Maple syrup urine disease
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The author explains that individuals with propionic acidemia are surviving into adolescence and adulthood; therefore, we are beginning to see additional complications of the disorder, such as psychiatric problems, optic neuropathy, and chronic renal failure in some of them.
• Propionyl-CoA carboxylase deficiency or propionic acidemia, an inherited metabolic disorder, is due to deficient propionyl-CoA carboxylase activity and usually presents during infancy and early childhood with neurologic symptoms, metabolic acidosis, hyperammonemia, and organic aciduria.
• Although propionyl-CoA carboxylase is a biotin-dependent enzyme, individuals with the disorder do not usually respond to biotin therapy.
• Individuals with propionic acidemia are usually treated with a protein-restricted, high-carbohydrate diet and carnitine supplementation.
• Children with propionic acidemia can be identified by mass spectroscopy on newborn screening, but they are also identified by the characteristic organic aciduria during infancy or childhood when they are symptomatic.
In 1961, a patient was described with ketosis and increased plasma glycine concentrations and was designated as having idiopathic hyperglycinemia (39; 132). The name of the disorder was subsequently changed to "ketotic hyperglycinemia" to distinguish it from disorders with hyperglycinemia without ketosis. Some patients excreted high concentrations of methylmalonic acid and were considered to have methylmalonic acidemia, whereas others excreted high concentrations of propionate derivatives in their urine and were considered to have propionic acidemia (161; 12). In 1968, a patient with propionic acidemia was found to have increased excretion of hydroxypropionate and odd-numbered carbon-chain fatty acids (77). These findings suggested that propionic acidemia was due to a defect in the conversion of propionyl-CoA to methylmalonyl-CoA. In 1969, the absence of propionate oxidation was demonstrated in the peripheral blood leukocytes of the sibling of the first patient described with ketotic hyperglycinemia (78). The next year, deficient propionyl-CoA carboxylase activity was shown in the fibroblasts of an affected patient (79). Propionyl-CoA carboxylase deficiency was shown in the liver extracts of another patient (63). Subsequently, more than 100 children with propionic acidemia have been reported. The human enzyme has been purified to homogeneity, the cDNA encoding for both of its two subunits have been sequenced, and various molecular mutations have been identified.
Propionic acidemia has been extensively reviewed (208). The symptoms and clinical complications of propionic acidemia are variable (203; 160; 60; 76; 137; 67; 146). Symptoms usually occur immediately after birth or in the first few weeks or months of life but may not occur until several years of age. The initial symptoms are usually nonspecific and include feeding problems, vomiting, hypotonia, lethargy, and dehydration. The infant may exhibit generalized or myoclonic seizures and hepatomegaly. Symptomatic children may not have acidosis (148). One child presented with ketolactic acidosis and hyperglycemia mimicking diabetic ketoacidosis (56). Some patients have presented with tachypnea, constipation, hypothermia, and jaundice. Several children with propionic acidemia have experienced visual hallucinations (172).
Thrombocytopenia, with and without petechiae or purpura, or neutropenia and pancytopenia have been seen in propionic acidemia, especially in the severely ill infant. Multiple children have exhibited optic atrophy (81; 117). One newborn presented with E coli sepsis (197). Chronically ill patients often have mild hypochromic normocytic anemia. Frequently, respiratory or gastrointestinal infections precipitate symptoms and metabolic compromise. An increasing number of children with propionic acidemia are exhibiting sensorineural hearing loss (26). Affected children may progress rapidly to coma. In a review of 49 symptomatic children with propionic acidemia who were diagnosed by selective testing, most exhibited symptoms during the first 3 months of life, and about one third died (163). The use of different therapeutic strategies is a probable explanation for the variation in outcomes. Rapid diagnosis and supportive intervention are essential for preventing irreversible brain damage.
