Clinical characteristics and genetic analysis of a child with Galactosemia due to compound heterozygous variants of GALT gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical features and genetic basis of a child with Galactosemia.@*METHODS@#A child who had presented at the Children's Hospital Affiliated to Zhengzhou University on November 20, 2019 was selected as the study subject. Clinical data of the child was collected. Whole exome sequencing was carried out for the child. Candidate variants were validated by Sanger sequencing.@*RESULTS@#Clinical manifestations of the child have included anemia, feeding difficulty, jaundice, hypomyotonia, abnormal liver function and coagulation abnormality. Tandem mass spectrometry showed increased citrulline, methionine, ornithine and tyrosine. Urine organic acid analysis showed increased phenyllactic acid, 4-hydroxyphenylacetic acid, 4-hydroxyphenyllactic acid, 4-hydroxyphenylpyruvate and N-acetyltyrosine. Genetic testing revealed that the child has harbored compound heterozygous variants of the GALT gene, namely c.627T>A (p.Y209*) and c.370G>C (p.G124R), which were respectively inherited from her healthy parents. Among these, c.627T>A (p.Y209*) was known as a likely pathogenic variant, while c.370G>C (p. G124R) was unreported previously and also predicted as a likely pathogenic variant(PM1+PM2_Supporting+PP3_Moderate+PPR).@*CONCLUSION@#Above discovery has expanded the spectrum of the GALT gene variants underlying Galactosemia. Patients with thrombocytopenia, feeding difficulties, jaundice, abnormal liver function and coagulation abnormality without obvious causes should be analyzed by screening of metabolic diseases in combination with genetic testing.

Clinical profiles and outcomes of the most common inherited metabolic diseases in the Philippines: A review of the National Institutes of Health - Institute of Human Genetics Metabolic Registry

@#<p><strong>OBJECTIVE:</strong> This study reviewed the profiles and outcomes of patients diagnosed to have the five most common inherited metabolic diseases (IMDs) in the Metabolic Registry of the National Institutes of Health - Institute of Human Genetics (NIH-IHG) from 1999 to 2016.</p><p><br /><strong>METHODS: </strong>The medical records of the patients diagnosed with the following inherited metabolic diseases were reviewed: maple syrup urine disease (MSUD), galactosemia, hyperphenylalaninemias (including classical phenylketonuria, mild hyperphenylalaninemia, and pterin defects), mucopolysaccharidoses (MPS), and adrenoleukodystrophy (ALD).</p><p><br /><strong>RESULTS:</strong> There was a total of 567 patients with IMDs, giving a minimum estimated burden of 1.9 per 100,000 livebirths (1:51,760). Clinical presentations were similar to those reported in literature. Majority of the cases of galactosemia and hyperphenylalaninemias presented with a positive newborn screening result. The local prevalence of MSUD and MPS II were higher compared to international data, which may be explained by reported founder mutations among Filipinos. Majority of the patients with IMDs were diagnosed late leading to preventable developmental delay or intellectual disability and death. Majority of patients with MSUD (80.6%) and MPS (94.7%) had intellectual disability or developmental delay. Mortality was 50.5% among patients with MSUD and 100% among patients with adrenoleukodystrophy.</p><p><br /><strong>CONCLUSION: </strong>There is a diversity of IMDs present in the country. A long-term strategic plan, such as the full implementation of the National Rare Disease Act, is foreseen to improve access to comprehensive healthcare and quality of life of patients with IMDs in the country.</p>

Report on the External Quality Assessment Scheme for Metabolite Testing in Korea (2016–2017)

External quality assessment (EQA) trials of conventional newborn screening tests for phenylketonuria, galactosemia, congenital adrenal hyperplasia, maple syrup urine disease, homocystinuria, and congenital hypothyroidism, as well as extended newborn screening tests using tandem mass spectrometry, were performed twice in 2016 and 2017. A total of 44 specimens in the form of dried blood spots were distributed in each trial to 16 laboratories. The response rate of these laboratories was 100%. The mean, standard deviation, coefficient of variation, median, and cut-offs were evaluated for each analyte in the newborn screening tests. EQA trials for the analyses of methylmalonic acid, vanillylmandelic acid, catecholamines, metanephrines, organic acids, and amino acids were also performed. A well-designed EQA program and continuous education would improve the performance of metabolite testing.

