[Analysis of clinical features, biochemical indices and genetic variants among children with Short/branched-chain acyl-CoA dehydrogenase deficiency detected by neonatal screening].

OBJECTIVE: To investigate the clinical manifestations, biochemical abnormalities and pathogenic variants among children with Short/branched-chain acyl-CoA dehydrogenase (SBCAD) deficiency detected by neonatal screening. METHODS: A total of 2 730 852 newborns were screened from January 2016 to December 2021 with liquid chromatography tandem mass spectrometry. Suspected SBCAD deficiency patients were diagnosed by urine organic acid analysis and high-throughput gene sequencing analysis. The clinical, biochemical and genetic changes of the confirmed cases were analyzed, in addition with guidance for diet and life management, L-carnitine supplement, and survey of growth and intellectual development. RESULTS: Twelve cases of SBCAD deficiency were diagnosed, which yielded a prevalence of 1/227 571. The lsovaleryl carnitine (C5) of primary screening blood samples was between 0.6 and 2.1 µmol/L, all exceeded the normal range. C5/acety1 carnitine (C2) was between 0.02 and 0.12, with 6 cases exceeding the normal range. C5/propionyl carnitine (C3) was between 0.1 and 1.16, with 5 cases exceeding the normal range. Free carnitine (C0) was between 18.89 and 58.12 µmol, with 1 case exceeding the normal range. Three neonates with abnormal screening results were recommended to have appropriate restriction for protein intake and two were given L-carnitine. During follow-up, their C5 has ranged from 0.22 to 2.32 µmol/L, C5/C2 has ranged from 0.01 to 0.31, C5/C3 has ranged from 0.14 to 1.7. C5 or C5/C2 and C5/C3 were transiently normal in all patients except for case 8 during the neonatal screening and follow-up. C0 was 17.42 ∼ 76.83 µmol/L Urine organic acid analysis was carried out in 9 of the 12 cases, and 2-methylbutyroglycine was elevated in 8 cases. Urine organic acid analysis was carried out in 9 cases, and 2-methylbutyrylglycine was increased in 8 cases. Genetic analysis was carried out for 11 children, and in total 6 ACADSB gene variants were identified, which included 4 missense variants (c.655G>A, c.923G>A, c.461G>A, c.1165A>G), 1 frameshift variant (c.746del) and 1 nonsense variant (c.275C>G). Among these, the C.461G>A variant was unreported previously. The most common variants were c.1165A>G (40.9%) and C.275C>G (22.7%). The patients were followed up for 18 days to 55 months. Only one patient had mental retardation, with the remainders having normal physical and mental development. CONCLUSION: SBCAD deficiency is a rare disease. The detection rate of newborn screening in this study was 1/227 571. Early intervention can be attained in most asymptomatic patients through neonatal screening. In this study, the common gene variants are c.1165A>G and c.275C>G.

Long-term prognosis of 35 patients with methionine adenosyltransferase deficiency based on newborn screening in China.

Methionine adenosyltransferase deficiency (MATD) is a rare metabolic disorder caused by mono- or biallelic MAT1A mutations that are not yet well understood. Of the 4,065,644 neonates screened between November 2010 and December 2021, 35 individuals have been diagnosed with an estimated incidence of 1: 116,161 by a cutoff value of methionine 82.7 µmol/L and follow-up over 11 years. MATD patients with autosomal recessive (AR) type had higher clinical and genetic heterogeneity than those with autosomal dominant (AD) type. Fifteen unrelated AD patients harbored one well-known dominant variant, c.791 G>A or c.776 C>T, and were clinically unaffected with a mean plasma methionine (Met) value <300 µmol/L. Twenty AR cases have unique genotypes and presented a wide range of clinical abnormalities from asymptomatic to white matter lesions. Of them, 10 AR patients displayed severe manifestations, such as verbal difficulty, motor delay, development delay, and white matter lesions, with mean Met >500 µmol/L and thereby were treated with a methionine-restricted diet alone or in combination with betaine, folate, or vitamin B6, and were healthy finally. Neurological abnormalities were evidenced in two patients (P16 and P27) with Met values >800 µmol/L by MRI scan. Neurological abnormalities were reversed here by liver transplantation or by the determination of S-adenosylmethionine supplementation. Additionally, 38 variants of MAT1A were distributed within patients and carriers, of which 24 were novel and mostly predicted to be damaged. Our findings with an extensive clinical and genetic dataset provided new insights into its diagnosis and treatment and will be helpful for its optimal management in the future.

Screening of multiple acyl-CoA dehydrogenase deficiency in newborns and follow-up of patients.

