MAPLE SYRUP URINE DISEASE (MSUD)
DEFINITION:
A disorder of branch-chain amino acid metabolism characterized by
the build-up of ketoacids resulting in episodes of vomiting,
dehydration, and severe metabolic acidosis.
EPIDEMIOLOGY:
- incidence: 1/125,000-300,000
- age of onset:
- newborn (within the first week of life)
- risk factors:
- familial - autosomal recessive
- chrom.#: 19q13.1-q13.2 (Type 1);1p31 (Type 2); 6p22-p21
(Type 3)
- genes: branched-chain alpha-ketoacid dehydrogenase E1a
subunit (Type 1); E2 subunit (Type 2); E1b subunit (Type 3)
- M = F
- Mennonites (1/760)
PATHOGENESIS:
- the enzyme system responsible for the decarboxylation of
the branched-chain amino acids (BCAA) - leucine, isoleucine,
valine
- a mitochrondrial enzyme consisting of 4 subunits: E1a,
E1b, E2, and E3 with the gene for each subunit located on
different chromosomes
- this enzyme system uses thiamine pyrophosphatase as a
coenzyme
- in the first step of BCAA degradation, leucine, isoleucine,
and valine are transaminated to branched-chain ketoacids (BCKA)
and in the next step these ketoacids are decarboxylated by the
dehydrogenase enzyme system
2. Genetic Defects
- genetic defects -> defective expression of a branched-chain
alpha-ketoacid dehydrogenase subunit -> build up of BCAA and
their metabolites (BCKA) in body fluids (blood, urine, CSF,
cerumen) -> metabolic and neurological manifestations
- in the three variants of MSUD, the activity of the
dehydrogenase system ranges from:
- Classic (<2%)
- Intermediate (2-8%)
- Intermittent (8-16%)
CLINICAL FEATURES:
- onset within the first week of life after a symptom-free
period of 3-4 days
- apneas
- hypoglycemia
- poor feeding
- maple syrup odour of the urine and sweat
- does not appear in the cerumen until 2 months of age
- best smelled on filter paper dipped in urine then
partially dried
- shrill cry
- vomiting
2. Neurological Manifestations
- lethargy -> coma (with hypertonicity)
- hypertonicity, muscle rigidity, opisthotonus
- boxing and pedaling movements of the limbs
- neonatal seizures
- bilateral ptosis, ophthalmoplegia, facial diplegia
2. Intermediate MSUD
- onset from infancy to adulthood
- may be accompanied by mild-moderate mental retardation and
developmental delays
- episodes precipitated by stress:
- intercurrent infections (otitis media, respiratory tract
infection, etc.)
- immunization
- sudden increase in dietary protein
- surgery
- episodes are characterized by:
- acute ataxia
- irritability
- maple syrup odour
- progressive lethargy
- vomiting (excessive)
3. Intermittent MSUD
- onset from childhood to adulthood
- same as for Intermediate MSUD
INVESTIGATIONS:
- deficiency of branched-chain alpha-ketoacid dehydrogenase
activity in leukocytes or cultured skin fibroblasts
- perinatal
- deficiency of branched-chain alpha-ketoacid dehydrogenase
activity in cultured chorionic villi or amniocytes
2. Serum
- metabolic acidosis, dehydration during an episode
- serum amino acids (chromatography)
- elevated leucine, isoleucine, valine, alloisoleucine
- depressed alanine (responsible for hypoglycemia)
- may be normal in the intermittent variant during
asymptomatic periods
3. Urine
- urine amino acids
- elevated leucine, isoleucine, and valine
- urine organic acids
- elevated ketoacids of leucine, isoleucine, and valine
- screening test (for acute episodes)
- 2,4-dinitrophenylhydrazine reagent (2,4 DNPH)
- 0.1% solution of DNPH in 2N HCl
- mix equal volumes of DNPH solution, urine, & distilled H2O
- positive test ranges from a mild turbidity (1+) to a
heavy yellow-orange precipitate (4+)
- the yellow precipitate is diphenylhydrazine
MANAGEMENT
- diagnosis, definition, epidemiology, treatment options,
prognosis
3. Goals of Therapy
- avoidance of and symptomatic control of acute episodes
- not curative
4. Management Strategies
- correct dehydration, electrolyte disturbances, and
metabolic acidosis
- may need peritoneal dialysis to remove ketoacids
- diet
- reverse catabolic state by providing sufficient calories
orally or intravenously (i.e., a high caloric, BCAA-free
diet - MSUD Formula or Product 80056)
- reduce protein intake
2. Chronic Management
- a chronic long-term disorder where the patient may
decompensate when stressed and is at risk for mental and
neurological deficits and sudden death
- plan for acute infections to avoid episodes
- aggressively treat infections
- moniter urine with 2,4 DNPH
- moniter behaviour and smell ears for maple syrup odour
- guidelines on when to contact the physician
2. Diet
- dietary consultation
- MSUD Formula - a formula low in BCAA
- Product 80056 - a high calorie BCAA-free product
- diet restricted in protein and daily requirements of
leucine, isoleucine, and valine
- vitamin B1 (thiamine) supplementation
3. Moniter
- growth parameters
- plasma leucine, isoleucine, and valine levels biweekly
- watch for a condition resembling acrodermatitis
enteropathica when the plasma concentration of isoleucine is
too low
- try to keep the leucine level <300 umol/L
5. Prognosis
- death within the first two years of life if untreated in the
Classical Variant
- depends upon the severity of the enzyme deficiency and
mangement of the initial and subsequent acute episodes ranging
from a normal life span to mental and neurological deficits to
death
- intellectual outcome varies inversely with the degree of
elevation of plasma leucine levels on a chronic basis (i.e.,
best to try and keep the plasma leucine levels <300 umol/L)
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