Diagnosis of two neonates with galactosemia by using next generation sequencing / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the genetic basis of two neonates suspected for galactosemia.</p><p><b>METHODS</b>Next generation sequencing(NGS) was used to screen the whole exome of the neonates. Suspected mutation was validated by PCR and Sanger sequencing. Potential impact of novel mutation was predicted by using PolyPhen-2, MutationTaste and SIFT software.</p><p><b>RESULTS</b>Both neonates harbored compound heterozygous mutations of the GALT gene inherited from their parents. One has inherited two novel mutations c.564G>C(p.Q188H) and c.116A>T(p.D39V) respectively from his father and mother. The other has inherited mutations c.754C>T(p.Q252X) and c.904+1G>T from her father and mother, respectively.</p><p><b>CONCLUSION</b>The galactosemia in the two neonates may be attributed to compound heterozygous mutations of the GALT gene. This is the first domestic report of using the NGS for the diagnosis of galactosemia.</p>

Clinical, biochemical and molecular profile of variant Galactosemia in children detected by National Newborn Screening: A pilot study

Objective@#The observed irregularities in the biochemical profile and the limited information on long-term outcomes among patients with Duarte variant (D/G) galactosemia have led to patient management variability. This study examined the molecular characteristics of Filipino patients with presumed variant galactosemia for confirmation of diagnosis. It also aimed to describe the corresponding biochemical, clinical and neurodevelopmental profiles in order to gain a better understanding of the patients with normal galactose metabolites in spite of low to absent GALT activity detected by the local newborn screening program. @*Methods@#Thirteen (13) patients who were presumed to have a variant form of galactosemia by national newborn screening between 2002 and 2010, and who previously underwent physical and neurodevelopmental assessment were included in the study. Repeat clinical, ophthalmologic and neurodevelopmental evaluations were done upon recruitment of participants. Direct sequence analysis of the coding region of the GALT gene was conducted to determine the patients’ genotypes. @*Results@#None of the patients’ genotypes were consistent with Duarte variant (D/G) galactosemia. Their genotypes reflect the normal total blood galactose levels in patients, but were inconsistent with the absent or trace GALT activity.@*Conclusion@#Molecular testing for the entire cohort of presumed “variant” galactosemia Filipino patients will provide better profiling of this condition. Re-evaluation and assessment of the current guidelines used by national newborn screening in classifying variant galactosemia are recommended.

Annual Report on the External Quality Assessment Scheme for Biochemical Genetics in Korea (2015)

Two external quality assessment (EQA) trials of conventional newborn screening tests for phenylketonuria, galactosemia, congenital adrenal hyperplasia, maple syrup urine disease, homocystinuria, and congenital hypothyroidism, as well as newborn screening tests using tandem mass spectrometry, were performed in 2015. A total of 44 specimens in the form of dried blood spots were distributed to 16 laboratories and the response rate of these laboratories was 100%. The mean, standard deviation, coefficient of variation, median, and cut-offs were evaluated for each analyte in the newborn screening tests. Two EQA trials for the analyses of methylmalonic acid, vanillylmandelic acid, catecholamines, metanephrines, organic acids, and amino acids were also performed. A well-designed EQA program and continuous education would improve the performance of biochemical genetics tests.

Prevalent congenital anomalies and metabolic disorders among live-born neonates in hospitals in General Santos City, Philippines (2009-2012)

