Clinical Guidance

Genotype-phenotype correlations observed include the following:

cblC

• Infantile-presentation (early-onset), severe disease is associated with the MMACHC pathogenic variants or in the homozygous or compound heterozygous state.

• Noninfantile presentation (late onset) is usually associated with MMACHC pathogenic variants and MMACHC

[, , , , ]. It may also be associated with MMACHC variant if individuals are compound heterozygotes for , , , or .

cblD. The location of pathogenic variants within MMADHC correlates with the type of enzyme deficiency:

Source: GeneReviews — "Disorders of Intracellular Cobalamin Metabolism"

Diagnostic Criteria

The disorders of intracellular cobalamin metabolism result from deficient synthesis of the coenzymes derived from vitamin B12:

• Adenosylcobalamin (AdoCbl) – the coenzyme for methylmalonyl-CoA mutase enzyme

• Methylcobalamin (MeCbl) – the coenzyme for the enzyme methionine synthase (MTR)

Source: GeneReviews — "Disorders of Intracellular Cobalamin Metabolism"

Differential Diagnosis

The following disorders may cause clinical manifestations and laboratory abnormalities similar to those seen in disorders of intracellular cobalamin metabolism.

Disorders causing both methylmalonic acidemia and homocystinuria

• Vitamin B12 deficiency. Individuals with vitamin B12 deficiency can have methylmalonic acidemia and homocystinuria, as can the newborns of mothers who have vitamin B12 deficiency. To establish the diagnosis of vitamin B12 deficiency, it is necessary to measure serum vitamin B12 concentrations in both affected newborns and their mothers.

Source: GeneReviews — "Disorders of Intracellular Cobalamin Metabolism"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with a disorder of intracellular cobalamin metabolism, the following evaluations are recommended. In an unstable individual:

• Serial metabolic evaluations of blood gases, electrolytes, glucose, ammonia, liver function, total and direct bilirubin, renal function, lactate dehydrogenase, plasma amino acids (methionine), plasma methylmalonic acid (MMA), and total plasma homocysteine (tHcy) to guide acute management until the individual stabilizes

• Complete blood count (CBC) with differential to evaluate for megaloblastic anemia or cytopenias

• Peripheral blood smear to evaluate for the presence of schistocytes, in the presence of other manifestations of hemolytic uremic syndrome (HUS)

Once the individual becomes stable:

• Clinical assessment of growth parameters, head circumference, ability to feed, developmental status, and neurologic status

• Laboratory assessment of nutritional status (electrolytes, albumin, prealbumin, plasma amino acids [with careful attention to methionine levels], vitamin levels [including thiamine and 25-hydroxyvitamin D], and trace minerals) and renal function; complete blood count to monitor for cytopenias

• Echocardiogram to screen for cardiac defects and cardiomyopathy

• EEG and brain MRI in symptomatic individuals

• Ophthalmologic examination

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

A set of guidelines for th...

Source: GeneReviews — "Disorders of Intracellular Cobalamin Metabolism"

Clinical Guidance

Potentially exacerbating circumstances:

• Prolonged fasting (longer than overnight without dextrose-containing intravenous fluids)

• Dietary protein intake below the recommended dietary allowance (RDA) for age

• Dietary protein intake greater than that prescribed by a metabolic specialist especially in individuals with cblC, cblD-combined, cblF, or cblJ

• Medical foods. Medical foods given to infants with isolated methylmalonic acidemia do not contain methionine and should be avoided as the decreased methionine intake may worsen hypomethioninemia and long-term use may contribute to poor head and linear growth , among other complications.

• Nitrous oxide, an anesthetic that is potentially toxic as it depletes the body stores of vitamin B12 and inhibits methionine synthase activity [, , , ]

Source: GeneReviews — "Disorders of Intracellular Cobalamin Metabolism"

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 — "Disorders of Intracellular Cobalamin Metabolism"

Surveillance Guidelines

The following evaluations are performed at different intervals depending on age and disease severity:

• During the first year of life, infants may need to be evaluated once or twice a month by a metabolic specialist.

• Toddlers and school-age children should be evaluated at least twice a year to adjust medication dosing (hydroxocobalamin, betaine) during growth and to evaluate nutritional status.

• Teens and adults may be seen on a yearly basis.

Clinical evaluation should assess the following:

• Growth including weight, linear growth, and head circumference

• Nutritional status

• Feeding ability

• Developmental and neurocognitive progress, as age-appropriate

Laboratory evaluation should include the following:

• Metabolic studies including urine organic acids, serum methylmalonic acid analysis, plasma amino acids (methionine), plasma tHcy concentration

• CBC to monitor for cytopenias

• Nutritional studies, if indicated: electrolytes, albumin, prealbumin, plasma amino acids, vitamin levels (including thiamine and 25-hydroxyvitamin D), essential fatty acids, and trace minerals

Routine evaluations should include the following:

Source: GeneReviews — "Disorders of Intracellular Cobalamin Metabolism"