BACKGROUND: Congenital disorders of glycosylation (CDG) are a continuously expanding group of monogenic disorders that disrupt glycoprotein and glycolipid biosynthesis, leading to multi-systemic manifestations. These disorders are categorized into various groups depending on which part of the glycosylation process is impaired. The cardiac manifestations in CDG can significantly differ, not only across different types but also among individuals with the same genetic cause of CDG. Cardiomyopathy is an important phenotype in CDG. The clinical manifestations and progression of cardiomyopathy in CDG patients have not been well characterized. This study aims to delineate common patterns of cardiomyopathy across a range of genetic causes of CDG and to propose baseline screening and follow-up evaluation for this patient population.
METHODS: Patients with molecular confirmation of CDG who were enrolled in the prospective or memorial arms of the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) natural history study were ascertained for the presence of cardiomyopathy based on a retrospective review of their medical records. All patients were evaluated by clinical geneticists who are members of FCDGC at their respective academic centers. Patients were screened for cardiomyopathy, and detailed data were retrospectively collected. We analyzed their clinical and molecular history, imaging characteristics of cardiac involvement, type of cardiomyopathy, age at initial presentation of cardiomyopathy, additional cardiac features, the treatments administered, and their clinical outcomes.
RESULTS: Of the 305 patients with molecularly confirmed CDG participating in the FCDGC natural history study as of June 2023, 17 individuals, nine females and eight males, were identified with concurrent diagnoses of cardiomyopathy. Most of these patients were diagnosed with PMM2-CDG (n = 10). However, cardiomyopathy was also observed in other diagnoses, including PGM1-CDG (n = 3), ALG3-CDG (n = 1), DPM1-CDG (n = 1), DPAGT1-CDG (n = 1), and SSR4-CDG (n = 1). All PMM2-CDG patients were reported to have hypertrophic cardiomyopathy. Dilated cardiomyopathy was observed in three patients, two with PGM1-CDG and one with ALG3-CDG; left ventricular non-compaction cardiomyopathy was diagnosed in two patients, one with PGM1-CDG and one with DPAGT1-CDG; two patients, one with DPM1-CDG and one with SSR4-CDG, were diagnosed with non-ischemic cardiomyopathy. The estimated median age of diagnosis for cardiomyopathy was 5 months (range: prenatal-27 years). Cardiac improvement was observed in three patients with PMM2-CDG. Five patients showed a progressive course of cardiomyopathy, while the condition remained unchanged in eight individuals. Six patients demonstrated pericardial effusion, with three patients exhibiting cardiac tamponade. One patient with SSR4-CDG has been recently diagnosed with cardiomyopathy; thus, the progression of the disease is yet to be determined. One patient with PGM1-CDG underwent cardiac transplantation. Seven patients were deceased, including five with PMM2-CDG, one with DPAGT1-CDG, and one with ALG3-CDG. Two patients died of cardiac tamponade from pericardial effusion; for the remaining patients, cardiomyopathy was not necessarily the primary cause of death.
CONCLUSIONS: In this retrospective study, cardiomyopathy was identified in ∼6% of patients with CDG. Notably, the majority, including all those with PMM2-CDG, exhibited hypertrophic cardiomyopathy. Some cases did not show progression, yet pericardial effusions were commonly observed, especially in PMM2-CDG patients, occasionally escalating to life-threatening cardiac tamponade. It is recommended that clinicians managing CDG patients, particularly those with PMM2-CDG and PGM1-CDG, be vigilant of the cardiomyopathy risk and risk for potentially life-threatening pericardial effusions. Cardiac surveillance, including an echocardiogram and EKG, should be conducted at the time of diagnosis, annually throughout the first 5 years, followed by check-ups every 2-3 years if no concerns arise until adulthood. Subsequently, routine cardiac examinations every five years are advisable. Additionally, patients with diagnosed cardiomyopathy should receive ongoing cardiac care to ensure the effective management and monitoring of their condition. A prospective study will be required to determine the true prevalence of cardiomyopathy in CDG.

