Methylmalonic aciduria

The phenotype spans a broad spectrum that is shaped by the underlying defect and, before newborn screening, was recognised largely as two patterns. The infantile, non-vitamin-B12-responsive form (the mut0 subtype) is one of the most common and most severe presentation. It typically manifests in the neonatal period with lethargy, tachypnoea, hypothermia, vomiting, and dehydration once protein-containing feeds are introduced, and without prompt treatment can progress to coma from hyperammonaemic encephalopathy. Partially deficient or vitamin-B12-responsive phenotypes (the mut- subtype, cblA, rarely cblB, and the cblD variant 2 form) present within the first months to years of life with feeding difficulties, failure to thrive, hypotonia, developmental delay, and episodes of metabolic decompensation. Methylmalonyl-CoA epimerase deficiency ranges from no symptoms to severe metabolic acidosis.

Even with early diagnosis and treatment, secondary complications may develop, including chronic kidney disease with tubulointerstitial nephritis, “metabolic stroke” affecting the basal ganglia during acute decompensation, growth failure, optic atrophy, and cardiac involvement. Canonical biochemical markers such as serum methylmalonic acid vary with diet and renal function, which complicates monitoring of disease burden.

Isolated MMA is rare. In Italian expanded newborn-screening data, methylmalonic acidaemia is consistently identified as a rare organic acid disorder. A single authoritative birth-incidence figure for the isolated form across all populations is difficult to state because published estimates depend strongly on the screened population and on screening methodology.

Isolated MMA is caused by biallelic pathogenic variants in one of several genes. The most common cause lies in MMUT, which encodes methylmalonyl-CoA mutase; complete deficiency defines the mut0 subtype and partial deficiency the mut- subtype. The remaining genes affect the synthesis or transport of the enzyme’s cofactor, adenosylcobalamin (5’-deoxyadenosylcobalamin): MMAA (cblA), MMAB (cblB), and MMADHC (cblD variant 2). Variants in MCEE, encoding methylmalonyl-CoA epimerase, account for a small number of cases. Responsiveness to vitamin B12 broadly tracks the genetic subtype: cblA, cblB, and many mut- cases are vitamin-B12-responsive (cblB less reliably than cblA), whereas the mut0 subtype is typically unresponsive.

Isolated MMA in all of these genes is inherited in an autosomal recessive manner. The parents of an affected individual are typically asymptomatic carriers. At conception, each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and a non-carrier. Affected newborns are commonly first identified through newborn screening. Once the familial pathogenic variants are known, carrier testing of relatives and prenatal or preimplantation genetic testing are possible.

Newborn screening flags affected infants through an elevated propionylcarnitine (C3) concentration on the dried blood spot, measured by tandem mass spectrometry. This marker is not specific: it is also raised in propionic acidaemia and in acquired maternal or infantile vitamin B12 deficiency, which is a recognised cause of false-positive screens. The diagnosis is therefore confirmed biochemically by demonstrating raised methylmalonic acid in blood and urine with normal plasma homocysteine, which distinguishes the isolated form from the combined cobalamin disorders. Molecular genetic testing of the panel genes identifies the causative biallelic variants and, because of its sensitivity and accessibility, can obviate the need for enzymatic testing in most instances. A normal newborn screen does not fully exclude the diagnosis, so the panel is also indicated in symptomatic individuals with biochemical findings suggestive of isolated methylmalonic acidaemia.

Main differential diagnoses include:

• Combined methylmalonic acidaemia with homocystinuria: raised methylmalonic acid accompanied by raised total homocysteine and low methionine, unlike the isolated form; these are intracellular cobalamin processing defects; MMACHC, MMADHC, LMBRD1, ABCD4
• : shares an elevated C3 on newborn screening, but methylmalonic acid is not elevated; PCCA, PCCB
• Acquired maternal or infantile vitamin B12 deficiency: non-genetic, with overlapping C3 and methylmalonic acid elevation, a recognised cause of false-positive newborn screens

• Genetic testing supports establishing the diagnosis by identifying the underlying biallelic pathogenic variants, confirming the biochemical findings and defining the genetic subtype
• A confirmed result supports condition-specific surveillance and management, including identification of likely vitamin-B12-responsive subtypes, which the treating physicians decide together with the affected individual.
• A known familial variant supports carrier and prenatal testing of at-risk relatives, so they can clarify their personal risk and access counselling where indicated

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