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The Pancytopenia of Isovaleric Acidemia
Pediatrics
Abstract
Severe pancytopenia developed in two infants with isovaleric acidemia. Previous reports indicate these hematologic abnormalities are a leading cause of death in affected infants. Our findings suggest that the pancytopenia may be due to arrested maturation of hematopoietic precursors. Prompt transfusion of appropriate blood components prevented complications due to the hematologic abnormalities.
... 22 In IVA, bone marrow suppression due to arrested maturation of hematopoietic precursors can result in pancytopenia as well. 23 Pediatricians should consider HLH if other features like persistent fever, organomegaly and laboratory abnormalities suggestive of HLH develop in addition to pancytopenia. 22,23 Bone marrow examination is important to confirm the diagnosis. ...
... 23 Pediatricians should consider HLH if other features like persistent fever, organomegaly and laboratory abnormalities suggestive of HLH develop in addition to pancytopenia. 22,23 Bone marrow examination is important to confirm the diagnosis. 22 In our patient with IVA, HLH was triggered by adenovirus, and he was managed with steroids and cidofovir for few weeks and he got better. ...
... 22 In our patient with IVA, HLH was triggered by adenovirus, and he was managed with steroids and cidofovir for few weeks and he got better. 23 In a country with high rates of consanguineous marriage like Oman, where familial HLH and other genetic predisposition to HLH may not be rare, distinguishing between these primary and secondary categories is of utmost importance. 6 A screening protocol of flow cytometry for perforin, XIAP and SAP expression, in addition to CD107a degranulation assay can capture primary HLH cases and it should be done for all the cases of HLH regardless of the age. ...
Background:
Little is known about viral-associated hemophagocytic lymphohistiocytosis (HLH) in Oman. This study was done to assess the epidemiology, clinical features and outcome of viral-associated HLH in our setting.
Methods:
We retrospectively reviewed children (0-18 years) managed for viral-associated HLH at the Sultan Qaboos University Hospital, Oman, over a 15-year period (2006-2020). Patients' medical records were used to describe their demographic, clinical and laboratory features, management and outcome.
Results:
Fifty-six children were managed for HLH at Sultan Qaboos University Hospital over the last 15 years (2006-2020) of whom a third (19; 34%) had a viral trigger. The median age at the time of diagnosis of viral-associated HLH was 83 (13-96) months. Fever, cytopenia, hyperferritinemia and evidence of hemophagocytosis in bone marrow were the most consistent findings. Most of these children had either genetic predisposition to HLH (8/19; 42%) or underlying immunodeficiency secondary to malignant conditions or chemotherapy/hematopoietic stem cell transplantation (6/19; 32%). Epstein-Barr virus (9; 47%) followed by cytomegalovirus (6; 31%) was the most common viral trigger in our setting. Treatment included antivirals (8; 42%), HLH 2004 protocol (4; 21%), rituximab (4; 21%) and hematopoietic stem cell transplantation (3; 16%). Fourteen children (74%) had full recovery.
Conclusions:
In our small cohort, viral-associated HLH was more frequently encountered in children with genetic predisposition to HLH or children with underlying immunodeficiency. In addition, we found that the outcome is overall good for children who have no genetic predisposition to HLH and children with genetic predisposition who underwent hematopoietic stem cell transplantation.
... Isovaleric aciduria, first described in 1966 by Tanaka et al. (1) was subsequently detected in numerous cases (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). It is an inborn error of metabolism due to a defect of isovaleryl-CoA dehydrogenase (E.C. 1.3.99.10) (19). ...
... The authors suggested that age of onset and the severity of clinical presentation were not caused by differences in impaired isovaleryl-CoA dehydrogenase, but by the competency of the glycine-N-acylase pathway to use accumulated isovaleric acid (24). When [2][3][4][5][6][7][8][9][10][11][12][13][14]C-leucine conversion to I4CO2 by intact cells was used as the enzyme assay, less than 2% residual activity was seen in acute isovaleric acidemia (25). Comparisons of clinical phenotype using this assay are not published. ...
... During the first categories: acute and chronic intermittent (1 8). The acute form month of life she required a diluted formula because full-strength (2)(3)(4)(5)(6)(7)(8) presents during the first days of life with poor feeding, formula resulted in vomiting, imtability, and diarrhea. Her tachypnea, and vomiting. ...
Although dietary leucine restriction and supplemental glycine are used to treat patients with isovaleric acidemia [deficient isovaleryl-CoA-dehydrogenase (E.C.1.3.99.10)], little quantitative information is available regarding their optimum relationship. Herein we compare different glycine supplements and quantitate isovalerylglycine produced in two patients with clinically different forms of isovaleric acidemia during restricted leucine intake and during oral leucine loading. We found that under stable conditions of leucine restriction, 150 mg glycine/kg/day is an optimum glycine supplement and that glycine supplements of more than 250 mg/kg/day may result in reduced isovalerylglycine production; that when isovaleric acid accumulation is increased, glycine supplements to 600 mg/kg/day will increase isovalerylglycine production; and that the phenotype of isovaleric acidemia is related not only to the extent of impaired isovaleryl-CoA dehydrogenase, but also the ability to detoxify accumulated isovaleryl CoA to isovalerylglycine.
... 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. ...
... 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]. The chronic intermittent form of isovaleric acidemia is usually manifested during the first year of life with episodes of vomiting, lethargy progressing to coma, aci-dosis with ketonuria, and the characteristic odor of sweaty feet. ...
... Therefore, avoiding antibiotics containing pivalate, which can increase acylcarnitine levels is recommended (26). It has also been reported that pancytopenia, isolated neutropenia and thrombocytopenia can occur due to bone marrow suppression (33). ...
