Cerebellar hemorrhage complicating isovaleric acidemia

Fischer, Asma Q.; Challa, Venkata R.; Burton, Barbara K.; McLean, William T.

doi:10.1212/wnl.31.6.746

Cited by 38 publications

(16 citation statements)

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“…Pancytopenia as well as isolated neutropenia and thrombocytopenia can occur due to bone marrow suppression [Kelleher et al, 1980]. Left untreated, patients may progress to coma and death often due to cerebral edema or hemorrhage [Fischer et al, 1981]. Overall, the clinical picture overlaps other organic acidemias including the β-oxidation defects as well as the urea cycle disorders and other primary causes of hyperammonemia, all of which must therefore be considered in the differential diagnosis.…”

Section: Clinical Presentationmentioning

confidence: 99%

Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity

Vockley

Ensenauer

2006

American J of Med Genetics Pt C

192

161

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Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of derivatives of isovaleryl-CoA. It was the first organic acidemia recognized in humans and can cause significant morbidity and mortality. Early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine are effective in promoting normal development in severely affected individuals. Both intra-and inter-familial variability have been recognized. Initially, two phenotypes with either an acute neonatal or a chronic intermittent presentation were described. More recently, a third group of individuals with mild biochemical abnormalities who can be asymptomatic have been identified through newborn screening of blood spots by tandem mass spectrometry. IVD is a flavoenzyme that catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. Human IVD has been purified from tissue and recombinant sources and its biochemical and physical properties have been extensively studied. Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. One missense mutation, 932C>T (A282V), is particularly common in patients identified through newborn screening with mild metabolite elevations and who have remained asymptomatic to date. This mutation leads to a partially active enzyme with altered catalytic properties; however, its effects on clinical outcome and the necessity of therapy are still unknown. A better understanding of the heterogeneity of this disease and the relevance of genotype/phenotype correlations to clinical management of patients are among the challenges remaining in the study of this disorder in the coming years.

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Section: Clinical Presentationmentioning

confidence: 99%

Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity

Vockley

Ensenauer

2006

American J of Med Genetics Pt C

192

161

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“…Metabolic acidosis with mild to moderate ketonuria and lactic acidemia is typical and there is a significant hyperammonemia. Thrombocytopenia and neutropenia [Beauvais et al, 1985;Fischer et al, 1981;Newman et al, 1967] and pancytopenia [Hou and Wang, 1990;Kelleher et al, 1980] are common, as is hypocalcemia [Fischer et al, 1981;Newman et al, 1967]. The typical cause of death is severe metabolic acidosis, cerebral edema, hemorrhage [Fischer et al, 1981;Mendiola et al, 1984;Truscott et al, 1981], or infections.…”

Section: Discussionmentioning

confidence: 99%

“…Thrombocytopenia and neutropenia [Beauvais et al, 1985;Fischer et al, 1981;Newman et al, 1967] and pancytopenia [Hou and Wang, 1990;Kelleher et al, 1980] are common, as is hypocalcemia [Fischer et al, 1981;Newman et al, 1967]. The typical cause of death is severe metabolic acidosis, cerebral edema, hemorrhage [Fischer et al, 1981;Mendiola et al, 1984;Truscott et al, 1981], or infections. If the patient survives the acute neonatal episode, the subsequent course is that of the chronic intermittent form [Cohn et al, 1978;Kelleher et al, 1980;Wilson et al, 1984].…”

Section: Discussionmentioning

confidence: 99%

Newborn infant with lethargy, poor feeding, dehydration, hypothermia, hyperammonemia, neutropenia, and thrombocytopenia

et al. 2000

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History on admission. A.P. was a 10-day-old Hispanic girl, admitted to the hospital because of a 3-day history of lethargy and increased sleeping. For one day, there was also inadequate feeding and low body temperature. There was no history of irritability or crying episodes, runny nose, cough, respiratory distress, apnea, or cyanosis. Vomiting and diarrhea were not present and there was no history of bloody stools. The mother stated that the infant was apparently voiding well.The infant was born at term, after an uneventful pregnancy, with a normal spontaneous vaginal delivery. Apgar scores were 8 at 1 minute and 9 at 5 minutes. Birth weight was 3.2 kg, length 47 cm, and head circumference 34 cm. Examination in the nursery on admission and on discharge revealed no morphological anomalies. Mother's rapid plasma reagin (RPR) and human immunodeficiency virus (HIV) were nonreactive, and there was no history of alcohol or other drug use. The infant was Type O+, and Coombs test was nonreactive. Mother and infant were discharged after two days. There were no pets at home. The mother was a smoker. There were three sibs, ages 9, 3, and 1 and 3/12 years. Family history was unremarkable.Before admission, the patient was receiving a diet of Similac 20 with iron, 2-3 ounces every three hours, which she accepted well until the day prior to admission.Physical examination on admission. Weight was 3.14 kg; temperature 35°C; pulse 112; respirations 20; and BP 114/63 mmHg. The infant was in no acute distress, was sleeping but arousable. The anterior fontanel was open and wide. The pharynx was normal, with no evidence of oral candida. Ear drums were normal. Pupils were equal and reacted to light and accommodation. Lungs were clear to percussion and auscultation, and there was no respiratory distress. The heart had a regular rate and rhythm and there were no murmurs. The abdomen was soft; no masses were palpable; the umbilicus was still crusted, but dry. Genitalia were normal for age. No skin rashes or petechiae were noted. Reflexes were present and normal.Laboratory findings on admission. Findings are shown in Tables I and II. The patient was dehydrated, leukopenic, and thrombopenic. A spinal tap was bloody (Table III).Course in hospital. On admission to the PICU, the patient was rehydrated intravenously. After culture of blood for sepsis, she was treated empirically with ampicillin and gentamicin. Her condition improved, and she was started on infant formula on day 3. Within 12 hours, she became hypothermic, hypotensive, and acidotic. She was given IV fluids and transfused with blood and platelets. Platelet count again fell rapidly.Her condition remained poor. She was poorly rousable, arid, and had poor Moro and sucking reflexes. Blood ammonia was 385 UM/L on day 7. Immunoglobulins (Table III) were normal. Serum free and total carnitine were reduced. Urinary carnitine esters were 80% of total. Additional studies were ordered.A bone marrow examination carried out because of the neutropenia and thrombocytopenia showed arrest of myel...

