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Chromosome Location

Maple symp urine disease: branched-chain alpha-keto acid dehydrogenase (E1, E2, and E3 subunits)

E1alpha : l9ql3/1-ql3/2: E* : 6p21-p22; E2:

lp31; and E3: 7q31-q32

Propionicacidemia: propionyl-CoA carboxylase

alpha subunit: 13q32; beta subunit

3ql3-3q22

Methylmalonicacidemia: methylmalonyl-CoA mutase, hydroxycobalamin reductases, adenosyl transferase and

Mutase: 6p12-p21.2

cobalamin A-F groups

Others are unknown

Urea cycle disorders: carbamoylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinic acid

CPS: 2p

(ASA) synthetase, ASA lyase

OTC: Xp21.1

ASA synthetase: 9q34

ASA lyase: 7cen-p21

Classic PKU: phenyllalanine hydroxylase

12q22-224.1

Biopterin-dependent PKU: GTP cyclohydrolase, 6-pyruvoyl tertrahydropterin synthase (6PTS), dihydrobiopterin

GTP cyclohydrolase: 14q22.1-q22.2

reductase (DHPR), and 4alpha-carbinolamine dehydratase (PCD) deficiencies

6PTS: cDNA available

DHPR: 4pl5.3

PCD: 10q22

Homocystinuria: cystathionine beta-synthase

2lq21-q22.1

Glutaricaciduria type 1: glutaryl-CoA dehydrogenase

l9pl3.2

Biotinidase deficiency: biotinidase

3p25

Figure 31-1 Maple syrup urine disease and homocystinuria. Clockwise, from left upper corner. The facial and generalized erythematous, scaly, weeping rash in acute, untreated maple syrup urine disease (MSUD). Spastic quadriparetic posture and increased fat pads in cheeks of an infant with poorly managed MSUD. CT of the brain showing left occipital infarct in patient with homocystinuria. Gangrenous fingertips in homocystinuria.

The symptoms of MSUD reappear as overwhelming illness and coma in patients with disorders that lead to protein catabolism, especially infections and diarrhea. When these conditions are not managed appropriately, they lead to further neurological deterioration or death. Clinical symptoms and the course of the disease are milder in infants who are diagnosed through neonatal screening and treated before the initial metabolic crisis. In contrast, a patient with late-diagnosed MSUD experiences frequent recurrent episodes, requires prolonged hospital care, and poses significant management problems without ever improving.

The odor of infants is that of burnt sugar, or maple syrup. It is easily recognized in the urine, hair, axillae, and perineum or in cerumen; it is best appreciated on the frozen urine, because the smell is caused by compounds with oily characteristics accumulating on the frozen surface.

When the levels of BCCA are not monitored frequently during dietary management, abnormal ratios of leucine/ isoleucine or of valine ensue. This situation manifests as severe dermatitis, described as scalded skin syndrome (see 31:1 ). The dermatitis will resolve when the ratios of amino acids are normalized.

A number of MSUD variants have been described.^

Differential Diagnosis. Clinically, the most important differential diagnoses are other causes of neonatal coma, and many can be differentiated by clinical ( .Table. 31-3 ) or by simple laboratory observations (.Table..31..::4 ). In the neonate, MSUD is almost always confused with sepsis or meningitis; and the disease is usually associated with either one. The diagnosis of MSUD is suspected only after the sepsis or meningitis workup reveals normal results. Precious therapeutic time will be lost, causing severe neurological crippling or death. MSUD must always be ruled out in any neonate with lethargy progressing to coma; with alternating tone changes; in the absence of changes in blood pH, glucose, and ammonia; and regardless of the presence of an infection. In variant forms of the disease, the diagnosis is usually reached when either blood amino acids or urine organic acids are studied in a child with periodic coma or in a child with pyramidal or cerebellar signs.

Evaluation. Test findings should be grouped into two age categories: one for neonatal and one for episodes after 6 months of age. In the neonatal period, the disease almost never causes significant hypoglycemia, nor acidosis, ketonuria, or hyperammonemia. Therefore, the presence of coma in a neonate who has nearly normal clinical biochemical findings should immediately suggest MSUD. Definite diagnosis is through determination of amino acids in plasma or in urine, which shows significant elevations of L-leucine, isoleucine, and valine. Leucine concentration in blood is always higher than that of the other BCAAs. BCAAs or BCKAD can be measured either by chromatographic techniques or more rapidly by tandem mass spectrometric determinations. A quick spot test of the BCKA in the urine is a strongly positive yellow flocculation when 2,3- dinitrophenylhydrazine is added. After 6 months of life, when recurrent acute metabolic decompensation occurs, it is accompanied by mild to moderate hypoglycemia, severe acidosis, and ketonuria.

