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Maple Syrup Urine Disease

Dr. Mohammed Al Jafari, MD

Outline

1. 2. 3. 4. 5. 6. 7.

What is MSUD? Epidemiology Pathophysiology Types of MSUD Presentations Diagnosis Management Of Crisis

MSUD
maple syrup found in body fluids especially urine autosomal Recessive varying forms results in mental retardation/death

Epidemiology 1:185,000 live births. Mennonites in Pennsylvania (1:200).

first known case: 1954

Prof. John Menkes (1928-2008)


Neurology and Pediatrics at the University of California School of Medicine

Pathophysiology

Branched Chain Amino Acids

Catabolism

dehydrogenase is thiamine dependent enzyme

most toxic Primary cause of neurotoxicity of MSUD. High leucine appear to impair regulation of cell volume, by decreasing serum Na+ and increased intracellular water, leading to cerebral edema.

Significant?

cause maple syrup smell

Acute Presentation

1. 2. 3. 4. 5. 6. 7. 8.

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

Types of MSUD
1. Classical: little or no enzyme activity <2% 2. Intermediate: more enzyme activity 3-8%. 3. Intermittent: even more enzyme activity 8-15%
4. Thiamine-responsive 5. E3-deficient

Classic:
is the most common form
Time 12-24 hours Symptom/Sign Maple syrup odor

2-3 days
4-5 days 7-10 days

Irritability, poor feeding, Ketonuria


Encephalopathy, apnea, atypical movements Coma and respiratory failure

Breastfeeding may delay onset of symptoms to the second week.

Intermediate: usually diagnosed between ages 5 months and 7years.


Intermittent: asymptomatic but at risk for metabolic crises during acute illness, usually infection. Thiamine-responsive: do not respond to thiamine supplementation alone, and dietary restriction of branched-chain amino acids is needed to achieve metabolic control.

E3-deficient: typically present in the newborn period

DIAGNOSIS
PRIMARY LEVEL TESTS: Blood Glucose & Electrolytes, Blood Gas Urine Ketones: Very reliable test in newborn to suggest presence of IEM Plasma Ammonia

SECONDARY LEVEL TESTS: Blood Tandem Mass Spectrometer (TMS) Highly reliable test, can diagnose up to 30 different IEM on a dried blood spot specimen. MSUD profile

MSUD profile: to measure plasma amino acids (fast 4hr before test)

isoleucine & valine levels may drop rapidly will keep the leucine level from dropping.

Add isoleucine & valine at 100-150 mg/kg/day to achieve the goal levels.

Newly diagnosed
Dietary therapy (MSUD formula): i. goal is to achieve normal plasma concentrations of BCAA, especially leucine. ii. Sufficient quantities of BCAA are provided to support normal growth and intellectual development. iii. throughout life.

MSUD profile every 1-2 weeks for the first 6-12 months of age. thiamine (50 to 300 mg/kg) should be given for four weeks to test for thiamine-responsiveness.

MSUD formula

Maxijul

Ketonex

Nan1

BCAA and thiamine

Management Of Crisis

Do not wait for the confirmation of diagnosis, as any delay will lead to poor neurological outcome.

collect all necessary tests, must be done before starting any treatment, as the treatment will alter the biochemical parameters.

1. Protein intake
protein should be restricted at the beginning to ONLY the medical formula without adding natural protein (Milk etc.) synthetic protein is started very quickly and is used as part of the emergency management.

2. Hydration:
should be kept NPO until mental status is improved. 1.5 times maintenance rate D10% + 0.9 NS +10 mmol kCl strict input|output if balance more than150 to give lasix

3. Caloric Supplementation:
intralipid 1.5g/kg/day given as IV pancreatic enzymes (amylase & lipase) should be checked before starting it

4. Correct Metabolic acidosis:


should slowly correct with rehydration and high caloric intake. Aims are: serum bicarbonate level over 24 meq/L absence of ketones in urine.

formula IV sodium Bicarbonate: 0.6 X Weight X Bicarbonate deficit = mmol bicarbonate required

5. Precipitating factors: Infection: Antibiotics. Surgery: D10 prior to and after surgery until oral fluids are tolerated. avoiding prolonged fasting to the extent possible. addressing pain issues. providing adequate calories to promote fast healing.

6. Hemodialysis indications: intractable metabolic acidosis. severe electrolyte disturbances and/or if patient is comatose.

Management Of Crisis:

1. Protein intake 2. Hydration 3. Caloric Supplementation 4. Correct Metabolic acidosis 5. Precipitating factors 6. Hemodialysis

7. Cerebral Oedema

inform senior staff immediately. Exclude hypoglycemia Elevate the head side of the bed Give Mannitol 0.5 g/kg stat (= 2.5 ml/kg Mannitol 20% over 15 minutes). This needs to be given within 10 minutes. Reduce rate of fluids to half immediately and recalculate to 2/3 maintenance and replace deficit over 72 rather than 24 hours. need to be moved to ICU. Arrange for the child to be intubated and if necessary hyperventilated to reduce blood pCO2. Exclude other diagnosis by CT Scan but only after ICU stabilization Repeated doses of Mannitol (above dose every 6 hours)

Monitoring
Clinical parameters
Mental status Hydration status/fluid balance/oral intake

Biochemical parameters:
-Urine for ketones with every void -MSUD profile (once daily) -amylase & lipase once daily -Glucose, CBC, U&E, blood gases, NH4 as indicated

Carnitine therapy for MSUD

Liver transplantation

Take Home Message

Metabolic crises are complex medical emergencies and must be treated with metabolic consultation to avoid death or serious brain injury.

References:
1. New England Consortium of Metabolic Programs [newenglandconsortium.org]. 2. uptodate.com 3. medscape.com 4. SQUH protocol 2008

Special thanks go to
Dr. Fathiya Al Murshedi, MD, M.Sc, FRCPC, FCCMG, CIP
Clinical and Biochemical Geneticist. SQUH