Symptoms of children with propionic acidemia who present in early childhood are similar to those that present in the newborn period or infancy. The seizures in childhood tend to be generalized or of absence type, with a few exhibiting focal seizures. One patient exhibited dysautonomia (75). It is common for affected individuals to have recurrent episodes of metabolic compromise due to infections, increased protein intake, or immunologic abnormalities (125).
Some patients appear to be more prone to infection. There may not, however, be an obvious predisposing condition for metabolic compromise. One child developed skin lesions that suggested acrodermatitis enteropathica (50).
Growth retardation is common. A number of patients exhibited osteoporosis on radiographic examination.
An increasing number have had evidence of cardiomyopathy (118; 115; 84; 154). The latter can be rapidly fatal. In a review of 10 children with propionic acidemia, most exhibited cardiac electrophysiological abnormalities, including prolonged QTc intervals, arrhythmias, reduced left ventricular function, and dilated cardiomyopathy (88; 17; 86; 22; 55; 99; 49). Cardiomyopathies and long QT intervals are common in older individuals with propionic acidemia in the Amish population (57). Some of these cardiac abnormalities are life-threatening, and early preventive intervention must be considered. The cardiomyopathies observed in individuals with propionic acidemia may be reversible with orthotopic liver transplantation (159; 190). A study has shown that high-dose coenzyme Q10 supplementation may be a potential adjuvant therapeutic to be considered in propionic acidemia-related cardiomyopathy (16).
As the individuals with propionic acidemia are living longer, it has been observed that many exhibit liver disease, such as fibrosis and cirrhosis (82). This was evident by elevations of serum alpha-fetoprotein.
Hearing loss has been described in some individuals with propionic acidemia, and there is evidence that the accumulated metabolites in untreated disease may cause long QT syndrome by inhibiting the KvLQT1/KCNE1 channel complex (65).
Individual patients have exhibited recurrent acute pancreatitis (27), cerebral infarction (89), and late-onset optic neuropathy (199). One child was described as having autism spectrum disorder (10; 200; 48).
Hyperechogenic nephromegaly has been reported in a child with propionic acidemia (21).
A rare finding in an affected infant was hemophagocytic lymphohistiocytosis (98).
A milder form of propionic acidemia has been reported in Japan, with the children exhibiting mild mental retardation or extrapyramidal symptoms, occasionally with metabolic acidosis (213).
EEGs are frequently abnormal (203; 179). Slow delta waves and loss of normal alpha rhythm may be due to hyperammonemia. The changes may vary from mild nonspecific abnormalities to grossly aberrant generalized or focal (temporal) patterns. Individuals with propionic acidemia appear to be prone to cortical dysfunction, which can result in background and epileptiform activity and a high frequency of clinical seizures (70). These individuals may also exhibit stroke-like episodes (166) and cerebral hemorrhage (192), especially during metabolic decompensation. MRI or CT scan of the head may indicate cerebral edema, ventricular dilation or cerebral atrophy, lucencies (leukoencephalopathy), and delayed myelination (61; 24; 20; 05). These findings, if persistent, appear to indicate poor prognosis. Transient basal ganglia lucencies were seen on CT scans following episodes of metabolic compromise in affected individuals who presented after the newborn period. No abnormalities were found in the concentration of neurotransmitters in the cerebrospinal fluid of these patients. An increasing number of patients have developed symptoms of basal ganglia lesions including variable degrees of dementia; extrapyramidal tract symptoms, such as dystonia, choreoathetosis, and rigidity; and acute infarction in the absence of metabolic compromise (69; 73; 141; 131; 09).
One infant with propionic acidemia had spontaneous resolution of his basil ganglia lesions (25). Magnetic resonance spectroscopy has been used to study metabolic alterations in affected children who are metabolically stable (37).
