Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Incomplete (WARNING: Incomplete Stage 2 curation.)

GENE/GENE PANEL: MUT, MMAA, MMAB, MMADHC, MCEE, MMACHC
Condition: Methylmalonic Academia
GENEDISEASE PAIRS: MUT251000 MMAA251100 MMAB251110 MMADHC277410 MCEE251120 MMACHC277400
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Prevalence of methylmalonic aciduria (MMA) has been estimated between 1/50,000 to 1/100,000.
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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.
1 2
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.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
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.
 
Family Management
Siblings of patients should be evaluated using biochemical testing. Genetic testing is possible when the mutation is known (Tier 4)
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Circumstances to Avoid
Patients are recommended to avoid fasting and increased dietary protein and to regulate their stress. (Tier 4)
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3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
 
Prevalence of Genetic Mutations
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)
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Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on penetrance was not available.
 
 
 
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 settting 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)
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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
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
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; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1231
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