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The following was adapted from an outline of the presentation given by Rebecca S. Wappner, M.D., Riley Hospital for Children, Indianapolis, Indiana at the National Coalition for PKU and Allied Disorders Metabolic Conference in Ohio in May 2001.

Symptoms of MSUD result from elevated body fluid levels of:

  • Branched-chain amino acids (BCAA): leucine, isoleucine & valine.
  • Keto acid (2-Oxoacid) derivatives: a-ketoisocaproate (KIC), a-ketomethylvalerate (KMV) a-ketoisovalerate (KIV).
  • Alloisoleucine - diagnostic compound from isoleucine metabolites.

Branched-chain amino acids (BCAA)

  • Essential amino acids - building blocks for the body.
  • Used to make:
    • Body tissue (especially skeletal muscle 35%).
    • Glucose (gluconeogenic).
    • Ketone bodies (ketogenic).
      • Fatty acids and cholesterol (needed to make hormones).
      • Energy.

MSUD results from

  1. Decreased activity of the enzyme Branched-Chain a-Keto acid Dehydrogenase (BCKD).
  2. BCKD - large complex molecule with 6 components, coded for by 6 different genes.
    1. Carboxylase (thiamine co-factor).
      1. Subunit a ( E1a), 22 mutations.
        1. Classic: Mennonites & others in U.S.
        1. Intermediate: Hispanic.
      2. Subunit b (E1b), 7 mutations.
        1. Intermediate & Intermittent.
        2. French Canadian, Afro-American & Whites.
    2. Transacylase (E2), 28 mutations: Japanese.
    3. Dehydrogenase (E3), 5 mutations.
      1. Japanese (Ashkenazi).
      2. Eastern European Jews.
    4. Kinase (activator).
    5. Phosphorylase (inactivator).

History

  1. 1954 Beginning of amino acid analysis.
  2. 1954 Menkes, Hurst, Craig: first to describe MSUD; identified urine odor.
  3. 1960 Dancis: demonstrated deficiency in decarboxylation of BCAA.
  4. 1964 Snyderman: developed diet restricting BCAA; determined amount of BCAAs needed by the body.
  5. 1971 Scriver: described a thiamine-responsive form of MSUD.
  6. 1976 Means of identifying organic acids became available.
  7. 1978 Reed: purification of the BCKD.
  8. 1980s Beginning of molecular genetics and the identification of the subunits of the enzyme, BCKD.
  9. 1990s Morton: improved treatment.

Types of MSUD

  1. Classic - less than 2% of normal activity of BCKD.
    1. Most severe, most common.
    2. Leucine more elevated than other BCAAs.
    3. Symptoms - usually begin appearing at 4-7 days of age.
      1. Lethargy.
      2. Poor suck.
      3. Decreased intake.
      4. Weight loss.
      5. Neurologic signs.
        1. Alternating increased & decreased motor tone.
        2. Abnormal movements (dystonia).
      6. Ketosis - positive DNPH (dinitrophenylhydrazine).
      7. Abnormal maple syrup odor (recognizable in ear wax before urine).
      8. Seizures, coma, cerebral edema, death.
    4. Even with newborn screening, some infants will be symptomatic before or at the time the testing results are known.
    5. Various degrees of disabilities in many depending on when treatment was started and how well controlled.
  2. Intermediate - 3-30% of normal activity of BCKD.
    1. Less severe than classic; less common.
    2. Symptoms appear later; may not be diagnosed until 5 months to 7 years of age when evaluated for delayed development.
    3. All BCAAs elevated, leucine less high than in classics.
    4. Catastrophic brain symptoms (encephalopathy) usually not present during newborn period.
    5. Delayed development, maple syrup odor, seizures.
  3. Intermittent - 5-20% of normal activity of BCKD.
    1. Less severe than classic; less common.
    2. Usually no symptoms during newborn period.
    3. Episodes of acute loss of metabolic control usually begin between 5 months and 2 years.
      1. Present with ketosis & hypoglycemia.
      2. During episodes:
        1. Difficulty walking and keeping balance.
        2. Lethargy.
        3. Behavior/personality changes.
        4. Maple syrup odor in urine.
      3. Abnormal BCAAs only present with episodes.
    4. Growth and development usually normal.
  4. Thiamine-responsive - 30-40% of normal activity of BCKD.
    1. Similar to intermediate/intermittent although less common.
    2. Usually no symptoms during newborn period.
    3. Episodes of acute loss of metabolic control may begin in infancy or early childhood.
    4. Abnormal BCAAs only present with episodes.
    5. Delayed development possible.
    6. Responsive to thiamine in daily doses of 100-150 mg.
  5. E3-combined dehydrogenase deficiencies (BCKD, pyruvate, 2-oxoglutarate).
    1. Similar to intermediate form; very rare (4 or 5 reported cases).
    2. Symptoms may appear during the newborn period, but more often, later.
    3. Symptoms include a severe lactic acidosis.
    4. Elevated lactic acid and 2-oxoglutarate.