In a survey of 20 patients with propionic acidemia, 11 initially developed symptoms during the first week of life, and nine developed symptoms after the newborn period; those who presented earlier had a higher mortality rate than those who presented later (182). Moreover, all the early-onset patients were retarded, and three had mild chorea and dystonia. Four individuals in the late-onset group had movement disorders. One 31-year-old man with propionyl-CoA carboxylase deficiency initially presented with adult-onset chorea and dementia (108; 168). In a review of the long-term follow-up of 19 children with propionic acidemia by a French group, the prognosis was in general poor, although aggressive treatment did prevent death in many children with neonatal onset of symptoms (162). Other studies indicate more favorable outcomes when there is good dietary compliance (186; 130). Autistic behaviors have been described in children with propionic acidemia (200).
Some patients with propionic acidemia have grown and developed normally on a protein-restricted diet. Several patients have had above average intelligence. In fact, one individual, who was detected because her brother had symptoms, has remained asymptomatic (205). One asymptomatic, healthy adult presented initially with dilated cardiomyopathy (103). Most affected children have some degree of developmental delay. A review of over 128 children with propionic acidemia, most of whom have had mutation analysis, reveals that those who have null mutations are more likely to have had severe clinical courses, whereas those who have missense mutations are more likely to have had later onset of symptoms and milder clinical courses (142). A consortium of clinical metabolic specialists reviewed the natural history of individuals with propionic acidemia (138).
Several adolescents have exhibited acute psychotic episodes, including hallucinations, panic, and disorganized behavior, for up to several months. Although these individuals had moderate metabolic compromise at the beginning of an episode, the psychiatric symptoms lasted longer (47).
An enzyme-deficient child developed rhabdomyolysis 1 to 2 weeks after a metabolic crisis (96). This was likely due to defective energy production caused by secondary mitochondrial dysfunction.
There are reports of children who suddenly deteriorated after minor infections, with and without metabolic acidosis or low plasma carnitine concentrations, and died from arrhythmias even though supportive therapy was rapidly administered (113). These examples suggest that cardiac complications are associated with this disorder.
Several children have exhibited optic neuropathy (13). Several children have exhibited renal failure in early infancy; and others have had chronic renal failure (92; 193).
Individuals with propionic acidemia identified by newborn screening appear to have a lower mortality rate than those found symptomatically; however, no clear benefit was demonstrated for the surviving individuals with regards to their clinical course, including the number of metabolic compromise episodes, physical and cognitive development and long-term complications (66). Even with the advances in management of propionic acidemia, in a study of 55 pediatric and adolescent individuals with disorder, most exhibited long-term neurocognitive impairment and complications affecting multiple organ systems (67).
Early diagnosis and treatment is essential for better outcomes; however, it is still difficult to predict overall outcomes in this disorder (91). Some patients develop hypoxia and shock, especially in the newborn period. Many patients who have been diagnosed and aggressively treated soon after birth still experience frequent episodes of metabolic compromise, growth delay, neurologic sequelae, mental retardation, and cardiac complications, such as arrhythmias or death.
A 3-day-old male infant had vomiting, lethargy, and hypotonia. After several hours, the infant developed generalized myoclonic seizures. An arterial blood gas revealed a pH of 7.20 with a bicarbonate concentration of 10 mEq/L and a base deficit of 24. There was marked hyperammonemia. A complete blood count revealed neutropenia and mild thrombocytopenia. Plasma amino acid analysis revealed an elevated glycine concentration, and urinary organic acid analysis showed hydroxypropionate and methylcitrate, consistent with a diagnosis of propionic acidemia. The infant was treated with intravenous fluids and gradually improved. Although dialysis was considered for the hyperammonemia, it was not started because the ammonia concentration decreased, the ketones cleared from the urine, and the child became more alert and active. Over the next several days, the child was given increasing amounts of a protein-restricted diet, particularly restricting the amino acids, isoleucine, threonine, and valine. The infant was given a trial of biotin, which was ultimately considered to be of no benefit. Propionyl-CoA carboxylase deficiency was confirmed by enzyme assay in extracts of peripheral blood leukocytes and in cultured fibroblasts. The child has thrived on a protein-restricted formula, with occasional episodes of metabolic compromise when stressed with an infection. Over the years, the child has had mild developmental delay.