BACKGROUND: Congenital disorders of glycosylation (CDG) are a type of inborn error of metabolism (IEM) resulting from defects in glycan synthesis or failed attachment of glycans to proteins or lipids. One rare type of CDG is caused by homozygous or compound heterozygous loss-of-function variants in mannosidase alpha class 2B member 2 (MAN2B2). To date, only two cases of MAN2B2-CDG have been reported worldwide.
METHODS: Trio whole-exome sequencing (Trio-WES) was conducted to screen for candidate variants. N-glycan profiles were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). MAN2B2 expression was evaluated by western blotting. MX dynamin like GTPase 1 (MX1) function was estimated via Thogoto virus (THOV) minireplicon assay.
RESULTS: Trio-WES identified compound heterozygous MAN2B2 (hg19, NM_015274.1) variants (c.384G>T; c.926T>A) in a CDG patient. This patient exhibited metabolic abnormalities, symptoms of digestive tract dysfunction, infection, dehydration, and seizures. Novel immune dysregulation characterized by abnormal lymphocytes and immunoglobulin was observed. The MAN2B2 protein level was not affected, while LC-MS/MS showed obvious disruption of N-glycans and N-linked glycoproteins.
CONCLUSIONS: We described a CDG patient with novel phenotypes and disruptive N-glycan profiling caused by compound heterozygous MAN2B2 variants (c.384G>T; c.926T>A). Our findings broadened both the genetic and clinical spectra of CDG.

BACKGROUND: Liver transplantation (LT) has been proposed as a viable treatment option for selected methylmalonic acidemia (MMA) patients. However, there are still controversies regarding the therapeutic value of LT for MMA. The systematic assessment of health-related quality of life (HRQoL)-targeted MMA children before and after LT is also undetermined. This study aimed to comprehensively assess the long-term impact of LT on MMA, including multiorgan sequelae and HRQoL in children and families.
METHODS: We retrospectively evaluated 15 isolated MMA patients undergoing LT at our institution between June 2013 and March 2022. Pre- and post-transplant data were compared, including metabolic profiles, neurologic consequences, growth parameters, and HRQoL. To further assess the characteristics of the HRQoL outcomes in MMA, we compared the results with those of children with biliary atresia (BA).
RESULTS: All patients had early onset MMA, and underwent LT at a mean age of 4.3 years. During 1.3-8.2 years of follow-up, the patient and graft survival rates were 100%. Metabolic stability was achieved in all patients with liberalized dietary protein intake. There was a significant overall improvement in height Z scores (P = 0.0047), and some preexisting neurological complications remained stable or even improved after LT. On the Pediatric Quality of Life Inventory (PedsQL™) generic core scales, the mean total, physical health, and psychosocial health scores improved significantly posttransplant (P < 0.05). In the family impact module, higher mean scores were noted for all subscales post-LT, especially family function and daily activities (P < 0.01). However, the total scores on the generic core scales and transplant module were significantly lower (Cohen\'s d = 0.57-1.17) when compared with BA recipients. In particular, social and school functioning (Cohen\'s d = 0.86-1.76), treatment anxiety, and communication (Cohen\'s d = 0.99-1.81) were far behind, with a large effect size.
CONCLUSIONS: This large single-center study of the mainland of China showed an overall favorable impact of LT on isolated MMA in terms of long-term survival, metabolic control, and HRQoL in children and families. The potential for persistent neurocognitive impairment and inherent metabolic fragility requires long-term special care. Video Abstract (MP4 153780 KB).

Urea cycle disorder (UCD) is a group of inherited metabolic diseases with high disability or fatality rate, which need long-term drug treatment and diet management. Except those with Citrin deficiency or liver transplantation, all pediatric patients require lifelong low protein diet with safe levels of protein intake and adequate energy and lipids supply for their corresponding age; supplementing essential amino acids and protein-free milk are also needed if necessary. The drugs for long-term use include nitrogen scavengers (sodium benzoate, sodium phenylbutyrate, glycerol phenylbutyrate), urea cycle activation/substrate supplementation agents (N-carbamylglutamate, arginine, citrulline), etc. Liver transplantation is recommended for pediatric patients not responding to standard diet and drug treatment, and those with severe progressive liver disease and/or recurrent metabolic decompensations. Gene therapy, stem cell therapy, enzyme therapy and other novel technologies may offer options for treatment in UCD patients. The regular biochemical assessments like blood ammonia, liver function and plasma amino acid profile are needed, and physical growth, intellectual development, nutritional intake should be also evaluated for adjusting treatment in time.
尿素循环障碍（UCD）是一组致死、致残率较高的遗传代谢病，需要长期饮食和药物治疗及管理。除希特林蛋白缺乏症和行肝移植治疗的患儿，其他慢性期患儿均需要终身低蛋白饮食，保证其相应年龄的安全蛋白质摄入量以及充足的碳水和脂肪的供能比，必要时补充必需氨基酸及无蛋白奶粉；药物治疗主要包括氮清除剂（苯甲酸钠、苯丁酸钠、苯丁酸甘油酯）、尿素循环激活/底物补充剂（N-氨基甲酰谷氨酸、精氨酸、瓜氨酸）等。规范饮食及药物治疗后未达预期效果、出现严重进展性肝病或出现反复发作的患儿建议行肝移植。基因疗法、干细胞疗法和酶替代疗法等新技术可能是UCD患儿治疗的新选择。UCD患儿需要定期检测血氨、肝功能和血氨基酸等生化指标，并评估体格生长、智力发育和营养摄入情况，及时调整治疗方案。.

