Organic Acidemias
ORGANIC ACIDAEMIAS
Introduction
The term `organic acidaemia' is not a precise one and is used to cover a wide variety of disorders. Conventionally, the term is used to refer to defects in the catabolism of the carbon skeleton of essential amino acids, particularly the branched-chain amino acids leucine, isoleucine and valine (Gompertz 1975). However, in some disorders the defect also involves other pathways, including /3-oxidation of fatty acids or ketone body metabolism. The inborn error may be caused by a defect in the apoenzyme or in the cofactor necessary for the normal activity of the enzyme.
Clinical presentation
These conditions may present in many ways. They can be divided most conveniently into four broad groups: neo natal, infantile, neurological and intermittent. Individual disorders vary widely. The most severely affected children present in the neonatal period, while those with mild disease may not present until they are much older, or may even remain asymptomatic.
Neonatal period
At birth these babies are normal, but within the first few days they commonly develop unexplained severe metabolic acidosis. The earlier symptoms are rarely specific, the most frequent being lethargy, feeding problems, vomiting and tachypnoea. Later neurological signs develop. The babies may become gradually less responsive and more hypotonic with loss of all reflex activity. They often develop apnoea and may need respiratory support. Sometimes they become irritable with hypertonia, fisting and abnormal movements.
Most affected babies are initially thought to have a sep- ticaemia. However, careful scrutiny of the history and investigations will often provide clues pointing to the under- lying diagnosis.
Infancy
Infants with less severe disease may present during the first year of life with failure to thrive and poor developmental progress. These children are often generally unwell with anorexia, persistent vomiting and hypotonia. Symptoms are usually worse during intercurrent infections.
Neurological presentation
Organic acidaemias may present with many different neurological symptoms and signs (Table 7.2). Mental retardation is common, and many other abnormalities have been recorded including ataxia, severe hypotonia, drug- resistant fits and dystonia.
Intermittent illness
Some children with mild variants of these disorders grow and develop normally, but at times of metabolic stress, for example with intercurrent infections or surgical operations, they may develop severe metabolic acidosis with an acute encephalopathy. These episodes maybe rapidly fatal (Kiil & Rokkones 1964).
Diagnosis
Since all these disorders have autosomal recessive inheritance, a history of parental consanguinity or of unexplained deaths of siblings in the neonatal period or later childhood should increase the clinician's suspicions.
Clinical examination
In most conditions there are no specific physical signs. During the acute illness, hepatomegaly is common but not invariable. A wide variety of neurological signs may be present and these may be focal. In the neonate the anterior fontanelle may be full.
Alopecia and erythematous skin rash at the mucocutaneous junction are characteristic of biotinidase deficiency.
Occasionally the baby or his urine has an unusual smell which can alert the clinician, the most striking being that of sweaty feet in isovaleric acidaemia and multiple acyl CoA dehydrogenase deficiency. However, most organic acidaemias have no characteristic odour.
Biochemical tests
Routine tests
Metabolic acidosis is usually present in those with symptoms in the neonatal period, although in some patients with maple syrup urine disease (MSUD) or propionic acidaemia this may not be marked. In the early stages of the illness only an isolated metabolic acidosis may be found, but as the child deteriorates, a mixed respiratory and metabolic acidosis is often present. In patients presenting less acutely, metabolic acidosis is often less marked, although in theintermittent variants the metabolic acidosis is often severe. Hypoglycaemia may be present during acute illness.
Plasma amino acids
During an acute attack, concentrations of the plasma amino acids will be diagnostic in MSUD (marked elevation of leucine, isoleucine, valine and allo-isoleucine), but in all other conditions the amino acids are not diagnostic although they may provide useful clues. Plasma glycine is commonly raised in methylmalonic and propionic acidaemia, but the amino acids may be normal.
Plasma ammonium
Plasma ammonium is often markedly elevated in methylmalonic and propionic acidaemia, particularly in the neonatal period. In other disorders plasma ammonium may be raised, although usually less so.
Organic acids
Persistent ketonuria is often present during acute attacks, and a heavy precipitate may form with 2, 4-dinitrophenylhydrazine, which demonstrates the presence of ketoacids. However, these tests are not specific and only indicate the need for more detailed studies. Organic acids should be measured by specific methods, either gas chromatography or high-performance liquid chromatography. Further confirmation of the identity of peaks requires mass spectrometry. Particular difficulties may occur in some disorders such as late-onset propionic acidaemia, as only small quantities of the metabolites may be present. Another problem is that in disorders of ketone body metabolism, only ketone bodies will be present, and their significance may be overlooked.
It is important to collect specimens under the right conditions, that is either during an acute illness or while the child has a metabolic acidosis. If neither of these conditions is fulfilled, then the child should be receiving an adequate protein intake (greater than 2.5 g/kg/d) since otherwise the diagnosis can be missed in patients with milder variants. If possible, the urine should not be collected while the child is receiving sodium valproate, as this is metabolized to a variety of propionate derivatives which can cause diagnostic difficulties.
