MRI and clinical features of maple syrup urine disease: preliminary results in 10 cases

PURPOSE:We aimed to evaluate the magnetic resonance imaging (MRI) and clinical features of maple syrup urine disease (MSUD).METHODS:This retrospective study consisted of 10 MSUD patients confirmed by genetic testing. All patients underwent brain MRI. Phenotype, genotype, and areas of brain injury on MRI were retrospectively reviewed.RESULTS:Six patients (60%) had the classic form of MSUD with BCKDHB mutation, three patients (30%) had the intermittent form (two with BCKDHA mutations and one with DBT mutation), and one patient (10%) had the thiamine-responsive form with DBT mutation. On diffusion-weighted imaging, nine cases presented restricted diffusion in myelinated areas, and one intermittent case with DBT mutation was normal. The classic form of MSUD involved the basal ganglia in six cases; the cerebellum, mesencephalon, pons, and supratentorial area in five cases; and the thalamus in four cases, respectively. The intermittent form involved the cerebellum, pons, and supratentorial area in two cases. The thiamine-responsive form involved the basal ganglia and supratentorial area.CONCLUSION:Our preliminary results indicate that patients with MSUD presented more commonly in classic form with BCKDHB mutation and displayed extensive brain injury on MRI

Clinical, biochemical, and molecular genetic characteristics of patients with primary carnitine deficiency identified by newborn screening in Shanghai, China

Background: Primary carnitine deficiency (PCD) is an autosomal recessive disease caused by mutations in the SLC22A5 gene, which encodes the organic cation transporter 2 (OCTN2). Patients with PCD may be at risk of skeletal or cardiac myopathy, metabolic decompensation, and even sudden death. This study aimed to analyze the biochemical, clinical, and genetic characteristics of PCD patients identified by newborn screening (NBS) in Shanghai.Methods: Dried blood spot (DBS) samples of newborns were analyzed through tandem mass spectrometry (MS/MS) from January 2003 to December 2021. Newborns with low free carnitine (C0) levels were recalled. Mutation in the SLC22A5 gene was analyzed on suspected positive newborns with low C0 levels after recall.Results: 1,247,274 newborns were screened by MS/MS and 40 newborns were diagnosed with PCD, therefore the incidence of PCD in Shanghai was approximately 1:31,200. The mean C0 level in newborns with PCD was 5.37 ± 1.79 μmol/L before treatment and increased to 24.45 ± 10.87 μmol/L after treatment with L-carnitine. Twenty-three different variants were identified in the SLC22A5 gene, including 8 novel variants, of which c.51C>G (p.F17L) was the most frequent (27.27%, 18/66), followed by c.1400C>G (p.S467C) (25.76%, 17/66). Almost all the screened PCD patients were asymptomatic.Conclusion: NBS via MS/MS was a quick and efficient method for the early diagnosis of PCD. The incidence of PCD in Shanghai was 1:31,200. Eight novel variants were identified, which greatly expanded the variant spectrum of SLC22A5. MS/MS combined with genetic testing could effectively improve the diagnostic accuracy of PCD

Genetic Evaluation of 114 Chinese Short Stature Children in the Next Generation Era: a Single Center Study

Background/Aims: The genetics of human height is a frequently studied and complex issue. However, there is limited genetic research of short stature. To uncover the subgroup of patients to have higher yield and to propose a simplified diagnostic algorithm in the next generation era. Methods: This study included 114 Chinese children with height SDS ≤ -2.5 and unknown etiology from 2014 to 2015. Target/whole exome sequencing (referred as NGS) and chromosomal microarray analysis (CMA) were performed on the enrolled patients sequentially to identify potential genetic etiologies. The samples solved by NGS and CMA were retrospectively studied to evaluate the clinical pathway of the patients following a standard diagnostic algorithm. Results: In total, a potential genetic etiology was identified in 41 (36%) patients: 38 by NGS (33.3%), two by CMA (1.8%), and an additional one by both (0.9%). There were 46 different variants in 29 genes and 2 pathogenic CNVs identified. The diagnostic yield was significantly higher in patients with facial dysmorphism or skeletal abnormalities than those without the corresponding phenotype (P=0.006 and P=0.009, respectively, Pearson’s χ2 test). Retrospectively study the cohort indicate 83.3% patients eventually would be evaluated by NGS/CMA. Conclusion: This study confirms the utility of high-throughput molecular detection techniques for the etiological diagnosis of undiagnosed short stature and suggests that NGS could be used as a primary diagnostic strategy. Patients with facial dysmorphism and/or skeletal abnormalities are more likely to have a known genetic etiology. Moving NGS forward would simplified the diagnostic algorithm

Analysis of the IDS Gene in 38 Patients with Hunter Syndrome: The c.879G>A (p.Gln293Gln) Synonymous Variation in a Female Create Exonic Splicing