Dried blood spot (DBS) cards from newborn screening (NBS) programs represent a wealth of biological data. They can be stored easily for a long time, have the potential to support medical and public health research, and have secondary usages such as quality assurance and forensics, making it the ideal candidate for bio-banking. However, worldwide policies vary with regard to the duration of storage of DBS cards and how it can be used. Recent advances in genomics have also made it possible to perform extended genetic testing on DBS cards in the newborn period to diagnose both actionable and non-actionable childhood and adult diseases. Both storage and secondary uses of DBS cards raise many ethical, clinical, and social questions. The openness of the key stakeholders, namely, parents and healthcare providers (HCPs), to store the DBS cards, and for what duration and purposes, and to extended genetic testing is largely dependent on local cultural-social-specific factors. The study objective is to assess the parents\' and HCPs\' awareness and receptivity toward DBS retention, its secondary usage, and extended genetic testing. A cross-sectional, self-administrated survey was adopted at three hospitals, out of which two were public hospitals with maternity services, between June and December 2022. In total, 452 parents and 107 HCPs completed and returned the survey. Overall, both HCPs and parents were largely knowledgeable about the potential benefits of DBS card storage for a prolonged period and its secondary uses, and they supported extended genetic testing. Knowledge gaps were found in respondents with a lower education level who did not know that a DBS card could be stored for an extended period (p < 0.001), could support scientific research (p = 0.033), and could aid public health research, and future policy implementation (p = 0.030). Main concerns with regard to DBS card storage related to potential privacy breaches and anonymity (Parents 70%, HCPs 60%). More parents, compared to HCPs, believed that storing DBS cards for secondary research does not lead to a reciprocal benefit to the child (p < 0.005). Regarding extended genetic testing, both groups were receptive and wanted to know about actionable childhood- and adult-onset diseases. More parents (four-fifths) rather than HCPs (three-fifths) were interested in learning about a variant with unknown significance (p < 0.001). Our findings report positive support from both parents and HCPs toward the extended retention of DBS cards for secondary usage and for extended genetic testing. However, more efforts to raise awareness need to be undertaken in addition to addressing the ethical concerns of both parents and HCPs to pave the way forward toward policy-making for DBS bio-banking and extended genetic testing in Hong Kong.

Renal calculus is a common disease with complex etiology and high recurrence rate. Recent studies have revealed that gene mutations may lead to metabolic defects which are associated with the formation of renal calculus, and single gene mutation is involved in relative high proportion of renal calculus. Gene mutations cause changes in enzyme function, metabolic pathway, ion transport, and receptor sensitivity, causing defects in oxalic acid metabolism, cystine metabolism, calcium ion metabolism, or purine metabolism, which may lead to the formation of renal calculus. The hereditary conditions associated with renal calculus include primary hyperoxaluria, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, Bartter syndrome, primary distal renal tubular acidosis, infant hypercalcemia, hereditary hypophosphatemic rickets with hypercalciuria, adenine phosphoribosyltransferase deficiency, hypoxanthine-guanine phosphoribosyltransferase deficiency, and hereditary xanthinuria. This article reviews the research progress on renal calculus associated with inborn error of metabolism, to provide reference for early screening, diagnosis, treatment, prevention and recurrence of renal calculus.
肾结石是一种病因复杂且易复发的常见疾病。人类基因组关联性研究发现多种基因突变导致的代谢缺陷与结石形成有关，其中单基因病例占比较高。基因突变引起酶功能、代谢通路、离子转运、受体敏感性等改变，导致草酸代谢、胱氨酸代谢、钙离子代谢、嘌呤代谢等缺陷，易产生遗传性肾结石。如原发性高草酸尿症、胱氨酸尿症、登特病、家族性低镁血症合并高钙尿和肾钙盐沉着症、巴特综合征、原发性远端肾小管酸中毒、婴儿高钙血症、遗传性低磷性佝偻病伴高钙尿症、腺嘌呤磷酸核糖基转移酶缺乏症、次黄嘌呤-鸟嘌呤磷酸核糖基转移酶缺乏症、遗传性黄嘌呤尿症等都与遗传性肾结石相关。本文就遗传性代谢缺陷所致肾结石的研究进展进行回顾，增加对草酸代谢、胱氨酸代谢、钙离子代谢、嘌呤代谢等缺陷致肾结石的认知，以便早期筛查、诊治及预防复发。.