586

TABLE 31-3 -- DIFFER

ENTIAL DIAGNOSES OF COMA IN NEONATE: CLINICAL FINDINGS

Disease

Tone

Seizures

Dysmorphia

Liver Disease

Infectious Complications

Maple syrup urine disease (MSUD)

Alternating tone

Myoclonic or clonic

Absent

Absent

Almost always present

MSUD (recurrent crisis)

Not specific

May be present

Absent

Absent

May be present

Urea cycle disorders

Severe hypertonia

Usually myoclonic

Absent

Absent

May be present

Various organic acidemias

Hypotonia (propionic), hypertonia (methylmalonicacidemia and isovalericacidemia)

Myoclonic or clonic

Facial and CNS dysmorphia present in propionicacidemia and pyruvate dehydrogenase deficiency

Present in cytochrome-c oxidase deficiency or oxidative phosphorylation diseases

Almost always present

Fatty acid oxidation disorders

Myopathy or cardiomyopathy

As caused by hypoglycemia

Only type 2 glutaric aciduria

Only type 2 glutaric aciduria

Usually absent

Nonketotic hyperglycinemia

Severe hypotonia, stridor, hiccups

Severe, usually myoclonic

CNS dysgenesis such as absent corpus callosum

Absent

Usually absent

Zellweger's syndrome

Severe hyopotonia

Severe, usually myoclonic

Facial, CNS dysgenesis, cysts in organs

Severe liver involvement

Usually absent

Nesidioblastosis

None

As caused by hypoglycemia

None

None

None

The electroencephalogram (EEG) of the newborn with MSUD has a characteristic sharp wave pattern described as comblike rhythm. [al After proper management, the EEG may be normal between attacks or there may be a generalized slowing of the background and paroxysmal discharges, indicative of the ongoing metabolic disease. In older patients, leucine loading may lead to EEG abnormalities. Even in well-controlled patients, seizure disorder may appear later during childhood, requiring anticonvulsive treatment.

Neuroimaging is a valuable tool, particularly when amino acid determination is not immediately available. In the neonate, it causes a characteristic appearance of white matter attenuation suggestive of brain edema that appears as early as 9 days of life despite dietary treatment. The MSUD edema initially involves the deep cerebellar matter, the dorsal part of the brain stem, the cerebral peduncles, and the dorsal limb of the internal capsule. Eventually, marked generalized diffuse edema appears in the central white matter and is particularly prominent in the frontal areas. The edema subsides after several months of treatment, with mild to severe atrophy of the brain remaining, as evidenced by enlarged ventricles and prominent sulci. The severity of these findings depends on the stage of the disease at which the treatment is initiated. In well-managed patients the neuroradiological sequelae may be increased cerebellar foliation, cerebellar white matter disease, or cerebellar atrophy supporting the clinical presence of ataxia; this last finding may be the only neurological sequela in such children.

Management. Treatment consists of emergency reduction of increased BCAAs in blood. In patients diagnosed early, peritoneal dialysis or hemodialysis should be attempted. A secure central line must be placed, because intensive parenteral nutrition and antibiotics are used for several weeks to prevent catabolism and prompt anabolism. Specific amino acid solutions without BCAA for parenteral nutrition, in MSUD and other disorders of BCAAs, are available from PharmThera (Memphis, TN).[7] Insulin drip, using diluted insulin solutions, must be initiated to ensure anabolism. Blood levels of BCAAs must be measured initially once or twice daily to monitor the reduction of the level of BCAAs; this is best done by tandem mass spectrometry. A simple clinical guideline to therapy is to follow weight gain in a nonedematous neonate. The treatment usually leads to daily weight increments for about 10 days, at which time the blood leucine level is reduced below 1000 pM. Oral intake of special mild formulas with restricted BCAAs must then be resumed, and parenteral nutrition must be discontinued gradually. A neonate with MSUD is usually difficult to feed, and either a nasogastric tube or temporary button gastrostomy may be used for this purpose.