OBJECTIVES: Birth defects are among the leading causes of infant mortality and morbidity in the Philippines. While affected infants make up a sizable portion of live births in General Santos City (GSC), no information is available about their actual numbers. This study aims to fill the knowledge gap about the prevalence and nature of congenital anomalies (CAs) and congenital metabolic disorders (CMDs) in the city from 2009 to 2012. METHODS: A retrospective study of in-patient records from six(6) medical facilities was done for CA/CMD cases from 2009-2012. Among the CMDs tested were congenital hypothyroidism (CH), congenital adrenal hyperlasia (CAH), galactosemia (GAL), hyperphenyalaninemia (HPA), phenylkentonuria  (PKU) and glucose-6-phosphate dehydrogenase deficiency (G6PD def). RESULT: Collected data revealed 109 cases of CAs with limb deformities, oro-facial clefting and neural tube disorders comprising majority of cases. There were 878 reported cases of CMDs with glucose-6-phosphate dehydrogenase deficiency (G6PD def) as the most prevalent at 829 cases. There was also a preponderance of CAs/CMDs in a government hospital for the indigent. CONCLUSION: These result underscore the emergence of CAs and CMDs as a major health problem among newborns in GSC. Higher incidences of birth defects in one district hospital also reveal a tentative link between CA/CMD incidence and socioeconomic status. It is of paramount importance therefore, to undertake expansion of the newborn screening program and to establish local birth registries so that a more comprehensive and realistic picture of CA/CMD prevalence in the city will be obtained.

Food Protein-Induced Enterocolitis Syndrome in a Neonate with Peripheral Epimerase Deficiency Galactosemia

Food protein-induced enterocolitis syndrome (FPIES) is a severe infantile form of non-immunoglobulin E-mediated gastrointestinal food hypersensitivity that manifests as profuse, repetitive vomiting, often with diarrhea, which leads to acute dehydration and lethargy and failure to thrive if chronic. Symptoms such as dehydration and lethargy are also observed in sepsis, viral infection, and food poisoning. It is difficult to differentiate FPIES from sepsis-like illness. The diagnosis is based on clinical criteria and/or an oral food challenge. FPIES developed in the patient with peripheral epimerase deficiency galactosemia after the use of soy formula. The change in feeding to soy formula is not required of a patient with peripheral epimerase deficiency galactosemia. Early intake of soy formula in our patient was harmful. Therefore, we think the changing the formula should be taken carefully. Another important point is the diagnosis. Late diagnosis and misdiagnosis are common, and inappropriate treatment or invasive treatment can occur.

Adultos jóvenes con deficiencia de metilentetrahidrofolato reductasa y aciduria etilenmalónica. Reporte de dos casos y revisión de tema / Female adults with ethylenmalonic aciduria and methylentretrahydropholate reductase deficiency: two cases report and review the literature / Adultos jovens com deficiência de metilentetrahidrofolato reductasa e aciduria etilenmalónica. Reporte de dois casos e revisão de tema

RESUMENLa combinación de la Aciduria etilmalónica y la homocistinuria son desórdenes del metabolismo heredados con un amplio espectro de manifestaciones clínicas que se pueden presentar desde la infancia hasta los adultos mayores. Sin embargo, con la detección temprana de estas enfermedades, en el periodo neonatal, se tendría la oportunidad de mejorar la calidad de vida de los pacientes afectados.

The impact of genomics in clinical medicine has been significant in recent years. Up to 2012, more than 3,000 genetic conditions have been implicated in clinical medicine. Today, with the new methodology of genome sequencing (next-generation sequencing (NGS) and comparative genomic sequencing (CGH), Mendelian conditions have been identified, as well as their role in genetic variations and polygenetic multifactorial disorders that affect the clinical prognosis and response to treatment.The integration of these diagnostic approaches in clinical practice requires an understanding of the basic principles of heredity, genome organization and molecular genetics. Generally, these conditions are single-gene disorders (also known as monogenic disorders), meaning that a single gene mutation is responsible for the disease.The genetic screening test analyzes hundreds of mutations for recessive genetic diseases. This test informs whether or not such mutations are present, which may lead to large-scale genotyping in children using multiple molecular probes.We report two cases of young adult women with symptoms and multiple medical consultations with disease recurrence and uncertain diagnosis, who underwent genetic testing and were determined to be carriers of heterozygous and homozygous mutant ethylmalonic aciduria and methylenetetrahydrofolate reductase deficiency, which could be responsible, in part, for their confusing symptoms.

A combinação da Aciduria etilmalónica e a homocistinuria são desordens do metabolismo herdados com um amplo espectro de manifestações clínicas que se podem apresentar desde a infância até os adultos maiores. No entanto, com a detecção precose destas doenças, no período neonatal, se teria a oportunidade de melhorar a qualidade de vida dos pacientes afetados.

