Screening and clinical analysis of isovaleric acidemia newborn in Zhejiang province / 浙江大学学报·医学版

OBJECTIVE@#To investigate the incidence,clinical,biochemical and genetic characteristics of isovaleric acidemia (IVA) in Zhejiang province.@*METHODS@#Between January 2009 and December 2019, a total of 3 510 004 newborns were screened for IVA using tandem mass spectrometry. Patients of IVA were confirmed by urine organic acid and @*RESULTS@#A total of 15 patients with IVA were diagnosed, with an incidence of 1/234 000. Three patients had acute neonatal IVA, and the rest were asymptomatic. The isovalerylcarnitine (C5) levels were increased in all patients. Twelve children underwent urinary organic acid analysis, of which 11 cases had elevated isovalerylglycine levels, 4 cases with 3-hydroxyisovalerate increased simultaneously. Eleven IVA patients underwent genetic testing, 9 patients were compound heterozygous variants in @*CONCLUSIONS@#The clinical manifestations of IVA are non-specific, and the gene spectrum is scattered. Newborn patients screened by tandem mass spectrometry can receive early diagnosis and treatment, so as to correct metabolic defects and pathophysiological changes.

Neurocognitive outcome in young child with Isovaleric Acidemia

Isovaleric Acidemia (IVA) is inherited as an autosomal recessive trait, caused by the deficiency of the enzyme isovaleryl CoA dehydrogenase. It has the prevalence of 1 in 62,500 (in parts of Germany) to 1 in 250,000 live births (in the United States). Acute episodes of metabolic decompensations may occur, which may mimic sepsis, ketosis or shock. Early diagnosis & early initiation of treatment has been reported to correlate with a good neurocognitive outcome. This is case of child presenting in Paediatric emergency department with fever, vomiting, increased respiratory activity and lethargy. Child had GCS score of 8/15, acidotic breathing, hypotonia with hyporeflexia. Sepsis screen, metabolic work up and neuroimaging were all normal except for high anion Gap acidosis with ketosis. So further neurometabolic screening work up was done in view of persistent metabolic acidosis, developmental delay, and bad obstetric history in mother. It revealed increased excretion of isovalerylglycine 1(IVG 1), Isovalerylglycine 2 (IVG2) Lactate, 3-Hydroxypropionate (3HP) and 3-Hydroxybutyrate (3 HB).Serum lactate 358.54 (control 1.1-208.1) confirming the diagnosis of Isovaleric Acidemia. After recovery from the acute attack, the patient was advised low-protein diet (1.0-1.5 g/kg/24 hrs.) and carnitine (100 mg/kg/24 hrs. orally) supplements. On follow up child is asymptomatic & showing neurological improvement as he started achieving further developmental milestones during 6 months follow up.Early diagnosis and early treatment of IVA cases definitely results in favorable outcome and better prognosis. But chronic intermittent cases presenting late should not be neglected, proper medical management can reverse neuromotor consequences in them also.

A Rare Case of Inborn Error of Metabolism – Isovaleric Acidemia

Background: Oral cancer being one of the most common malignancies in the low-income group in India. It usually presents in an advanced stage limiting treatment options. The mainstays of treatment being surgery and radiotherapy both being lifestyle changing procedures. Aims and objectives: The purpose of this study is to evaluate the quality of life for oral cancer survivors after surgery in comparison with radiotherapy using ICF questionnaire Materials and methods: Oral cancer patients who underwent surgery (25 patients) and Radiotherapy (25 patients) in Stanley medical college for stage 1 and stage 2 lesions of oral carcinoma for past 3 Years (2013-2015) were enrolled. Results: The study showed that surgery as primary therapy provided a better quality of life than radiotherapy alone in the treatment of oral cancer patients. Conclusion: After comparing the results primary surgery for oral malignancy seems to be the treatment of choice as long as the tumor is amenable to surgical resection. Radiotherapy though resulting in a lower quality of life is very efficacious for unresectable tumors.