Once the acute metabolic decompensation is controlled, the patient is placed on BCAA-restricted formulas such as Ketonex or other MSUD formulas. Chronic management is difficult because it requires provision of BCAAs in amounts that permit growth but that do not cause significant BCAA elevations. This requires frequent amino acid analysis and can be achieved only in tertiary care centers where easy access to high-performance liquid chromatography or tandem mass spectrometry is available. Patients should receive thiamine supplementation and L-carnitine; and, when metabolic decompensation occurs, leucine should be restricted.

Prognosis, Prevention, and Prenatal Diagnosis. Prognosis depends on early detection and treatment. Patients whose disease is diagnosed before the initial metabolic attack will grow as nearly normal children, despite recurrent attacks in later infancy. Successfully managed

587

TABLE 31-4

-- DIFFERENTIAL DIAGN

OSES OF CO

MA IN NEONATE: LABORATORY FINDINGS

Disease

Blood pH

Blood Glucose

Blood Ammonia

Blood Lactic Acid

Urine Ketones

Special Findings

Maple syrup urine disease (MSUD)

Normal

Normal

Normal

Normal

Trace or absent

Elevated branched-chain amino acids and branched-chain ketoacids in urine

MSUD (recurrent crisis)

Acidosis

Moderate/severe hypoglycemia

Normal

Normal

Moderate/severe ketonuria

As in neonatal period

Urea cycle disorders

Alkalotic or normal

Normal

Rapid elevation

High in argininosuccinicaciduria and citrullinemia

Absent

Citrulline values differentiate various types; high oroticaciduria in certain types

Various organic acidemias

Overt/compensated acidosis w/large-base excess

May be mild/moderately low

Usually elevated

Usually elevated

Trace/strong ( + ) in various disorders

Urine organic acids, blood acylcarnitines

Fatty acid oxidation disorders

Usually normal

Usually moderately/severely low

Variable, but usually normal

May be elevated

Absent

Urine organic acids, blood and urine acylcarnitines

Nonketotic hyperglycinemia

Normal

Normal

Normal

Normal

Normal

Elevated glycerine in blood and cerebrospinal fluid

Zellweger's syndrome

Normal

Normal

Normal

Normal

Normal

Elevated liver enzymes and very long chain fatty acids in blood; pipecolic acid in urine

Nesidioblastosis

Normal

Low with inappropriately elevated insulin levels

Normal

Normal

Normal

Blood glucose and insulin determined at the same time

patients will have a near-normal IQ and normal school performance. [sJ , [9] A neonatal screening should be mandatory in countries where the disease is prevalent. The safety window of classic MSUD is only a few days; therefore, newborns should be screened for this disease at 24 to 48 hours of life. This can be achieved either by a Guthrie test or, more easily, by tandem mass spectrometry. The BCKAD activity can be measured in cultured amniotic cells. [io] If the mutation is known, this can be achieved by molecular genetic studies.

UREA CYCLE DISORDERS

Pathogenesis and Pathophysiology. Recognized only during the past 40 years, the urea cycle disorders (UCDs) include argininosuccinicaciduria (ASA uria; ASA lyase deficiency), y citrullinemia (ASA synthetase deficiency),y ornithine transcarbamoylase (OTC) deficiencies, y and carbamoylphosphate synthetase (CPS)

deficiency (. Fig 31-2 ).[14] Ammonia is detoxified through five synthetic enzymes and one enzyme that synthesizes an activator for the initial step. The initial three enzymes are in the mitochondria, and the latter three are in the cytosol. This cyclic process both generates and hydrolyzes L-arginine, which is an essential amino acid in infants and important for normal development of brain. When only one of the activities on this pathway is deficient, hyperammonemia and CNS symptomatology ensue. This usually occurs during the first few days to weeks of life and is one of the major causes of devastating metabolic disease of the newborn.

The UCDs cause hyperammonemia, and the clinical picture is similar in all forms of neonatal UCD. The gene locations of urea cycle enzymes are shownin T§b!e,..3.1-2 , and complementary DNA is available for most of them.

