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* Clinic for Special Children, Strasburg Pennsylvania
Kennedy Krieger Institute and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Methods. Family histories and molecular testing for the Y393N mutation of the E1
subunit of the branched-chain -ketoacid dehydrogenase allow us to identify infants who were at high risk for MSD. Amino acid concentrations were measured in blood specimens from these at-risk infants between 12 and 24 hours of age. An additional 18 infants with MSD were diagnosed between 4 and 16 days of age because of metabolic illness.
A treatment protocol for MSD was designed to 1) inhibit endogenous protein catabolism, 2) sustain protein synthesis, 3) prevent deficiencies of essential amino acids, and 4) maintain normal serum osmolarity. Our protocol emphasizes the enhancement of protein anabolism and dietary correction of imbalances in plasma amino acids rather than removal of leucine by dialysis or hemofiltration. During acute illnesses, the rate of decrease of the plasma leucine level was monitored as an index of net protein synthesis. The treatment protocol for acute illnesses included the use of mannitol, furosemide, and hypertonic saline to maintain or reestablish normal serum sodium and extracellular osmolarity and thereby prevent or reverse life-threatening cerebral edema. Similar principles were followed for both sick and well outpatient management, especially during the first year, when careful matching of branched-chain amino acid intake with rapidly changing growth rates was necessary. Branched-chain ketoacid excretion was monitored frequently at home and branched-chain amino acid levels were measured within the time of a routine clinic visit, allowing immediate diagnosis and treatment of metabolic derangements.
Results. 1) Eighteen neonates with MSD were identified in the high-risk group (n = 39) between 12 and 24 hours of age using amino acid analysis of plasma or whole blood collected on filter paper. The molar ratio of leucine to alanine in plasma ranged from 1.3 to 12.4, compared with a control range of 0.12 to 0.53. None of the infants identified before 3 days of age and managed by our treatment protocol became ill during the neonatal period, and 16 of the 18 were managed without hospitalization.
2) Using our treatment protocol, 18 additional infants who were biochemically intoxicated at the time of diagnosis recovered rapidly. In all infants, plasma leucine levels decreased to <400 µmol/L between 2 to 4 days after diagnosis. Rates of decrease of the plasma leucine level using a combination of enteral and parenteral nutrition were consistently higher than those reported for dialysis or hemoperfusion. Prevention of acute isoleucine, valine, and other plasma amino acid deficiencies by appropriate supplements allowed a sustained decrease of plasma leucine levels to the therapeutic range of 100 to 300 µmol/L, at which point dietary leucine was introduced.
3) Follow-up of the 36 infants over >219 patient years showed that, although common infections frequently cause loss of metabolic control, the overall rate of hospitalization after the neonatal period was only 0.56 days per patient per year of follow-up, and developmental outcomes were uniformly good. Four patients developed life-threatening cerebral edema as a consequence of metabolic intoxication induced by infection, but all recovered. These 4 patients each showed evidence that acutely decreased serum sodium concentration and decreased serum osmolarity were associated with rapid progression of cerebral edema during their acute illnesses.
Conclusions. Classical MSD can be managed to allow a benign neonatal course, normal growth and development, and low hospitalization rates. However, neurologic function may deteriorate rapidly at any age because of metabolic intoxication provoked by common infections and injuries. Effective management of the complex pathophysiology of this biochemical disorder requires integrated management of general medical care and nutrition, as well as control of several variables that influence endogenous protein anabolism and catabolism, plasma amino acid concentrations, and serum osmolarity.
