Download MAPLE SYRUP URINE DISEASE

MAPLE SYRUP URINE DISEASE
Hedyeh Saneifard
Pediatric Endocrinologist
Shahid Beheshti University of Medical
Science
Definition
 Branched-chain organic acidurias or organic
acidemias are a group of disorders that result from
an abnormality of specific enzymes involving the
catabolism of branched-chain amino acids (BCAAs)
 Decarboxylation of leucine, isoleucine, and
valine is accomplished by a complex enzyme
system (branched-chain α-ketoacid
dehydrogenase) using thiamine pyrophosphate
(vitamin B1) as a coenzyme
 incidence : 1:185,000 live births
Clinical Diagnosis
 Maple syrup odor in cerumen : first clinical sign ,
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12-24 hours after birth
Elevated plasma concentrations of branchedchain amino acids (BCAAs) (leucine, isoleucine,
and valine) and allo-isoleucine : 12-24 hours of
age on a normal protein intake
Ketonuria, irritablity, and poor feeding : age two
to three days
Signs of deepening encephalopathy : age four to
five days
Coma and central respiratory failure : age seven
to ten days
 acute leucine intoxication (leucinosis) after protein
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degradation precipitated by infection, surgery,
injury, or psychological stress
cerebral edema after episode of acute leucinosis
Transient periods of MSUD encephalopathy : fully
reversible
prolonged amino acid imbalances, particularly
during the early years of brain development :
structural and functional neurologic damage
Attention deficits, impulsivity, and hyperactivity
Non-central nervous system
involvement in MSUD
 Iatrogenic essential amino acid deficiency : Anemia,
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acrodermatitis, hair loss, growth failure, arrested head
growth
Iatrogenic nutritional deficiencies : zinc, selenium,
and omega-3 fatty acid
Osteoporosis : radius and femoral neck, but not lumbar
spine
Recurrent oroesophageal candidiasis : T-cell
inhibitory effects of elevated plasma leucine
Acute pancreatitis : day 2-3 of hospitalization as the
plasma leucine concentration is returning to normal
Intermittent MSUD
 normal growth and intellectual development
throughout infancy and early childhood
 When they are well, they generally tolerate a
normal leucine intake
 During infections or other physiologic stress, they
develop the clinical and biochemical features of
classic MSUD
Intermediate MSUD
 BCKAD activity : 3%-30%
 appear well during the neonatal period
 maple syrup odor in cerumen
 consistently abnormal plasma amino acid profile
 feeding problems, poor growth, and developmental
delay during infancy
 intellectual disability later in life
 diagnosed 5 mon – 7 year
 Severe leucinosis, brain swelling, and death when
subjected to sufficient catabolic stress
Thiamine-responsive MSUD
 BCKAD enzyme activity of up to 40%
 are not ill in the neonatal period
 present later in life with a clinical course similar to
intermediate MSUD
 they are treated with a combination of thiamine
(doses ranging from 10 to 1000 mg per day) and
dietary BCAA restriction
Testing
 decreased activity of the branched-chain alpha
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ketoacid dehydrogenase complex (BCKAD)
four subunit components (E1a, E1b, E2, and E3)
The severity of the metabolic phenotype is
determined by the amount of residual BCKAD
activity relative to dietary BCAA excess
Residual enzyme activity is typically less than 3% of
control values in persons with the classic phenotype
Residual enzyme activity in fibroblasts varies from
3% to 40% in persons with intermittent or
intermediate MSUD
Newborn screening
 Tandem mass spectrometry (MS/MS)-based
amino acid profiling of dried blood spots
 between 24 and 48 hours of life
 whole blood concentration ratios of (leucine +
isoleucine) to alanine and phenylalanine
 test is sensitive and specific for MSUD
Testing Strategy
 Confirming the diagnosis in a proband : newborn
suspected of having MSUD
1. Smell cerumen for odor of maple syrup 12-24 hours
after birth
2. Allow ad libitum protein intake after birth and obtain
quantitative plasma amino acid profile by HPLC or
MS/MS between 18 and 24 hours of life
 If plasma amino acid profile is equivocal, repeat the
test between 24 and 36 hours of life
 If diagnostic of MSUD, begin dietary therapy and