When any of the aforementioned enzymes is deficient, ammonia cannot be converted into urea, leading to hyperammonemia within the first week of life. Unlike hepatic coma, in which ammonia is only one of the many putative toxins, in neonatal UCD, ammonia is the only cause of encephalopathy. Blood ammonia concentrations exceeding 300 pM are highly neurotoxic, particularly when prolonged. Primate models with induced hyperammonemia closely mimic the clinical, neurophysiological, and neuropathological findings observed in human neonatal UCD. In late-onset forms of ASA synthetase and lyase deficiencies, levels of citrulline, ASA, and ASA anhydride are elevated between crises when the patient is asymptomatic. This suggests that the acute neonatal symptoms of these disease are due to hyperammonemia and not to elevated levels of urea cycle amino acids. Support for this theory is the family reported by Issa and associates y in which one neonate with citrullinemia died with hyperammonemia while her twin brother remained asymptomatic with elevated levels of citrulline. This point is of paramount importance for the management and prognosis of UCDs.

The swelling of astrocytes in UCDs is due to hyperammonemia and might be caused by the concomitant elevation of glutamine. When glutamine synthetase is inhibited, cerebral edema caused by hyperammonemia can be prevented. In OTC deficiency, the hyperammonemia encephalopathy

Figure 31-2 Algorithm for approach to neonatal-onset hyperammonemia. Abbreviations: NKHG, nonketotic hyperglycinemia; THAN, transient hyperammonemia of the newborn; CPS, carbamyl phosphate synthetase; OTC, ornithine transcarbamylase; AL, argininosuccinate lyase; AS, argininosuccinate synthetase; NAGN-acetylglutamate synthetase; ASA, arginosuccinic acidReproduced with permission from Lippincott-Raven Publishers, from Batshaw ML: Errors of Urea Synthesis. Ann Neurol 1994:35:133-141.)

is shown to be related to brain glutamine accumulations, as demonstrated by magnetic spectroscopic studies.

Epidemiology and Risk Factors. Fortunately, the UCDs are rare disorders. All, except OTC deficiency, are inherited as autosomal recessive traits. The OTC gene is on chromosome X, and its severe form is encountered only in males. The heterozygote female is discussed among UCDs of late onset. The cumulative frequency of all types of neonatal UCDs in Japan is 1 in 46,000 births; and the frequency for OTC deficiency in Japan was reported to be 1 in 80,000. In the Massachusetts screening program, the incidence of ASA lyase deficiency was 1 in 70,000, y and in a Quebec screening program it was 1 in 77,000.y Approximately 65 cases of ASA lyase deficiency have been reported. The incidence of ASA synthetase deficiency (citrullinemia) in the Quebec program was 1 in 250,000 births. ^ In the Middle East, the most common forms of neonatal UCD are ASA lyase and synthetase deficiencies and they might occur in 1 in 2000 to 3000 births.

Clinical Features and Associated Disorders. All forms of neonatal UCDs manifest nearly identical clinical symptoms. The infant is usually the product of normal pregnancy and delivery, with normal Apgar scores, and remains normal usually for 24 to 72 hours. Shortly thereafter, however, the infant becomes lethargic and refuses to feed; this quickly progresses to coma and is associated with hypothermia, hyperventilation, and respiratory alkalosis. Because cerebral edema appears early in the acute event, the bulging fontanelle erroneously leads to a diagnosis of meningitis with sepsis or pneumonia. If a coma workup is neglected, the neonate will die within a few days with a missed diagnosis. Brittle hair showing trichorrhexis nodosa in ASA lyase deficiency is encountered later during infancy and is not a prominent feature if the infant is given adequate amounts of L-arginine. Patients with ASA lyase deficiency might also have moderate to severe hepatomegaly. Phenotypical variability is the function of different mutations. Metabolic consequences also depend on the availability of compounds that might serve as an ammonia sink; for example, OTC deficiency is less severe than CPS deficiency and ASA synthesis that proceeds normally from citrulline might serve as a store for waste nitrogen.

Differential Diagnosis. The diagnosis is quickly reached by the uniform clinical presentation of the neonatal UCD. Differential diagnosis for neonatally important organic acidemias is by measurement of blood pH, lactic acid, ketone bodies, and glucose (see Table 31:4 ). The hyperammonemia observed in organic acidemias is associated with overt or compensated metabolic acidosis, whereas in UCDs the blood pH is usually normal or alkalotic. Blood glycine and urine ketones are elevated in the major ketotic organic acidemias of the neonate, which is not the case in UCDs. It is important to differentiate various types of UCD from CPS and OTC deficiencies. This differential diagnosis is essentially reached by measurements of specific amino acids in plasma and of orotic acid in the urine. The M-acetylglutamate (NAG) synthetase deficiency may be proven clinically by normalization of ammonia after administration of 250 to 500 mg/kg/day NAG in a suspect case. It is now possible to diagnose citrullinemia and ASA uria rapidly within a few hours in a suspected case by tandem mass spectrometry. The simultaneous measurement of acylcarnitines with amino acids particularly eliminates any confusion rising from other diseases with co-existent lactic acidemia.