A Rare Cause of Recurrent Acute Pancreatitis in a Child: Isovaleric Acidemia with Novel Mutation / 대한소아소화기영양학회지

Recurrent acute pancreatic attacks is a rare clinical condition (2-5% of all acute pancreatis) in children and is mainly idiopathic in most cases. Sometimes it may be associated with congenital anomalies, metabolic diseases or hereditary conditions. Isovaleric acidemia (IVA) is a rare autosomal recessive amino acid metabolism disorder associated with isovaleryl coenzyme A dehydrogenase deficiency presenting the clinical findings such metabolic acidosis with increased anion gap, hyperammonemia, ketonemia, hypoglycemia, “the odor of sweaty feet,” abdominal pain, vomiting, feeding intolerance, shock and coma. Recurrent acute pancreatitis associated with IVA have been rarely reported. Herein; we report a child who admitted with recurrent acute pancreatic attacks and had the final diagnosis of IVA. Mutation analysis revealed a novel homozygous mutation of (p.E117K [c.349G>A]) in the IVA gene. Organic acidemias must kept in mind in the differential diagnosis of recurrent acute pancreatic attacks in children.

Clinical and genetic analysis of two Chinese patients with isovaleric acidemia and review of literature / 中华实用儿科临床杂志

Objective To discuss the clinical features and treatment of isovaleric academia (IVA) patients,and to gain more comprehensive understanding of isovaleryl-CoA dehydrogenase(IVD) mutation in 2 siblings in order to raise awareness to prevent the occurrence of IVA.Methods The clinical history and laboratory test of 2 cases of children with IVA were carried out.The exons and neighboring introns of IVD gene of the whole family were PCR-amplified for DNA sequencing.The literature review of IVA in China was also conducted.Results Organic acid analysis of urine by GC/MS for both siblings showed extremely elevated concentrations of isovaleric glycine.For the older sibling,an acute episode of IVA caused severe metabolic stress and eventually death in the neonatal period.However,the disease was well-controlled for the younger sibling due to timely treatment and follow-up care for 2 years.The DNA sequencing of the IVD gene in the family revealed a novel c.1016G ＞ A(C339Y) heterozygous mutation in mother and both of the siblings.No IVD mutation was detected in father or in any of the 50 cases of healthy controls.According to literature review,15 cases of IVA were reported in recent 15 years in China,including neonatal onset (11 cases),acute episode (12 cases),odor of sweaty feet (12 cases),pancytopenia (9 cases),hyperammonemia (5 cases),hypocalcemia (6 cases),and 6 cases of death were reported.Additionally,5 cases that received treatment of BCAA-free formula milk showed positive outcome.However,only 2 cases were followed up for more than 2 years.Conclusions Two new IVA patients carrying c.1016G ＞ A(C339Y) mutation were reported in China.The mutation may lead to conformational change and functional deficient of the IVD protein.It is also necessary to point out that using direct DNA sequencing can not identify all patients with IVA due to limitations of this technology,and thus clinicians should be aware of the possibility of genetic misdiagnosis.Moreover,there is a trend of increasing IVA in China in recent years.

Encefalopatía metabólica en acidemia isovalérica: Informe de caso / Metabolic encephalopathy in isovaleric academia: Case report

La acidemia isovalérica (AIV) es un trastorno congénito raro (prevalencia 1/105), herencia autosómica recesiva, en la vía metabólica de la leucina. Es causado por la deficiencia selectiva de la enzima mitocondrial isovaleril-CoA deshidrogenasa, la actividad reducida de esta enzima lleva a la acumulación tóxica del ácido isovalérico en el plasma y a un incremento en la concentración urinaria de isovalerilglicina. Han sido reportadas tres formas clínicas de presentación: aguda neonatal, crónica intermitente y una forma lentamente progresiva que puede ser asintomática. Caso clínico: Preescolar femenina de 3 años que ingresa a urgencias pediátricas por vómitos y somnolencia, sin déficit motor ni signos meníngeos; respiración profunda y rápida con olor particular. Historia negativa para trauma, infección o enfermedad metabólica definida. Citoquímica de líquido cefalorraquídeo normal; acidosis metabólica severa, hiperamonemia, disfunción hematológica y hepática motivaron el estudio metabólico, evidenciándose en orina Isovalerilglicina 38.290 mmol/mol creatinina, 3 OH Isovalérico, presente, 3 OH butírico 3.530 mmol/mol creatinina, orientando el diagnóstico a Acidemia Isovalérica. El diagnóstico de Acidemia Isovalérica debe considerarse ante la presencia de vómitos, deterioro neurológico progresivo y/o antecedentes familiares de muerte súbita neonatal. La posibilidad de evitar la mortalidad temprana y mejorar el resultado neurocognitivo por el diagnóstico y el tratamiento precoz favorece el diagnóstico preclínico y refuerza que la AIV sea incluida en el programa de cribado neonatal en Venezuela.

