Pediatric Summary Report

Secondary Findings in Pediatric Subjects

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

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Entered 0.0.0
• Status (Adult): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: MUT, MMAA, MMAB, MMADHC, MCEE
• Condition: Methylmalonic Acidemia
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• MUT ⇔ 251000 (methylmalonic aciduria due to methylmalonyl-coa mutase deficiency): Assertion Pending
• MMAA ⇔ 251100 (methylmalonic aciduria, cbla type): Assertion Pending
• MMAB ⇔ 251110 (methylmalonic aciduria, cblb type): Assertion Pending
• MMADHC ⇔ 277410 (methylmalonic aciduria and homocystinuria, cbld type; mahcd): Assertion Pending
• MCEE ⇔ 251120 (methylmalonyl-coa epimerase deficiency): 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

Gene Condition Pairs: MUT ⇔ (OMIM:251000) MMAA ⇔ (OMIM:251100) MMAB ⇔ (OMIM:251110) MMADHC ⇔ (OMIM:277410) MCEE ⇔ (OMIM:251120)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity (B12 responsive and unresponsive form) / Metabolic management (includes dietary modification, l-carnitine, antibiotics)	2	3C	2B	2	9CB
Morbidity (B12 responsive only) / Injectable vitamin B12	2	3C	2B	3	10CB

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 as 1-9 per 100,000. [1, 2, 3, 4]

Clinical Features

MMA is an inborn error of vitamin B12 metabolism characterized by gastrointestinal and neurometabolic manifestations. It is caused by complete or partial deficiency of methylmalonyl-CoA mutase (MUT; mut- and mut0 subtypes, respectively), a defect in transport or synthesis of its cofactor adenosyl-cobalamin (MMAA cblA type; MMAB, cblB type; MMADHC, cblD-MMA type), or deficiency of methylmalonyl-CoA epimerase (MCEE). Presentation is variable:
• Infantile completely deficient (mut0) or non-B12-responsive (clbB) is the most common phenotype and presents during infancy. Infants are normal at birth, but develop lethargy, vomiting, and dehydration within the first few months of life. They may also exhibit hepatomegaly, hypotonia, encephalopathy, metabolic acidosis, ketosis and ketonuria, hyperammonemia, and hyperglycemia.
• Partially deficient (mut-) or B12-responsive (cblA, cblD, rarely cblB) is an intermediate phenotype that can occur in the first few months or years of life. Symptoms include feeding problems, failure to thrive, hypotonia, and developmental delay. Some have protein aversion and vomiting, and lethargy after protein intake.
• Methylmalonyl-CoA epimerase (MCEE) deficiency is a persistent, moderate phenotype where findings in infants/children range from complete absence of symptoms to severe metabolic acidosis. Symptoms include ataxia, dysarthria, hypotonia, mild spastic paraparesis, and seizures.
• An atypical or benign/adult version is associated with increased, albeit mild, urinary excretion of methylmalonate. It is uncertain whether these individuals will develop symptoms.
Secondary complications can include intellectual disability, tubulointerstitial nephritis with progressive impairment of renal function, neurologic findings, pancreatitis, growth failure, functional immune impairment, bone marrow failure, optic nerve atrophy, and hepatoblastoma. [1, 2, 3, 4, 5, 6]

Natural History

Onset ranges from the neonatal period to adulthood. All phenotypes demonstrate periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. Episodes of catabolic stress are associated with rapid production and accumulation of toxic metabolites which can cause decompensation, and lead to life threatening complications. MMA is associated with substantial morbidity and mortality that correlates with the underlying defect. Individuals with the mut0 and cblB subtypes tend to be more severely affected and have a higher rate of mortality than those with the mut-, cblA, and cblD subtypes. Survival in MMA has improved over time, mainly ability of newborn screening to detect MMA before early childhood encephalopathy. [1, 2, 3, 4, 5]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following a diagnosis of this condition: https://www.acmg.net/PDFLibrary/Elevated%20C3%20Acylcarnitine%20PA%20and%20MA.pdf

To establish the extent of disease in an individual diagnosed with MMA, the following evaluations are recommended:
• Serum chemistry panel, complete blood count with differential, arterial or venous blood gas, plasma ammonium and lactic acid concentration, formal urinalysis, quantitative plasma amino acids, and urine organic acid analysis by gas chromatography and mass spectrometry (GC-MS)
• Measurement of plasma concentrations of methylmalonic acid, methylcitrate, free and total carnitine, and acylcarnitine profile to document propionylcarnitine (C3 species) concentration
• Biochemical genetics consultation. (Tier 4) [1]

Specialists in physiatry, physical therapy, and occupational therapy can help address the complex challenges faced by patients and families, maximize functionality, and improve quality of life. (Tier 3) [1]

In MMA, the aim is to stabilize patients on a diet that maintains metabolic homeostasis while allowing normal growth and development. Dietary management includes low natural protein intake, limiting but ensuring essential requirements of the propionic acid precursor amino acids, isoleucine, valine, methionine, and threonine to reduce elevated concentrations of metabolites. (Tier 2) [4]

Response to vitamin B12 (cobalamin) should be assessed in every patient. For responders, hydroxocobalamin should be used as long-term treatment. (Tier 2) [4]

L-carnitine is useful in the long-term treatment of patients. It enhances propionyl group elimination, regenerates CoA, and transforms toxic CoA esters into less toxic carnitine esters that can be eliminated in the urine. (Tier 2) [4]

Oral antibiotics, such as metronidazole, greatly reduce the production of intestinal propionic acid producing bacteria, which may account for a large proportion of total body propionate. (Tier 2) [4]