Etiology, clinical spectrum and outcome of metabolic liver diseases in children

To determine the etiology, clinical spectrum and outcome of metabolic liver diseases [MLD] in children admitted in a tertiary care hospital of Eastern India. An observational study. Paediatric Liver Clinic and Paediatrics Inpatient Department of Nilratan Sircar Medical College and Hospital, Kolkata, Eastern India, from April 2009 to March 2011. All children aged 0 - 12 years having characteristic clinical features along with diagnostic hallmark of any MLDs were included in this study and data were collected on a pre-designed proforma. After appropriate management and discharge, all patients were followed-up for next 6 months. Fifty one children with mean age 4.34 +/- 3.78 years [range 2 days - 12 years], male: female ratio 1.55:1, were studied. The etiologies were Wilson's disease [33.33%, n = 17]; glycogen storage disorder [23.53%, n = 12]; galactosemia [19.61%, n = 10]; non-alcoholic fatty liver disease [11.76%, n = 6]; Gaucher disease [5.88%, n = 3]; mucopolysaccharidoses [3.92%, n = 2] and familial hyperlipoproteinemia type-I [1.96%, n = 1]. Jaundice [n = 24] and hepatomegaly [n = 47], was the commonest symptom and sign respectively. Of the 17 non-responders, most were Wilson's disease [n = 7] cases. There was statistical difference in outcome with respect to INR > 1.3 at diagnosis [p = 0.026]. High index of suspicion, early detection and screening, simple dietary modification and cost effective drugs along with good compliance are sufficient to treat and even prevent evolution of most causes of the MLDs

Avaliação econômica em saúde: triagem neonatal da galactosemia / Newborn screening for galactosemia: a health economics evaluation

Este trabalho avalia a eficiência da adição do exame da galactosemia junto ao Teste do Pezinho. Baseado na incidência média estimada de galactosemia, de 1:19.984 recém-nascidos, no Estado de São Paulo, Brasil, este estudo desenvolve um modelo de análise de custo-benefício, utilizando a relação benefício/custo (B/C), a taxa de juros de 9,25 por cento ao ano para descapitalização dos resultados obtidos. Também se realiza uma análise de sensibilidade, em função da variação da taxa de juros entre 0 e 20 por cento e do intervalo de 95 por cento de confiança da incidência da galactosemia (1:7.494 a 1:59.953 recém-nascidos). A economia obtida com a melhora da saúde das crianças doentes identificadas precocemente é superior aos custos (B/C = 1,33), caracterizando como eficiente a política de adição do exame neonatal para galactosemia no Teste do Pezinho. Quanto menor a taxa de juros vigente na economia, mais eficiente é a política de triagem neonatal, não considerados os custos sociais intangíveis evitados.

This study assesses the efficiency of the galactosemia add-on test in neonatal screening performed on regular Guthrie card blood spots. Based on estimated average incidence of galactosemia (1:19,984 newborns) in São Paulo State, Brazil, the study develops a cost-benefit analysis model, using a B/C ratio and a 9.25 percent annual interest rate in order to decapitalize the results. Sensitivity analysis is also performed, varying (as a function of the interest or discount rate) from 0 and 20 percent and according to the 95 percent confidence interval (1:7,494-1:59,953 newborns). The results show that the savings obtained by improved health of galactosemic patients detected early by add-on neonatal screening is superior to the costs (B/C=1.33), characterizing galactosemia add-on testing in neonatal screening as an efficient policy. The lower the prevailing interest rate in the economy, the more efficient the neonatal screening policy.

Generalized epimerase deficiency galactosemia.

Galactosemia is caused by inherited deficiencies in one of three enzymes involved in the metabolism of galactose: galactose- 1-phosphate uridyltransferase (GALT), galactokinase (GALK), and uridine diphosphate galactose-4-epimerase (GALE). The rarest and most poorly understood form of galactosemia is due to epimerase deficiency. We are reporting such a rarest form of galactosemia presenting with progressively increasing cholestatic jaundice and failure to thrive at one month of age. After confirmation of decreased epimerase level in RBC hemolysate, the patient was put on galactose restricted diet and vitamins supplementation, which reversed the clinical signs as well as altered liver function. Patient is on regular follow-up and now at 15 months of age he has no marked developmental delay.