proceed to confirmatory DNA sequencing of genes
encoding BCKAD subunits
3. Analysis of urine organic acids by gas
chromatography-mass spectrometry
4. BCKAD enzyme activity can be measured in skin
fibroblasts, lymphocytes, or biopsied liver tissue but is of
variable accuracy and may not be necessary
Carrier testing for at-risk relatives : requires prior
identification of the disease-causing mutations in the
family
Prenatal diagnosis and preimplantation genetic
diagnosis : for at-risk pregnancies require prior
identification of the disease-causing mutations in the
family
Differential Diagnosis
 birth asphyxia, hypoglycemia, status epilepticus,
kernicterus, meningitis, and encephalitis
 Hyperketosis syndromes ( beta-ketothiolase def )
 Urea cycle defects
 non-ketotic hyperglycinemia
 Propionic or methylmalonic acidemia (rarely)
 4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone), is
also found in maple syrup, fenugreek, and lovage
 Maternal ingestion of fenugreek during pregnancy has
resulted in false suspicion of MSUD
Treatment of Manifestations
 Home therapy : DNPH reagent allows home detection of
high urine BCKAs during metabolic decompensation
 Acute decompensation : Dietary indiscretion causes
plasma BCAAs to increase but only rarely results in acute
decompensation and encephalopathy
 infections and injuries can precipitate metabolic crisis and
hospitalization
 treating the precipitating stress (e.g., infection, dehydration,
pain, fever) plus delivering sufficient calories, insulin, free
amino acids, isoleucine, and valine to stimulate net protein
synthesis in muscle and liver
 The primary goals of in-hospital therapy:
 Decrease plasma leucine concentration at greater than
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750 µmol/L per 24 hrs
Provide isoleucine and valine supplementation sufficient
to maintain plasma concentrations of 400-600 µmol/L
during the acute phase of illness
Maintain serum sodium concentration of 138-145 mEq/L
with minimal fluctuation
Avoid osmolarity changes of greater than 5 mosm/L per
day or 0.25 mosm/L per hour
Maintain urine output of 2-4 ml/kg/hr and urine
osmolarity of 300-400 mosm/L
Minimize exposure to hypotonic fluid sources
Minimize painful or invasive procedures
 Methods of achieving these goals:
 Identify and treat precipitating events
 antiemetics (odansetron 0.15 mg/kg/dose) to control
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nausea and vomiting
Provide at least 1.5 times the weight or body surface
area-adjusted estimated energy requirement ,with 40%50% of calories as lipid
BCAA-free essential and non-essential amino acids:
2.5-3.5 g/kg/day
specific amino acid supplements during metabolic crisis
Isoleucine and valine. 20-120 mg/kg/day each
Glutamine and alanine. Total intake: 150-400
mg/kg/day each
 Control of brain edema : decrease in blood osmolarity
of more than 8 mosm/L per day
Neurologic assessments
 Measure head circumference and fontanel size in
neonates
 signs of increased intracranial pressure : Papilledema ,
Disorientation, Depressed level of consciousness ,
Refractory vomiting
 signs of impending brain herniation : Hyperactive gag ,
Pupillary asymmetry , Ophthalmoplegia , Decorticate
posturing
 Hemodialysis/hemofiltration : renal replacement
methods can achieve rapid corrections of BCAAs and
BCKAs during the acute phase of MSUD crisis
 peritoneal dialysis and venovenous hemofiltration are
less effective
 Hemodialysis must be coupled with effective nutritional
management
 Other potential complications :
 Acute pancreatitis : develop two to three days into the
treatment of a metabolic decompensation
 Infection : Superficial and invasive Candida infections
are common
Prevention of Primary Manifestations
 Dietary management
goals :
 Normal weight gain, linear growth, & head growth
 Normal psychomotor development
 Age-appropriate tolerance of leucine, isoleucine, and
valine
 Avoidance of essential amino acid, fatty acid, and
micronutrient deficiencies
 Goals of laboratory monitoring
 Plasma leucine concentration: 150-300 µmol/L with an
age-appropriate intake
 Plasma isoleucine concentration approximately equal
to plasma leucine concentration
 Plasma valine concentration at least twofold plasma
leucine concentration
 Indices of calcium, magnesium, zinc, folate, selenium,
and omega-3 essential fatty acid sufficiency