Oral/dental surgical care in patients with chronic medical comorbidities, such as isovaleric acidemia (IVA), can be challenging. In addition to technical complications, different comorbidities also present a complex range of concerning factors/challenges, which can increase the incidence of morbidity and mortality associated with surgery. IVA, a congenital error of metabolism, is a rare organic acidemia with a predisposition towards acute acidosis and life-threatening metabolic decompensation during stressful conditions, such as prolonged fasting and surgery. In addition, schizophrenia, a major neurological disorder, can result in manifestation of severe dental or periodontal conditions, including pericoronitis. The condition is associated with significant risk factors of postoperative complications, such as dangerous behaviors and adverse interactions between antipsychotic drugs and anesthetic agents. A case of comorbid dental disease with two coexisting chronic and life-threatening medical conditions, one of which is rare, is an unusual encounter in oral/dental surgery that is seldomly published. Moreover, implementing a safe and effective surgical intervention in such patients requires several informed considerations. However, only a few reported experiences or guidelines exist, reporting appropriate perioperative management strategies to minimize risks. Hence, in this case report, our experience of managing one of these rare encounters of a 20-year-old man who suffered from bilaterally partially erupted third molars, associated with chronic pericoronitis and dental caries of both the maxilla wisdom teeth with coexisting IVA and schizophrenia comorbidities is described. Additionally, the presentation and anticipated complications of the comorbid disorders of the patient are briefly reviewed. In this case, the pericoronitis and dental caries were treated by surgically removing the impacted third molars and the antagonist maxilla wisdom teeth under regional anesthesia and application of antibiotics for 3 days. The patient recovered without any postoperative complications after 1 year of follow-up.
... Although the clinical syndrome of isovaleric acidemia is dominated by the neurologic findings, haematologic abnormalities are frequent. 58,59 Also, the unpleasant odour of IVA in urine is typical. Our study may provide some molecular mechanisms to explain the clinical phenotype of isovaleric acidemia. ...
Osteoclasts (OCs) play important roles in bone remodelling and contribute to bone loss by increasing bone resorption activity. Excessively activated OCs cause diverse bone disorders including osteoporosis. Isovaleric acid (IVA), also known as 3‐methylbutanoic acid is a 5‐carbon branched‐chain fatty acid (BCFA), which can be generated by bacterial fermentation of a leucine‐rich diet. Here, we find that IVA suppresses differentiation of bone marrow‐derived macrophages into OCs by RANKL. IVA inhibited the expression of OC‐related genes. IVA‐induced inhibitory effects on OC generation were attenuated by pertussis toxin but not by H89, suggesting a Gi‐coupled receptor‐dependent but protein kinase A‐independent response. Moreover, IVA stimulates AMPK phosphorylation, and treatment with an AMPK inhibitor blocks IVA‐induced inhibition of OC generation. In an ovariectomized mouse model, addition of IVA to the drinking water resulted in significant decrease of body weight gain and inhibited the expression of not only OC‐related genes but also fusogenic genes in the bone tissue. IVA exposure also blocked bone destruction and OC generation in the bone tissue of ovariectomized mice. Collectively, the results demonstrate that IVA is a novel bioactive BCFA that inhibits OC differentiation, suggesting that IVA can be considered a useful material to control osteoclast‐associated bone disorders, including osteoporosis.
... As far as IVA clinical course is concerned, metabolic decompensations are the most serious complication. Laboratory investigations show metabolic acidosis and ketoacidosis, hyper-or hypoglycemia (especially in neonatal period), hyperglycinemia (inhibition of glycine degradation), hyperammonemia (inhibition of the urea cycle), neutropenia, or pancytopenia (bone marrow suppression) [7,8]. Since acute metabolic decompensation is almost always precipitated by a stressor, it is important to identify and eliminate it [9]. ...
Isovaleric acidemia (IVA) is an autosomal recessive leucine inborn error of metabolism caused by isovaleryl-CoA dehydrogenase deficiency. The disease has various courses, from severe ones manifesting in newborns to the intermittent form with first manifestation in children and adults. The aim of this study was to analyze clinical and neurological outcomes in Polish patients with IVA. Ten patients diagnosed and treated in The Children’s Memorial Health Institute were included in the study. The diagnosis was based on tandem MS (increased level of C5 acylcarnitine) and urine GCMS (increased isovalerylglycine, and 3-hydroxyisovaleric acid). Molecular analysis was performed in seven patients (70%) leading to the detection of pathogenic variants in the IVD gene in all of them. A retrospective analysis of patients’ medical records included: demographics, symptoms at diagnosis, medical management, and biochemical and clinical outcomes following therapy. The median follow-up time (median; Q1–Q2) was 2.5 years (1.5–9.0) for newborn screening (NBS) and family screening (FS) children, and 17 years (5.0–20) for symptomatic patients. Five patients were in a good clinical state, four children presented mild neurological symptoms, and one—severely delayed child. In the IVD gene, five known and two novel variants (p.466C>G, c.1132G>A) were identified. Molecular analysis was performed in seven patients leading to identification of biallelic pathogenic variants in the IVD gene in all of them. We can conclude that long-term clinical and neurological outcomes of patients with IVA were satisfactory as a result of an early diagnosis and proper management. Although early treatment did not prevent decompensations, they were milder in these patients.
... The laboratory findings were metabolic acidosis, hyperammonemia, hyper-or hypoglycemia, and hypocalcemia. Pancytopenia, due to bone marrow suppression, could occur as well as isolated neutropenia, and thrombocytopenia (16,17,22). ...
Isovaleric Acidemia (IVA) is an autosomal recessive Inborne Error of Metabolism (IEM), i.e., caused by the mutation of isovaleric-CoA dehydrogenase. Two phenotypes of IVA are reported; acute and chronic.
The case was a 3-year-old boy with chronic intermittent presentation. Elevated 3-hydroxybutyric acid and isovaleric glycine in urinary acid profile was reported. We also performed a brief review about the presented case; IVA in international databases for English language articles on children.
Several manners exist to screen IVA patients and the best one is GC-MS in urine analysis. The prognosis of the disease depends on the early interventions.
... Kellehe et al. reported severe pancytopenia in two infants with IVA which could be the toxic effect of organic acids on hematopoietic cells and secondary hemophagocytic syndrome [6]. In our patient, neutropenia and profound thrombocytopenia were observed. ...
... Pancytopenia, thrombocytopenia and neutropenia can lead to severe haemorrhage or infection. In bone marrow of IVA patients a maturation arrest of precursor cells can be found for which the cause is obscure (Kelleher et al., 1980). Methylmalonic Aciduria (MMA) and Propionic aciduria (PA) are two more frequent OADs that cause high amounts of organic acid to accumulate in the body. ...
