Normally:

1. Protein → amino acids
2. Certain amino acids (valine, isoleucine, methionine, threonine) are broken down
3. The enzyme methylmalonyl-CoA mutase (with vitamin B12) converts these into a harmless energy molecule
4. Energy production continues normally

In MMA:

• This enzyme is absent or faulty
• OR vitamin B12 cannot be used correctly
• Methylmalonic acid builds up → becomes toxic
• The body enters “metabolic crisis” during stress, fasting, or illness

1. Enzyme Defect Types

• mut⁰ — no enzyme activity (most severe)
• mut⁻ — partial enzyme activity

2. Vitamin B12–Related Types

• cblA, cblB — often B12 responsive
• cblC, cblD, cblF — may also affect homocysteine pathway
• Some types respond to B12; others do not

3. B12-Responsive vs. Unresponsive MMA

• B12-responsive: Improved with high-dose vitamin B12; better long-term outcome
• B12-unresponsive: No improvement with B12; requires stricter diet and closer monitoring

Early symptoms often appear in the first days or weeks of life:

• Poor feeding, vomiting
• Excessive sleepiness or difficulty waking
• Weak or floppy muscles
• Rapid or difficult breathing
• Dehydration
• Seizures or unusual movements
• Episodes of metabolic crisis (acidosis, high ammonia)

Symptoms in Childhood:

• Poor growth or “failure to thrive”
• Developmental delays
• Feeding difficulties
• Frequent vomiting
• Low energy, muscle weakness
• Recurrent metabolic crises during illness
• Learning difficulties in some children

Even with treatment, some children may develop:

• Kidney disease: Most common long-term issue
• Neurologic problems: Movement disorders, metabolic strokes, seizures
• Vision problems: Especially in cblC type
• Blood abnormalities: Anemia or low white blood cells
• Liver enlargement or dysfunction

Early diagnosis and strict management greatly reduce the severity of complications.

1. Newborn Screening:

Most MMA cases are detected through routine heel-prick screening by identifying high C3 (propionylcarnitine).

2. Confirmatory Testing:

• Blood and urine methylmalonic acid (very high in MMA)
• Ammonia, blood gases, electrolytes
• Carnitine levels
• Vitamin B12 responsiveness test
• Genetic testing to determine subtype

MMA requires lifelong, daily treatment and emergency planning.

1. Special Diet (Cornerstone of Treatment):

• Controlled low-protein diet
• Avoiding excess methionine, threonine, valine, isoleucine
• Use of medical formulas low in offending amino acids
• Frequent meals to avoid fasting
• Higher calories to prevent the body from breaking down its own protein

Diet is supervised by a metabolic dietitian.

2. Vitamin B12 Therapy:

Applies only to B12-responsive types (cblA, some cblB, some cblC):

• High-dose B12 injections or oral therapy
• Monitoring methylmalonic acid to assess response

3. Carnitine Supplementation:

• Helps remove toxic metabolites
• Usually given daily
• Improves energy and reduces crisis frequency

4. Medications to Reduce Toxin Production:

• Metronidazole (intermittent): Reduces gut-derived organic acids
• Bicarbonate or citrate: Corrects chronic acidosis

5. Managing a Metabolic Crisis:

A crisis may occur during:

• Fever or infections
• Poor intake
• Surgery
• Fasting or dehydration

Emergency care includes:

• High-glucose IV fluids
• Correction of acidosis
• Temporary stopping of natural protein
• Treating high ammonia
• Dialysis in severe cases

Families should always carry a written emergency protocol.

Liver Transplant:

Helps in severe or unstable MMA by:

• Reducing methylmalonic acid levels
• Decreasing crisis frequency
• Liberalizing diet somewhat

Important: Liver transplant does not cure MMA.
Kidney disease and neurologic issues may still progress.

Combined Liver–Kidney Transplant:

Considered in children with advanced kidney disease.

Children require follow-up every 3–6 months, including:

• Blood MMA levels
• Kidney function
• Growth and nutrition assessments
• Neurologic evaluation
• Eye and hearing exams
• Screening for anemia and low white blood cells

Most children with MMA can:

• Attend school
• Participate in normal activities
• Grow and develop well with proper care
• Avoid crises with good sick-day management

Families benefit from:

• Early education on diet and emergency care
• Support from metabolic specialists
• Connection with family support groups
• Genetic counseling for future pregnancies

• MMA is serious but manageable
• Early diagnosis through newborn screening greatly improves outcomes
• Diet and daily medications are essential
• Never allow prolonged fasting in a child with MMA
• Seek medical help immediately for vomiting, fever, or lethargy
• With proper management, children can live healthy, active lives