Key Words: branched-chain ketoacid dehydrogenase • maple syrup disease • Mennonite • newborn screening • leucine • isoleucine valine • essential amino acid deficiencies • neutral amino acid transporter • blood brain barrier • dystonia • metabolic disease • Guthrie bacterial inhibition assay • tandem mass spectrometry
Abbreviations: MSD, Maple syrup disease • BCKD, branched-chain -ketoacid dehydrogenase • BCAA, branched-chain amino acids • CSC, Clinic for Special Children • MRI, magnetic resonance imaging • L1-NAA-t, L1-neutral amino acid transporter.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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-ketoacid dehydrogenase (BCKD), the second enzyme in the pathway for the degradation of the 3 branched-chain amino acids (BCAA), leucine, isoleucine, and valine. Although a rare genetic disorder in most populations, MSD, by virtue of a founder effect, has an incidence as high as 1 in 200 births in certain Mennonite settlements in Pennsylvania, Kentucky, New York, Indiana, Wisconsin, Michigan, Iowa, and Missouri.1 The complex pathophysiology of MSD is caused primarily by the accumulation of leucine in plasma and organs, a condition referred to as leucinosis. In MSD, metabolic intoxication becomes apparent with relatively mild increases in plasma leucine concentration, whereas there is little apparent toxicity associated with increased levels of isoleucine or valine.2,3 The most severe episodes of biochemical intoxication are caused by catabolism of endogenous protein, which may be provoked by physiologic "stress" and fasting in the neonatal period, and by infections, fasting, exercise, injuries, and surgery in older infants and children.4,5 Acutely sick children or adults with MSD suffer muscle fatigue, epigastric pain, vomiting, and acute neurologic dysfunction manifest as decreased cognitive ability, hyperactivity, anorexia, sleep disturbances, hallucinations, dystonia, ataxia, and stupor. The neurologic syndrome is associated with diffuse subcortical gray matter edema. Death during acute metabolic decompensation results from central transtentorial herniation.2,6 Prolonged deficiencies of 1 or more of the BCAA caused by excessive dietary restriction causes poor growth, anemia, breakdown of mucosal barriers, immunodeficiency, as well as dysmyelination, abnormal neuronal dendritic branching, poor head growth, and global developmental delays.2,6 In addition, as discussed below, neuronal deficiency of tyrosine secondary to leucinosis may contribute directly to acute dystonia and choreoathetosis. In the neonate with classical MSD, normal postpartum endogenous protein catabolism causes a progressive increase in the levels of all 3 BCAA from birth, independent of dietary protein intake. Within 48 hours of delivery, untreated infants develop ketonuria and become irritable, lethargic, difficult to feed, and dystonic. By age 4 days, neurologic signs include dystonia, apnea, alternating lethargy and irritability, seizures, and signs of focal cerebral edema.7 By the time of diagnosis, many infants with MSD are severely encephalopathic and require emergency therapy to lower the BCAA levels and prevent brain injury.
Although MSD is one of the most intensely studied inborn errors of amino acid metabolism, there is little consensus regarding the management of either the acutely sick newborn or the prospectively identified newborn, or the older patient with MSD. We present here 1 approach to care of these patients.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Clinical and Laboratory Assessment of Patients
Neonates 1 to 32 (Table 1) were examined and managed, both at birth and subsequently, by authors D.H.M. and D.L.R. For patients (numbers 33–36), who were initially treated as neonates by other physicians, data for Table 1 were taken from their medical records.
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Treatment Plan
The approach to management of the asymptomatic neonate is summarized in Table 2. Asymptomatic, at-risk infants were managed exclusively with oral feedings. Treatment of the sick neonate is summarized in Table 3. The variables managed and the goals of therapy listed in Table 3 were the same for enteral or intravenous management. Reversal of acute metabolic intoxication depended on lowering plasma and tissue leucine concentrations through the inhibition of protein catabolism and enhancement of protein synthesis. In our approach, sustained control of metabolism by enhanced anabolism was favored over the more invasive, less physiologic removal of leucine by dialysis or hemofiltration. During acute leucine intoxication, plasma concentrations of isoleucine and valine were maintained between 500 to 800 µmol/L, which is well above their physiologic ranges, to increase the transport of these essential amino acids into organs, including the brain, in the face of competition from increased levels of blood leucine. To prevent deficiencies of the other 6 L-neutral amino acids that compete with leucine for membrane transport, essential amino acids were provided by proprietary MSD formulas and by supplementation of individual amino acids. Glutamine and alanine 250 mg/kg for 24 hours were also routinely added to the formula or intravenous solution to help limit protein catabolism.10–12 For hospitalized children who demonstrated or who were at risk of hyponatremic cerebral edema, hypertonic saline, mannitol, and furosemide were used to maintain serum sodium concentrations between 140 to 145 mEq/L and serum osmolarity above 290 mosm/L.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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MSD was diagnosed in 18 infants after age 3 days, 13 because of illness and 5 because of an abnormal neonatal screening test. The distinctive maple syrup-like odor of MSD was present in the cerumen at the time of diagnosis in all infants examined by the first author, as early as 12 hours after birth. Urinary ketones were large and the urine DNPH test was positive by the fourth day in all untreated cases. At the time of hospitalization, all 18 sick infants had dystonic posturing and markedly abnormal serum leucine to tyrosine (Leu/Tyr) molar ratios (22–140; normal: 0.5–3.5). Ten neonates had full fontanels, and 5 of these also had seizures. The average length of hospitalization for infants with MSD diagnosed between ages 4 and 15 days was 6 days with a range of 4 to 8 days. Infant 32, a Mennonite from Kentucky where neonatal screening for MSD is not done, was not identified until age 16 days. This infant had severe dystonia, diffuse cerebral edema, seizures, and respiratory failure. His hospital course was prolonged by Candida albicans sepsis, probably from an infected femoral catheter.