... We hypothesize Hematologic problems can be seen in patients with inborn errors of branched-chain amino acid metabolism. Various cytopenias, attributed to the toxic effect of organic acids on hematopoietic cells and secondary heamophagocytic syndrome have been reported in IVA (9). In our patient, anemia, neutropenia and profound thrombocytopenia were observed and red blood cell and platelet transfusions were administered. ...
Isovaleric acidemia (IVA) is characterized by periodic vomiting, lethargy, coma, ketoacidosis and a 'sweaty feet' odor. Hyperglycemia, ketonemia, ketonuria and metabolic acidosis are the main clinical features of diabetic ketoacidosis (DKA) and these same symptoms can also be seen in acute attacks of metabolic diseases. We report a 2-year-old patient who presented with acute encephalopathy, hyperglycemia, metabolic acidosis, increased anion gap, ketosis and a preliminary diagnosis of DKA. Further investigation revealed IVA. This case is of interest because of the rarity of this presentation and detection of a splicing mutation in the isovaleryl-CoA dehydrogenase gene.
... Secondary hyperammonemia is presumed to be due to inhibition of N-acetylglutamate synthetase by isovaleryl-CoA and/or intracellular depletion of acetyl-CoA leading to reduced Nacetylglutamate synthesis and impairment of the urea cycle [Coude et al., 1979;Stewart and Walser, 1980]. 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]. ...
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 interfamilial 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.
Isovaleric acidemia (IVA) is an autosomal recessive inherited metabolic disease caused by the deficiency of isovaleryl-CoA dehydrogenase (IVD). The symptoms of IVA mimic sepsis, delaying the diagnosis. It can progress to coma and death if untreated. Thrombocytopenia and/or pancytopenia and hyperammonemia are the notable metabolic abnormalities. We report a neonate who presented to us with thrombocytopenia and encephalopathy. Tandem mass spectrometry was suggestive of IVA. Clinical exome sequencing identified a homozygous mutation in the IVD gene at codon 320 (p.Gln320His). The infant responded to specific treatments for IVA, such as carnitine and glycine supplementation. The infant attained appropriate development despite prolonged encephalopathy.
Most immune deficiencies have a genetic component, and numerous primary immune deficiencies are now known to be due to single gene defects. In primary immune deficiencies, the patient generally comes to medical attention because of manifestations due to defective immune function. Most have no phenotypic abnormalities except for immune deficiency. However, immune defects may also be associated with abnormalities in other organ systems, often as part of recognizable syndromes. We term these conditions “syndromic immune deficiencies.” In syndromic immune deficiencies, organ system involvement in addition to the immune system are prominent. Patients may present either with evidence of immune deficiencies or with extra-immune features. Across the different conditions, numerous organ systems may be affected, including the skeletal, neurologic, dermatologic, or gastrointestinal systems. Many of these conditions are due to a defect in a single gene, although they may also be caused by developmental abnormalities, chromosomal aberrations, or teratogens. The presence of immune defects in a patient with extra-immune organ system involvement should prompt consideration of whether an underlying genetic syndrome is present. Proper and timely diagnosis of a syndromic immune deficiency is important for assessment of other organ systems, and correct prognosis.
Background:
Isovaleric acidemia (IVA), a rare autosomal recessive disorder in leucine metabolism caused by defected IVD gene, is characterized by episodes of acute metabolic crisis and psychomotor development retardation. This study aimed to determine the clinical, biochemical, and mutation spectrum of patients with IVA from mainland China.
Methods:
Eight patients (three boys and five girls) from eight unrelated families were collected, IVD gene mutations and phenotypes were examined.
Results:
The patients were admitted because of vomiting, feeding difficulty, psychomotor retardation and "dirty sock" odor. Elevated blood isovaleryl (C5)-carnitine and urine isovalerylglycine were detected from all our patients. Fourteen mutations of the IVD gene were detected, eight of them are novel, c.145C>T (p.Q49Ter), c.359G>A (p.R120Q), c.424C>T (p.R142C), c.458T>C (p.L153P), c.466-1G>T, c.676_677insA (p.T226Nfs*13), c.1039G>A (p.A347T) and c.1076A>G (p.D359G). With this study, a total of 34 alleles were studied in the Chinese population. c.1208A>G (p.Y403C), the common mutation in Taiwan, accounts for 9/34 alleles (7 in previous reports and 2 in this study).
Conclusions:
We described eight novel mutations detected from eight unrelated Chinese patients and provided evidence to support that the p.Y403C is the hotspot mutation in this population.
Organic acidemias or acidurias are a class of disorders characterized by the excretion of organic acids in the urine. This class of inborn error is typically caused by a deficiency in enzymatic activity involved with the catabolism of amino acids, though other biochemical pathways may be involved as well. The clinical presentation may present itself at any time; however, the neonatal or infantile period is of greatest importance. Commonly identified signs and symptoms include coma, lethargy, and developmental delay. Typical complaints upon presentation include vomiting, poor feeding, and seizures. Common laboratory abnormalities at the time of presentation include metabolic acidosis with an increased anion gap, hypoglycemia, hyperammonemia, lactic acidemia, and ketosis.¹ The most commonly used test for identifying organic acidemias is urine organic acid analysis, though acylcarnitine profiles are helpful too. Various biomarkers can be identified using these tests. Management of an organic acidemia typically involves a modified diet containing both restrictions and additions specific to the disorder.
In most primary immunodeficiencies, frequent infections and complications arising from defective immune function are the predominant clinical manifestations. Most frequently, there will not be any phenotypic abnormalities except for those related to the immunodeficiency. In contrast, in syndromic immunodeficiencies, abnormalities in other organ systems in addition to the immune defects are significant manifestations. Many of these conditions are recognizable genetic syndromes and in some cases may be due to single gene defects. In syndromic immunodeficiencies, the immunodeficiency may not present as the major clinical problem, and the immune abnormality may be characterized only after the underlying syndrome has been diagnosed. In addition, in some of these conditions, the immune defect may be present in only a subset of the patients. A number of genetic disorders, such as Wiskott-Aldrich syndrome and ataxia-telangiectasia, have been categorized as primary immunodeficiencies, but may also be considered as syndromic immunodeficiencies since such conditions have both characteristic organ dysfunction and/or dysmorphology unrelated to the immune system as well as a consistent, well-defined immunodeficiency. Syndromic immunodeficiencies may arise from several diverse processes, including single-gene mutations, defective embryogenesis, metabolic derangements, chromosomal abnormalities, or teratogenic disorders. Recognition of an underlying syndrome is critical for optimal clinical care so that both the immune system and the other involved organ systems can be properly treated or even diagnosed before clinical symptoms arise.