BACKGROUND: Hunter syndrome (mucopolysaccharidosis type II, MPS II) is a rare disease inherited in an X-linked autosomal recessive pattern. It is the prevailing form of the mucopolysaccharidoses in China. Here we investigated mutations of IDS (iduronate 2-sulfatase) gene in 38 unrelated Chinese patients, one of which is a female. METHODS: Peripheral leucocytes were collected from the patients and the IDS gene was amplified to looking for the variations. For a female patient, the X chromosome status was analyzed by androgen receptor X-inactivation assay and the mutation impact on RNA level was further performed by reverse transcription polymerase chain reaction. RESULTS: We discovered that point mutations constituted the major form while mutations in codon p.R468 defined the largest number of patients in our cohort. Consistent with data from other ethnic groups, exons 9 and 3 had comparatively more mutations, while exon 2 had quite a few mutations unique to Chinese patients. Of the 30 different mutations identified, only 9 were novel: one was a premature termination mutation, i.e., c.196C>T (p.Gln66X); three were missense mutations, i.e., c.200T>C (p.Leu67Pro), c.215T>C (p.Leu72Pro), c.389C>T (p.Thr130Ile); one was a small deletion, i.e., c.1104_1122del19 (p.Ser369ArgfsX16); and one was a deletion that spanned both exons 8 and 9 deletion leading to gross structural changes in the IDS gene. In addition, a synonymous mutation c.879G>A (p.Gln293Gln) was identified in a female Hunter disease patient, which resulted in loss of the original splicing site, activated a cryptic splicing site upstream, leading to a 28 bp deletion and a premature termination at p. Tyr285GlufsX47. Together with concurrent skewed X-inactivation this was believed to facilitate the development of Hunter disease in this girl. CONCLUSIONS: In conclusion, the molecular analysis of IDS gene in Chinese patients confirmed the Hunter disease diagnosis and expanded the mutation and clinical spectrum of this devastating disorder

Current Status and Prospects of Screening for Newborn Hereditary Metaboolic Disease

Newborn screening is an effective measure for early detection and early treatment of rare genetic diseases. Among the three-level preventive measures to reduce birth defects, newborn screening has a significant preventive effect, and continues to develop with the advancement of new therapies and new technologies. Newborn screening is also relatively more reliable to obtain data on the prevalence of rare diseases. This article introduces the history and current status of neonatal screening for newborn hereditary metabolic disease in China, presents the disease spectrum and prevalence of 7 819 662 cases of neonatal screening by tandem mass spectrometry, and proposes 12 rare diseases as the primary targeting diseases for newborn screening by tandem mass spectrometry in China. At last, the article raises and discusses the issues of requirement for technology development and ethics of newborn screening

Identification of a distinct mutation spectrum in the <it>SMPD1</it> gene of Chinese patients with acid sphingomyelinase-deficient Niemann-Pick disease

<p>Abstract</p> <p>Background</p> <p>Clinical observations and molecular analysis of the <it>SMPD1</it> gene in Chinese patients with acid sphingomyelinase deficiency Niemann-Pick disease (NPD) are scarce.</p> <p>Methods</p> <p>A cohort of 27 Chinese patients diagnosed with acid sphingomyelinase deficiency, within the past five years, were collected and investigated for genotype, phenotype, and their correlations.</p> <p>Results</p> <p>The majority of our patients (25/27) were under 18 years of age. From the cohort group, eight (30%) fulfilled characters of type A. Four other patients experienced neurologic involvement after two years of age, these were classified as intermediate type. The remaining fifteen presented without clear neurologic involvement and were regarded as type B. One patient, from the type B group, presented with the unusual symptom of a secondary amenorrhea. Three patients, one from the type B group and two from the intermediate group, presented with pronounced proteinuria, in the late stages of the disease, indicating possible kidney involvement in NPD. Twenty-four <it>SMPD1</it> gene mutations had been identified; eighteen of these are novel ones. These included four exonic small deletions/duplications (c.4delC, c.147_150del4, c.842-849dup8, c.1307-1312dup6), one termination mutation (p.Glu248X), and thirteen exonic point mutations (p.Gly336Ser, p.Trp342Cys, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser, p.Trp437Arg, p.Thr451Pro, p.His461Pro, p.Ala484Val, p.Ser486Arg, p.Tyr500His, p.Pro533Leu, p.Val559Leu). Notably, eight mutations had more than one occurrence with c.4delC and p.Glu248X accounting for ~30% of all alleles. Correlation analysis of genotype and phenotype indicated eight mutations, c.842-849dup8, p.Glu248X, p.Arg230Cys, p.Trp437Arg, p.His461Pro, p.Ala484Val p.Ser486Arg, and p.Pro533Leu,to be severe mutations. Five mutations, c.4delC, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser and p.Val559Leu were projected to be mild mutations. Interestingly, three intermediate individuals carried combinations of a mild mutation, c.4delC, on one allele and a severe mutation on the other allele.</p> <p>Conclusions</p> <p>The Chinese population may have a comparably high incidence of sphingomyelinase-deficient Niemann-Pick disease type A. This study has identified some novel genotype and phenotype correlations in this rare and devastating disorder.</p

Summary of statistical values of OPLS-DA with different scaling methods for data obtained from LC-MS analyses^a.

a<p>Including the different cumulated modeled variations in X [R²X(cum)] and Y [R²Y(cum)] matrix on spectral datasets and predictability of the model [Q²(cum)].</p

The amino acid and acylcarnitine with a VIP value above 1.0 were identified as markers to discriminate the two comparing group.

<p>The Variables were aligned in descending order of their VIP values. From model A and model B, we can obtain the identified metabolites of BA and NHS. From model C, we can verify these metabolites obtained above can distinguish BA from NHS. From model D, we can exclude the interference of metabolites in hyperbilirubinemia infants.</p

VIP value of the potential metabolites in the differences of NHS and BA^a.

a<p>VIP: The variable importance for projection.</p