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Maple Syrup Urine Disease (MSUD)

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This acute illness protocol is a guideline for healthcare professionals treating the sick infant or child who is known to have maple syrup urine disease (MSUD), an organic acid disorder. The protocol was developed at Boston Children’s Hospital under the direction of Dr. Harvey Levy, Senior Physician in Medicine/Genetics and Dr. Jonathan Picker, Fragile X Program Director, and was updated by Dr. Patroula Smpokou, Clinical Genetics Fellow.

Disclaimer
Metabolic crises in infants and children with organic acid disorders are complex medical emergencies and must be treated as such to avoid death or serious brain injury. This protocol is only a guideline and should not be used for definitive treatment without metabolic consultation. It is essential to call or page the on-call genetics/metabolism fellow, or failing this, the on-call metabolic attending at your hospital or nearest pediatric tertiary care center, as rapidly as possible.
Please read our Terms of Use.

Introduction

Maple Syrup Urine Disease (MSUD) is an autosomal recessive organic acid/amino acid disorder due to a defect in the Branched Chain Ketoacid Dehydrogenase (BCKD) enzyme, which catalyzes the breakdown of branched chain ketoacids. These ketoacids form from the breakdown of the branched chain amino acids (BCAA): leucine, isoleucine, and valine. As a consequence, the ketoacids and their precursor BCAA accumulate in blood with the toxic metabolic components being leucine and the ketoacids.

Pathophysiology

Catabolic stress such as normal perinatal catabolism or an acute illness (e.g. infection, injury, surgery, febrile illness) produces endogenous protein breakdown leading to increase in the BCAA and related branched chain ketoacids. When excessive protein is ingested, a similar increase in available amino acids occurs.

Metabolic consequences include:

Increased ketoacids -> ketosis, metabolic acidosis
Increased glucose utilization -> ketosis
Increased leucine -> brain toxicity

Acute Presentation

  • Lethargy, irritability
  • Poor feeding
  • Nausea, vomiting
  • Hypotonia, hypertonia, dystonia
  • Ataxia
  • Seizures
  • Coma
  • Maple syrup odor (urine, ear wax)

Laboratory findings:

  • Metabolic acidosis with anion gap
  • Ketosis, ketonuria
  • Increased BCAA (plasma amino acid analysis)

The types of presentations of MSUD include the classic (most severe and most common form at risk for major metabolic crisis in newborn and later periods), intermediate (elevations in metabolites with little or no risk for metabolic crisis), and intermittent (asymptomatic but at risk for metabolic crises during acute illness, usually infection).

Parents of children with diagnosed metabolic disorders know the signs of decompensation in THEIR children. It is important to listen to the parents’ insight into their child’s illness.

Immediate Assessment

  • Dextrose stick for blood glucose
  • Vital signs, cardiovascular stability
  • Hydration status
  • Presence of fever; signs of infection
  • Neurologic status; evidence of increased intracranial pressure, “leucine encephalopathy”**

Labs

Blood

- Venous blood gas for blood pH
– Electrolytes, measured CO2, glucose
– Renal function (BUN, creatinine)
– Plasma amino acids (high leucine, isoleucine, valine; Alloisoleucine in blood is pathognomonic of MSUD)
– CBC, differential WBC count, platelet count
– Blood culture (if indicated)
– Serum amylase, lipase

Urine

- Urinalysis for specific gravity and ketones
– Urine for organic acids
– Urine DNPH test for ketoacids (if available)
– Urine culture (if indicated)

**NOTE: increased concentrations of leucine are toxic to the brain and accumulations may result in cerebral edema. Caution should be exercised when considering the need for a lumbar puncture.

Management

Specific management guidelines are listed here, with details below:

  1. Stop all protein intake
  2. Provide hydration with high caloric supplementation
  3. Correct metabolic abnormalities
  4. Eliminate toxic metabolites
  5. Treat precipitating factor(s)
  6. Provide cofactor supplementation
  7. Prevent associated sequelae

1. Protein intake

All protein intake should be halted for 48-72 hours in the setting of a metabolic crisis. When the patient is recovering, protein should be introduced slowly in the forms of parenteral nutrition and/or a specialized formula mixture that contains only “non-offending” aminoacids (see “hydration/caloric supplementation” category below).