Carnitine
Total carnitine concentrations in plasma may be reduced with low free and raised acyl carnitines (Chalmers et al 1984). Specific acyl carnitines may be detected using sophisticated techniques.
Enzyme studies
Final confirmation of the precise enzyme defect should be made by measuring the enzyme activity in white cells or cultured skin fibroblasts. Provided the enzyme deficiency is expressed in the latter, prenatal diagnosis is possible using cultured amniocytes and probably in most cases using chorionic villus biopsy. In some disorders it is also possible to measure the concentration of organic acids in the amniotic fluid using sensitive techniques
Treatment
Cofactor therapy
In those conditions in which the disorder may be caused by a defect of the specific cofactor (Table 7.3), the administration of pharmacological doses of this cofactor or one of its precursors may correct the metabolic defect partially or completely. Of all the nutritional strategies available, this therapy is by far the simplest and safest for the patient. When the disorder is fully responsive, it is also the most effective. Newly diagnosed patients with one of the conditions known to have cofactor-responsive variants should always be given a trial of cofactor therapy. However, in some patients it may be difficult to distinguish the effect of other measures taken simultaneously. In these circumstances the effect of the cofactor should be reassessed when the patient is in a steady metabolic state. In some patients it may be found that a combination of cofactor therapy and dietary modification is needed to maintain metabolic balance.
Dietary management
For those who do not respond to cofactor therapy, other treatment will be needed; in most this will be restriction of dietary protein combined with a generous energy intake. The aim of this diet is to reduce the accumulation of organic acids and yet to meet the requirements for normal growth and development. The amount of protein restriction necessary to do this varies widely. Thus, in some conditions the patient may tolerate a protein intake of 2 g/kg/d, whereas in the more severe variants of propionic acidaemia it may be difficult to provide an adequate protein intake without making the children ill. In these cases a supplement of an amino acid mixture, which provides all the amino acids except those broken down to form the organic acids which accumulate, may improve metabolic control. Gut sterilization may improve control in disorders of propionate metabolism since bacterial fermentation in the gut produces propionic acid which is then absorbed (Bain et al 1988).
In some disorders additional dietary strategies may be needed. In 3-hydroxy-3-methylglutaric aciduria, organic acids are formed from the breakdown of leucine, but the defect also reduces the synthesis of ketone bodies. Reducing the fat intake combined with an increase in carbohydrates may improve metabolic control (Berry et al 1981).
Carnitine and additional therapy
In some conditions it is possible to increase the removal of toxic metabolites, thereby improving the metabolic control. Administration of L-carnitine in many organic acidaemias increases the excretion of acyl carnitine, a less toxic metabolite, and although the total excreted is often fairly small, there is some evidence that metabolic control improves (Roe et al 1983, Duran et al 1986, Dasouki et al 1987). Carnitine is useful in propionic acidaemia. It seems most effective in isovaleric acidaemia in which administration of glycine increases the formation of isovalerylglycine which is also rapidly excreted by the kidney, thereby reducing the organic acid concentrations (Yudcoff et al 1978).
Monitoring therapy
The effect of the therapy should be monitored by the measurement of urine or plasma organic acids and the plasma amino acids. In the longer term the child's growth, height, weight and developmental progress are important indices of health. The diet must be continued indefinitely.
Acute illness
During acute illness, which may be precipitated by intercurrent infection or may follow any metabolic stress such as an anaesthetic, large quantities of organic acids may be formed which can precipitate metabolic acidosis and encephalopathy. The purpose of the acute treatment is to suppress the protein catabolism, giving a protein-free high energy intake. All dietary protein is stopped and a high calorie intake, usually as concentrated carbohydrate solutions, is given. Some patients will tolerate the use of fat emulsions to increase the energy intake (Clow et al 1981), but most will not do so when they are unwell. If oral fluids are not tolerated then intravenous therapy with concentrated glucose solutions is necessary. Metabolic acidosis may need to be controlled with sodium bicarbonate, either orally or intravenously. L-carnitine should be given intravenously if the child fails to respond to this therapy. Dialysis, either haemodialysis (Roth et al 1987) or peritoneal dialysis (Russell et al 1974), or exchange transfusion (Wendel et al 1982) may be needed to remove organic acids and correct the acidosis. Since acute episodes of acidosis are often precipitated by infection, this should always be sought carefully and treated vigorously. In view of studies (e.g. Bain et al 1988) suggesting that propionate production from the gut is an important source of organic acids, treatment with metronidazole to reduce this should be considered. If there is any concern about raised intracranial pressure, it should be monitored if possible.
Prognosis
Untreated, most children with organic acidaemia presenting in the neonatal period will die and those who survive frequently do not thrive and make slow developmental progress. However, children who present later will often do very well. The outcome is often determined by the neurodevelopmental status at the time of diagnosis. The outlook for growth and development is good in cofactor- responsive disorders provided the disease is diagnosed before serious neurological damage occurs.
Features of specific organic acidaemias
see also
- Leigh's syndrome (Leigh's Subacute Necrotizing Encephalomyelopathy)
