Table 3. [Phenotype Correlations by Gene and Enzymatic Subtype of Isolated Methylmalonic Acidemia]. - GeneReviews®

Methylmalonic Acidemia Phenotype	Gene	Enzymatic Subtype	Clinical Correlation
Infantile / non-B₁₂-responsive ¹	MMUT	mut ⁰	Most common & severe form, typically presenting in infancy Higher rate of mortality & neurologic & other multisystem complications than in those w/mut^– & cblA subtypes Renal disease may manifest in childhood in ~43%-60%, w/median age of onset 6-11 yrs. ²
MMUT	mut ^–	Onset may occur later, in 1st few mos or yrs of life. Symptoms often incl feeding problems, failure to thrive, hypotonia, & DD. Catastrophic decompensation can occur when diagnosis is delayed, incl injury in basal ganglia → movement disorder. Some persons have isolated renal tubular acidosis or chronic renal failure as primary finding.
MMAB	cblB	Most affected persons have phenotype that resembles mut⁰, although certain pathogenic variants may be assoc w/milder phenotype. Higher rate of mortality & neurologic & other multisystem complications than in those w/mut^– & cblA sybtypes Chronic renal failure occurs in ~66% & is less frequent than in those w/cblA subtype.
B₁₂-responsive ³	MMAA	cblA	If diagnosed early & consistently treated w/injectable B₁₂ ⁴: Milder disease course Normal life expectancy Slower decline in renal function w/≈9%-12% developing chronic renal failure ⁵ Better neurocognitive outcomes than in mut⁰/mut^– & cblB subtypes If not adherent to diet & injectable B₁₂ therapy: at risk for significant neurologic & multiorgan complications ⁶
MMADHC ⁷	cblD-MMA	Metabolic acidosis, respiratory distress, hyperammonemia, & neurologic symptoms
MMAB	cblB	Only rarely is this subtype responsive to injectable B₁₂ therapy. May present w/isolated renal tubular acidosis or chronic renal failure
MMUT	mut ^–	See Infantile/non-B₁₂-responsive; this phenotype is rarely B₁₂-responsive.
MCEE deficiency	MCEE	MCEE	In general, milder features ranging from no symptoms to severe metabolic acidosis. Not responsive to injectable B₁₂ therapy A rare cause of persistent moderate MMA

Methylmalonic Acidemia Phenotype

Gene

Enzymatic Subtype

Clinical Correlation

Infantile / non-B₁₂-responsive ¹

MMUT

mut ⁰

Most common & severe form, typically presenting in infancy
Higher rate of mortality & neurologic & other multisystem complications than in those w/mut^– & cblA subtypes
Renal disease may manifest in childhood in ~43%-60%, w/median age of onset 6-11 yrs. ²

MMUT

mut ^–

Onset may occur later, in 1st few mos or yrs of life.
Symptoms often incl feeding problems, failure to thrive, hypotonia, & DD.
Catastrophic decompensation can occur when diagnosis is delayed, incl injury in basal ganglia → movement disorder.
Some persons have isolated renal tubular acidosis or chronic renal failure as primary finding.

MMAB

cblB

Most affected persons have phenotype that resembles mut⁰, although certain pathogenic variants may be assoc w/milder phenotype.
Higher rate of mortality & neurologic & other multisystem complications than in those w/mut^– & cblA sybtypes
Chronic renal failure occurs in ~66% & is less frequent than in those w/cblA subtype.

B₁₂-responsive ³

MMAA

cblA

If diagnosed early & consistently treated w/injectable B₁₂ ⁴:

Milder disease course
Normal life expectancy
Slower decline in renal function w/≈9%-12% developing chronic renal failure ⁵
Better neurocognitive outcomes than in mut⁰/mut^– & cblB subtypes

If not adherent to diet & injectable B₁₂ therapy: at risk for significant neurologic & multiorgan complications ⁶

MMADHC ⁷

cblD-MMA

Metabolic acidosis, respiratory distress, hyperammonemia, & neurologic symptoms

MMAB

cblB

Only rarely is this subtype responsive to injectable B₁₂ therapy.
May present w/isolated renal tubular acidosis or chronic renal failure

MMUT

mut ^–

See Infantile/non-B₁₂-responsive; this phenotype is rarely B₁₂-responsive.

MCEE deficiency

MCEE

In general, milder features ranging from no symptoms to severe metabolic acidosis.
Not responsive to injectable B₁₂ therapy
A rare cause of persistent moderate MMA

From: Isolated Methylmalonic Acidemia

GeneReviews^® [Internet].

Adam MP, Feldman J, Mirzaa GM, et al., editors.

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