Propionic acidemia is due to a deficiency of propionyl-CoA carboxylase activity (63; 79). The deficiency is inherited as an autosomal recessive trait. Genetic complementation studies using heterokaryons formed from the pair-wise fusion of fibroblasts from patients with propionyl-CoA carboxylase deficiency have revealed two major groups, pccA and pccBC; the latter is further divided into the pccB and pccC subgroups (64; 201). Heterozygotes of the pccA group have about 50% of mean normal activity in leukocytes and fibroblasts, whereas heterozygotes of the pccBC group have normal enzyme activity (206). Human propionyl-CoA carboxylase has been purified to homogeneity, and the enzyme protein has been characterized in many patients (133). The cDNA for the two subunits of propionyl-CoA carboxylase, alpha (to which the biotin is covalently bound) and beta, have been cloned and sequenced (101; 105; 29). The alpha and beta subunits have been localized to chromosome 13q32 and 3q13.3-22, respectively (101; 95). Individuals with propionyl-CoA carboxylase deficiency belonging to the pccA complementation group have defects in the alpha subunit, and those belonging to the pccBC complementation group have defects in the beta subunit (104; 135). Various mutations in both the alpha and beta subunits of the enzyme causing propionic acidemia have been elucidated (106; 185; 134; 136; 152; 30; 31; 127; 153; 188; 150; 42; 97; 213; 139; 140; 43; 52; 210; 51; 100; 191; 38; 68; 180; 155; 08; 196; 111; 114). The effects of some of these mutations on enzyme activity and subunit assembly and stability have been studied (126; 40). Different mutations in the same beta-subunit may exhibit intragenic complementation due to stabilization of the subunits, thereby partially correcting the loss of enzyme activity (157). Studies of several mutations in the beta-subunit have revealed that the assembled abnormal enzymes have reduced activity and decreased thermostability but normal molecular mass and secondary structure (87). This suggests that propionic acidemia due to these and similar mutations may be amenable to chaperone therapy. As yet, there is no correlation between the residual enzyme activity, complementation groups, or mutation and the clinical features of the disorder.
Most individuals with propionic acidemia have been shown to have missense mutations in either the PCCA or PCCB gene. However, multiple patients with propionyl-CoA carboxylase deficiency have not been found to have a detectable alteration in one or both of their alleles. Of these, several have now been shown to have relatively large deletions of the PCCA gene that were not detected by routine sequencing (93; 53).
Propionyl-CoA carboxylase is a mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA, which subsequently is metabolized to succinyl-CoA that enters the tricarboxylic acid cycle. Propionyl-CoA is formed from the catabolism of several branched-chain amino acids, isoleucine, threonine, methionine, and valine, the oxidation of odd-numbered carbon-chain fatty acids, and the 3-carbon side chain of cholesterol. Enzyme activity is present in most human tissues, including the liver, brain, kidney, skin fibroblasts, and peripheral blood leukocytes and lymphoblasts.
Propionic acidemia usually presents with various degrees of metabolic acidosis, hyperammonemia, and ketosis. Patients have been symptomatic with and without acidosis, hyperammonemia, or ketosis (194; 160). The metabolic acidosis is usually accompanied by an increased anion gap and lactate elevations. The ketosis is due to the accumulation of abnormal organic acid metabolites of propionate in blood and beta-hydroxypropionate, methylcitrate, hydroxyvalerate, propionylglycine, tiglylglycine, acetoacetate, and beta-hydroxybutyrate in urine (203). Hyperammonemia plays a major role in causing the lethargy, somnolence, and coma seen in the disorder (169; 204). The hyperammonemia is due to the secondary inhibition of N-acetyl-glutamate synthetase, which produces N-acetylglutamate, the activator of carbamyl phosphate synthetase in the urea cycle (44). Hyperglycinemia is often seen particularly in infants, but its etiology and effects are not well understood (169; 11). Patients usually develop serum carnitine deficiency due to the conjugation of propionyl derivatives with carnitine and the urinary excretion of these acylcarnitines. Prior to treatment, the urinary ratio of the concentrations of acylcarnitine to free carnitine is greatly elevated. Hypoglycemia is not common in the disorder, unless there is severe metabolic compromise or impending death (209). Liver and kidney functions are usually normal, unless there is kidney failure from severe metabolic compromise or dehydration.
