Actualización sobre la lactancia materna en los recién nacidos con errores innatos del metabolismo intermediario / Update on breastfeeding in newborns with inborn errors of intermediary metabolism

Resumen Los errores innatos del metabolismo intermediario (EIMi) son un grupo de enfermedades monogénicas que afectan alguna vía del metabolismo de las proteínas, los hidratos de carbono o los lípidos; cuando no son tratados a tiempo, se asocian con una elevada morbimortalidad. A la fecha, la piedra angular del tratamiento de los EIMi ha sido la terapia nutricional, cuyo propósito es evitar la acumulación de metabolitos tóxicos al restringir los sustratos que están involucrados en la vía afectada. El manejo nutricional en lactantes incluye una fórmula metabólica sin los nutrimentos involucrados en el EIMi más el aporte de alimentación al seno materno o fórmula infantil. Por el perfil de aminoácidos, la proporción de ácidos grasos esenciales y la protección contra enfermedades, la leche materna resulta un alimento ideal para los pacientes con EIMi. El objetivo de esta revisión de la literatura sobre la lactancia materna en algunos EIMi es servir de guía para el personal de salud involucrado en la atención médica de estos pacientes. La lactancia materna puede ser llevada a cabo de forma exitosa en pacientes con EIMi siempre que exista un seguimiento estrecho y continuo, de preferencia en centros especializados. El profesional de la nutrición y el pediatra deben individualizar las recomendaciones para proporcionar una lactancia a libre demanda en conjunto con una fórmula metabólica o una lactancia materna cuantificada, y con ello lograr una adecuada evolución en estos pacientes.

Abstract Inborn errors of intermediary metabolism (IEiM) are a group of monogenic disorders that affect a metabolic pathway of proteins, carbohidrates, or lipids; when not treated timely, IEiM are associated with high morbidity and mortality. To date, nutritional therapy is the cornerstone of treatment for patients with IEiM, which aims to prevent the accumulation of toxic metabolites by restricting the substrates involved in the affected pathway. Nutritional management in infants includes a metabolic formula free of the nutrients involved in IEiM and breastmilk or infant formula. Because of its amino acid profile, the content of essential fatty acids, and protection against disease, breast milk is an excellent food for patients with IEiM. This literature review on breastfeeding in some IEiM aims to serve as a guide for health care personnel involved in the medical care of these patients. Breastfeeding can be successfully carried out in patients with IEiM as long as there is a close and continuous follow-up, preferably in specialized centers. The nutrition professional and the pediatrician should individualize the recommendations to provide on-demand breastfeeding in conjunction with metabolic formula or quantified breastfeeding to achieve a good clinical evolution in this group of patients.

Case report of living donor liver transplantation for pediatric propionic acidemia combined with dilated cardiomyopathy / 中华实用儿科临床杂志

To analyzed a case of pediatric patient with propionic acidemia combined with dilated cardiomyopathy retrospectively, who underwent living donor liver transplantation at the Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University in March 2019.A 2 years and 6 months female child was admitted to hospital for propionic acidemia.The pretransplant echocardiogram showed left ventricular dilatation and systolic dysfunction, and thus dilated cardiomyopathy was considered.A living donor liver transplant was performed using her mother′s left latera-llobe.On the 14 months postoperatively, the child was on a liberated protein diet, but still required levocarnitine supplementation.Her hepatic and cardiac function returned normal, but growth retardation was still present.During the follow-up period, further propionic acidemia-related complications like metabolic decompensation, or any transplant-related complications were not reported.This case report suggested that liver transplantation is effective on pediatric propionic acidemia combined with cardiomyopathy, which reverses cardiomyopathy, improves cardiac function, relieves strict protein restriction, reduces the risk of metabolic decompensation, and significantly improves quality of life.

Acidemia propiónica: diagnóstico clínico vs. cribado neonatal / Propionic acidemia: clinical diagnosis vs newborn screening

La acidemia propiónica es una rara enfermedad metabólica (prevalencia: 1/100 000), cuya detección puede hacerse de forma precoz mediante el cribado neonatal en las primeras 72 horas de vida. Puede tener una presentación neonatal grave, tardía intermitente o crónica progresiva. El tratamiento de las crisis consiste en la inversión del catabolismo que detiene la ingesta proteica con aporte intravenoso de calorías no proteicas. La mortalidad depende, fundamentalmente, de los episodios de descompensación aguda, mientras que la evolución asocia una alta tasa de secuelas neurológicas y déficits cognitivos.Se presenta el caso de una recién nacida de 11 días de vida con clínica de estancamiento ponderal, letargia, acidosis metabólica e hiperamonemia, que, debido a una falla en el proceso de cribado, no se benefició del diagnóstico precoz.A pesar de la ya existente detección por cribado, es vital mantener un alto índice de sospecha en casos sugestivos de metabolopatías.