The presence of clinical signs and symptoms (e.g., vomiting, lethargy, respiratory distress) and common biochemical signs of acute decompensation compared to the patient’s baseline should trigger further evaluation and potential adjustment of therapy and monitoring to prevent complications. In addition, any intercurrent illness must prompt closer monitoring and evaluation, given well-documented cases of complications following acute illnesses without biochemical disturbances. (Tier 2) [4]

A letter given to the family to present to emergency department physicians that specifies the recommended acute management protocol should be standard of care. Medic Alert bracelets and emergency treatment protocols outlining fluid and electrolyte therapy should be available for all affected individuals. (Tier 4) [1]

Special considerations regarding choices of anesthetic agents in this patient population may apply. (Tier 3) [1]

Patients who are usually well controlled can easily decompensate during surgery precipitated by a combination of stress and fasting. Thus, it is important to follow an appropriate protocol, minimizing catabolism by providing adequate amounts of calories. (Tier 2) [4]

Successful pregnancies have been reported in mild MMA with no serious problems reported. However, pregnancy should be planned ahead, and metabolic control optimized prior to conception. During pregnancy, labor and delivery, post-partum, and breastfeeding the protein demand/tolerance and carnitine requirements may increase requiring regular monitoring. Treatment should be initiated and adapted accordingly. (Tier 2) [4]

Surveillance

Patients require lifelong monitoring with clinical, nutritional, biochemical, neurodevelopmental and psychological assessments that aim at optimizing patient development and performance with age-adapted dietary and drug treatment. This includes regular monitoring of metabolic parameters, along with measures of protein nutrition and overall nutritional status. Intervals between visits should be decided individually on the basis of age, growth, severity, metabolic stability and compliance with diet and therapy. (Tier 2) [4]

Regular monitoring for long term complications (renal and cardiac complications) are indicated including a neurologic exam at each visit, biochemistry for kidney and pancreatic function every 6 months, annual cardiac exam (ECG, echocardiography), and annual ophthalmologic exams. In general, when detected, these complications are treated with the same established therapeutic principles of patients without MMA. (Tier 2) [4]

Circumstances to Avoid

Patients are recommended to avoid fasting, increased dietary protein, and stress. Patients should also avoid supplementation with the individual propiogenic amino acids valine and isoleucine, as they directly increase the toxic metabolite load in patients with disordered propionate oxidation. (Tier 4) [1]

Steroids administered by a systemic route should be avoided if possible due to their catabolic effects on the muscle. If it is unavoidable (e.g., emergency situation), they should be used with caution. (Tier 2) [4]

Drugs containing pivalic acid (antibiotic) and valproate decrease L-carnitine concentration in plasma and tissues and should be avoided. Sodium valproate should be used with great caution due to its interference with intermediary metabolism unless there are no other antiepileptic drug alternatives. Nephrotoxic drugs should be avoided due to their potential to precipitate or aggravate renal disease. Immunosuppressive drugs (e.g. cyclophosphamide) should be used with caution. Medications known to prolong the QTc-interval (such as prokinetic drugs) should be avoided if possible. (Tier 2) [4]

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

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

Virtually all cases of MMA are attributed to a pathogenic variant in one of the following genes: MUT (60%), MMAA (25%), MMAB (12%), MCEE (unknown proportion), or MMADHC (unknown proportion). Thus the prevalence of genetic pathogenic variants should be similar to prevalence estimates for MMA (between 1/50,000 to 1/100,000). (Tier 4) [1]

Penetrance

Information on penetrance based on molecular detection were not available. However, the following signs/symptoms have been reported in individuals with MMA (including those with infantile and childhood onset):
• Developmental delay: 25-65%
• Seizures/epilepsy: 16-35%
• Movement disorders: 30-45%
• Metabolic stroke like events: 35%
• Chronic renal failure: 28-47% (median age of onset: 6.5 years, range: 1.5-18.6 years)
• Cardiomyopathy: rare, isolated case reports
• Pancreatitis: rare, isolated case reports. (Tier 3) [4]

Relative Risk

Information on relative risk was not available.

Expressivity

Clinical presentation of MMA 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. The clinical phenotype depends on a number of factors that cannot be accurately predicted by the genotype. (Tier 4) [1]

4. What is the Nature of the Intervention?

Nature of Intervention

Identified interventions include emergency management plans, dietary management supplementation, B12 administration, avoidance of fasting and increased dietary protein, antibiotics, and stress regulation. L-carnitine is well-tolerated with few side effects, including transient nausea and vomiting, abdominal cramps, diarrhea, and fish body odor. No risks related to high levels of free and total carnitine have been reported. Chronic antibiotic therapy is not innocuous and introduces the risk of repopulation with resistant flora. This could pose a significant infectious threat and could be especially dangerous in an individual with MMA since most deaths are related to metabolic decompensation, often precipitated by infection.

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

Chance to Escape Clinical Detection

Newborn screening programs identify newborns with MMA. Without newborn screening, an individual could likely escape detection prior to their first episode. (Tier 4) [1]

Date of Search: 05.13.2014

Reference List

1. 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

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

3. Vitamin B12-responsive methylmalonic acidemia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=28

4. Baumgartner MR, Horster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, Huemer M, Hochuli M, Assoun M, Ballhausen D, Burlina A, Fowler B, Grunert SC, Grunewald S, Honzik T, Merinero B, Perez-Cerda C, Scholl-Burgi S, Skovby F, Wijburg F, MacDonald A, Martinelli D, Sass JO, Valayannopoulos V, Chakrapani A. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. (2014) 9:130.

5. Vitamin B12-unresponsive methylmalonic acidemia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=27

6. Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=308425