Phenotype

Clinical Symptoms

(prior to treatment)

Biochemical

% BCKD activity

Classical

Neonatal onset, poor feeding, lethargy, altered tone, ketoacidosis, seizures. Symptoms often present prior to learning NBS results. Prenatal testing in at-risk siblings can allow dietary intervention at birth. Nearly all due to mutations in the E1 BCKD subunits

↑↑ allo-ILE, BCAA, BCKA

0 -2

Intermediate

Failure to thrive, ketoacidosis and developmental delay; classical symptoms can occur during catabolic illness/stress

↑ allo-ILE, BCAA, BCKA

3 - 30

Intermittent

Normal early development, episodic ataxia/ketoacidosis, severe symptoms may be precipitated by catabolic illness/stress. May be missed by MS/MS NBS

Normal BCAA, BCKA when asymptomatic

5 - 20

Thiamin (B1) responsive

Similar to intermediate. Often due to mutations in E2 BCKD subunit

↑ allo-ILE, BCAA, BCKA ↓BCKA and/or BCAA with thiamin therapy

2 - 40

Lipamide dehydrogenase deficiency

Normal neonatal period, failure to thrive, hypotonia, lactic acidosis, developmental delay, movement disorder. Due to mutations in the E3 BCKD subunit - a component of both pyruvate dehydrogenase and α-ketoglutarate dehydrogenase

Moderate BCAA and BCKA, ↑ α-ketoglutarate, pyruvate

0 - 25

Laboratory test/symptom

Symptomatic

Pre-symptomatic/treated

MS/MS NBS on blood spot

↑↑BCAA, especially LEU;

LEU:PHE ratio > 4.5-5

<24 hr of age : normal or slight ↑BCAA;

> 24 hr of age : slight ↑to ↑BCAA

Treated in good control: normal or slight ↑BCAA

Plasma amino acids

↑↑BCAA (especially LEU), allo-ILE present; without TX, VAL and ILE may become normal or low. As LEU increases, see decreases in other essential and non-essential AA

normal or slight ↑BCAA; allo-ILE present

Urine DNPH Rx

++ after day 2-3 of life

-

Urine organic acid analysis

↑BCKA

normal or slight ↑

Ketonuria (urine keto sticks)

++

-

Ammonia

May be ↑ or ↑↑

-

BCKD activity

0-3%

0-3%

Blood glucose

↓ or normal

normal

Weight

↓

normal

Lethargy, intermittent apnea, opisthotonus

+

-

Maple syrup odor (in urine)

+ usually by 72+ hr, (first apparent in cerumen by 12-24 hr)

-

Irritability, poor feeding

+

-

Vomiting

+

-

Ataxia

+

-

Visual hallucinations

+

-

Coma, respiratory failure by 7-10 days of life without treatment

+

-

Nutrient

Recommendation

Source

LEU

Sufficient intake to allow adequate protein synthesis for growth, repair and health maintenance and to achieve LEU levels in recommended treatment range.

LEU allowance is also dependent on residual BCKD activity, age, weight, sex, life stage and health of the individual with MSUD.

In the newborn, the recommended intake is: 40-100 mg LEU/kg/day

• Intact protein (PRO)

In infants: breast milk or infant formula with known LEU content

In children and adults: foods such as fruits/vegetables, some grains/cereals that are typically low in protein and for which there is known LEU content

PRO

DRI ¹

Plus additional 20-40% if an amino acid-based medical food is used

• Intact PRO (as above)
• BCAA-free medical food

VAL, ILE

VAL and ILE are essential amino acids and may need to be supplemented when BCAA are restricted to achieve appropriate LEU blood levels. To promote anabolism of LEU, when LEU blood levels are high, additional supplementation of VAL and ILE is often required

• Intact PRO
• Supplemental VAL, ILE²

KCAL

DRI ¹

• Intact PRO
• BCAA-free medical food
• Free foods ³
• Modified low PRO food ⁴

Other nutrients, minerals and vitamins ⁵

DRI ¹

• Intact PRO
• BCAA-free medical food
• Supplemental nutrients, vitamins and minerals ⁶

NUTRIENT

AGE

LEU

mg/kg

ILE

mg/kg

VAL

mg/kg

PROTEIN

g/kg

ENERGY

kcal/kg

FLUID

ml/kg

0 to 6 mo

40-100

30-90

40-95

2.5-3.5

95-145

125-160

6 to 12 mo

40-75

30-70

30-80

2.5-3.0

80-135

125-145

1-3 yr

40-70

20-70

30-70

1.5-2.5

80-130

115-135

4-8 yr

35-65

20-30

30-50

1.3-2.0

50-120

90-115

9-13 yr

30-60

20-30

25-40

1.2-1.8

40-90

70-90

14-18 yr

15-50

10-30

15-30

1.2-1.8

35-70

40-60

19 yr +

15-50

10-30

15-30

1.1-1.7

35-45

40-50

Ref

Trimester

Total protein (g/kg body weight)

Intact protein (g/kg body weight)

BCAA-free protein (g/kg body weight)

F.102

Pre-pregnancy

1.0 – 1.2 g

0.6 – 0.8 g

0.4 g

First trimester

1.2 g

0.6 g

0.6 g

Second trimester

~

0.8 g¹

~

Postpartum

~

1.0 g

~

F.78

First trimester

1.1 g

0.1 g

0.9 g

Second trimester

1.5 g

0.4 g

1.1 g

Third trimester

1.1 g

0.4 g

0.8 g

Diagnosis (Problem)

Related to (Etiology)

As evidenced by

(Signs and Symptoms)

INTAKE (NI)

Excessive energy intake NI 1.5

Inadequate energy intake NI 1.4

Inadequate intake from enteral nutrition NI 2.3

Excessive intake from enteral nutrition NI 2.4

Inadequate fat intake NI 5.6.1

Excessive fat intake NI 5.6.2

Excessive protein intake NI 5.7.2

Inappropriate intake of (specify amino acids) NI 5.7.3

CLINICAL (NC)

Impaired nutrient utilization NC 2.1

Altered nutrition-related lab values NC 2.2

BEHAVIORAL (NB)

Food and nutrition-related knowledge deficit NB 1.1

Limited adherence to nutrition-related recommendations NB 1.6

Limited access to food NB 3.2

Other

Excessive intake of (specify food or beverage)

Poor appetite due to (specify metabolic disorder)

Nutrition prescription no longer meeting energy needs

Nutrition prescription exceeding energy needs

Protein restriction necessitated by MSUD

LEU, VAL, and ILE restriction necessitated by MSUD

Metabolic disorder (MSUD)

New diagnosis of MSUD

Lack of adequate insurance coverage to pay for special metabolic formulas

Lack of adequate insurance coverage to pay for low-protein foods

Other

BMI (or weight-for-height) >97^th percentile

BMI (or weight-for-height) >85^th percentile

BMI (or weight-for-height)

< 3^rd percentile

(specify weight change) weight gain/loss over the past (specify time frame)

EFA deficiency

Dietary recall

Altered lab values (specify)

Elevated amino acids (specify)

Reports of higher than recommended amino acid intake (specify)

Abnormal newborn screen

Lack of appreciation for the importance of making nutrition-related changes

Presentation to clinic for initial nutrition education

Denial by insurance company to provide payment

Other