Evaluation. Any neonate with coma and devastating metabolic disease should receive a battery of clinical biochemical tests, including a determination of ammonia in addition to blood gases, pH, blood glucose, urea, and lactate (see Table.31:4 ). These data provide a provisional diagnosis of a UCD within hours, and a definite diagnosis can be made by the measurement of specific amino acids and orotic aciduria.

Management. Prompt intervention before the emergence of significant hyperammonemia is beneficial. The treatment consists of two phases: (1) rescue of the neonate from hyperammonemic coma and (2) maintenance of normal physical and intellectual growth between metabolic crisis with recurrent hyperammonemia. The essential medications for both phases of treatment in UCD are phenylacetate or phenylbutyrate and L-arginine. These medications bind and remove ammonia through alternate pathways as hippurate (1 M ammonia per mole of benzoate) and phenylacetylglutamine (2 M of ammonia per mole of phenylacetate or phenylbutyrate). In ASA synthetase and lyase deficiencies, L-arginine is used because it is converted into citrulline and ASA, respectively, and thus provides an ammonia sink. To avoid cerebral edema, recurrent episodes of hyperammonemia should be treated vigorously at the earliest clinical sign of decline, such as lethargy, irritability, vomiting, or behavior change, or before the plasma ammonia level increases to three times its normal limit. y

Treatment between episodes of metabolic decompensation provides enough protein to ensure adequate growth but avoids hyperammonemia and elevated plasma glutamine levels. In CPS and OTC deficiencies, during the first 6 months of life, a diet that contains a 0.7-g/kg/day mixture of essential amino acids (using UCD formulas available from Mead Johnson, Princeton NJ, or Milupa, Hillington, Middlesex, UK) together with normal milk protein 0.7 to 2 g/kg/day is given and the plasma amino acids levels are monitored. More recently, orthoptic liver transplantation has been recommended for the definitive treatment of UCD; the rewarding results of this treatment in seven patients with UCD have been reviewed. y

Mortality relates directly or indirectly to the consequences of acute brain edema. Even if this complication is prevented, acute hyperammonemia either initially or intermittently can lead to intracerebral and subdural hemorrhage. No infant with a UCD should be given valproate because it may cause liver failure and death. y

Prognosis and Prevention. Neurological outcome and morbidity depend on early diagnosis and appropriate treatment. Long-term studies suggest that use of phenylbutyrate with diet therapy offers the best chance of survival. Hyperammonemia of acute decompensation in ASA lyase and synthetase deficiencies is easily controlled by intravenous or oral administration of L-arginine; with subsequent use of diet and phenylbutyrate, the survival rate is 90 percent.

The neurological outcome in CPS and OTC deficiencies, even when treated appropriately, is only fair, with an average IQ score of 53 ± 6. y Spastic gait is the eventual neurological sequela. The relatively poor prognosis in these two diseases is due to the unusual severity of hyperammonemia,

its early onset, and its difficult management with frequent recurrent hyperammonemic episodes. On the other hand, both argininosuccinicaciduria and citrullinemia have a better neurological prognosis if they are identified before the initial acute metabolic decompensation and treated appropriately.

No large-scale study for the neonatal screening of UCD has been reported. The short safety window requires screening procedures that provide rapid results. The method should also have low false-negative results and be able to identify the milder forms of the disease. The newly described tandem mass spectrometry procedure using dried blood spots has been able to identify both citrullinemia and argininosuccinicaciduria before the emergence of hyperammonemia and thus is useful for such mass screening of these two disorders. When the tandem mass spectrometry-based orotic acid screen becomes possible, OTC deficiency should also be screenable. At present there is no possibility of screening for the CPS deficiency. All subsequent newborns in a family with a previous newborn with UCD should be treated as such, until proven otherwise.

PROPIONICACIDEMIA

Of the disorders that present as devastating neonatal metabolic disease listedin Table,,.31-1 , propionicacidemia and methylmalonicacidemia are encountered more frequently than the others.