Propionic acidemia is a rare metabolic disease (prevalence 1/100,000) that can be early detected with the newborn metabolic screening within the first 72 hours of life. It can have a severe neonatal presentation, a late intermittent onset or a chronic and progressive course. The treatment in the crisis consists in inverting the catabolism by pausing the protein intake and giving intravenous non-protein calories. Mortality depends mainly on acute episodes of decompensation, while evolution and prognosis associate a high rate of neurological sequelae and cognitive deficiencies.We present the case of an 11-day-old female newborn with failure to thrive, lethargy, metabolic acidosis and hyperammonemia that, because of a failed newborn screening process, could not be early diagnosed.In spite of the existence of early detection with the newborn metabolic screening, it is very important to keep a high suspicion in cases that suggest metabolic disorders.

Hallazgos clínicos, bioquímicos y moleculares de la acidemia propiónica / Clinical, biochemical and molecular findings of propionic acidemia

La acidemia propiónica es un trastorno infrecuente con patrón de herencia autosómico recesivo causado por la deficiencia de la enzima mitocondrial propionil-CoA carboxilasa, que convierte el propionil-CoA a D-metilmalonil-CoA. Se expone el caso de un recién nacido masculino con signos de dificultad respiratoria, vómitos y cansancio durante la alimentación. Presentó acidosis metabólica, cuerpos cetónicos en el suero y la orina positivos, hiperamonemia, anemia, trombocitopenia e hipoproteinemia. El estudio bioquímico por cromatografía de gases acoplada a espectrometría de masas en la muestra de orina fue sugestivo de acidemia propiónica. El estudio molecular en el gen PCCA encontró las mutaciones c.893A>G (p.K298R) en el padre y c.937C>T (p.R313X) en la madre. Existe la necesidad de establecer el diagnóstico de esta entidad infrecuente para implementar las medidas terapéuticas disponibles y aportar el oportuno asesoramiento genético.

Propionic acidemia is an infrequent disorder with an autosomal recessive inheritance pattern caused by the deficiency of the mitochondrial enzyme propionyl-CoA carboxylase that converts propionyl-CoA to D-methylmalonyl-CoA. We present the case of a male newborn who showed signs of respiratory distress, vomiting and tiredness during feeding. He presented metabolic acidosis, positive serum and urine ketone bodies, hyperammonemia, anemia, thrombocytopenia and hypoproteinemia. The biochemical study by gas chromatography coupled to mass spectrometry in a urine sample was suggestive of propionic acidemia. The molecular study in the PCCA gene found the mutations c.893A>G (p.K298R) in the father and c.937C> T (p.R313X) in the mother. There is a need to establish the diagnosis of this infrequent entity to implement the therapeutic measures available and provide the appropriate genetic counseling.

Hiperlisinemia Como Hallazgo Sugestivo De Acidemia Propiónica. Reporte De Caso / Hyperlisinemia As A Suggestive Finding Of Propionic Acidemia. Case Report

RESUMEN Introducción: La acidemia propiónica (AP) es una acidemia orgánica (AO) con presentación clínica de inicio neonatal o de forma tardía. Causada por deficiencia de la enzima propionil-CoA carboxilasa que ocasiona acumulación de ácido propiónico y metabolitos relacionados con propionil-CoA en los tejidos. Es característica la hiperglicinemia, pero puede presentarse hiperlisinemia. Este trabajo describe un caso clínico de AP de inicio neonatal con desenlace fatal y alteración llamativa de los aminoácidos. Caso clínico: Recién nacido (RN) femenina ingresa a unidad neonatal al tercer día de vida por hipoactividad, vómito y letargia. Posterior dificultad respiratoria y realiza paros cardiacos, falleciendo antes de establecer un diagnóstico bioquímico. Paraclínicos iniciales evidenciaron acidosis metabólica, leucopenia, hipoglicemia, posteriormente se documenta hiperglicininemia, hipercistinemia y severa hiperlisininemia. La cromatografía de ácidos orgánicos en orina identificó ácido 3-hidroxi-propionico, metilcitrato y propionilglicina entre otros metabolitos tóxicos, confirmando el diagnóstico. Conclusiones: La AP es un error innato del metabolismo autosómico recesivo de baja incidencia. La presencia de acidosis metabólica severa, pancitopenia, hipoglicemia y antecedentes familiares deben alertar sobre este diagnóstico. Adicionalmente, aunque el diagnóstico bioquímico definitivo son los ácidos orgánicos en orina, la presencia de hiperamonemia, hiperglicinemia e hiperlisinemia pueden ser altamente sugestivas de este trastorno.

