a life-threatening condition that involves muscle cell destruction. Among its etiologies, severe hyper-natremia is a less common cause. We report a teenage girl with congenital central hypoventilation syndrome and hypothalamus dysfunction syndrome who presented with extreme hypernatremia (sodium, 211 mmol/L) with rhabdomyolysis (creatine kinase, 32,850 U/L) and acute renal failure (creatinine, 6.1 mg/dL) following gastroenteritis with 7-kg weight loss. Rhabdomyolysis subsequently led to acute renal failure and hyperkalemia. Acute hemodialysis was initiated on hospital day 3 for hyperkalemia. This resulted in a 13 mmol/L fall in serum sodium in 3 hours despite using a 156 mmol/L sodium bath, but without the development of cerebral edema or neurological defect. This report highlights an unusual cause of rhabdomyolysis in children and the experience of managing such a difficult clinical situation. [J Chin Med Assoc 2009;72(10):555–558] [Copyright &y& Elsevier]

Background: Information regarding growth hormone (GH) therapy in neonatal patients with methylmalonic acidemia (MMA) is lacking. We present our experience with GH therapy in neonatal patients with MMA. Methods: Four neonatal patients with mut 0 type MMA were identified through newborn screening for elevated propionylcarnitine (C3) levels. GH therapy (0.6 IU/kg/week, subcutaneously) was prescribed for patient 1 after 1 month of admission, and was prescribed for patients 2, 3 and 4 on the 1st day of admission. We evaluated weight, skin erosion, hospital stay, and serum levels of C3 after GH therapy. Results: All of the neonatal patients with MMA displayed obvious weight gain and distinct improvement in skin erosions after GH therapy. The duration of hospital stay for patients 2, 3 and 4 was reduced compared to that of patient 1. However, the metabolic effects of GH therapy on reducing serum levels of C3 seem to be indeterminate. Conclusion: Our clinical findings suggest that GH therapy has potentially beneficial effects on neonatal patients with MMA. [Copyright &y& Elsevier]

Background/purpose: Osteogenesis imperfecta (OI) (MIM 166200, 166210, 259420 and 166220) is a congenital disorder characterized by increased bone fragility and low bone mass. Information regarding the clinical features of this genetic disorder is lacking in Taiwan. This study aimed to characterize the clinical features of OI patients in Taiwan to establish a practical correlation for distinguishing different clinical subtypes of the disorder.Methods: A review of medical records identified 48 patients with OI (33 female and 15 male; age range, 2 months to 53 years) from January 1996 to June 2008. Diagnosis and classification, using the classification system outlined by Sillence et al, were based on clinical and radiological characteristics. We also analyzed the clinical presentation, physical examination and bone mineral density (BMD) among the different subtypes of OI.Results: Retrospective analysis of the medical records revealed that 48 OI patients could be classified into types I (n = 19), III (n = 10), and IV (n = 19). There were statistically significant differences between these three types in terms of height, weight, BMD, dentinogenesis imperfecta, bone deformity, scoliosis, walking ability, annual fracture rate, and family history. However, no significant differences were noted for blue sclera (p = 0.075) and hearing loss (p = 0.832).Conclusion: Nine of the 11 clinical features examined---height, weight, BMD, dentinogenesis imperfecta, bone deformity, scoliosis, walking ability, fracture rate, and family history---were significantly different among the three types of OI patients. This finding may be of help in evaluating patients and establishing their prognosis. [ABSTRACT FROM AUTHOR]

Highlights from the article: Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome; OMIM 253000) is a rare autosomal-recessive inherited disorder caused by N-acetylgalactosamine-6-sulfatase (GALNS) deficiency which leads to excessive lysosomal storage of glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate in various tissues and organs. For two patients who started ERT at a younger age (1.4 and 2.8 years, respectively), z scores for LVMI, IVSd, and LVPWd all decreased after ERT. This is the first report regarding the clinical benefits and safety of long-term ERT in Taiwanese patients with MPS IVA.

A case of homocystinuria with lenticular subluxation was misdiagnosed as Marfan syndrome since the patient had no apparent mental impairment and had had a negative neonatal screen for homocystinuria. The delayed diagnosis of homocystinuria was due to a negative prior neonatal screen which was checked when he was a breastfed healthy newborn. In the absence of an autosomal dominant family history, and because of prior poor school performance, amino acid analysis and mutational analysis of the cystathionine b-synthase gene were performed, which revealed the presence of homocystinuria. Low methionine diet with vitamin B6, folic acid, betaine, dipyridamole and aspirin was prescribed for emergency ophthalmologic surgery to prevent thromboembolic events. Fortunately, the operation was completed uneventfully. The patient has been followed-up for 4 years without any significant complaints under diet and medical control. Since homocystinuria is easily missed in neonatal screening programs, it should be suspected in patients who present with lenticular subluxation, even after a negative neonatal screen. [Copyright &y& Elsevier]

Objective: To evaluate whether very early treatment in our patients would result in better clinical outcomes and to compare these data with other infantile-onset Pompe disease (IOPD) cohort studies.Methods: In this nationwide program, 669,797 newborns were screened for Pompe disease. We diagnosed IOPD in 14 of these newborns, and all were treated and followed in our hospital.Results: After 2010, the mean age at first enzyme-replacement therapy (ERT) was 11.92 days. Our patients had better biological, physical, and developmental outcomes and lower anti-rh acid α-glucosidase antibodies after 2 years of treatment, even compared with one group that began ERT just 10 days later than our cohort. No patient had a hearing disorder or abnormal vision. The mean age for independent walking was 11.6 ± 1.3 months, the same age as normal children.Conclusions: ERT for patients with IOPD should be initiated as early as possible before irreversible damage occurs. Our results indicate that early identification of patients with IOPD allows for the very early initiation of ERT. Starting ERT even a few days earlier may lead to better patient outcomes. [ABSTRACT FROM AUTHOR]