Two children, one infant and one adolescent, exhibited MRI findings of diffuse cortical or subcortical restriction with volume loss or vermian atrophy. The authors suggested that these unique radiological findings may help the radiologist to suggest the diagnosis.
Thrombocytopenia, neutropenia, or pancytopenia is probably due to the effect of abnormal organic acids on bone marrow (183; 181). These abnormalities or hypogammaglobulinemia caused by decreased protein intake may predispose affected individuals to infection. Anemia is probably due to nutritional deficits or frequent blood drawing.
Growth retardation is likely due to decreased protein intake or to repeated episodes of metabolic compromise that require hospitalization or restricted protein for various lengths of time. Plasma L-arginine and L-valine concentrations in individuals with propionic acidemia and the protein-to-energy prescription ratio are positively associated with height (121). Optimizing these plasma amino acid concentrations is critical in achieving normal growth and increasing protein tolerance.
Individuals with propionic acidemia may also be prone to develop secondary mitochondrial or respiratory chain deficiencies (195), such as a functional defect of coenzyme Q (58).
At autopsy, the brains of affected individuals have shown demyelination, swelling, spongy degeneration, and Alzheimer II cells (173; 203; 19). Livers have shown fatty infiltration, swollen hepatocytes, and degeneration. The fatty infiltration is likely due to carnitine deficiency because hepatomegaly usually resolves following carnitine supplementation.
The exact incidence and prevalence of propionic acidemia are not known, but it is one of the most common organic acidemias. In 1973, amino acid screening of 350,000 newborns in Massachusetts detected only one patient with propionic acidemia on the basis of hyperglycinuria (109). This certainly represents an underestimation of the true incidence.
Newborn screening for propionic acidemia is possible using electrospray tandem mass spectroscopy (171). With the incorporation of this technology into an increasing number of newborn screening programs, propionic acidemia should be diagnosed more rapidly and treatment initiated sooner. False-positive newborn screening results are common because the test is designed to identify elevation of C3 or propionylcarnitine metabolites. Second-tier measurement of 3-OH-propionic acid in the same blood spots can reduce the false-positive rate (102; 03).
Prenatal diagnosis of propionic acidemia is possible. Propionyl-CoA carboxylase can be determined in amniocytes and chorionic villi (62; 184; 32). 14C-propionate incorporation into trichloroacetic acid material in amniocytes has also been performed (198), but there was a reported discrepancy when the procedure was carried out in chorionic villi (129). Direct enzymatic assay in combination with molecular mutation analysis in chorion villi has been shown to be a rapid and reliable method of prenatal diagnosis (143). Abnormal concentrations of methylcitrate can be measured by isotope dilution assay or by gas-liquid chromatography of amniotic fluid (54; 85; 83). Methylcitrate is undetectable in normal amniotic fluid, but it is detectable and greatly increased in fluid from affected fetuses as early as 11 weeks' gestation. Prenatal diagnosis of propionic acidemia has also been performed by measuring elevated concentrations of propionylcarnitine in amniotic fluid (170). Measurement of the metabolites in amniotic fluid is advantageous; results can be obtained in several days, the samples can be easily transported to appropriate diagnostic centers without deterioration, and there is no risk of maternal contamination of amniocytes, as has been described. Prenatal diagnosis should be performed by a laboratory with experience. Preimplantation genetic diagnosis was successful in the delivery of healthy twins (02).