Of the 32 patients treated within the first 2 weeks after birth, 21 were managed by enteral therapy alone, 8 by enteral formula with intravenous dextrose and lipid, and 3 by enteral formula with intravenous dextrose and lipid combined with a BCAA-free parenteral amino acid mixture prepared in our hospital pharmacy. For the hospitalized patients, the plasma leucine level decreased to <400 µmol/L by 2 to 4 days after diagnosis, regardless of the treatment method used.
The total medical cost for outpatient diagnosis and management of MSD for the first 14 days at CSC was between $200 to $400. This compares with a daily cost of $500 to $1200 in the general hospital that serves Lancaster County, and with total neonatal hospitalization costs of $17 500 to >$100 000 at the major pediatric centers that serve the same patient population. The variation in hospital costs depended primarily on the number of days in intensive care units, the cost of the MSD parenteral amino acid solution, the level of nursing care required, and the severity of illness (Table 1).
Patient Follow-up
Patients listed in Table 1 have been managed over 11 years (1990–2001) for a total of 219 patient years of follow-up. Beyond the neonatal period, the rate of hospitalization during the first year was 0.56 days per patient with a range from 0 to 4 days, and 25 (70%) of 36 infants had no hospitalizations. Over the 11-year period, there were 373 hospital days for an overall hospitalization rate of 0.94 days per patient per year of follow-up. However, single hospitalizations for 2 patients—30 days for patient 17 and 63 days for patient 34—accounted for 25% of these hospital days. Of the remaining 34 patients, 6 had no hospitalizations, and all averaged <1 day in the hospital per year of follow-up. Four patients developed life-threatening cerebral edema during intercurrent infectious illnesses but recovered fully. Two patients (17 and 34) also developed acute pancreatitis with epigastric pain, vomiting, and elevated serum amylase and lipase activities. Both patients recovered fully. In patient 32, cerebral edema and hyponatremia were associated with increased MRI T2 signal throughout deep gray matter and a plasma natriuretic factor level greater than 250 pg/mL (normal: 20–77 pg/mL) and urine sodium concentrations as high as 213 mEq/L.
After the newborn period, all metabolic illnesses and hospitalizations were associated with common childhood illnesses, such as otitis media streptococcal pharyngitis, gastroenteritis, and appendicitis. During such illnesses, plasma leucine levels increased because of endogenous protein catabolism, regardless of restriction of dietary leucine. None of these hospitalizations were necessary because of high leucine levels resulting from dietary indiscretion. Recurrent otitis media was the most common cause of outpatient visits and metabolic illnesses and required tympanostomy tubes in 12 (33%) of 36 patients. Chronic and recurrent mucosal candidal infections also were common. Fractured limbs occurred during falls in 6 patients, provoking metabolic illnesses that required 48 to 72 hours of outpatient sick-day management because of the stress of injury and/or limb immobilization.