Pathogenesis and Pathophysiology. Propionicacidemia was first described by Nyhan and associates in an infant with episodic ketoacidosis, elevated plasma glycine (ketotic hyperglycinemia), and protein intolerance. y The disease is caused by the deficiency of propionyl-CoA carboxylase (PCC) and the inheritance is autosomal recessive. Propionyl-CoA is generated through the breakdown of l- isoleucine, valine, threonine, methionine, cholesterol, and odd chain-numbered fatty acids. The enzyme is a polymer composed of nonidentical subunits (alpha and beta), with the native enzyme being a hexamer. Its cofactor is biotin, which is bound to an epsilon-amino group of lysine in the alpha subunit. The chromosomal locations of subunits are known, and complementary DNA is available (see Iable,.3:!,:2 ). The deficiency of either subunit causes propionicacidemia.

Deficiency of PCC results in the accumulation of propionyl-CoA, which passes into circulation as propionylcarnitine or propionylglycine. Alternate pathways generate methylcitric acid, 3-hydroxypropionic acid, and tiglic acid. The toxic effects in CNS, bone marrow, and other tissues may be due to the accumulation of excess propionyl-CoA, depletion of the intramitochondrial free CoA pool, or toxic effects of compounds formed secondarily. Hyperglycinemia may be nonspecific and be due to inhibition of glycine cleaving enzyme. Hyperammonemia might be due to the inhibition of CPS I by the accumulating propionyl-CoA. Hypoglycemia might be due to the inhibition of pyruvate carboxylase or malate shuttle by elevated intramitochondrial propionyl-CoA. Despite the association of severe ketoacidosis during metabolic crisis the mechanism of excess ketone body generation is not clear.

Epidemiology and Risk Factors. The disease may be rare in the United States and Canada, affecting 1 in 250,000 to 500,000 births. However, in the Middle East, particularly in Saudi Arabia, it may be as high as 1 in 1,000 births.

Clinical Features and Associated Disorders. The disease manifests from newborn to late infancy with acute decompensation as seen in other organic acidurias. A prodrome of vomiting and refusal to feed progresses to lethargy and coma within days. The infant becomes quickly dehydrated and may experience clonic, myoclonic, or grand mal seizures. Physical examination reveals severe central hypotonia, both during and in between crises. The oral mucosa, angles of the mouth, and perineal area usually show evidence of candidiasis. Facial appearance is usually typical, with depressed nasal bridge and long philtrum; there may be associated abnormalities of the nipple. y Vomiting may be so severe that the infant might be operated on for pyloric stenosis or intestinal obstruction. Approximately 30 percent of the infants might present with immune deficiency, seizure disorder, or acute extrapyramidal signs such as choreoathetosis and dystonia. y

Differential Diagnosis. Two organic acidemias, methylmalonicacidemia and isovalericacidemia, in the neonate cause severe ketoacidosis, but both show increased muscle tone, whereas the tone in propionicacidemia is severely decreased. Patients with isovalericacidemia in crisis usually have a "sweaty feet" smell known to be associated with the disease. Propionicacidemia associated with immune deficiency might be confused with other disorders with immune deficiency. y The urine and blood in infants with multiple carboxylase deficiency will show other intermediates, such as methylcrotonylglycine or isovalerylcarnitine.

All neonates with organic acidemia, all infants with symptoms suggestive of immune deficiency in association with thrombocytopenia or ketosis, and all infants with idiopathic seizure disorder or acute extrapyramidal tract signs should be tested for propionicacidemia, particularly where its prevalence is high.

Evaluation. In early neonatal form, hyperammonemia is severe, usually exceeding 1 mM; in repeated episodes it is usually moderate, rarely exceeding 300 pM; there is severe acidosis with accumulation of massive amounts of ketone bodies. Lactic acidosis is mild, rarely exceeding 6 mM. Hypoglycemia is usually moderate, rarely decreasing below 2 mM. Propionicacidemia has serious deleterious effects on bone marrow cells; neutropenia and thrombocytopenia are common. The platelet count usually drops several days after the onset of coma, while ketonuria is waning. y If it is not appreciated, the patient will have bleeding, particularly intracranially. Propionicacidemia causes severe depletion of T lymphocytes, and the patient will experience frequent infections and sepsis due to unusual gram-negative organisms or Candida.

The diagnosis is made by detecting 3-hydroxypropionic acid, propionylglycine, and methylcitrate in the urine by gas chromatography/mass spectrometry or by estimating elevated glycine and propionylcarnitine and decreased free carnitine levels in blood through tandem mass spectrometry. Propionylcarnitine will be elevated both in propionic- acidemia and methylmalonicacidemia; if desired, PCC activity can be measured in leukocytes and cultured fibroblasts. Biochemical findings of propionicacidemia are also

seen in multiple carboxylase deficiency owing to holocarboxylase synthetase or biotinidase deficiencies.