Nonspecific clinical symptoms, including vomiting, hypotonia, and seizures, are often characteristic of treatable disorders, such as sepsis, gastrointestinal obstruction, and cardiorespiratory problems. After exclusion of these conditions, or when these findings are accompanied by metabolic ketoacidosis or hyperammonemia, the presence of an inborn error of metabolism should be considered. Both holocarboxylase synthetase deficiency and biotinidase deficiency may present initially with these clinical features, and both conditions have been misdiagnosed as other disorders before they were correctly identified (198).
Most affected children have metabolic acidosis and large anion gaps with elevated concentrations of lactate in serum and urine, although not all do (01). An amino acid analysis may reveal hyperglycinemia, which is also found in other organic acidemias, such as the methylmalonic acidemias and isovaleric acidemia and nonketotic hyperglycinemia. The latter is not accompanied by organic acidemia; nevertheless, propionic acidemia has been misdiagnosed as nonketotic hyperglycinemia (74).
Urinary organic acid analysis can be used to determine the type of organic acidemia or carboxylase deficiency. Elevated concentrations of propionate metabolites, such as beta-hydroxypropionate, methylcitrate, tiglic acid, and propionylglycine, in the absence of methylmalonic acid or isovaleric acid, suggest a diagnosis of propionic acidemia. The methylmalonic acidemias must be differentiated from propionic acidemia because some of the former are vitamin responsive. Elevated urinary concentrations of beta-hydroxyisovalerate, beta-methylcrotonylglycinuria, or lactate, in addition to methylcitrate and beta-hydroxypropionate, are indicative of multiple carboxylase deficiency.
Propionic acidemia can be differentiated from the multiple carboxylase deficiencies by direct assay of the carboxylases. Biotinidase deficiency can easily be excluded by direct enzymatic assay. Propionic acidemia can be confirmed by demonstrating deficient activity of propionyl-CoA carboxylase and normal activities of beta-methylcrotonyl-CoA and pyruvate carboxylase in peripheral blood leukocytes or in cultured fibroblasts (79; 206).
Several children were described with an infantile mitochondrial DNA depletion syndrome that is characterized by elevated urinary organic acids. Decreased activities of beta-methylcrotonyl-CoA carboxylase and propionyl-CoA carboxylase were found in their fibroblasts. The depleted mtDNA is assumed to result in aberrations in normal mitochondrial function altering carboxylase activities (211).
Prenatal diagnosis of propionic acidemia is also possible by determining mutations in fetal DNA isolated from maternal blood (28).
Elevated concentrations of propionate metabolites, such as beta-hydroxypropionate, methylcitrate, tiglic acid, and propionylglycine (in the absence of methylmalonic acid or isovaleric acid) on urinary organic acid analysis suggest a diagnosis of propionic acidemia. Propionate is elevated on organic acid analysis of plasma. The organic acids are usually still elevated even when the patient is metabolically stable. Propionic acidemia can also be diagnosed by finding elevated concentrations of propionylcarnitine in plasma or in blood-soaked filter paper spots (149). Propionic acidemia is definitively diagnosed by demonstrating deficient propionyl-CoA carboxylase activity and normal activities of beta-methylcrotonyl-CoA and pyruvate carboxylase in peripheral blood leukocytes, skin fibroblasts, or other tissues from suspected affected patients (78; 63; 79). Decreased incorporation of 14C-propionate into trichloroacetic acid-precipitable material in fibroblasts or leukocytes can be used to determine a defect in the propionate pathway, but it does not differentiate between propionyl-CoA carboxylase deficiency and the various methylmalonic acidemias (198).
