Methylmalonic Academia

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Mode(s) of Inheritance: Autosomal Recessive
• Literature Search: 08/18/2015
• Curation Status: Released - Under Revision (1.0.1)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
No assertions found.

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity from methylmalonic aciduria / Protein restriction (Vitamin B12 responsive)	2	3D	1C	2	8DC
Morbidity from methylmalonic aciduria / Monitor kidney function (Vitamin B12 responsive)	2	3D	2D	3	10DD
Morbidity from methylmalonic aciduria / Vitamin B12 (Vitamin B12 responsive)	2	3D	2C	3	10DC
Morbidity from methylmalonic aciduria / Protein restriction (Vitamin B12 non - responsive)	2	3D	1C	2	8DC
Morbidity from methylmalonic aciduria / Monitor kidney function (Vitamin B12 non - responsive)	2	3D	2D	3	10DD

Severity of Outcome

Prevalence of the Genetic Condition

Prevalence of methylmalonic aciduria (MMA) has been estimated between 1/50,000 to 1/100,000.

Clinical Features (Signs / symptoms)

MMA is an inborn error of vitamin B12 metabolism characterized by gastrointestinal and neurometabolic manifestations resulting from decreased function of the mitochondrial enzyme methylmalonyl-CoA mutase. Clinical signs, which typically present neonatally or during infancy, include lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, and muscle hypotonia, as well as developmental delay, intellectual disability, hepatomegaly and coma. Longterm consequences of the disorder include neurological damage due to metabolic stroke affecting the brain stem, and end stage renal failure. The adult or “benign” form of MMA is associated with a mildly increased urinary excretion of methylmalonate, but it is uncertain if some of these individuals will develop symptoms. This form of MA is not well understood, though patients are typically viewed as stable, but may be prone to acute metabolic decompensation.

Natural History (Important subgroups & survival / recovery)

Onset ranges from the neonatal period to adulthood. The most common MMA phenotype presents during infancy where infants are normal at birth, but rapidly develop clinical manifestations. All phenotypes demonstrate periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. Survival expectancy depends on the MMA subtype.

Likelihood of Outcome

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

1-2 in 50000

Virtually all cases are attributed to a mutation in MUT, MMA, MMAB, MCEE, or MMADHC. Thus the prevalence of genetic mutations should be similar to prevalence estimates for methylmalonic aciduria (between 1/50,000 to 1/100,000).

Tier 4

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown

Information on penetrance was not available.

Tier Not provided

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

Information on relative risk was not available.

Expressivity

Clinical presentation of methylmalonic aciduria can vary and may present with severe manifestations during the neonatal period or as an atypical or “benign” form with onset during adulthood with mild clinical outcomes.

Tier 4

Intervention Effectiveness

Patient Management

To establish the extent of disease in an individual diagnosed with isolated MMA, the following evaluations are recommended:

- serum chemistry panel (Na , K , CI , glucose, urea, creatinine, AST, ALT, alkaline phosphatase, bilirubin [T/U], triglycerides, and cholesterol)

- complete blood count with differential

- arterial or venous blood gas

- plasma ammonium concentration

- formal urinalysis

- quantitative plasma amino acids

- urine organic acid analysis by gas chromatography and mass spectrometry (GC-MS)

- if possible, measurement of plasma concentrations of methylmalonic acid, methylcitrate, free and total carnitine, and an acylcarnitine profile to document propionylcarnitine (C3 species) concentration.

Tier 4

Nutritional management should include a low-protein, high-calorie diet.

Tier 4

Patients who are vitamin B12 responsive, should be administered hydroxocobalamin injections every day to every other day. This regimen should be adjusted for the patient’s age and weight.

Tier 4

Carnitine can be given daily as a dietary supplement to increase intracellular CoA pools and enhance the excretion of propionylcarnitine.

Tier 4

Antibiotics can be used to reduce the production of proprionate from gut flora, though the recommended types, dosage, frequency may vary

Tier 4

Medic Alert bracelets allow for easily accessed detailed emergency treatment protocols to

facilitate care in the event of an episode

Tier 4

Surveillance

Information on surveillance was not identified.

Circumstances to Avoid

Patients are recommended to avoid fasting and increased dietary protein and to regulate their stress.

Tier 4

Nature of Intervention

Nature of Intervention

Identified interventions include Medic Alert bracelets, B12 administration, avoidance of fasting and increased dietary protein, and stress regulation.

Context: Adult

Chance to Escape Clinical Detection

Without newborn screening, an individual with the adult onset form would likely escape detection prior to their first episode.

Context: Adult

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers

References List

I Manoli, JL Sloan, CP Venditti. Isolated Methylmalonic Acidemia. (2005) [Updated Jan 07 2016]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1231/

Methylmalonic acidemia without homocystinuria. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=293355