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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]

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]

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/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]

6-Pyruvoyl-tetrahydropterin synthase (6PTPS) deficiency is a major cause of biopterin deficiency. 6PTPS patients usually have an elevated serum phenylalanine level, a deficiency of neurotransmitters (serotonin and dopamine), and neurological symptoms, if without treatment. We herein investigated the possibility of neurological dysfunction in early-treated patients. In the study, 12 early-treated 6PTPS patients were studied. Their auditory simple reaction time, movement rhythm variation (MRV), somatosensory evoked potentials to median nerve stimulation, and hand muscle responses to transcranial magnetic stimulation, were measured. MRV is a test of repetitive voluntary movements, and was used with and without auditory cues at 0.3 Hz. The 6PTPS patients had an increased motor threshold but normal motor and sensory central conduction times. They performed very well in simple reactions (6PTPS 208.4±16.7 ms, control 200.3±11.7 ms, p=0.18), but not in continuous tasks. The continuous performance tests showed that MRV had increased in the 6PTPS patients (with cues: 6PTPS 7.35±0.94, control 5.47±0.80, p<0.0001; without cues: 6PTPS 9.87±1.44, control 6.59±0.68, p<0.0001). Without cues, MRV had increased in both the 6PTPS and control groups, but more significantly in the 6PTPS patients (6PTPS 2.51±0.97, control 1.25±0.42; p=0.0001). Our findings indicate that early-treated 6PTPS patients have subtle neurological dysfunctions. They may not maintain movement rhythm as well as normal subjects, even with external cues. Hence, MRV is a good method to assess motor control. [Copyright &y& Elsevier]

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.

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]

Abstract: Background: Interest in lysosomal storage diseases in newborn screening programs has increased in recent years. Two techniques, fluorescence (4-MU) and tandem mass spectrometry (MS/MS) methods are frequently used. We report a pilot study of large scale newborn screening for Fabry, Pompe, Gaucher, and MPS I diseases by using the MS/MS method in Taiwan and compared the performance of the MS/MS with 4-MU methods. Methods: More than 100,000 dried blood spots (DBSs) were collected consecutively as part of the national Taiwan newborn screening programs. The enzyme activities were detected by the MS/MS method from a DBS punch. Mutation analysis was further performed for newborns with detected enzyme deficiency. Results: The DNA sequence analysis for suspected cases revealed 64 newborns with confirmed Fabry mutations, 16 were classified as infantile or late-onset Pompe disease, and 1 was characterized as Gaucher disease. The positive predict value increased from 4.0% to 7.1% in the Pompe study, and from 61.0% to 95.5% in the Fabry study by the MS/MS method compared to 4-MU assay. Conclusions: The MS/MS method has been validated as a more specific, powerful and efficient tool than the 4-MU assay. It also provided a multiplex solution of newborn screening for lysosomal storage diseases. [Copyright &y& Elsevier]

Background Fabry disease is a lysosomal storage disorder with an incidence of 1:1600 for the late-onset IVS4 + 919G > A cardiac variant mutation in Taiwan. Signs and symptoms of this cardiac variant include left ventricular hypertrophy, mitral insufficiency and/or arrhythmias. The search for biomarkers that might predict the clinical outcomes and guide treatment options is important. We thus investigated relationships between Fabry disease biomarkers (such as globotriaosylceramide (Gb 3 ), globotriaosylsphingosine (lyso-Gb 3 )/related analogues) and age, gender, enzyme activity, clinical manifestations and severity of the disease in these patients. Method Urine and plasma biomarkers were analyzed using tandem mass spectrometry. A large cohort of 191 adult and pediatric Fabry patients carrying the IVS4 + 919G > A mutation was studied. Some patients were members of the same family. Results Our results show that the plasma lyso-Gb 3 level, and urinary analogue levels of lyso-Gb 3 at m / z (+ 16), (+ 34), and (+ 50) adjusted for gender and age had a positive association with the left ventricular mass index, and/or the Mainz Severity Score Index. Conclusions It might thus be of particular interest to monitor children with high levels of these biomarkers, as part of a longitudinal study in order to determine if the excretion profile at a young age is predictive of the outcomes of disease severity in adulthood. [ABSTRACT FROM AUTHOR]