Association of fungal sepsis and galactosemia.

Galactosemia is one of the rare inborn errors of metabolism, which if detected early can be treated effectively. Galactosemic infants have a significant increased risk of developing sepsis. E. coli sepsis is a known entity, and also an important cause of early mortality in these children. But fungal sepsis in these patients is rarely reported. Here is a case of 45 day-old child who presented with fungal sepsis, which on investigation turned out to be galactosemia.

A Case of Infantile Hepatic Hemangioendothelioma Incidentally Detected during the Evaluation of Galactosemia

Galactosemia is a group of inherited enzyme deficiencies characterized by increase in the blood galactose levels. This condition may be associated with deficiencies of galactose-1-phosphate uridyl transferase, galactokinase, or uridine diphosphate galactose-4-epimerase. However, the elevated galactose identified by neonatal screening tests has several other possible etiologies, including hepatic hemangioendothelioma, hepatic hemangioma, and patent ductus venosus with hypoplasia of the portal vein. We report a 13-day-old Korean male with hepatic hemangioendothelioma, which was incidentally detected during the evaluation for suspected galactosemia. Laboratory studies revealed that mildly elevated levels of galactose, galactose-1-phosphate and alpha-fetoprotein, at the time of admission, were gradually decreased to the normal range over the 6 months of observation. Ultrasonography showed a well-defined heterogeneous hypoechoic mass in the liver, and magnetic resonance imaging study showed multiple enhanced mass lesions, which was compatible with the diagnosis of a hepatic hemangioendothelioma. Thus, hepatic imaging, especially ultrasonography, should be performed if neonatal screening suggests galactosemia.

Annual Report on External Quality Assessment in Metabolic Disorders in Korea (2009) / 임상검사와정도관리

Two trials of external quality assessment for conventional newborn screening tests for phenylketonuria, congenital hypothyroidism, galactosemia, maple syrup urine disease and homocytinuria and for the newborn screening tests using tandem mass spectrometry (MS/MS) were performed in 2009. Total 20 specimens were distributed to 13 laboratories. All the control materials were send as dried blood spots. The response rate was 100%. The mean, SD, CV, median and range were analyzed. In addition, two trials of external quality assessment for glycohemoglobin (HbA1c) were performed in 2009. Total 6 samples were distributed to 196 laboratories and the response rate was 97.2% (175/180) and 98.5% (193/196) in each trial. From this trial, we performed accuracy-based survey which used challenge specimens that were free from matrix effects and had target values traceable to certified reference material. Bias between each participants result and reference target value were evaluated.

Galactosemia with chorea--an unusual presentation.

Galactosemia, an inborn neurometabolic disorder, results from an aberrant galactose metabolism due to the deficiency of serum galactose-1-phosphate uridyltransferase activity. It manifests in the central nervous system in the form of hypotonia, seizures, mental retardation, tremor, ataxia, and progressive cerebellar as well as extrapyramidal features. To the best of our knowledge, chorea due to galactosemia has not been reported in infancy.

Screening for phenylketonuria and galactosemia among Egyptian newborns in Menoufiya governorate

Was to study the prevalence of phenylketonuria and galactosemia in Menoufiya Governorate newborns. Among 3000 newborns, their mean ages were 9.3 +/- 2.43 days; mean weight was 3.1 +/- 0.82 Kg. Among them 1800[60%] males and 1200 [40%] females who attended the central hospital and medical units for BCG vaccination in the duration from March 2005 to May 2008. The results showed that the mean of phenylalanine level was 3.19 +/- 1.82 mg/dl and the mean total galactose level was 3.34 +/- 2.23mg/ dl, among the 3000 neonates, 2183 [72.8.%] had phenylalanine levels ranging from 2-5 mg /dl, 705 [23.5%] had levels ranging from 5-7 mg/dl, 111[3.7%] had levels ranging from 7-10 mg/dl and one newborn [0.033%] had phenylalanine level of 22 mg/dl. The results for galactosemia screening assay showed that 2528 neonates [84.3%] had galactose levels ranging from 2-6 mg/dl, 450 [15%] had levels ranging from 6-8 mg/dl, 21[0.7%] had levels ranging from 8-12 mg/dl and one newborn [0.033%] had galactose level of 19 mg/dl. The child was reassayed and was found to be true hypergalactosemia l20mg/dl. We concluded that the prevalence of each of phenylketonuria and galactosemia in Menoufiya Governorate in the 3000 newborn tested was 1/3000 [0.03%]. So, we estimate that about 333 neonates are affected every year with PKU and 333 with galactosemia as one million babies are born yearly, which could be prevented. The prevention of such treatable disorders depends on planning an efficient screening programme especially within three weeks after birth. So we recommend multicenter studies to encourage national neonatal screening programmes specialy for these treatable diseases