In syndromic immune deficiencies, organ system involvement in addition to the immune system are prominent. Patients may present either with evidence of immune deficiencies or with extra-immune features. Across the different conditions numerous organ systems may be affected, including the skeletal, neurologic, dermatologic, or gastrointestinal systems. Many of these conditions are due to a defect in a single gene, although they may also be caused by developmental abnormalities, chromosomal aberrations, or teratogens. The presence of immune defects in a patient with extra-immune organ system involvement should prompt consideration of whether an underlying genetic syndrome is present. Proper and timely diagnosis of a syndromic immune deficiency is important for assessment of other organ systems, and correct prognosis.
Isovaleric acidemia is a rare organic acidemia due to a deficiency in isovaleryl co-enzyme dehydrogenase, which catalyzes the conversion of isovaleric acid to 3 methyl crotonyl during the degradation of leucine. A chronic intermittent form of isovaleric acidemia in a four-year-old boy is reported. There was a history of episodes of vomiting, lethargy, and obnibulation since two weeks of age. Investigations for a neurological or gastrointestinal cause were negative. Chromatography of plasma amino acids demonstrated a moderate increase in the glycine level. Gas chromatography of organic acids showed massive accumulation of isovaleryl glycine, thus establishing the diagnosis of isovaleric acidemia. The course was marked by attacks of vomiting and lethargy that were precipitated by stress and infections and responded well to an infusion of parenteral glucose with nothing per os. Following initiation of a low protein diet with 250 mg/kg/d of glycine, the attacks decreased in frequency and severity. Early diagnosis and management are essential in isovaleric acidemia since appropriate treatment can ensure a favorable outcome.
In syndromic immunodeficiencies, clinical features not directly associated with the immune defect are prominent.
Patients may present with either infectious complications or with extra-immune medical issues.
In addition to the immunologic abnormality, a wide range of organ systems may be affected. A number of different conditions feature symptoms related to the skeletal, neurologic, dermatologic, or gastrointestinal systems.
Many of these conditions are associated with single gene defects, although they may also be caused by developmental abnormalities, chromosomal aberrations, or teratogens.
The finding of immune deficits in a patient with extra-immune organ system involvement should prompt investigations to determine if an underlying genetic syndrome is present.
Isovaleric acidemia and the inherited disorders of propionate metabolism, which include propionic and methylmalonic acidemias (PA, MMA), constitute the most commonly encountered abnormal organic acidemias in pediatrics. More than 100 patients have already been described in each category.
Isovaleric acidemia (IVA) results from a defect in isovaleryl-CoA dehydrogenase (IVCoADH), which metabolizes IVCoA produced by the oxidative decarboxylation step of leucine, to methylcrotonyl-CoA. Biochemically, the disease is characterized by a greatly increased excretion of 3-hydroxyisovaleric acid, isovalerylglycine, and isovalerylcarnitine, whereas the concentration of isovaleric acid itself can be normal. Regardless of the clinical phenotype, residual IVCoADH has been found to be very low (0%–3%). No complementation groups have been defined, while at the molecular level different types of mutation have been detected.
PA and MMA share many characteristic features due to accumulation of propionyl-CoA. Isoleucine, valine, methionine, and threonine are essential amino acids which are metabolized to propionyl-CoA. Although leucine is catabolized to acetyl-CoA, there is evidence for its potential toxicity in PA and IVA. The β-oxidation of odd-numbered carbon fatty acids, which are minor components of dietary fats, and the side chain of cholesterol are also minor precursors of propionyl-CoA. In addition, the potential importance of propionate synthesis by gut bacteria has recently been reemphasized. Propionyl-CoA is further metabolized to succinyl-CoA through propionyl-CoA carboxylase (PCC), MMCoA racemase, and MMCoA mutase.
PA is secondary to a defect of PCC. It is characterized by high plasma and urinary propionate levels and by excretion of multiple organic acid byproducts, of which methylcitrate and 3OH-propionate are major diagnostic metabolites. At the molecular levels, there are two major complementation groups pcc A and pcc BC which correspond to the genes coding for the alpha and the beta chain, respectively.
Inherited MMA is secondary to either a MMCoA mutase mutation or to a defect of adenosylcobalamin (AdoCbl), synthesis. Impairment of mutase activity leads to accumulation of MMCoA and propionylCoA, which is reflected by the presence of greatly increased amounts of methylmalonic and propionic acid and other organic byproducts in blood and urine. Nine classes of MMA are defined on the basis of complementation studies. About one half of patients have a vitamin B12-unresponsive mutase apoenzyme defect divided into mut° and mut− groups, the latter corresponding to a defective apoenzymecoenzyme affinity. The remaining patients are cobalamin variants (registered CblA to CblG). CblA is due to a mitochondria) cobalamin reductase deficiency and CblB to defective AdoCbl transferase. All CblA patients and 40% of CblB are B12 responsive in vivo. MMCoA mutase has recently been cloned, and several mutants have been already investigated at the gene level.
Children with IVA, PA, and MMA have many symptoms in common. Although several patients are asymptomatic, most of them present with one of the three clinical onset types:
In the severe neonatal form, babies, after an initial symptomfree period, undergo relentless deterioration which has no apparent cause and does not respond to symptomatic therapy. Major features include poor sucking, vomiting, anorexia, lethargy, generalized hypertonic episodes, large amplitude tremors, truncal hypotonia, dehydration, and at a more advanced state, respiratory distress, bradycardia, and hypothermia. A strong odor of sweaty feet in urine and skin is present in IVA. Metabolic acidosis, ketonuria, hyperammonemia, hypocarnitinemia, moderate hypocalcemia, neutropenia, thrombocytopenia, and macrocytic anemia are almost constant findings. Hyperglycinemia is present in PA and MMA. The final diagnosis of all these organic acidemias is made by identifying specific abnormal metabolites by GLC-MS.