Life-threatening illnesses developed in patients 27 and 34 after a series of respiratory tract infections. In both patients, intermittent restrictions of dietary leucine over a period of several weeks contributed to essential amino acid deficiency syndromes with growth arrest, breakdown of mucosal membranes, and an apparent acquired immunodeficiency state. Although patient 27 recovered quickly after changes in her dietary management, the other infant developed invasive Candidiasis and required prolonged hospital care.
Neurologic Outcomes
Neurologic examinations, gross motor development, and speech have been normal in 34 of 36 patients. Patient 33, who was severely ill as a neonate, is an "A" student in her fourth year of school. Patient 34, who was ill as a neonate and had a prolonged hospitalization at 2 years of age for fungal sepsis, cerebral edema, and coma, has regained normal reflexes and age-appropriate fine and gross motor skills but does have attention deficit disorder, which worsens when his plasma leucine level is high. At 8 years old, he is treated with methylphenidate (Ritalin) but attends a regular school program and learns age-appropriate material. The other 7 prospectively treated children attend school in regular classrooms.
Two patients, 32 and 36, who were severely ill at diagnosis at age 16 and 10 days, respectively, have lower limb hyperreflexia, positive Babinski reflexes, mild gross motor delays, and language delays. In the neonatal period, patient 36 had chronic elevations of plasma leucine, prolonged deficiency of valine and isoleucine, hyponatremia, and cerebral edema. When first examined at CSC at 12 months of age, she had signs of corticospinal tract dysfunction and delayed development. Nevertheless, both of these patients currently are able to communicate, feed and care for themselves, have normal hand control, can walk and run, and attend school with normal children. Patient 36 is in a classroom for slower learners.
In 1995, we recognized an association between hyponatremia, decreased serum osmolarity, and progressive cerebral edema in patients with MSD during episodes of acute metabolic intoxication. Our treatment protocol includes routine use of intravenous furosemide, 5% saline, and mannitol. Patient 22 was the first sick MSD neonate managed with this protocol. At diagnosis at age 9 days, he was semi-comatose, had a plasma leucine level of 2067 µmol/L, and a serum sodium of 132 mEq/L. Despite hyponatremia, urinary sodium losses in excess of 15 mEq/kg in 24 hrs were documented. Hypertonic saline was therefore given intravenously to replace urinary sodium losses and maintain the serum sodium level above 140 mEq/L. The patient’s nutritional goals (Table 3) were met by enteral feedings with MSD formula. His serum leucine level decreased from 2067 to 100 µmol/L in 72 hours. By hospital day 3 (age 12 days) he was able to take all feedings from a bottle and was discharged from the hospital the next day. Despite late recognition of MSD, his fontanel remained soft throughout the hospital course and his head circumference increased by only 0.5 cm. He had no seizures or vomiting, and his neurologic examination was normal by discharge. His growth and development have been the same as that of his unaffected fraternal twin brother. Patients 25 and 26, in whom MSD was diagnosed on day 6, and who had evidence of free water retention, renal salt wasting, and hyponatremia, were similarly managed and had equally rapid reversal of their encephalopathy.
Dystonia was seen in all intoxicated neonates with MSD. Particularly characteristic was dystonic rigidity of the arms and hands, opisthotonic posturing, rigidity of the jaw and hypopharnyx with dysphagia. Athetoid movements and slow bicycling of the arms and legs also occurred frequently. As is characteristic of basal ganglial dysfunction, dystonia, and the athetoid movements increased with agitation and stopped during periods of sleep or unconsciousness. As shown in Table 1, dystonia in the MSD infants was associated with high serum leucine to tyrosine molar ratios, which ranged from 26 to 366 (normal range: 0.5–3.5). Patients 30, 28, and 24, who were given enteral tyrosine supplements to lower the (Leu/Tyr) ratio to <5, showed resolution of dystonia within 12 to 24 hours after the start of treatment.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Improvements in Management and Outcome
In the last 30 years, the treatment of the sick neonate with MSD has improved substantially, partly from the cumulative experience of the metabolic community and partly from improved resources, such as MSD-specific elemental amino acid formulas and parenteral nutritional solutions. The oldest patient with MSD currently followed at CSC remained in a university hospital for 6 months after her diagnosis in 1967. She was semi-comatose for months, had frequent and prolonged seizures, and did not regain her birth weight for 4 months. At 33 years old, she is fully dependent on others for daily care. Her niece (patient 3) was asymptomatic when MSD was diagnosed at 14 hours of age, and MSD formula was started. She remained at home after birth, and in 6 years of follow-up, she has not been hospitalized, and she has grown and developed normally. Such ease and success in the treatment of neonatal MSD diagnosed in the first day has been made possible, in part, by the availability of rapid methods of amino acid chromatography that permit detection of an increased leucine/alanine ratio within less than an hour after the first blood sample is drawn.