2. Hydration/caloric supplementation

In a metabolic crisis, a patient with MSUD should receive high rate intravenous fluids (either peripherally or via a central venous catheter) for rehydration purposes and also for provision of calories. High dextrose-containing fluids (10% glucose) should be administered with the addition of electrolytes (half or full normal saline, and also potassium if urine output is adequate and renal function is sufficient) at the high rate of 1.5 times maintenance rate. Intravenous fluids should be maintained until oral fluids are tolerated.

Any patient with MSUD in metabolic crisis should receive high caloric supplementation to achieve an anabolic state (120-140 kcal/kg/day). Catabolism precipitated by any stressor can contribute to underlying metabolic decompensation and promote worsening metabolic acidosis, and ketosis. An intravenous lipid infusion consisting of even-chain fatty acids (e.g. intralipid) should be considered to provide increased calories.

Amino acid therapy may be very beneficial in facilitating clinical improvement but should be implemented only by or under the direction of a physician and/or nutritionist with experience in metabolic management.  Providing an amino acid preparation which excludes the offending amino acids (i.e., leucine, isoleucine, and valine) stimulates anabolism. Supplements of isoleucine and valine are added to maintain their levels above normal. This reduces the transport of leucine into brain during the initial crisis period. If the patient is not significantly compromised neurologically, this preparation can be provided enterally, either orally or by nasogastric tube. Where there exists a high risk for aspiration or other contraindication to enteral feeding, the patient can be given a specialized parenteral MSUD amino acid solution available through specific pharmacies.

3. Correct metabolic abnormalities

a. Metabolic acidosis/ketosis: this should slowly correct with rehydration and high caloric intake; if serum bicarbonate is below 14 meq/L and blood pH < 7.2, give IV bolus NaHCO3 as 2.5 meq/kg over 30 minutes, then 2.5 meq/kg/day until serum bicarbonate is 24-28 meq/L.
Aims are:
— serum bicarbonate level over 24 meq/L
— absence of ketones in urine
— negative urine DNPH test

b. Maintain serum sodium at 140-145 meq/L. Monitor urine sodium output to establish loss and replacement requirement. As serum sodium approaches 140-145 meq/L, reduce IV fluids to D10/ 1/2 normal saline and monitor serum sodium closely (hyponatremia enhances brain edema). After 24 hours, adjust sodium intake to provide 4 meq/kg/day. Too much sodium will complicate fluid management.

c. Measure plasma amino acids every 12 hours. The goals for BCAA levels during an acute crisis should be:
— leucine  < 300 umol/L
— isoleucine  100-300 umol/L
— valine  200-400 umol/L

It is important to realize that isoleucine and valine levels may drop rapidly and very low levels (isoleucine < 100 umol/L and valine < 200 umol/L) will keep the leucine level from dropping by limiting protein synthesis (and increase the blood:brain barrier transport of leucine due to less inhibition by isoleucine and valine; increased brain leucine produces or enhances brain edema).  Add isoleucine and valine at 100-150 mg/kg/day to achieve the goal levels.

d. If blood glucose rises > 200 mg/dL with high IV dextrose infusion, begin insulin infusion at 0.05-0.1 unit/kg/hr until blood glucose is controlled.

4. Eliminate toxic metabolites

Hemodialysis: this is indicated in cases of intractable metabolic acidosis, severe electrolyte disturbances, and/or if patient is comatose. Also, hemodialysis should be a last resort but may be lifesaving in a neonate who presents with coma and seizures and in whom IV therapy may not correct the profound metabolic derangements in time to prevent death from cerebral edema with brain stem compression. This mode of intervention should be instituted in consultation with a pediatric nephrology service.

5. Precipitating factors

Acute metabolic decompensation in a patient with MSUD is almost always precipitated by a stressor, such as infection, injury, surgery, hormonal changes, or significant dietary changes (involving increased protein intake). It is of utmost importance to identify and address the precipitating factor for the patient’s metabolic decompensation as treatment of the stressor will facilitate treatment of the metabolic derangements.