One third of patients present with a late onset form. Recurrent attacks of coma or lethargy with ataxia are frequent, precipitated by infections, excessive protein intake, or catabolism, but sometimes without apparent cause. In between the child may seem to be entirely normal. The most frequent varieties of comas are those presenting with ketoacidosis with normo-, hypo-, or hyperglycemia. Some patients may mimic diabetic coma. Neurologic signs such as hemiplegia, hemianopsia, and metabolic stroke can be observed, simulating a cerebrovascular accident or cerebral tumor. Few patients with MMA developed acute extrapyramidal disease.
Acute ataxia, unexplained dehydration, persistent anorexia, failure to thrive, hypotonia, myopathy, progressive developmental delay, neutropenia, recurrent infections, and chronic mucocutaneous candidiasis are other common chronic presentations. Generalized staphylococcal cutaneous epidermolysis is a possible complication. Chronic renal impairment with tubulointerstitial nephritis is a frequent long-term complication in MMA and may be also a revealing symptom.
The emergency management of organic acidurias in the neonate has two main goals: toxin removal and promotion of anabolism. Toxin removal is achieved with blood exchange transfusions and peritoneal dialysis in PA, hydration and exchange transfusions in IVA and MMA. Additionally, glycine 500 mg/kg/day in IVA, biotin in PA, and vitamin B12 in MMA should be tried in all cases, although the neonatal forms of these defects are rarely vitamin responsive. l-Carnitine (200 mg/kg) is systematically given in all three disorders. Additional treatment such as insulin or growth hormone may be considered. Anabolism is met by early effective continuous enteral nutrition with a protein-free diet. A special amino acids mixture free of precursors can be added to the formula as soon as ammonia levels are below 80 μmol/l.
Long-term dietary treatment is aimed at reducing accumulated toxic metabolites, while maintaining normal development and nutrition status and preventing catabolism. In IVA, leucine intake can be increased up to 800 mg/day during the 1st year and then most children can tolerate 20–30 g/day of vegetable protein if associated with oral l-glycine and l-carnitine therapy. In most PA and MMA early onset forms, the intake of valine must be rigidly restricted to 250–500 mg/day for the first 3 years of life, subsequently slowly increased to 600–800 mg/day by the age of 6–8 years. Supplementation with a synthetic mixture of amino acids containing none of the amino acid precursors is generally recommended, although still controversial. In general, these infants are severely anorectic, and the entire diet must be delivered through a nocturnal gastric drip feeding using a peristaltic pump. Long-term carnitine treatment may be considered. Metronidazole has been recently found to be very effective in reducing excretion of propionate metabolites because of its activity against gut anaerobic bacteria.
Most of late onset forms are easier to manage, tolerate up to 1.5–2 g/kg per day of protein, and amino acid mixtures are no longer necessary. In all CblA and 40% of Cb1B patients, hydroxocobalamin at a dose of 1 mg/day IM is very efficient. Some patients have gradually interrupted chronic B12 therapy without apparent discomfort. These late onset forms, as well as the vitamin-responsive forms, have an excellent long-term prognosis although they may decompensate at any age and in unpredictable situations.
All forms of IVA, PA, and MMA can be diagnosed early in pregnancy by measuring the defective enzyme activity in uncultured chorionic villi and by directly measuring abnormal metabolites accumulated in amniotic fluid as early as the 12th week of gestation.
Haematological symptoms can be helpful for the diagnosis of metabolic diseases. A megaloblastic anemia orientates to folate and cobalamine anomalies when associated with homocystinemia and decreased plasma methionine levels, or to congenital oroticuria (hypochromia), Pearson syndrome (sideroblasts and vacuolisation of precursors) and thiamine transporter abnormality (sideroblasts) in the absence of homocystinuria. An hemolytic anemia orientates to anomalies of anaerobic glycolysis, heme synthesis, or iron metabolism, and Wilson disease. A pancytopenia orientates to organic aciduria, lysinuric protein intolerance, mevalonic aciduria and lysosomal storage diseases (Gaucher, Niemann Pick, Wolman) when hepatosplenomegaly is present. Uremic hemolytic syndrome and hemophagocytic lymphohistiocytosis respectively orientate to B12 anomalies, lysinuric protein intolerance, lysosomal storage diseases and organic aciduria.
The knowledge of different cytological aspects of metabolic diseases can be a precious help to their diagnosis. In fact, the diversity of medullary aspects in inborn errors of cobalamin metabolism might lead to diagnostical errors. These diseases should be thought of when giant granulocytes or hypersegmented or ribbonned nuclei neutrophiles are seen even if an erythroid hypoplasia or an excess of myeloid precursors are observed on the bone marrow.
The dysplastic features, found in different metabolic diseases, should not be taken for a myelodysplastic syndrome.
Vacuolization of marrow precursors and a Perl's staining revealing ring sideroblasts can lead to suspect mitochondrial cytopathy. The morphological abnormalities of megakaryocytes observed in some organic aciduria disappear with an appropriate treatment.
Although variable, some medullar aspects, such as selectif phagocytosis of nude nuclei by histiocytes or granulocytes precursors are typical of lysinuric protein intolerance.
Organic acidemias are disorders of intermediary metabolism that lead to accumulation of organic acids in biologic fluids, disturb acid-base balance, and derange intracellular biochemical pathways. Their clinical presentation reflects the resultant systemic disease and progressive encephalopathy. While in some organic acidemias, disturbed acid-base metabolism is the predominant presenting feature, in others it is less prominent or even absent. The etiologies of the more than 50 different phenotypes include impaired metabolism of branched-chain amino acids, vitamins, glucose, lipids, glutathione, and γ-aminobutyric acid and defects of oxidative phosphorylation. Most organic acidemias present with neurologic manifestations, which include acutely or subacutely progressive encephalopathy that involves different parts of the nervous system. The age of presentation and the associated systemic, hematologic, and immune findings provide additional guidelines for differential diagnosis. We summarize major organic acidemias, while emphasizing their usual and unusual neurologic presentations. ( J Child Neurol 1991;6:196-219).
Isovaleric acidemia (IVA) is an autosomal recessive disorder caused by deficiency of isovaleryl-CoA dehydrogenase (IVD). Clinical features include vomiting, lethargy, metabolic acidosis, and "sweaty feet" odor. The pathognomonic metabolite, isovalerylglycine, is detected on urine organic acid analysis. Clinical diagnosis of IVA can be confirmed on mutation analysis of the IVD gene.