To investigate the incidence rate, clinical and gene mutation characteristics of multiple acyl-CoA dehydrogenase deficiency (MADD) in newborns in Zhejiang province. A total of 3 896 789 newborns were screened for MADD using tandem mass spectrometry in Zhejiang Neonatal Screening Center during January 2009 and December 2020. Patients of MADD were confirmed by urine organic acid and electron transferring flavoprotein (or electron transferring flavoprotein dehydrogenase () gene detection. MADD patients were given diet and life management, supplemented with L-carnitine, riboflavin and coenzyme Q 10 treatment, and their growth and intellectual development were evaluated during the followed up.Thirteen patients with MADD were diagnosed, with an incidence of 1/299 753. One patient was type Ⅱ, and the rest were type Ⅲ. Patients were followed up for 1 case died, 4 cases had acute metabolic disorders with hypoglycemia as the main manifestation due to infection, 1 case had hypotonia, and the rest 7 cases developed well. Patients had raised levels of C4-C18:1 acylcarnitines in the initial screening. Thirteen children were genetically tested, 1 case with compound heterozygous mutation in the gene, 1 case with homozygous mutation in the gene, 1 case with compound heterozygous mutation in the gene, 8 cases with compound heterozygous mutation and 1 case with homozygous mutation in the gene, 1 case that only 1 locus of gene was detected. The c.250G>A was the hotspot mutation in this study.The clinical manifestations of MADD are highly heterogeneous. The neonatal-onset form is serious, and late onset form usually has no obvious clinical symptoms. C4-C18:1 acylcarnitines usually increased in the initial screening, and the hotspot gene mutation is c.250G>A.

The antitumor effect of static and extremely low frequency magnetic fields against nephroblastoma and neuroblastoma.

Certain magnetic fields (MF) have potential therapeutic antitumor effect whereas the underlying mechanism remains undefined. In this study, a well-characterized MF was applied to two common childhood malignancies, nephroblastoma and neuroblastoma. This MF has a time-averaged total intensity of 5.1 militesla (mT), and was generated as a superimposition of a static and an extremely low frequency (ELF) MF in 50 Hertz (Hz). In nephroblastoma and neuroblastoma cell lines including G401, CHLA255, and N2a, after MF exposure of 2 h per day, the cell viability decreased significantly after 2 days. After 3 days, inhibition rates of 17-22% were achieved in these cell lines. Furthermore, the inhibition rate was positively associated with exposure time. On the other hand, when using static MF only while maintaining the same time-averaged intensity of 5.1 mT, the inhibition rate was decreased. Thus, both time and combination of ELF field were positively associated with the inhibitory effect of this MF. Exposure to the field decreased cell proliferation and induced apoptosis. Combinational use of MF together with chemotherapeutics cisplatin (DDP) was performed in both in vitro and in vivo experiments. In cell lines, combinational treatment further increased the inhibition rate compared with single use of either DDP or MF. In G401 nephroblastoma tumor model in nude mice, combination of MF and DDP resulted in significant decrease of tumor mass, and the side effect was limited in mild liver injury. MF exposure by itself did not hamper liver or kidney functions. In summary, the antitumor effect of an established MF against neuroblastoma and nephroblastoma is reported, and this field has the potential to be used in combination with DDP to achieve increased efficacy and reduce side effects in these two childhood malignancies. Bioelectromagnetics. 39:375-385, 2018. © 2018 Wiley Periodicals, Inc.

Integrating disease progression models, non-clinical pharmacokinetic data and treatment response endpoints to optimize intravitreal dosing regimens.

OBJECTIVE: To rapidly identify patients who will ultimately respond to 1 year of therapy, and optimize their inter dose interval. MATERIALS AND METHODS: An intravitreal (IVT) ophthalmic dosing paradigm was designed based on clinical efficacy, nonclinical pharmacokinetics (PK), and disease progression modeling. Relevant non-clinical PK models were used to extrapolate IVT drug concentrations to patients. RESULTS: Modeling predicted that > 80% of patients who would respond to 1 year of IVT treatment with an improvement in best-corrected visual acuity (BCVA) could be identified after the first 2 doses of treatment. These 2 initial doses produced ~ 75% of the maximum improvement in BCVA attainable. Moreover, the models also predicted those patients who responded after 1 year of treatment may tolerate an extension of the inter dose interval to 12 weeks without significant deterioration of BCVA. In contrast, > 70% of responsive patients who did not respond to 1 year of treatment showed inadequate responses after 2 doses. CONCLUSIONS: These models use data from 2 doses to identify those patients likely to benefit after 1 year of treatment, and thereafter can lengthen their inter dose interval without deleterious effects. This method identifies potential treatment responders early, and lengthens the inter dose interval during long-term administration while allowing non-responders to pursue alternative therapies earlier, thereby minimizing risk to the patient.