Table 10.

Acute Inpatient Treatment in Individuals with Methylmalonic Acidemia

ManifestationTreatment 1Consideration/Other
↑ catabolism (due to fever, perioperative/peri-interventional fasting periods, repeated vomiting/diarrhea)
  • Administration of high-energy IV fluids (D10/0.45 or 0.9 saline) at 1.5x maintenance rate to achieve age-appropriate glucose infusion rate (GIR), &, if needed insulin 2, 3
  • Lipid emulsion is often necessary to provide sufficient calories at a dose of 1- 2 g/kg/day.
  • Address electrolytes & pH imbalances w/bicarbonate bolus, expect need for potassium replacement, as needed. 4
  • ↓ or omit total protein for ≤24-48 hours. 5
  • L-carnitine IV supplementation at 50-100 mg/kg/day either BID or QID
  • Blood glucose, electrolyte concentrations (particularly sodium, potassium & bicarbonate concentrations), blood gases (w/monitoring of the anion gap), complete blood count & differential, serum lactate, urine ketones & urine output should be followed serially.
  • Central or peripheral TPN, which typically contains glucose & amino acids, & in some instances lipids, may be required. Thiamine may be added, esp in the presence of lactic acidosis.
  • Lipid infusions must be used w/caution due to risk of pancreatitis.
  • Dietary protein should be reintroduced enterally as soon as is feasible given the clinical scenario & may need to be further augmented w/TPN.
  • Nasograstric or orogastric feeding should be strongly considered so that enteral feedings can be reintroduced w/o delay.
Hyperammonemia
  • N-carbamylglutamate (NCG, Carbaglu®) 4, 6
  • Administer IV sodium benzoate 4, 7; if hyperammonemia persists consider sodium phenylbutyrate/acetate.
  • Hemodialysis or hemofiltration in consultation w/nephrologist may be required in the event of treatment failure (uncontrollable acidosis &/or hyperammonemia).
  • A STAT plasma ammonia level should be obtained in the ED or on admission.
  • NCG activates the first step in the urea cycle (CPS1 enzyme) & is effective in lowering ammonia concentration during acute crises in patients w/MMA. Chronic or periodic use has been attempted in cases w/frequent decompensations, but has not obtained regulatory approval. 6
  • Use of phenylacetate may accentuate low glutamine levels by generating phenylacetylglutamine & deplete 2-ketoglutarate in the TCA cycle.
New or evolving neurologic symptoms (↓ consciousness, seizures, dystonic/ choreoathetotic movements of face/extremities, changes in visual acuity)
  • Initiate the treatment listed above for ↑ catabolism.
  • Neurologic consultation
  • Brain MRI
Symptoms of mvmt disorder can evolve gradually & periodic neurologic exam during crises is important for early initiation of PT to preserve function.
Bone marrow failure 8 Granulocyte-colony stimulating factor may be considered.Supportive care of the metabolic disease typically results in resolution of this finding.

BID = twice a day; ED = emergency department; PT = physical therapy; QID = four times a day; TPN = total parenteral nutrition

1.

Inpatient emergency treatment should:
(1) take place at the closest medical facility,
(2) be started without delay, and
(3) be supervised by physicians and specialist dieticians at the responsible metabolic center, who should be contacted without delay.

2.

Intravenous glucose solutions should preferably consist of D10 or D12.5 (10 - 12.5% dextrose).

3.

Use of insulin if hyperglycemia emerges; intravenous insulin given at a starting dose of 0.01-0.02 IU/kg/hour in the event of persistent hyperglycemia (>150-180 mg/dL in plasma, or glucosuria)

4.

Consult published guidelines, Baumgartner et al [2014], Fraser & Venditti [2016], and Forny et al [2021]. Emergency laboratory studies can include amylase/lipase, plasma amino acid levels (to guide TPN prescription), plasma free and total carnitine levels (to guide carnitine supplementation), and serum MMA level.

5.

Total protein can be gradually reintroduced depending on the patient's acid-base balance and remaining laboratory values, including ammonia, lactic acid, and plasma amino acids, among others.

6.

The dose of N-carbamylglutamate (NCG) is 100 mg/kg bolus, followed by 25-62 mg/kg every 6 hours PO (orally). NCG is an N-acetylglutamate analog that allosterically activates CPS1 (carbamyl phosphate synthetase 1), the first step of the urea cycle [Tuchman et al 2008, Ah Mew et al 2010, Valayannopoulos et al 2016, Alfadhel et al 2021, Kiykim et al 2021].

7.

The dose of sodium benzoate is 250 mg/kg as a bolus given over 90-120 min, followed by 250 mg/kg/day for maintenance, administered in 10% dextrose IV (intravenously). The same dose regimen is used for sodium phenylbutyrate (PBA). The maximum dose of sodium benzoate or sodium PBA is 5.5 g/m2 or 12 g/d.

8.

May include both bone marrow hypoplasia and/or dysplasia

From: Isolated Methylmalonic Acidemia

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