Diagnosis of MSD in the Neonate
Few studies have been published on the prospective diagnosis and treatment of the neonate with MSD. In one of the first and most comprehensive of such studies, DiGeorge et al7 described the management of 12 at-risk neonates with oral glucose-water or MSD formula, while testing and waiting for a diagnostic rise in the level of 1 or more branched-chain amino acids. The authors showed for the first time a rapid and diet-independent increase in the plasma level of leucine during the first 24 hours in the 3 patients in whom MSD was diagnosed prospectively. They also were the first to suggest that although the level of leucine might not exceed the "normal" range for >24 hours, the increasing level of leucine in a neonate with MSD compared with the decreasing leucine level of unaffected infants would be diagnostic by 12 hours of age. Of note, 1 of the unaffected siblings of our MSD patients had an initial leucine level of 575 µmol/L, which exceeded that of all but 1 of the 18 infants with prospectively diagnosed MSD. However, the leucine/alanine ratio in the same specimen was much lower than that of any of the MSD infants (Table 1). Because of the abnormal decrease in the plasma alanine level and abnormal rise in the plasma leucine level that are characteristic of MSD, the leucine/alanine ratio provides a more sensitive measure of the abnormal biochemistry of MSD than the leucine level alone. As DiGeorge et al7 concluded from their experience with 1 MSD patient fed MSD formula, a substantial intake of MSD formula from birth can blunt or possibly even prevent a diagnostic rise in the level of the BCAAs. However, as shown in Table 1, the leucine/alanine ratio is indeed a sensitive and accurate test for MSD, which has been definitive in all our patients with MSD tested between 12 and 24 hours of birth, before there were any clinical signs of the disorder other than the odor of maple syrup in cerumen. The ability of the leucine/alanine ratio in children not fed MSD formula to diagnose MSD definitively in the first 24 hours allows us to provide at-risk infants and their families an almost normal birth experience, usually at home attended by a midwife, and at no substantial risk to the affected infant.
The advantages of early diagnosis of MSD for both the child and the family are obvious. As shown in Table 1 for patients 1 to 18, when treatment for MSD is started before 72 hours of age, morbidity, mortality, and the cost of medical care are markedly reduced. Our experience also shows that informed health care providers can diagnose MSD between 1 to 4 days of age by clinical signs combined with the distinctive maple syrup odor of cerumen, which is the earliest and most specific sign of the disease. In contrast, the maple syrup odor in fresh urine may be difficult to detect in the first few days of life, and may become more apparent only when a urine-soaked diaper is allowed to dry. Ketonuria and a positive urinary DNPH reaction are important confirmatory tests but may not be abnormal before the age of 3 days. Because ketosis is unusual in a normal neonate, even with prolonged fasting or severe illness, ketonuria in a neonate should always be considered pathologic and should be assumed to indicate an underlying metabolic disorder. In the neonate with ketonuria, plasma amino acid and urine organic acid analysis must be done emergently, and empiric metabolic therapy should be started pending results of biochemical tests.