Treatment (Classic type)

  1. Acute newborn crisis or acute metabolic crisis:
    1. Goal: to achieve control of leucine levels by providing enough calories and special medical food to stop catabolism (breaking down of own body stores).
    2. Hyper-caloric approach: is preferred treatment used today - superior to dialysis used in the past.
    3. Monitor BCAA levels every 12 hours to guide therapy.
    4. Stop all sources of protein including those from formulas and breast milk.
    5. Start special medical food (devoid of BCAAs). Give by nasogastric tube (NG) if cannot be taken by mouth due to poor suck.
    6. Add leucine to diet in the form of regular formula or table foods only when leucine levels are normalized.
    7. If special medical food cannot be tolerated, use special IV hyperalimentation [TPN] (complete feeding) low in the BCAAs.
    8. Supplement with other amino acids.
      1. Isoleucine and valine. (Inversely related to the leucine levels; can protect the brain from high leucine levels - important to keep these levels from becoming deficient.)
      2. Tyrosine (also decreases leucine brain levels.)
      3. Glutamine and alanine (Brain levels of these neurotransmitters are low if leucine is high.)
    9. May need:
      1. IV intralipids 20% to increase calories.
      2. IV Insulin (promotes glucose intake in cells).
      3. IV Propanolol (catecholamine antagonist).
    10. Cerebral edema (brain swelling) must be prevented - the usual cause of death.
      1. Behavior changes are an important predictor.
      2. Use hypertonic saline solutions (high normal sodium, diuretics, Mannitol).
  2. Treatment of asymptomatic MSUD newborns [diagnosed before clinical symptoms appear]:
  1. Start special medical food to prevent catabolism.
  2. Initial leucine intake: zero.
  3. Add glutamine, alanine, and salt.
  4. Add isoleucine and valine in approximately two days.
  5. Give thiamine, 10mg/Kg daily on a trial basis, if not Mennonite classic.
  6. Monitor blood levels at least daily.
  7. Add leucine when leucine levels normalize.
  1. Long Term Treatment
    1. Requires the use of special medical food to provide protein intake of 2-2.5 gm/kg daily.
    2. Diet low in leucine - only amount needed for growth.
      1. Varies with age - most needed per kg of weight during newborn period.
      2. By age 2-3 years, 300-600 mg and maintained daily for rest of life.
      3. Select and use one food list consistently.
        1. Leucine values vary from list to list
        2. Leucine can be figured in milligrams or exchanges.
    3. Supply isoleucine and valine.
      1. To meet growth needs and avoid deficiencies.
      2. To protect against high leucine levels.
    4. Add glutamine and alanine to prevent low levels of these two amino acids.
    5. Add table salt (sodium chloride) to offset high salt loss through kidneys, especially when leucine is high.
    6. Avoid prolonged low levels of the BCAA - leads to poor growth, decreased appetite, rashes and skin infections.
  1. Provide adequate caloric intake - the mainstay in the treatment of MSUD
    1. To promote growth and avoid catabolism.
    2. Initially supplied by formula, later from table foods.
    3. Based on age and activity.
  2. Thiamine
    1. Give approximately 10 mg/Kg daily (50-300 mg per day) for at least 3 weeks as a trial.
    2. Mennonite classic is not a thiamine-responsive type.
  3. Blood monitoring
    1. Quantitative measurement of BCAAs using blood or blood filter paper card.
    2. Quick turn-around time very important.
    3. Done weekly until age 6-12 months; thereafter depending on leucine tolerance.
    4. When ill or suspect elevated levels.
    5. After changing diet.
  4. DNPH (2,4 dinitrophenylhydrazine) monitoring
    1. Usually positive with leucine level over 450 ┬Ámol/l (6 mg/dl).
    2. Best done on morning urine specimen.
    3. Daily when starting initial treatment.
    4. When ill or suspect elevated levels.
    5. After changing diet.
  5. Traveling
    1. Plan daily intake ahead of time.
    2. Take enough supplies, including for illness.
    3. Check itinerary for available resources along the route - children's hospitals, medical centers, etc.?
    4. Contact and alert the specialist in your travel area.
    5. Carry a "Help Letter" from your doctor - include enough information to prompt the local ER physician into action.
  6. "Sick Day" management
    1. Have a "sick day" diet plan. (Update every time recommended intake changes.)
    2. Usual plan: give special medical food - no regular formula - and extra isoleucine and valine. (Give extra formula, not extra clear fluids.)
    3. Leucine intake from table food is minimal/zero.
    4. Give extra calories! calories! calories!
    5. Routine treatment for other medical illnesses (i.e., antibiotics for ear infection, etc.).
    6. Zofran may help for nausea and vomiting (not a sedative but stops vomiting at the brain stem).
    7. Monitor BCAAs levels as often as daily.
    8. If no improvement within 12 hours, or symptoms are worse, seek professional help.