The cases of five unrelated Thai patients with IVA, identified on urine organic acid analysis, are described. Mutation analysis of the IVD gene was performed using polymerase chain reaction sequencing of the entire coding regions.
Four out of the five IVA patients had an acute neonatal form. The hematologic abnormalities were common and thus could be presenting symptoms in the absence of metabolic acidosis. As for the neurological outcome, only one patient had normal intelligence. Mutation analysis of the IVD gene identified the mutations c.457-3_2CA>GG, c.1199A>G (p.Y371C), c.281C>G (p.A65G), c.358G>A (p.G91R), and c.827T>C (p.L247P). The poor outcome in most patients might be explained by the delayed diagnosis and initial unavailability of the metabolic formulas and medications in Thailand. The c.457-3_2CA>GG mutation was identified in all of the present patients. This suggests that it is the most common mutation in the Thai population. Therefore, it could be a founder mutation in Thai subjects. One of the present Thai IVA patients also had the p.Y371C mutation, which is common in Han Chinese subjects. In addition, two novel mutations, p.A65G and p.L247P, were identified.
The present study provides additional knowledge on the genotype-phenotype of IVA, suggesting that IVD mutations in Asian populations are distinct from these in Western populations.
It is unusual for inborn errors of metabolism to be considered in the investigative work-up of pancytopenia. We report a family in which the proband presented with failure to thrive at 2 months of age and subsequent bone marrow failure. A previous sibling had died at 7 months of age with suspected leukaemia. Haematological findings in the proband were significant for pancytopenia, and bone marrow aspiration showed dysplastic changes in all cell lineages. Urinary organic acid analysis revealed elevated methylmalonic acid. The synthesis of transcobalamin II (transcobalamin, TC) by cultured fibroblasts was markedly reduced, confirming the diagnosis of TC deficiency. The proband and his younger asymptomatic sister (also found to have TC deficiency) were homozygous for R399X (c.1195C>T), a novel mutation resulting in the loss of the C- terminal 29 amino acids of TC, a highly conserved region. Response to parenteral vitamin B(12) in the proband was dramatic. At 6 years 3 months of age, physical examination is normal and developmental level is age appropriate. His sister is clinically asymptomatic and is also developing normally. Propionylcarnitine concentrations were not elevated in the newborn screening cards from the proband and sister, but that was for specimens retrieved from storage after 7 years and 5 years, respectively. Inherited and acquired cobalamin disorders should both be considered in the differential diagnosis of bone marrow failure syndromes in young children. Early detection of the metabolic causes of bone marrow failure can ensure prompt recovery in some cases involving the vitamin B(12) pathway.
This article reviews the major syndromic immunodeficiencies with significant antibody defects, many of which may require intravenous immunogammaglobulin therapy. The authors define syndromic immunodeficiency as an illness associated with a characteristic group of phenotypic abnormalities or laboratory features that comprise a recognizable syndrome. Many are familial with a defined inheritance pattern. Immunodeficiency may not be a major part of the illness and may not be present in all patients; thus, these conditions differ from primary immunodeficiency syndromes, in which immune abnormalities are a consistent and prominent feature of their disease.
Isovaleric acidemia is caused by an inherited defect in isovaleryl-CoA dehydrogenase (E.C. 1.3.99.10). L-leucine restriction and glycine supplementation are used to decrease the toxic accumulation of isovaleric acid (IVA). Supplemental glycine augments conversion of IVA to isovalerylglycine gVG) through the alternate pathway glycine-N-acylase (E.C. 2.3.1.13). Two clinical phenotypes are described, acute and chronic-intermittent, and are differentiated by enzyme activity in cultured fibroblasts. In this study we determined the optimum therapeutic glycine supplement for treating isovaleric acidemia under stable conditions of restricted leucine intake as compared to oral leucine loading. Under stable clinical conditions and on a restricted leucine intake of 55 mg/kg/day a nine year old with chronic intermittent IVA excreted 12.3 ± 5.8 of IVG which rose to 33.6 ± 14.2 mmoles IVG/gm creatinine as glycine supplements were increased from 0 to 50 mg/kg/day at weekly intervals. Excretion of IVC plateaued between glycine intakes of 50–150 mg/kg, but unexpectedly fell to 13.8 ± 0.5 and 16.3 ± 0.9 mmoles/gm creatinine when glycine supplements were further increased to 300 and 600 mglkglday. IVG excretion increased in a two year old with acute IVA while ingesting 45 mg leucine/kg/day from 5.5 ± 2.8 on no glycine supplement to 10.6 ± 0.8 mmoleslgm creatinine on 600 mg/kg glycine supplements. IVG production was compared in the older patient with chronic intermittent IVA. During acute leucine loads, glycine supplements of 190 or 600 mg/kg/day, resulted in urinary IVG of 194 and 419 mmoles/gm creatinine, respectively.
This study investigated the hematologic abnormalities of an infant with propionic acidemia and reversible pancytopenia. Light and electron microscopy of her bone marrow revealed severely disturbed cellular morphology with trilineage dysmyelopoiesis, hemophagocytosis, and numerous multinucleated histiocytes and megakaryocytes. The effects of her serum and of organic acids associated with propionic acidemia were studied on hematopoiesis in vitro. Mouse erythroid (CFU-E) and granulocyte-monocyte colonies (CFU-GM) were assayed by fibrin clot technique; human CFU-GM were grown in agar culture. The infant's serum reduced mouse CFU-E and CFU-GM by 43 and 32%, respectively, compared with normal human sera, but had no effect on human CFU-GM in our culture system. Buffered propionic acid caused concentration-dependent inhibition of mouse CFU-E and human CFU-GM over a range reported in sera of acutely ill infants with propionic acidemia. Neither cell viability nor subsequent colony formation was diminished by preincubation of bone marrow cells with propionic acid for 48 h. The three other organic acids studied, tiglic acid, 3-OH propionate, and glycine, did not inhibit growth of mouse CFU-E, CFU-GM, or human CFU-GM, and glycine significantly enhanced formation of the latter. Evaluation of the infant's hematologic abnormalities suggests that inhibition of bone marrow proliferation and maturation and, perhaps, shortened red blood cell survival were responsible for her pancytopenia. The studies performed in vitro implicate propionic acid in this hematopoietic dysfunction.