Unfortunately, the advantages of diagnosis of MSD in the first 4 days of life are lost to neonatal screening programs that use the Guthrie bacterial inhibition method for screening. The Guthrie test lacks sensitivity before 24 hours of age, requires a 24-hour incubation, and has a relatively high false-positive rate, all of which delay diagnosis and treatment of MSD.13,14 Many state newborn screening programs require that specimens be collected after 24 hours of age, and results are typically reported when infants are between 6 and 10 days of age, by which time all infants with classic MSD are very sick. If, as in New York State, neonatal screening samples are not collected until 3 days after delivery and results are not reported until age 10 to 14 days, all MSD infants identified by screening will be severely ill and at high risk for neurologic injury and death. Fortunately, however, the use of highly sensitive and accurate tandem mass spectrometry to quantify amino acids in whole blood filter paper specimens shortens the time to diagnosis in those states and laboratories where it is being used.14,15 Tandem mass spectrometry permits earlier collection of specimens, provides immediate and accurate determination of the leucine/alanine ratio, avoids false-negatives caused by antibiotics, and eliminates the 24-hour incubation period of the Guthrie test, all of which should allow diagnosis and initiation of therapy for MSD and other amino acid and organic acid disorders between 3 and 5 days of age.
Determinants of Outcome
Common teaching is that the developmental outcome is poor for infants in whom MSD is diagnosed after 7 days of age, and uniformly bad when the diagnosis is made after 14 days.16–18 However, as indicated in Table 4, the age at diagnosis is only 1 factor that determines neurologic outcome in children with MSD. Our most severely ill infant, patient 32, was admitted to a hospital at age 10 days, found to have MSD by amino acid analysis only at 16 days when the leucine level was 2443 µmol/L, and transferred to our care at age 18 days. His neonatal course was complicated by cerebral edema, seizures, and respiratory failure. However, within 36 hours after admission, and with combined enteral and parenteral feeding with supplemental isoleucine and valine, his serum leucine level had fallen to 300 µmol/L, and he was weaned from the ventilator. By hospital day 7, cerebral edema had resolved, seizures stopped, and full oral feeds were established. Despite this difficult neonatal course, he sat at 8 months of age, walked by 20 months, has only mild residual lower extremity hyperreflexia, and now, at 3 years old, speaks both German and English.
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Cerebral Edema and Hyponatremia
High leucine concentrations seem to impair the normal mechanisms by which cell volume is regulated. In the setting of leucine intoxication, a decrease in the serum sodium concentration leads to abnormal redistribution water into intracellular space. Early stages of brain edema are readily detected by magnetic resonance imaging (MRI) and correlate with neurologic findings (Fig 1). Increased cellular enzymes and organ tenderness suggest that edema also develops in cells of muscle, liver, and pancreas. Sodium is 1 of the major contributors to extracellular osmolarity. In our experience, critical brain swelling and abnormal brainstem function develops in patients with leucinosis when the serum sodium level decreases by only 8 to 10 mEq/L. The hyponatremia that commonly occurs in patients with MSD can be explained, in part, by natriuresis induced by atrial naturetic hormone. Patient 32 had urinary sodium losses in excess of 15 mEq/kg in 24 hours, which were associated with increased MRI T2-water signal in the hypothalamus and high plasma naturetic hormone levels. This may represent a form of the cerebral salt-wasting syndrome19,20 but may also be a physiologic response to circulatory volume expansion from intravenous or enteral solutions necessary to deliver sufficient calories and amino acids to support protein synthesis. Decreased serum sodium and osmolarity may also be cause by increased circulating vasopressin. We have recently encountered rapidly evolving cerebral edema and high plasma vasopressin levels in an ill patient with MSD who presented with protracted vomiting, hypernatremic dehydration, and hyperglycemia—3 factors known to be stimulants for vasopressin release.
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Based on the pioneering studies of amino acid transport of Halvor Christensen21,22 and Quentin Smith,23 we hypothesize that the vulnerability of MSD patients to cerebral edema arises from 3 interrelated factors: 1) intracellular entrapment of osmotically active amino acids caused by high intracellular leucine levels, 2) impairment of the normal regulatory volume defense of brain cells including disruption of intracellular protein synthesis by unbalanced transport of essential L-neutral amino acids, and 3) pathologic or iatrogenic decreases of serum sodium and serum osmolarity with rapid pathologic water flux into cells.
