Clinical Guidance

The severity of the MSUD metabolic phenotype is determined by the amount of residual BCKD enzyme activity relative to dietary BCAA excess and the large demands for BCAA oxidation that accompany fasting, illness, or other catabolic stresses . Although there are some established relationships between genotype and biochemical phenotype (i.e., classic vs intermediate), clinical and functional outcomes (e.g., FSIQ, psychiatric illness, executive dysfunction) cannot be predicted from genotype .

Source: GeneReviews — "Maple Syrup Urine Disease"

Diagnostic Criteria

Maple syrup urine disease (MSUD) is caused by decreased activity of the branched-chain alpha-ketoacid dehydrogenase complex (BCKD), the second enzymatic step in the degradative pathway of the branched-chain amino acids (BCAAs), which includes leucine, isoleucine, and valine.

Scenario 1. Abnormal newborn screening (NBS) result

• NBS for MSUD is primarily based on quantification of the ratios of (leucine + isoleucine) to alanine and phenylalanine concentrations on dry blood spots.

• A positive screening value (i.e., those above the cutoff reported by the screening laboratory) require follow-up biochemical testing with quantitative plasma amino acid and alloisoleucine analyses. If either is abnormal, treatment and testing to establish the diagnosis should be initiated concurrently.

Source: GeneReviews — "Maple Syrup Urine Disease"

Differential Diagnosis

Entities to exclude in the encephalopathic neonate include birth asphyxia, hypoglycemia, status epilepticus, kernicterus, meningitis, and encephalitis. The few inborn errors of metabolism that present with neonatal encephalopathy include the following:

• Hyperketosis syndromes (e.g., beta-ketothiolase deficiency [OMIM 203750])

• Urea cycle defects (See Urea Cycle Disorders Overview.)

• Glycine encephalopathy (nonketotic hyperglycinemia)

• Propionic acidemia or isolated methylmalonic acidemia (rarely)

Source: GeneReviews — "Maple Syrup Urine Disease"

Management Guidelines

Evaluations Following Initial Diagnosis

When maple syrup urine disease (MSUD) is suspected during the diagnostic evaluation (i.e., due to elevated concentration of leucine, isoleucine, valine, and/or alloisoleucine), metabolic treatment should be initiated immediately. Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach to care with oversight and expertise from a specialized metabolic center. Consensus nutritional guidelines have been published (full text) and two peer-reviewed articles provide general guidelines about the comprehensive treatment and monitoring of MSUD: see (full text), (full text). To establish the extent of disease and needs in an individual following initial diagnosis of MSUD, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis of Maple Syrup Urine Disease

Evaluation/System | Comment

Consultation w/metabolic physician / biochemical geneticist specialist metabolic dietician1 | • Transfer to specialist center w/experience in management of inherited metabolic diseases (strongly recommended).

Source: GeneReviews — "Maple Syrup Urine Disease"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Maple Syrup Urine Disease"

Surveillance Guidelines

Table 10.

Recommended Surveillance for Individuals with Maple Syrup Urine Disease

Manifestation | Evaluation | Frequency/Comment

Control of amino acid other nutrient levels1

| Full amino acid profile (either from plasma or filter paper) | • For rapidly growing infants, monitoring 1x or 2x/wk

• Weekly in children, adolescents, adults2,3

Measurement of calcium, magnesium, zinc, folate, selenium omega-3 essential fatty acid | As indicated based on clinical signs of deficiency

Visit w/metabolic specialist | At least monthly in infancy

Delayed acquisition of developmental milestones

| Monitor developmental milestones4,5 | At each visit or as needed

1. See Goals of laboratory monitoring (following) for target concentrations for various amino acids and other nutrients.

2. The frequency of amino acid monitoring varies by age, metabolic stability, adherence, and regional clinical practice.

3. The frequency of amino acid monitoring correlates directly with metabolic control and long-term measures of intelligence .

4. The Denver Developmental Screening Test II or a comparable tool is useful for monitoring development of infants and young children with MSUD.

5. School-age children, adolescents, and adults should have neurocognitive testing if indicated by school performance or behavior problems .

Goals of laboratory monitoring

Source: GeneReviews — "Maple Syrup Urine Disease"