Infection: Antibiotics should be provided to treat the particular infection.

Surgery: Prevention of metabolic decompensation as a result of the stress of surgery requires intravenous fluids with D10 prior to and after surgery until oral fluids are tolerated, avoiding prolonged fasting to the extent possible, addressing pain issues, and providing adequate calories to promote fast healing.

Hormonal Changes: The specific situation needs to be assessed and possible dietary changes should be undertaken in accordance with the patient’s hormonal status (e.g. puberty, growth spurt, menarche, thyroid disorder).

Change in Diet: A change in the patient’s diet, with excessive protein intake, should be assessed since this would be an easy situation to address by adjusting the protein intake.

6. Cofactor supplementation

Some patients with MSUD are responsive to thiamine supplementation (in the long-term, not during an acute metabolic episode). These patients are more likely to have intermediate rather than classic MSUD with persistent elevations of MSUD metabolites but no major metabolic crises.

7. Clinical sequelae associated with an acute crisis

a. Cerebral edema: If neurological signs develop or worsen (vomiting, lethargy, hyperreflexia, clonus), suspect cerebral edema. Critical edema most often occurs during IV therapy, either due to low serum sodium (below 135 meq/L) or continued ketosis and vomiting. Brain edema (with associated brain stem herniation) is the most frequent cause of death in MSUD. If cerebral edema is suspected, obtain brain CT or MRI. If cerebral edema is confirmed, infuse mannitol at 1- 2 grams/kg over 30-40 minutes. Add IV lasix for diuresis but carefully monitor serum sodium to maintain concentration in the 140-145 meq/L range. One can infuse hypertonic saline to maintain sodium in this range.

b. Vomiting is the nemesis of MSUD. It provokes and/or exacerbates ketoacidocis and complicates enteral therapy. Zofran at 2-4 mg every 6-8 hours can be effective in controlling vomiting.

c. Acute pancreatitis: this can sometimes accompany acute metabolic episodes. Monitor serum amylase and lipase.

Monitoring the Patient

Clinical parameters

  • Mental status
  • Hydration status/fluid balance/oral intake
  • Evidence of bleeding (if thrombocytopenic)
  • Symptoms of infection (if neutropenic)
  • Monitor for signs/symptoms of renal failure

Biochemical parameters

  • Electrolytes, measured CO2, glucose, blood gases (q 4-6 hours or as indicated)
  • CBC with differential, platelets (if needed)
  • Renal function (if needed)
  • Urine for ketones and specific gravity with every void
  • Plasma amino acids (once daily)

Recovery

The patient should be kept NPO until his/her mental status is improved. Anorexia and nausea/vomiting during the acute crisis make a significant oral intake unlikely and can exacerbate the ketoacidosis. Once the patient is stable and accepting enteral feeding, the plasma amino acids must be monitored daily to reestablish amino acid homeostasis. On the basis of these levels, the medical formula with added source of branched-chain amino acids and the low protein foods are adjusted to aim for plasma levels as follows:

  • leucine : 100-200 umol/L
  • isoleucine : 100-200 umol/L
  • valine: 200-400 umol/L
  • other amino acids: in the normal range

This will require careful attention to the amount of medical formula ingested, the amount of protein added to the formula, the amount of low protein foods ingested and the amount of supplemental isoleucine and valine added to the formula (each supplement should be available in the pharmacy as a 100 mg/10 ml solution). Dietary treatment should only be done by or with the guidance of a metabolic physician and nutritionist.

Disclaimer
Metabolic crises in infants and children with organic acid disorders are complex medical emergencies and must be treated as such to avoid death or serious brain injury. This protocol is only a guideline and should not be used for definitive treatment without metabolic consultation. It is essential to call or page the on-call genetics/metabolism fellow, or failing this, the on-call metabolic attending at your hospital or nearest pediatric tertiary care center, as rapidly as possible.
Please read our Terms of Use.

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