Outcome

  1. Best outcomes occur in siblings of older affected children (diagnosed at birth) and in those on diet by 10 days of age.
  2. Those diagnosed and treated later than 14 days of age rarely have a normal outcome.
  3. Approximately 1/3 have IQs over 90 (normal); 1/3 have IQs between 70 and 90 (borderline); and 1/3 have IQs less than 70 (handicapped).
  4. May have problems with attention span and learning disabilities.
  5. May have problems with motor control (some severe, similar to what is seen with cerebral palsy).
  6. Special education and rehabilitation services may be needed.
  7. Strict dietary control is needed for life.
  1. Older individuals not on strict diet can have problems with "dysmyelination" which affects ability to function.
  2. Improvement may be seen after return to strict dietary control from a lenient diet.

The chart illustrates the rapid rate of growth in the first year of life, especially during the first 6 to 8 months. This is why the protein per kilogram of weight is much greater in infancy than at any other time in life. At some time between 8 and 12 months, the growth significantly slows and blood monitoring and diet adjustments are critical to prevent loss of control. An increase in the rate of growth occurs during teen years, but it does not compare with the early growth rate.

Family

  1. Genetic counseling: The family has a 1 in 4 (25%) chance of having another affected baby with each subsequent pregnancy.
    1. Prenatal diagnosis is available.
    2. Early detection and treatment during the newborn period improves the outcome.
  2. Carrier testing can be done by means of the newer molecular genetic tests that are available.
    1. If the gene mutations are known in the family.
    2. If the family is of Mennonite [Swiss/German] background.

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The MSUD Family Support Group is currently funding several research projects and we are proactively looking for researchers interested in developing new treatments or finding a cure for MSUD. Significant funding is necessary if we are to accomplish this goal.
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