Management guidelines have been reported (59). Propionic acidemia must be treated rapidly and aggressively (203; 108). A consortium of clinical metabolic specialists reviewed the acute treatment of propionic acidemia (35). There have been guidelines presented for the general treatment of individuals with propionic acidemia (18) and for their acute illness (04). Affected individuals should be adequately hydrated, especially if there is evidence of dehydration. Large quantities of parenteral fluids help to facilitate excretion of abnormal organic acid metabolites. Adequate nutrition is essential (23). Acutely, protein is usually restricted because the branched-chain amino acids specifically are a source of organic acids, and the protein, in general, is a source of nitrogen for the hyperammonemia. Care must be taken to reintroduce protein with formulas that are restricted in isoleucine, threonine, methionine, and valine. However, intake of protein in excess of recommended quantities is likely to result in worse clinical outcomes (122). In addition, N-carbamoyl-L-glutamate, together with a protein-restricted diet and carnitine supplementation, may be effective in treating the hyperammonemia associated with propionic acidemia (167; 176; 187). Determinations of various metabolites in filter-paper blood and urinary samples can be used to more closely and more frequently follow the biochemical and clinical course of individuals with propionic acidemia (177).
If protein is restricted for too long a period, the child may still develop hyperammonemia from the degradation of endogenous protein. Because inadequate caloric intake can result in tissue breakdown and endogenous protein degradation, it is imperative to supply sufficient calories in the form of parenteral glucose or oral polysaccharides. Some patients have been treated with parenteral hyperalimentation or continuous insulin infusion (90). Care must be taken not to cause hyperosmolar feedings, particularly when an individual has gastrointestinal problems.
Severe acidosis may require bicarbonate supplementation in addition to hydration. Severe metabolic acidosis and hyperammonemia may require exchange transfusion, hemodialysis, or peritoneal dialysis (156; 80). Evidence supports that severe hyperammonemia can be successfully treated with sodium benzoate or phenylacetate, which conjugate amine-containing compounds, thereby facilitating their excretion (80). These compounds, however, may aggravate the acidosis. Use of an intestinal motility agent resulted in a significant and rapid decrease in blood ammonia and a rise in the ratio of free to total carnitine (145). Enhancement of gut motility may be useful in maintaining metabolic stability in these children.
Intervening infections must be diagnosed and treated aggressively. Mineral and electrolyte concentrations should be carefully monitored. Serious bacterial infections and disseminated intravascular coagulopathy must be excluded in the severely ill child with thrombocytopenia, neutropenia, or pancytopenia.
Although propionyl-CoA carboxylase is a biotin-dependent enzyme, pharmacological doses of biotin (10 mg per day) have not resulted in true vitamin-responsiveness or increased carboxylase activity (202). Several patients with vitamin-responsive propionic acidemia have been reported, but on further investigation none have been substantiated. Biotin supplementation may help to optimize residual enzyme activity in those with some carboxylase activity (201).
Carnitine (100 mg/kg per day) is useful in resupplying the body with carnitine that is excreted as acylcarnitines, especially during severe organic acidemic episodes (158; 33). Carnitine supplementation can decrease the size of the liver in those patients with hepatomegaly, probably by adequately mobilizing the storage of acyl-derivatives during secondary carnitine deficiency.
Carglumic acid supplementation together with standard treatments in individuals with propionic acidemia have resulted in a decreased number of visits to the emergency department for hyperammonemia (07).
One report indicated that coQ10 was decreased in metabolically compromised individuals with propionic acidemia that was likely due to mitochondrial dysfunction (178). Ubiquinol supplementation increased the urinary excretion of citrate and the citrate/methylcitrate ratio in these individuals, indicative of improved anaplerosis. The authors suggested further studies are necessary to confirm these results.
Three children with propionic acidemia who were treated with growth hormone (two had decreased hormone secretion) exhibited increased linear growth. Protein tolerance was also increased during hormone treatment. Growth hormone therapy may be useful in the treatment of children with propionic acidemia, particularly those with growth retardation (116).