UNASSIGNED: The purpose of this study was to investigate whether baseline cerebral magnetic resonance imaging (MRI) characteristics could predict therapeutic responsiveness in patients with cobalamin C (cblC) defects.
UNASSIGNED: The cerebral MRI results of 40 patients with cblC defects were evaluated by a neuroradiologist. Neuropsychological scores and imaging data were collected. Neuropsychological tests were performed before and after standardized treatment.
UNASSIGNED: Thirty-eight patients initially underwent neuropsychological testing [developmental quotient (DQ)]. CblC defects with cerebellar atrophy, corpus callosum thinning and ventricular dilation had significantly lower DQs than those without (P < 0.05). Through a multivariate linear stepwise regression equation after univariate analysis, ventricular dilation was the most valuable predictor of lower DQs. Thirty-six patients (94.7%) underwent follow-up neuropsychological testing. The pre- and post-treatment DQ values were not significantly different (Z = -1.611, P = 0.107). The post-treatment DQ classification (normal, moderately low, or extremely low) showed nearly no change compared to the pretreatment DQ classification (k = 0.790, P < 0.001).
UNASSIGNED: Ventricular dilation, cerebral atrophy and corpus callosum thinning are the main MRI abnormalities of cblC defects, and these manifestations are significantly correlated with delayed development in children. MRI findings can be considered an important tool for determining the severity of cblC defects.

BACKGROUND: Inborn error of bile acid synthesis type 4 is a peroxisomal disease with impaired bile acid synthesis caused by a-methylacyl-CoA racemase (AMACR) gene mutation. The disease is usually found in children with mild to severe liver disease, cholestasis and poor fat-soluble vitamin absorption. At present, there is no report of inborn errors of bile acid synthesis type 4 in adults with liver disease and poor fat-soluble vitamin absorption.
METHODS: A 71-year-old man was hospitalized in our department for recurrent liver dysfunction. The clinical manifestations were chronic liver disease and yellow skin and sclera. Serum transaminase, bilirubin and bile acid were abnormally increased; and fat-soluble vitamins decreased. Liver cirrhosis and ascites were diagnosed by computed tomography. The patient had poor coagulation function and ascites and did not undergo liver puncture. Genetic testing showed AMACR gene missense mutation. The patient was diagnosed with inborn error of bile acid synthesis type 4. He was treated with ursodeoxycholic acid, liver protection and vitamin supplementation, and jaundice of the skin and sclera was reduced. The indicators of liver function and the quality of life were significantly improved.
CONCLUSIONS: When adults have recurrent liver function abnormalities, physicians should be alert to genetic diseases and provide timely treatment.

Inherited metabolic liver disease is a wide-range of diseases that cause abnormal metabolism, resulting from genetic defects. Notably, some inherited metabolic liver diseases are closely associated to infection on account of specific substances abnormal metabolism or key enzyme activities deficiency. Therefore, understanding the inherited metabolic liver disease-associated infection would be helpful to clinical practice and improve patient prognosis.
遗传代谢性肝病是因基因缺陷导致代谢异常的一大类疾病。一些遗传代谢性肝病由于特定物质代谢异常或关键酶活性缺乏，与感染关系密切。了解遗传代谢性肝病相关感染，有助于指导临床实践、改善患者预后。.

Citrin deficiency is one of the most common inborn errors of metabolism in East Asians, which may manifest as neonatal cholestasis, failure to thrive and dyslipidaemia, or recurrent hyperammonaemic encephalopathy. Its molecular diagnosis requires confirmation of the presence of biallelic pathogenic variants in SLC25A13 gene by sequencing, and analysis for a common insertion IVS16ins3kb. However, patients with compatible biochemical features but only one monoallelic pathogenic variant have remained a diagnostic challenge. Here we report the development, validation and application of a multiplex ligation-dependent probe amplification (MLPA) assay using an in-house oligonucleotide probemix and a customised Coffalyer.NET worksheet for detection of exonic copy number variations in SLC25A13. With this MLPA assay, we successfully identified the presence of a heterozygous exonic deletion in SLC25A13 in three of 15 (20%) unrelated individuals with only one monoallelic pathogenic variant detected using conventional methods. Three exonic deletions, two novel involving exon 14 and one reported involving exon 5, were subsequently confirmed with Sanger sequencing. In summary, we developed, evaluated, and demonstrated the clinical utility of an in-house MLPA assay to look for exonic deletions in SLC25A13 in patients with citrin deficiency. With the discovery of novel deletions, MLPA should be considered a test of choice for molecular diagnosis of citrin deficiency when the sequencing result is inconclusive.