Medical Care During Intercurrent Illnesses
A second reason for poor outcome in patients with MSD is inadequate planning of follow-up care. Common infections and injuries provoke rapid and significant biochemical disturbances and often require changes in management to prevent metabolic intoxication. All hospitalizations of the 36 patients in Table 1 were made necessary by common intercurrent illnesses. A follow-up program for patients with MSD that does not specifically plan for clinical and metabolic evaluations during common intercurrent illnesses will not have optimal patient outcomes. Achievement of normal developmental milestones in almost all of our patients treated in the last 11 years indicates that carefully managed therapy for MSD allows normal development. However, a child with MSD who has a normal neurologic examination, does well in school, and has normal scores on formal tests when MSD is well-controlled may only hours later become encephalopathic as acute biochemical intoxication evolves. The adverse effects of MSD on the health of the patient can be prevented only if general medical care and metabolic management are well-integrated at all ages.
Essential Amino Acid Deficiencies
The third factor in the poor outcome for neonates and infants with MSD arises from poor management of acute and chronic essential amino deficiencies. The clinical syndrome of chronic isoleucine and valine deficiency in MSD was first described and effectively managed by supplementation with isoleucine and valine many years ago.24,25 However, the equally important need for supplementation with isoleucine and valine during acute intoxications is commonly overlooked. During the initial period of management of a sick neonate, as outlined in Table 3, a high rate of intracellular protein synthesis must be induced to consume excess leucine and thereby reduce plasma and tissue leucine concentrations. Approximately 10% of normal infant weight gain is protein.26 We can achieve net whole body protein synthetic rates of 0.8 to 1.5 g/kg in 24 hours during the acute phase of therapy. Because average human protein is 10% leucine by weight, 80 to 120 mg/kg of leucine is removed from the body pools each day to support this rate of protein synthesis. Not surprisingly, then, because isoleucine and valine each constitute approximately 6% of the weight of human protein, we find that isoleucine and valine typically must be given at a rate of 60 to 100 mg/kg/d to support maximal rates of protein synthesis and thereby achieve an optimal rate of decrease of the pathologically increased leucine concentrations. Furthermore, based on the studies of Christensen and Smith,21,22 plasma levels of isoleucine and valine must be maintained above the physiologic range (eg, 500–800 µmol/L) at the outset of acute therapy to compete effectively with the high levels of leucine for transport into cells. There is little toxicity associated with increased plasma concentrations of isoleucine and valine,2,27 but failure to provide sufficient isoleucine, valine, and other essential amino acids for protein synthesis during acute metabolic decompensation slows the rate of decrease of leucine and prolongs encephalopathy.
The role of essential amino acid deficiencies in MSD is more complex than is first apparent. Nine amino acids—phenylalanine, tryptophan, leucine, methionine, isoleucine, tyrosine, histidine, valine, and threonine—gain entry into brain and other organs by the L1-neutral amino acid transporter (L1-NAA-t). Leucine has a high affinity for the transporter (a low Km), whereas tyrosine, histidine, valine, and threonine have low affinities for the transporter. High plasma concentrations of leucine, derived primarily from endogenous catabolism, cause low rates of uptake and intracellular deficiencies of other L-neutral amino acids in other tissues, especially the brain.21,22 The special vulnerability of the brain to unbalanced transport of L-neutral amino acids is especially important. The role of specific L-neutral amino acids deficiencies in the evolution of the acute neurologic syndrome of MSD is suggested by our observations about dystonia. Rapid resolution of dystonia in patients 24, 28, and 30 after supplementation with tyrosine and correction of the plasma leucine/tyrosine ratio suggests that the dystonia of MSD may arise from acute deficiency of tyrosine and, secondarily, dopamine in the striatum. Acute choreoathetosis, sensitivity to phenothiazines, and attention deficit disorder are other common problems in patients with MSD and suggest that depressed dopamine and norepinephrine synthesis may have a significant role in the neuropathophysiology of the disease. Not only does tyrosine have a low affinity for the L1-NAA-t but the formulas and intravenous amino acid mixtures used to manage MSD contain very low concentrations of tyrosine because of its limited solubility. Kinetic studies of the L1-NAA-t by Quentin Smith et al23 predict that at a leucine/tyrosine ratio of 100, the rate of transport of tyrosine would be reduced to <10% of normal. In animal studies, a 30% reduction in the normal in flow of one essential amino acid is associated with inhibition of protein synthesis in the central nervous system.28 Similar reductions in transport of valine, histidine, and threonine during acute leucinosis also are predicted by the kinetics of L1-NAA-t.