The profound metabolic disturbances which occur in isovaleric acidaemia are due to the intramitochondrial accumulation of isovaleryl coenzyme A (CoA) with a consequent reduction in the availability of free CoA. Secondary carnitine insufficiency is also a feature of this and other disorders of organic acid metabolism. A patient who presented at 2.5 years of age was diagnosed using capillary GC-MS as having isovaleric acidaemia. She showed the full spectrum of abnormal organic acids previously associated with the 'neonatal' form of the disease despite her late presentation, indicating that it is inappropriate to refer to acute early and late onset forms of isovaleric acidaemia. Instead, a spectrum of disease exists, determined by environmental factors, residual enzyme activities and modifying effects of different phenotypes in different individuals. She also showed evidence of carnitine insufficiency. An oral challenge with L-carnitine resulted in the excretion of large amounts of urinary acylcarnitines which were shown by use of fast atom bombardment mass spectrometry to be primarily isovalerylcarnitine. Regular glycine supplementation caused no significant increase in urinary isovalerylglycine and had to be stopped because of side-effects after 5 days. An oral L-carnitine challenge during glycine supplementation resulted in a marked increase in isovalerylglycine excretion, again associated with the excretion of large amounts of isovalerylcarnitine. Carnitine acts by removing (detoxifying) intramitochondrial isovaleryl groups and, in the presence of glycine, it promotes the formation of isovalerylglycine. We believe L-carnitine supplementation is of value in the treatment of isovaleric acidaemia and that, in the present case, L-carnitine together with a moderate dietary restriction has proved to be the optimum form of therapy.
A variety of phagocytic cell and lymphocyte assays were employed to evaluate the immune status of four patients with methylmalonicaciduria. One patient had a depressed absolute granulocyte count and two patients had depressed neutrophil and monocyte chemotactic responses. All subjects had normal neutrophil phagocytic and bactericidal activities. One patient had a decreased T-cell number; blastogenic responses to phytohaemagglutinin and pokeweed mitogen were normal in all subjects. B lymphocyte measurements were variably abnormal; two children had decreased B-cell numbers; two had marginally decreased IgG levels; a third had an undetectable rubella titre; and two had elevated serum IgE concentrations.In vitro exposure of normal cells to methylmalonic acid concentrations up to 50mg/100 ml did not affect chemotactic or lymphoproliferative responses.
In conclusion, although B-cell function may be affected, no consistent abnormality of lymphocyte or phagocytic cell functions could be attributed to the metabolic disorder.
Using cultured skin fibroblasts, we studied the heterogeneity of inborn errors of leucine metabolism such as isovaleric acidemia (IVA), glutaric aciduria type II (GA II), and multiple carboxylase deficiency (MC). We first developed a simple macromolecular-labeling test to measure the ability of cells to oxidize [1-14C]isovaleric acid in situ in culture. Cells from two different lines were fused using polyethylene glycol, and the ability of the heterokaryons to oxidize [1-14C]isovaleric acid was tested by the macromolecular-labeling test. The MC line complemented with all 10 IVA lines tested; heterokaryons showed 99 +/- 68% more activity than the unfused mixture of component cells. GA II/IVA heterokaryons exhibited poor growth, but when the culture remained confluent, the GA II cells complemented with all six IVA lines tested, showing a 71 +/- 41% increase in activity. The relatively large standard deviations are due to a few experiments in which significant enhancement of macromolecular-labeling test activity was not observed upon fusion, but significant complementation was clearly observed in repeats of the same combinations. These results are consistent with our previous findings, which indicated that the decreased ability of GA II cells to oxidize isovaleryl-CoA involves a defective electron-transporting system rather than a defective isovaleryl-CoA dehydrogenase. IVA/IVA heterokaryons showed no complementation in any combination tested, indicating no detectable heterogeneity in isovaleric acidemia. This finding indicates that the same gene is mutated in all IVA lines. Previous results indicated that this gene codes for isovaleryl-CoA dehydrogenase.
The clinical and biochemical features of an infant affected by holocarboxylase synthetase deficiency are presented. The patient was the sibling of the deceased child in whose cultured skin fibroblasts the precise enzymatic disorder was first determined. This fact permitted administration of specific therapy in the form of oral biotin, resulting in immediate improvement from impending respiratory failure and shock. The clinical response to biotin was accompanied by recovery of the biochemical mechanisms known to be biotin-dependent, as manifested by disappearance of intermediates in urine and blood. The variability of biotin responsiveness and the diversity of clinical presentation in the patients originally thought to have a deficiency of beta methylcrotonylCoA carboxylase, a biotin-dependent enzyme, raises the question of a separate, specific apocarboxylase defect.
n-Butyrate inhibits the growth of colon cancer cell lines. In the HCT 116 cell line, butyrate-induced growth inhibition is almost fully reversible, whereas in the VACO 5 cell line, a subpopulation undergoes apoptosis within 30 hr of treatment with butyrate. Concurrent treatment of VACO 5 cells with butyrate and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) accelerates and increases the incidence of cell death to nearly 100% of the population, whereas HCT 116 cells largely remain alive during treatment with this combination. The action of butyrate as an inhibitor of histone deacetylase was assessed in these cell lines by examining extracted core histones for their electrophoretic mobility in Triton/acid/urea gels. The concentrations of butyrate that were effective for inducing apoptosis were similar to the concentrations that caused hyperacetylation of core histones in the VACO 5 cell line. Furthermore, an examination of other carboxylic acids for induction of apoptosis revealed a rank order that corresponded to the order of potency in causing hyperacetylation of core histones. Specifically, the active acids were 3-5 carbons in length and lacked substitution at the 2-position. Isovaleric and propionic acids, in particular, proved to be effective inducers of both hyperacetylation and apoptosis at 5 mM concentrations, a finding of potential relevance to the unusual pancytopenia occurring after acidotic episodes in isovaleric and propionic acidemias. The duration of butyrate treatment required for chromatin fragmentation (10-20 hr) corresponded to the time required for histone H4 to become predominantly tetraacetylated. Furthermore, trichostatin A, a structurally dissimilar inhibitor of histone deacetylase, mimicked butyrate-induced apoptosis of VACO 5 cells and growth inhibition of HCT 116 cells. The dramatic enhancement of VACO 5 cell death by TPA, and the high level resistance of HCT 116 cells to butyrate were not evident from histone acetylation determinations. Thus, applications of butyrate for cytoreduction therapy will benefit from pharmacodynamic assessment of histone acetylation, but will require additional work to predict susceptibility to butyrate-induced death.