Background Propionyl-CoA carboxylase (PCC) is a mitochondrial enzyme involved in the catabolism of several essential amino acids and odd chain fatty acids. Previous PCC assays have involved either a radiometric assay or have required mitochondria isolation and/or enzyme purification. Methods We developed an enzymatic method to analyze PCC activity in phytohemagglutinin (PHA) stimulated lymphocytes that involves high performance liquid chromatography. Results The method shows good linearity and sensitivity. PCC activity was unaffected even when lymphocytes were isolated and PHA stimulated after a whole blood sample had been stored at 4 °C for 5 days. This indicates that this method is suitable for analyzing samples from distant medical centers. The PCC activity of patients with propionic acidemia was found to be much lower than that of normal individuals and carriers. However, this PCC assay is significantly affected by the red blood cell contamination. In conclusion, this is a reliable method for performing PCC assays and only requires 0.5 to 1.0 ml of whole blood from newborns. Conclusions The PCC assay established in this study is useful for the confirmation of PA in individuals, and prenatal diagnosis and genetic counseling for the affected families. [ABSTRACT FROM AUTHOR]

Abstract: The manifestations of glycogen storage disease type 1a (GSD 1a) are usually so prominent in childhood that it is readily diagnosed by pediatricians. However, a mild form of the disease may only become apparent during adolescence or adulthood. We observed a brother and sister with subtle manifestations of the disease, which was discovered after the brother''s son was diagnosed with typical GSD 1a. The adult siblings never suffered from hypoglycemia, had normal fasting blood glucose and liver transaminases at the time of diagnosis, and were taller than average for Chinese. Their only notable disease manifestations were recurrent gouty arthritis associated with hyperuricemia and hyperlipidemia during adolescence. When diagnosed, the brother had multiple benign and malignant hepatic tumors, and died of fulminant metastatic hepatocellular carcinoma 6months after liver transplantation. p.M121V/p.R83H and p.M121V/p.M121V genotypic constellations of the G6PC gene were identified in this family. Both siblings were homozygous for the newly identified p.M121V mutation. The infant had compound heterozygous mutations, p.R83H and p.M121V. We recommend that mild GSD should be considered in the adolescents with unexplained hyperuricemia and hyperlipidemia, despite the presence of normal blood glucose levels. This report also reminds us that hepatocellular carcinoma could develop even in very mild GSD 1a patients. [Copyright &y& Elsevier]

Abstract: In this study, we attempted to determine if different locations of a tumor influence the hypothalamopituitary axis function and outcomes with childhood craniopharyngiomas. The preoperative, postoperative, and long-term follow-up endocrinological disturbances of 66 children with a craniopharyngioma were retrospectively studied. The patients were divided into two subgroups according to the location of the tumor (intrasellar and third ventricle floor). The mean age at onset was 8.02 (range, 1.42–17.58)years. These patients were followed-up for a median duration of 7.2 (range, 2–22)years. Vision problems as the first symptom were more common in Group One (with intrasellar tumors) compared to Group Two (55.6% vs 15.4%; p =0.001; Fisher’s exact test). Increased intracranial pressure was the most common initial symptom in patients in Group Two (51.3%) and the second most common symptom in Group One (37%). The majority of patients in both Group One and Group Two required some forms of pituitary hormone supplements (96% vs 84%). At the last follow-up, more patients with intrasellar craniopharyngiomas needed cortisone supplements (79.2% in Group One vs 45.9% in Group Two; p =0.016; Fisher’s exact test); however, children with third ventricle floor tumors had more prevalent weight gain (4.2% in Group One vs 27.0% in Group Two; p =0.038; Fisher’s exact test). There were different initial presentations and endocrinological outcomes between children with intrasellar and third ventricle floor craniopharyngiomas. The intrasellar tumors had greater pituitary hormone disturbance. However, at the long-term follow-up, children with third ventricle floor tumors had a greater prevalence of being overweight and obese, which was associated with hypothalamic dysfunction. [Copyright &y& Elsevier]

Abstract: A 4-month-old male baby was diagnosed with Permanent Neonatal Diabetes Mellitus. We identified a novel missense heterogeneous mutation in the KCNJ11 gene at codon 167 (aTC→tTC) in a region that corresponds to a predicted intracellular gate of the ATP-sensitive potassium channel. [Copyright &y& Elsevier]