Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Incomplete (Consensus scoring is Incomplete)
• Curation Status (Adult): Released - Under Revision 1.0.1
• GENE/GENE PANEL: MUT, MMAA, MMAB, MMADHC, MCEE, MMACHC
• Condition: Methylmalonic Academia
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• MUT ⇔ 251000: Assertion Pending
• MMAA ⇔ 251100: Assertion Pending
• MMAB ⇔ 251110: Assertion Pending
• MMADHC ⇔ 277410: Assertion Pending
• MCEE ⇔ 251120: Assertion Pending
• MMACHC ⇔ 277400: Assertion Pending

Actionability 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.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the 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

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Prevalence of methylmalonic aciduria (MMA) has been estimated between 1/50,000 to 1/100,000. [1, 2]

Clinical Features

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. [1, 2]

Natural History

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. [2]

2. How effective are interventions for preventing harm?

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) [2]

Nutritional management should include a low-protein, high-calorie diet. (Tier 4) [2]

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) [2]

Carnitine can be given daily as a dietary supplement to increase intracellular CoA pools and enhance the excretion of propionylcarnitine. (Tier 4) [2]

Antibiotics can be used to reduce the production of proprionate from gut flora, though the recommended types, dosage, frequency may vary (Tier 4) [2]

Medic Alert bracelets allow for easily accessed detailed emergency treatment protocols to
facilitate care in the event of an episode (Tier 4) [2]

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) [2]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

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) [2]

Penetrance

Information on penetrance was not available.

Relative Risk

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) [2]

4. What is the Nature of the Intervention?

Nature of Intervention

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

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Without newborn screening, an individual with the adult onset form would likely escape detection prior to their first episode. (Tier 4) [2]

Date of Search: 08.18.2015

Reference List

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

2. I Manoli, JL Sloan, CP Venditti. Isolated Methylmalonic Acidemia. 2005 Aug 16 [Updated 2016 Jan 07]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1231