Recurrent and chronic inhibition of protein synthesis in the brain results in the paucity of dendritic branching and the underdevelopment of myelin, which is characteristic of the brains of poorly-managed patients with phenylketonuria and MSD29 as well as the brain of children who die after chronic severe protein malnutrition.30 Our clinical observations suggest that neurotransmitters derived from tyrosine, tryptophan, and histidine are affected by acute disruptions of amino acid transport. As plasma leucine levels increase, patients with MSD develop dystonia, ataxia, and loss of fine motor skills. Sick children with MSD also show changes in memory, appetite, wakefulness, and behavior, which not only evolve rapidly, but also reverse rapidly with correction of relative concentrations of leucine to the other L-neutral amino acids.
Our understanding of the pathophysiology and treatment of MSD has been fundamentally changed through an appreciation of the work of Halvor Christensen and Quentin Smith.21,23,31 MSD, the disease caused by a deficiency of BCKD, is best understood as a disorder of interorgan amino acid flux caused by leucinosis. To use Halvor Christensen’s term, MSD is a disease of amino acid homeorhysis.31 Indeed, the complex natural history of MSD can be best explained in terms of the influence of leucine on the transport of the amino acids out of and into cells and organs. MSD is a difficult disorder to manage because it disrupts several fundamental and complex cellular and physiologic systems, but it is also an important disorder to study for the same reasons. In patients with absent BCKD activity, the underlying mutations and enzyme defects have no relevance to the disease process other than causing a pathologic accumulation of leucine. Little insight into the natural history of the disease has come neither from the recent plethora of molecular biological studies of MSD nor from detailed kinetic and stable isotopic studies of enzyme kinetics and in vivo function. Instead, the principles of medical care and insights into biology and pathophysiology of MSD derive almost entirely from frequent examination of sick and well patients, careful observation of the natural history of disease, and amino acid profiles combined with careful reading of an old literature about water, electrolytes, and amino acid metabolism in nutrition and physiology.
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ACKNOWLEDGMENTS |
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We thank Lisa Kratz, PhD, for her help with the assay for the Y393N mutation.
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FOOTNOTES |
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Reprint requests to (D.H.M.) Clinic for Special Children, Box 128, Strasburg, PA 17579
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REFERENCES |
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 S. Kolker, S. W. Sauer, J. G. Okun, G. F. Hoffmann, and D. M. Koeller Lysine intake and neurotoxicity in glutaric aciduria type I: towards a rationale for therapy? Brain, August 1, 2006; 129(Pt 8): e54 - e54. [Full Text] [PDF]
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W. J. Zinnanti, J. Lazovic, E. B. Wolpert, D. A. Antonetti, M. B. Smith, J. R. Connor, M. Woontner, S. I. Goodman, and K. C. Cheng A diet-induced mouse model for glutaric aciduria type I Brain, April 1, 2006; 129(4): 899 - 910. [Abstract] [Full Text] [PDF]
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 M. Yudkoff, Y. Daikhin, I. Nissim, O. Horyn, B. Luhovyy, A. Lazarow, and I. Nissim Brain Amino Acid Requirements and Toxicity: The Example of Leucine J. Nutr., June 1, 2005; 135(6): 1531S - 1538S. [Abstract] [Full Text] [PDF]
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H. Mitsubuchi, M. Owada, and F. Endo Markers Associated with Inborn Errors of Metabolism of Branched-Chain Amino Acids and Their Relevance to Upper Levels of Intake in Healthy People: An Implication from Clinical and Molecular Investigations on Maple Syrup Urine Disease J. Nutr., June 1, 2005; 135(6): 1565S - 1570S. [Abstract] [Full Text] [PDF]
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 E. J. Schoen, J. C. Baker, C. J. Colby, and T. T. To Cost-Benefit Analysis of Universal Tandem Mass Spectrometry for Newborn Screening Pediatrics, October 1, 2002; 110(4): 781 - 786. [Abstract] [Full Text] [PDF]
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