ABSTRACT Introduction: Propionic acidemia (AP) is an organic acidemia (AO) with clinical presentation of neonatal onset or late. Caused by deficiency of the enzyme propionil-CoA carboxilasa that causes accumulation of propionic acid and metabolites related to propionyl-CoA in tissues. Hyperglycinemia is characteristic, but hyperlysinemia may occur. This work describes a clinical case of AP of neonatal onset with fatal outcome and striking alteration of amino acids. Clinical case: Female newborn (RN) admitted in the neonatal unit on the third day of life due to hypoactivity, vomiting and lethargy. Subsequent respiratory distress and cardiac arrest occurred, dying before a biochemical diagnosis was established. Initial paraclinics evidenced metabolic acidosis, leukopenia, hypoglycemia, later documented hyperglycinemia, hypercystinemia and severe hyperlysinemia. The organic acid chromatography in urine identified 3-hydroxy-propionic acid, methyl citrate and propionylglycine among other toxic metabolites, confirming the diagnosis. Conclusions: AP is an inborn error of autosomal recessive metabolism of low incidence. The presence of severe metabolic acidosis, pancytopenia, hypoglycemia and family history should alert about this diagnosis. Additionally, although the definitive biochemical diagnosis is organic acids in urine, the presence of hyperammonemia, hyperglycinemia and hyperlysinemia can be highly suggestive of this disorder.

Propionic Acidemia with Novel Mutation Presenting as Recurrent Pancreatitis in a Child

Screening, diagnosis and treatment of propionic academia / 中华实用儿科临床杂志

Propionic acidemia or propionic aciduria, is a rare autosomal recessive inherited metabolic disease.It is a metabolic disorder of branched amino acids and odd-chain fatty acids caused by propionyl-CoA carboxylase deficiency, resulting in brain, heart, liver, bone marrow or multi-organ damages leading to disabilities even death.Patients with propionic acidemia have various clinical manifestations.Most patients presented in the neonatal period or early infancy.Nonspecific clinical presentations of the patients make the clinical diagnosis difficult, a definite diagnosis relies on the blood amino acids and acylcarnitines determination, urine organic acids analysis, and gene testing.The treatment for the patients in acute and stable phase should be individualized, including L-carnitine, dietary management, symptomatic intervention and liver transplantation.If not treated timely, patients have a high risk of death and disability.Early screening, diagnosis and treatment can greatly improve the patients′ clinical outcomes.

Screening, diagnosis and treatment of propionic acidemia / 中华实用儿科临床杂志

Propionic acidemia or propionic aciduria,is a rare autosomal recessive inherited metabolic disease.It is a metabolic disorder of branched amino acids and odd-chain fatty acids caused by propionyl-CoA carboxylase deficiency,resulting in brain,heart,liver,bone marrow or multi-organ damages leading to disabilities even death.Patients with propionic acidemia have various clinical manifestations.Most patients presented in the neonatal period or early infancy.Nonspecific clinical presentations of the patients make the clinical diagnosis difficult,a definite diagnosis relies on the blood amino acids and acylcarnitines determination,urine organic acids analysis,and gene testing.The treatment for the patients in acute and stable phase should be individualized,including L-carnitine,dietary management,symptomatic intervention and liver transplantation.If not treated timely,patients have a high risk of death and disability.Early screening,diagnosis and treatment can greatly improve the patients' clinical outcomes.

Newborn screening and gene mutations of patients with propionic acidemia in Xuzhou City / 中国新生儿科杂志

Objective To study the newborn screening program,morbidity,laboratory findings,gene mutations,treatment and follow-up of neonatal propionic academia (PA) in Xuzhou City.Method From September 2015 to September 2018,the blood sample of neonates from newborn screening program in Xuzhou were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) method to examine the blood acylcarnitine level.The diagnosis was confirmed by urine gas chromatography mass spectrometry (GC-MS) and gene analysis.The clinical manifestation,laboratory findings,gene analysis,treatment and prognosis were retrospectively analyzed.Result A total of 297 610 live birth infants blood samples were screened using MS/MS,and 8 cases were diagnosed with PA,with a prevalence of 1∶37 201.Among the 8 patients,7 had no clinical symptoms before the diagnosis and one already had symptoms including recurrent vomiting,drowsiness,tachypnea and hypotonia.Gene analysis revealed that 6 cases carried propionyl-CoA carboxylase α (PCCA) gene mutations and 2 cases carried propionyl-CoA carboxylase β (PCCB) gene mutations.A total of 10 types of PCCA gene mutations were detected,including 5 missense mutations,4 splicing mutations and 1 synonymous mutation,among which 7 were de-novo mutations.A total of 4 types of PCCB gene mutations were detected,including 2 missense mutations,1 frameshift duplication and 1 splicing mutation,among which 3 were de-novo mutations.1 patient died after refusing treatments.The other 7 cases showed significant decline of the blood propionyl-carnitine level,the ratio of propionyl-carnitine to acetylcarnitine,3-OH-propionate and methylcitrate level in urine after treatment.4 cases had normal growth and development,and 3 cases showed various psychomotor retardation on follow-up.Conclusion Newborn screening using LC-MS/MS method is important for early diagnosis of PA.The incidence of PA is relatively high in Xuzhou City.The major clinical manifestations of PA were neurological symptoms.The main cause is PCCA gene defects and missense mutation is most common.