Management. Treatment of initial or acute crisis is by administration of high amounts of glucose and bicarbonate, together with insulin drip, intravenous L-carnitine (50 to 75/mg/kg every 6 hours), and optimum antibiotic coverage to treat sepsis, if present. When amino acid mixtures with restricted BCAAs are available, they can be added to the total parenteral nutrition. Vomiting during or between crises is controlled by intravenous or oral administration of ondansetron. Platelet count should be monitored daily during acute episodes; and when it decreases below 50,000/ mm3 , platelet transfusions should be given. It is advisable to place a gastrostomy with fundoplication during the first few years to manage chronic anorexia and vomiting. Once the patient's condition has stabilized, oral feeding with special propionicacidemia formula restricted in isoleucine and valine should be resumed, together with oral carnitine, 100 to 200 mg/kg/day, and Polycitra solution, 2 to 4 ml/kg/ day. The patient should never be permitted to fast because excessive odd chain-numbered fatty acids stored in the adipose tissue of propionicacidemia patients will mobilize and prompt a crisis. Metronidazole at a dose of 7.5 mg/ kg/day should be used to decrease intestinal sources of propionate. Human growth hormone has been used as an adjunctive treatment. Sepsis, intracranial bleeding, and pancreatitis are dreaded complications.

Prognosis and Prevention. The prognosis in propionicacidemia is usually poor, with 50 percent of the patients dying and at least 25 percent showing mental retardation. Chronic hypotonia causes delayed acquisition of motor milestones. A routine neonatal screening test is not uniformly available. Preliminary results of a tandem mass spectrometry-based procedure indicated its value in detecting the disease within 24 to 48 hours, before the initial crisis.

METHYLMALONICACIDEMIA

Pathogenesis and Pathophysiology. Methylmalonic- acidemia was first described by Oberholzer and co-workers in 1967 in infants critically sick with profound ketoacidosis and accumulation of methylmalonic acid in blood and urine. y The disease is a family of disorders caused by defective activity of methylmalonyl-CoA mutase (mutase [0] or mutase [-] complementation groups) or by defective intramitochondrial processing of vitamin B12 (cblA and cblB complementation groups). Other disorders of vitamin B12 will cause methylmalonicaciduria but are not associated with periodic acidotic crisis of methylmalonicacidemia. They are associated with homocystinuria and are presented in the section on neurological diseases associated with homocystinuria. y

Genetic heterogeneity of the disease is evidenced by some phenotypes being responsive to large doses of vitamin B 12 whereas no response is observed in others. The defects in the mutase are either (0) with no, or (-) with little, residual activity. The cofactor of the enzyme is 5

-deoxy- adenosylcobalamin, and complementation groups cblA and cblB represent its defective synthesis. The toxic effects of intracellular accumulating methylmalonyl-CoA are similar to those of propionyl-CoA. All variants of methylmalonic- acidemia are determined by autosomal recessive genes. The chromosome location of the mutase is known, and its complementary DNA is available (see T§b!e.,31:2. ).

Epidemiology and Risk Factors. The incidence of methylmalonicacidemia in the Massachusetts screening program was 1 in 48,000. y The disorder is more common in the Middle East, probably occurring in 1 in 1,000 or 2,000 births.

Clinical Features and Associated Disorders. The usual presentation in the neonate is as a typical organic acidemia with overwhelming illness, similar to the presentation of propionicacidemia or isovalericacidemia. These episodes recur either as a consequence of excessive protein intake or from increased protein catabolism through vomiting or infections. The acidosis is usually so severe that the patient will be admitted in shock and might die. Mucocutaneous candidiasis is common, disappearing with appropriate management. The patient usually has increased muscle tone. Seizures, when present, are clonic or myoclonic. As in propionicacidemia, patients with methylmalonicacidemia are prone to a variety of infections and sepsis by unusual organisms. Facial dysmorphia includes high forehead, epicanthal folds, and a triangular mouth. Between episodes the patient will appear normal, with only mild or no developmental delay.