A retrospective study is reported on the clinical outcome of six patients with isovaleric acidemia (IVA) diagnosed during the last 20 years at the Metabolic Unit of Hacettepe University Children's Hospital. IVA is only one of many inborn errors of metabolism that may have an acute or a late, intermittent presentation. Generally, the diagnosis cannot be made by clinical or routine clinical chemical investigations, although the odor of "sweaty feet" is a presenting symptom. An unusual urinary odor, which was present in all of our patients, should lead to a thorough screening for organic acidemia at any age. Here, we have reported six patients with IVA. Two pairs were siblings. All, except one patient, had positive family history of sibling deaths and all parents were related. In our series, only two patients presented during the neonatal period and both died during the acute crisis. The other four patients presented after the neonatal period and were categorized as having a chronic intermittent form of IVA. Two cases showed normal development despite repeated metabolic decompensations; one patient was diagnosed during the first attack, but he was mentally and motor retarded. The other one died during the metabolic crisis. The presented cases illustrate that IVA can be managed successfully once the diagnosis is made. But lack of early recognition may lead to severe psychomotor retardation or death.
Isovaleric acidemia, an autosomal recessive disorder, is due to isovaleryl-coenzyme A dehydrogenase deficiency and is one of the branched-chain aminoacidopathies. Isovaleric acidemia may present in the neonatal period with an acute episode of severe metabolic acidosis, ketosis, and vomiting and may lead to coma and death in the first 2 months of life. This report concerns an infant who presented at 10 days of age because of lethargy, poor feeding, hypothermia, cholestasis, and thrombocytopenia, leukopenia, and profound pancytopenia. Death occurred at 19 days of age. Autopsy showed mild fatty change in the liver and extramedullary hematopoiesis, generalized Escherichia coli sepsis, and myelodysplasia of the bone marrow with arrest of the myeloid series at the promyelocytic stage. The appearance resembled promyelocytic leukemia, but the diagnostic 15:17 translocation was not present. The maturation arrest in granulopoiesis in isovaleric acidemia appears to be most likely due to a direct metabolic effect on granulocyte precursor cells.
The psychological reactions of 22 parental couples and 3 single parents were investigated after disclosure of genetic test results of their children. The children were tested for the early-onset, monogenetic cancer disorder multiple endocrine neoplasia type 2. Participants came from 13 different families and were aged between 28 and 47 years. Parents who were informed that their child was a gene carrier reacted with resignation, showed moderate to high levels of test-related and general anxiety, but few psychological complaints. Daily activities were disturbed in 43% of the parents with carrier-children. There was little disruption of the parents' future perspective, apart from some socioeconomic disadvantages and increased parental concern for the carrier-children. Most parents with carrier-children showed restraint with respect to short-term prophylactic treatment. Parents with favorable test results showed significantly less anxiety and no disturbance in their daily activities. They did not, however, seem to be reassured by the DNA test result. These parents questioned the reliability of the DNA test, wanted confirmation of the test results, and were eager to continue screening of their noncarrier children. Parents, especially those with a lower level of education and/or a pessimistic view of the future, were distressed by unfavorable test results. Additional counseling is advised to prevent parents of carrier-children worrying unnecessarily, or parents with children in whom the disease gene was not found being not reassured. Am. J. Med. Genet. 94:316-323, 2000.
In syndromic immunodeficiencies, clinical features not directly associated with the immune defect are prominent. Patients may present with either infectious complications or extra-immune medical issues. In addition to the immunologic abnormality, a wide range of organ systems may be affected. Patients may present with disturbances in skeletal, neurologic, dermatologic, or gastrointestinal function or development. These conditions can be caused by developmental abnormalities, chromosomal aberrations, metabolic disorders, or teratogens. For a number of these conditions, recent advances have resulted in an enhanced understanding of their genetic basis. The finding of immune deficits in a number of defined syndromes with congenital anomalies suggests that an underlying genetic syndrome should be considered in those patients in whom a significant non-immune feature is present.
Early detection and therapy of haematological abnormalities and/or diseases may improve the prognosis of metabolic disorders. Accordingly, we aimed to evaluate the frequency and types of haematological abnormalities in children[-31pc] with various inherited metabolic disorders. The study group comprised 46 children with metabolic disorders who were followed at the Pediatric Metabolism Unit and were referred to the Pediatric Hematology Unit for evaluation of anaemia between June 2000 and 2005. The mean age of the children was 55.2 +/- 64.8 months at haematological evaluation (range 1 month-18 years, median 22.0 months); 16 were female and 30 were male. Of these 46 patients with anaemia, 25 of (54.3%) had anaemia of chronic disease (ACD), 9 (19.6%) had iron-deficiency anaemia (IDA), 7 (15.2%) had megaloblastic anaemia due to vitamin B(12) deficiency, 3 (6.5%) had chronic haemolytic anaemia, 2 (4.3%) had autoimmune haemolytic anaemia, 1 had beta-thalassaemia major, and 1 had hereditary spherocytosis. In addition to the anaemia, bicytopenia or pancytopenia was found in 8 of 46 children (17.4%). The study indicated that in organic acidaemias including methylmalonic acidaemia, propionic acidaemia, isovaleric acidaemia, and argininosuccinic acidaemia, the majority of patients had ACD (75%), which was followed by vitamin B(12) deficiency anaemia and IDA (p < 0.001). In PKU, both nutritional anaemias and ACD were present at about same frequency: 46.7% and 40%, respectively (p > 0.05). This study suggested that congenital anaemias such as hereditary spherocytosis or thalassaemias should be kept in mind as a coexisting haematological diseases in young patients with inborn errors of metabolism. In conclusion, ACD and nutritional anaemias are the most prevalent anaemias seen in patients with inborn errors of metabolism. Early detection of the disease, early administration of specific diet, and close monitoring of the patients are very important factors to prevent the development of haematological diseases in patients with inborn errors of metabolism.
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