Several children with propionic acidemia who had frequent and severe metabolic compromise have undergone orthotopic liver transplantation at 7 to 9 years of age (165; 94). The results have been equivocal even when the children were maintained on a protein-restricted diet supplemented with biotin and carnitine. However, in another study, a child was transplanted with a living-related liver (214). The metabolic abnormalities corrected, and the child tolerated a protein diet up to 2 g/kg per day. In addition, the child’s growth and development improved. Living donor liver transplantation or partial liver grafts from asymptomatic obligate heterozygous (parental) donors in propionic acidemia is being performed successfully (215). Preliminary results indicate that although there is a high survival rate, pretransplant growth retardation adversely affects posttransplant outcomes (124; 164). A review of 12 children who have undergone liver transplantation revealed clinical improvement, including cessation of decline in neurologic and cognitive function, in some even to the point of reducing or discontinuing the need for protein restriction or other medical treatments (15). The study suggested that transplantation should be considered in those children who continued to experience severe metabolic compromise in spite of maximal medical intervention (45). Moreover, transplantation may limit the degree of developmental delay and cardiomyopathy (159; 14). Two centers have reported the early and late complications of liver transplantation in propionic acidemia (36). There has been a cost-effectiveness analysis of liver transplantation for propionic acidemia (110). Additional experience and careful follow-up, especially when performed before major neurologic irreversible effects, have occurred. Favorable long-term outcomes of auxiliary liver transplantation in this disorder are being reported (151; 190; 128; 14; 82; 41; 144; 06; 46; 212; 216). It is important to follow these individuals diligently long-term because they can rapidly become compromised or develop strokes (174).
A mouse with propionyl-CoA carboxylase deficiency, which causes death soon after birth, was successfully treated with a liver-specific carboxylase delivered transgenically after birth (120). An adeno-associated virus gene transfer successfully rescued a neonatal lethal mouse with propionic acidemia (34).
During periods of metabolic stability, therapy consists of restricting the dietary intake of the various branched-chain amino acids that are not metabolized in this disorder. During infancy this is accomplished by using artificial commercial formulas. These formulas are usually supplemented with normal formulas and should be adjusted on a regular basis by a dietitian trained in metabolic disorders. Dietary restriction is lifelong, with an increasing dependency on using natural foods. For enzyme-deficient children, the diet is usually supplemented with carnitine and biotin. There should be routine consultations with metabolic specialists and dietitians as well as periodic developmental assessments and psychosocial support of the patient and family. Studies have suggested that citrate may be an anaplerotic therapy for individuals with propionic acidemia by increasing the downstream concentrations of intermediates in the Krebs cycle (112). A study determined that parents of individuals with propionic acidemia often make adjustments in their child’s diet (107). These alterations may not correspond to the recommendations of the metabolic team, and the parents may not inform the team about the changes made in the diet.
Because one of the long-term complications of organic acidemias is impaired mitochondrial metabolism, elevations of the biomarker, fibroblast growth factor 21 (FGF-21), were found in individuals with metabolic compromise compared to that in individuals with stable metabolic disease (123).
The Inborn Errors of Metabolism Collaborative found that newborn screening identified individuals with propionic acidemia earlier than those who presented with symptoms (119). There was no correlation between the genotype and C3 acylcarnitine concentrations. Further studies are needed to evaluate the long-term outcomes based on the mode of ascertainment.
The outcomes of individuals with propionic acidemia has been variable, with many exhibiting complications, such as cardiac arrhythmias (71; 72). Systematic collaborations and follow-up is necessary for developing better management guidelines for individuals with propionic acidemia at all ages (18). As described above, more individuals with propionic acidemia are being treated with liver transplantation. Systematic evaluation of outcomes of this intervention is essential to determine its efficacy (46; 212).
One pregnant woman with mild propionic acidemia who was maintained on a protein-restricted diet and carnitine supplementation delivered a healthy child (189).
Surgeons and anesthesiologists must have a though understanding of the volatility of this disorder before and during surgery, particularly liver transplantation (147). There has been a report of peripheral nerve block in an individual with the disorder (175).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Barry Wolf MD PhD
Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.See Profile
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