Hepatomegaly: a major clinical sign in some metabolic disorders

This study included 18 cases with hepatomegaly referred to the Human Genetics Department, National Research Centre with a suspicion of a metabolic disorder from 2006 to 2008. The aim of our study was to find out the importance of hepatomegaly as sign for many metabolic disorders and their frequency among other disorders with hepatomegaly. All cases were subjected to clinical and biochemical studies. 12 cases, 66%, [10 males 83.4% and 2 females 16.6%] were diagnosed with a metabolic disease. 8 cases with mucopolysaccharidosis [MPS] [3 cases MPS I, 3 cases MPS II, one case MPS III and one case MPS VI]; one case with glycogen storage disease [GSD]; one case with galactosemia and 2 cases with Niemann-Pick disease type C. 75% of the diagnosed cases showed positive consanguinity and the remaining 25% were three patients with MPS II with an X linked mode of inheritance

Cost-benefit analysis of the newborn screening program of the Philippines

BACKGROUND: Newborn Screening (NBS) is a public health activity aimed at the early identification of infants who are affected by certain genetic/metabolic/infectious conditions. A cost analysis is critical for national implementation for integration as a public health program. OBJECTIVES: 1) To determine the incidence rates of congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH), galactosemia (GAL), phenylketonuria (PKU) and glucose-6-phosphate dehydrogenase (G6PD) deficiency; and 2) To determine whether NBS is cost-beneficial for each disorder individually or in combination, from a societal perspective. STUDY DESIGN: Cross sectional survey and cost-benefit analysis. SUBJECTS AND METHODS: The study was conducted through a screening survey of the original 24 Metro Manila hospitals. Newborns were screened for CH, CAH, GAL, PKU and G6PD deficiency after the 24th hour of life. Those who screened positive underwent serum confirmatory testing. Using incidence rates from the screening survey, a population of 1.5 million, and different screening combinations, the costs for the detection and treatment of the five disorders were compared to the benefits projected from preventing the corresponding complications and consequent productivity losses. For economic evaluation, we compared sequential analysis of doing tandem/multiple testing for the different disorders vs a "do-nothing" alternative. Sensitivity analyses for different incidence and discount rates were conducted to test the strength of the conclusions. RESULTS: The incidences of the disorders with 95% confidence intervals are: CH is 1:3 235 (1:2 219 - 1:5 946); CAH is 1:7 455 (1:4 046 - 1: 14245); GAL is 1: 106 006 (1: 44 218-1:266 796); and G6PD deficiency is 1:167 (1:151 - 1: 186). Screened individually, CH and G6PD deficiency had net benefits of US$ 5.29 M and US$ 15.44 M, respectively. The other conditions yielded net costs when screened individually - CAH (US$ 2.61 M), GAL (US$ 0.90 M) and PKU (US$ 6.74 M). Pairing the disorders with CH showed the following benefit:cost ratios - CH + CAH, 1.3; CH + GAL, 2.0; CH + G6PD deficiency, 3.4; and CH + PKU, 0.9. Combining disorders resulted in the following benefit:cost ratios - CH + CAH + GAL, 1.2; CH + CAH + GAL + PKU, 0.8; and CH + CAH + GAL + G6PD deficiency, 2.1. Screening for the 5 disorders in tandem resulted in a benefit:cost ratio of 1.4 and a net benefit of US$ 11.42 M.