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“…There is also a report of a patient with IVA with promyelocytic myeloproliferative syndrome [6,7]. In patients with IVA, hematologic problems are usually reported in early infancy [1,2,6]. Compatible with this, no patients have been reported in the English literature with IVA diagnosed later in childhood with neutropenia, thrombocytopenia or pancytopenia.…”

Section: To the Editormentioning

confidence: 99%

“…In the acute phase of this disease, thrombocytopenia, neutropenia or pancytopenia may be common features [1][2][3][4]. However, the physiopathology of the bone marrow suppression in this disease is still unclear.…”

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confidence: 99%

Late onset of isovaleric acidemia presenting with bicytopenia

Malbora¹,

Avcı²,

Hasanoğlu³

et al. 2010

Turk J Hematol

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Isovaleric academia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase. In the acute phase of this disease, thrombocytopenia, neutropenia or pancytopenia may be common features [1][2][3][4]. However, the physiopathology of the bone marrow suppression in this disease is still unclear. Here, we report the case of an IVA patient who presented with thrombocytopenia and neutropenia at the age of 31 months.A 31-month-old male patient had been admitted to our hospital with fever, vomiting, fatigue, and loss of appetite. There was no history of any drug use. On physical examination, the patient was lethargic. Vital signs were normal except for mild tachycardia and tachypnea. Skin turgor and tonus were found to be decreased.The results of a complete blood count revealed the following: white blood cells (WBC) count 1.4x10 9 /L; absolute neutrophil count 0.92x10 9 /L; hemoglobin 11 g/dl; and platelet count 57.5x10 9 /L. The bone marrow aspiration showed normal maturation of three lineages without any hemophagocytosis, megaloblastic cells, extramyeloid cells, fatty changes, or myelodysplasia. There were numerous necrotic cells. The number and the morphology of megakaryocytes were normal. In the aspiration smear, 18% myelocyte, 35% metamyelocyte, 11% polymorphonuclear leukocyte, 28% lymphocyte, 2% normoblast, 1% monocyte, 1% eosinophil, and 4% lymphoblast-like cells were present. Bone marrow flow cytometry did not reveal lymphoblasts. Biochemical analyses were within normal limits except for hypocalcemia, hyperammonemia, and mildly increased aspartate aminotransferase and lactate dehydrogenase. Serum C-reactive protein and erythrocyte sedimentation rate were in normal range. Ketonuria was determined. The results of blood, throat, urine, stool, and cerebrospinal fluid cultures were negative. Viral serology of the cerebrospinal fluid and serum were also negative. Serum Brucella agglutination and Salmonella agglutination were negative. Serum lactate and pyruvate levels were 4 mmol/L (normal range: 0.7-2.1 mmol/L), and 2.74 mg/dl (normal range: 0.3-1 mg/ dl), respectively. The urine organic acid examination showed that the excretions of isovaleryl glycine and methyl malonic acid were significantly increased: 1299 mmol/mol creatinine (normal: 0 mmol/mol creatinine) and 42.7 mmol/mol creatinine (normal: 0 mmol/mol creatinine), respectively. Tandem mass spectrometry of spot serum, free carnitine and amino acid profiles were normal. There was an increase in the isovaleryl and 3-OH butyryl carnitine levels, whereas there was a decrease in the levels of acetyl, propionyl, and palmitoylcarnitine. Lymphocyte isovaleryl-CoA dehydrogenase activity was 0.02 nmol/min.mg [controls mean±SD: 1.51±0.31 nmol/min.mg].We initiated antibiotic therapy and protein-poor diet. Carnitine and L-glycine were added to the treatment. During this period, his laboratory examination revealed WBC count of 0.64x10 9 /L (absolute neutrophil count, 0.43x10 9 /L

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Cerebellar hemorrhage complicating isovaleric acidemia

Cited by 38 publications

References 0 publications

Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity

Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity

Newborn infant with lethargy, poor feeding, dehydration, hypothermia, hyperammonemia, neutropenia, and thrombocytopenia

Late onset of isovaleric acidemia presenting with bicytopenia

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