Patients who are poorly managed, particularly those with vitamin B12 -unresponsive variants, might suffer infarcts (metabolic stroke) in the globus pallidus or internal capsule and may develop hemiplegia and acute dystonia. Failure to thrive and failure of linear growth are common. As in propionicacidemia, anorexia and chronic vomiting are usual. The patient may develop acute pancreatitis. y Poorly managed children with methylmalonicacidemia will develop nephropathy due to tubulointerstitial nephritis or less often to urate nephropathy.

Differential Diagnosis. Most considerations listed for propionicacidemia are also true for methylmalonicacidemia; both propionicacidemia and isovalericacidemia present with massive ketonuria during crisis, the differential diagnosis of which is given in the previous section on propionicacidemia. Ihe same criteria that are listed under propionicacidemia should be used to evaluate any child for possible methylmalonicacidemia.

Evaluation. Ihe acute episode is characterized by severe acidosis with massive ketone body accumulation. Initial episode in a newborn is always accompanied by significant hyperammonemia, whereas blood ammonia values are only mildly elevated in repeated episodes. Hypoglycemia is usually moderate and rarely below 3 mM. Ihere may be mild elevation of plasma glycine levels. During acute episodes, neutropenia and thrombocytopenia are common. Poorly controlled patients show hyperuricemia. A definite diagnosis of the disease is made by detecting massive methylmalonicaciduria; a neonate may excrete up to 1 g/day (normal adult, <5 mg/day). Plasma concentrations of methylmalonic acid in crisis may be as high as 0.2 to 2.5 mM (normally not detectable). Levels of propionylcarnitine in blood are elevated both during and between crises. Other organic acids in urine are those seen in propionicacidemia. Mutase activity may be measured in a variety of ways in specialized laboratories. Ihe cblA and cblB mutants are

identified by complementation studies. Clinical follow-up is by determination of blood levels of methylmalonic acid.

Management. Ihe treatment of acute metabolic crisis is similar to those measures described for propionicacidemia. Exceptions for methylmalonicacidemia are the use of overhydration with adequate calories and no requirement for insulin drips. A patient with methylmalonicacidemia in crisis should be given excessive amounts of intravenous fluids, to clear the circulation from methylmalonic acid. Acidosis in methylmalonicacidemia is usually more severe than in propionicacidemia, requiring very large amounts of bicarbonate, which might quickly lead to hypernatremia. In such instances, tromethamine (Iham) 40 ml/kg/day in six divided doses may be used for 2 to 3 days. Ihe intravenous use of carnitine shortens the crisis significantly.

All patients with methylmalonicacidemia are restricted in their intake of isoleucine, valine, threonine, and methionine, using the same diet for patients with propionicacidemia. Every patient with methylmalonicacidemia should be tested for response to vitamin B 12 by administering daily 1 mg hydroxocobalamin intramuscularly. Patients with cblA, methylmalonicacidemia with mutase (-), and half of the patients with cblB or mutase (0) will respond to vitamin B 12 . Ihe outcome in the responsive patient is favorable, requiring less stringent control of protein intake. Protein requirement of vitamin B 12 -unresponsive patients must be individualized, providing a minimal amount of the restricted amino acids that will permit growth but that will not lead to frequent decompensation. Generous amounts of calories are supplied through lipids and carbohydrates. Management of unresponsive methylmalonicacidemia is not easy, requiring enormous effort from physician, dietitian, and parents. Other therapeutic measures include metronidazole, 7.5 mg/kg/d; oral carnitine, 100 to 200 mg/kg/ day; Shohl's solution, 2 to 4 ml/kg/day; and intramuscular hydroxocobalamin, 1 mg every other day. Patients with methylmalonicacidemia tend to be short and obese; human growth hormone has been used to increase growth and lean body mass and to decrease adipose tissue.

Ihere is no treatment for renal disease due to interstitial nephritis. Allopurinol may be used in patients with high uricacidemia. Patients with methylmalonicacidemia who have basal ganglia infarcts might have cblC or cblD mutations, and homocystinuria should always be investigated in any patient with methylmalonicacidemia. No therapeutic measures, other than standard supportive therapy, are available for pancreatitis.

Prognosis. Ihe addition of L-carnitine and metronidazole to the management of this disorder has changed the prognosis. Van der Meer and colleagues y have pointed out that although most patients before 1985 died, those after 1985, when these drugs were introduced, survived with improved general health. Ihe lifestyle of a well-managed patient with methylmalonicacidemia will be normal, without mental retardation, developmental or motor delay.

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