Severe anemia, malnutrition, hypotonia and aggravation of the conscious disturbance, methyl malonic acidemia or propionic acidemia? / 中华实用儿科临床杂志

The patient was a 21 days-old baby girl,admitted to Guangdong Women and Children Hospital because of "poor intake,seldom crying and no activity in 1 day".The major clinical manifestations included hypotonia,aggravation of the conscious disturbance,pancytopenia,intractable acidosis and hyperammonemia,so,inherited metabolic disorders should be considered.Screening of inherited metabolic diseases with blood and urine samples,genetic test and active treatments were carried out.After targeted next-generation sequencing,a novel homozygotic frame shift mutation in PCCB gene:c.838_839insC (L280Pfs * 11) was identified,which was validated by Sanger sequencing.This mutation had not been reported in the mutation database,and bioinformatic analysis of this mutation indicated disease-causing.So,the diagnosis of propionic acidemia was identified.The baby was in a critical condition,and despite active treatment,her conscious disturbance was aggravated,and the spontaneous breathing disappeared.Subsequently,the baby died of pneumonia.Propionic acidemia is a relatively common genetic metabolic disease in newborns.The severity and the clinical phenotypes of propionic acidemia varied,which often made the diagnosis difficult.When the baby is presented with developmental delay,hypotonia,recurrent convulsion and vomiting,etc,which can't be explained by common diseases of children,propionic acidemia may be considered.Next generation sequencing analysis of the complicated cases can easily to pinpoint a disease-causing gene,which lays a solid foundation for accurate diagnosis and treatment of the patients.

Intractable metabolic acidosis in a child with propionic acidemia undergoing liver transplantation: a case report / 대한마취과학회지

Propionic acidemia (PA) is a rare autosomal recessive disorder of metabolism caused by deficient activity of the mitochondrial enzyme propionyl-CoA carboxylase. The clinical manifestations are metabolic acidosis, poor feeding, lethargy, vomiting, osteoporosis, neurological dysfunction, pancytopenia, developmental retardation and cardiomyopathy. Liver transplantation has recently been considered as one of the treatment options for patients with PA. This case report describes several anesthetic considerations for patients with PA undergoing liver transplantation. Understanding the patient's status and avoiding events that may precipitate metabolic acidosis are important for anesthetic management of patients with PA. In conclusion, anesthesia should be focused on minimizing the severity of metabolic acidosis with following considerations: (1) maintaining optimal tissue perfusion by avoiding hypotension, (2) preventing hypoglycemia, and (3) providing bicarbonate to compensate for the acidosis.

Nursing care of 4 children with organic acidemia / 中华护理杂志

Nursing experiences on 4 children with organic acidemia were summarized. The nursing care focused on correct collection of samples for early diagnosis,prompt opening of an effective intravenous route to manage water,electrolyte,acid-base and metabolic imbalances,special medication nursing,strict diet control to prevent relapse,health education to keep normal growth and development. Three children were followed up for 1 month,7 months and 1 year respectively with disease controlled and a child was withdrawn treatment from.

A Case of Propionic Acidemia

Propionic acidemia is an autosomal-recessive inborn error of branched-chain amino acid metabolism. It is caused by deficient activity of propionyl-coenzyme A carboxylase and is characterized by a spectrum of clinical and biochemical findings. It usually manifests in the neonatal period or early infancy. Since Childs et al first described the propionic acidemia of infants in 1961, it has rarely been reported. There have been no previous report of this organic acidemia in Korea. We present a case of propionic acidemia in a 4-day old male, who had poor feeding, dehydration, and hyperammonemia and died at 12 days of age. Diagnosis was established by gas chromatography and mass spectrometry, and this case is the first reported propionic acidemia in literature in Korea. A review of the related literature was included.

A Case of Propionic Acidemia

Propionic acidemia is an autosomal-recessive inborn error of branched-chain amino acid metabolism. It is caused by deficient activity of propionyl-coenzyme A carboxylase and is characterized by a spectrum of clinical and biochemical findings. It usually manifests in the neonatal period or early infancy. Since Childs et al first described the propionic acidemia of infants in 1961, it has rarely been reported. There have been no previous report of this organic acidemia in Korea. We present a case of propionic acidemia in a 4-day old male, who had poor feeding, dehydration, and hyperammonemia and died at 12 days of age. Diagnosis was established by gas chromatography and mass spectrometry, and this case is the first reported propionic acidemia in literature in Korea. A review of the related literature was included.