Isovaleric acidemia (IVA) is a rare autosomal recessive inborn error of leucine metabolism (prevalence 1/105) caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase resulting in the accumulation of derivatives of isovaleryl-CoA, the diminished activity of this enzyme leads to toxic accumulation of isovaleric acid in the plasma and an increase in urinary concentration of isovalerylglycine. There have been reported three clinical forms: acute neonatal form, a chronic intermittent form and a slowly progressive form which may be asymptomatic. Case report: We report the case of a 3 years old female with vomiting and drowsiness, sensorineural depression without motor deficit, no meningeal signs, CSF cytochemical normal, fast deep breathing and a "particular smell”, the presence of severe metabolic acidosis, hyperammonemia, hematologic and hepatic dysfunction motivated a metabolic study, showing in urine isovalerylglycine 38.290 mmol / molcreatinine, 3 OH isovaleric present, 3 OH butyric 3.530 mmol / molcreatinine, guiding the diagnosis to Isovaleric acidemia. The diagnosis of Isovaleric acidemia must be considered in the presence of vomiting, progressive neurological deterioration and / or family history of sudden infant death. The possibility of avoiding early mortality and improve neurocognitive outcome for diagnosis and early treatment promotes pre-symptomatic diagnosis and reinforces that IVA is included in the neonatal screening program in Venezuela.

Chronic intermittent form of isovaleric aciduria in a 2-year-old boy / 소아과

Isovaleric aciduria (IVA) is caused by an autosomal recessive deficiency of isovaleryl-CoA dehydrogenase (IVD). IVA presents either in the neonatal period as an acute episode of fulminant metabolic acidosis, which may lead to coma or death, or later as a "chronic intermittent form" that is associated with developmental delays, with or without recurrent acidotic episodes during periods of stress, such as infections. Here, we report the case of a 2-year old boy with IVA who presented with the chronic intermittent form. He was admitted to Asan Medical Center Children's Hospital with recurrent vomiting. Metabolic acidosis, hyperammonemia, elevated serum lactate and isovalerylcarnitine levels, and markedly increased urine isovalerylglycine concentration were noted. Sequence analysis of the IVD gene in the patient revealed the novel compound mutations-a missense mutation, c.986T>C (p.Met329Thr) and a frameshift mutation, c.1083del (p.Ile361fs*11). Following stabilization during the acute phase, the patient has remained in a stable condition on a low-leucine diet.

Continuous Renal Replacement Therapy in a 4-year-old Child with Rhabdomyolysis Following Parainfluenza Virus Infection and Hyperammonemia due to Isovaleric Acidemia

Parainfluenza virus infection is one of the causes of fatal rhabdomyolysis. Rhabdomyolysis can be aggravated by mitochondrial fatty acid beta-oxidation disorders during prolonged periods of fasting. Moreover, in patients with late-onset isovaleric acidemia, hyperammonemia may occur following catabolic stress. In the present report, we describe a case of a 4-year-old boy with parainfluenza virus infection and late-onset isovaleric acidemia that rapidly progressed to coma, seizures, and cardiorespiratory collapse. His serum ammonia and creatinine kinase (CK) levels were 385 microMol/L and 23,707 IU/L, respectively. Continuous renal replacement therapy (CRRT) was initiated using continuous venovenous hemodiafiltration, after which the ammonia and CK levels returned to normal. Thus, we recommend the immediate initiation of CRRT in the management of patients with life-threatening rhabdomyolysis and hyperammonemia.

Isovaleric Acidemia in Siblings Diagnosed by Organic Acid Analysis

Isovaleric acidemia is an inborn error in metabolism due to a defect in isovaleryl-CoA dehydrogenase. Accumulation of serum isovaleric acid causes poor feeding, vomiting, lethargy, hypothermia, convulsion, mental retardation, etc. It is inherited as an autosomal recessive trait. Since the first reports of isovaleric acidemia by Tanaka et al in 1966, more than 60 cases have been reported. There are two clinically different presentations of isovaleric acidemia, with about half the patients presenting with an acute severe neonatal form and about half with a chronic intermittent forrn. The difference in clinical presentation may not be a consequence of differing severities of the causative mutation, but a result of the timing of application of catabolic stress or the ability to form isovalerylglycine. We described here clinical and organic acid analytical findings of brothers with chronic intermittent form of isovaleric acidemia. (J Korean Pediatr Soc 2000;43:828-831)