Test ID: MAHMS
Methylmalonic Aciduria and Homocystinuria, cblC Type, Full Gene Analysis
Secondary ID 
A test code used for billing and in test definitions created prior to November 2011
NY State Approved Indicates the status of NY State approval and if the test is orderable for NY State clients.
Useful For Suggests clinical disorders or settings where the test may be helpful
Confirmation of diagnosis of methylmalonic aciduria and homocystinuria, cblC type
Distinguishing between cblC, cblD, and cblF types when methylmalonic aciduria and homocystinuria are identified
Carrier screening in cases where there is a family history of methylmalonic aciduria and homocystinuria, but disease causing mutations have not been identified in an affected individual
Reflex Tests Lists test(s) that may or may not be performed, at an additional charge, depending on the result and interpretation of the initial test(s)
| Test ID | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| FBC | Fibroblast Culture for Genetic Test | Yes | No |
Testing Algorithm Delineates situation(s) when tests are added to the initial order. This includes reflex and additional tests.
If skin biopsy is received, fibroblast culture for genetic test will be added and charged separately.
Special Instructions and Forms Describes specimen collection and preparation information, test algorithms, and other information pertinent to test. Also includes pertinent information and consent forms to be used when requesting a particular test
Method Name A short description of the method used to perform the test
MAHMS/89436: Polymerase Chain Reaction (PCR) Followed by DNA Sequence Analysis
FBC/80333: Cell Culture
(PCR is utilized pursuant to a license agreement with Roche Molecular Systems, Inc.)
Reporting Name A shorter/abbreviated version of the Published Name for a test; an abbreviated test name
Aliases Lists additional common names for a test, as an aid in searching
Cobalamin C
Homocystinuria
Methylmalonic Acidemia
Methylmalonic Aciduria (MMA)
MMA (Methylmalonic Aciduria)
MMACHC
Specimen Type Describes the specimen type needed for testing
Specimen Required Defines the optimal specimen. This field describes the type of specimen required to perform the test and the preferred volume to complete testing. The volume allows automated processing, fastest throughput and, when indicated, repeat or reflex testing.
Forms:
1. Molecular Genetics-Biochemical Disorders Patient Information Sheet (Supply T527) in Special Instructions
2. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (Supply T576) is available in Special Instructions.
3. If not ordering electronically, submit a Molecular Genetics Request Form (Supply T245) with the specimen.
Specimen must arrive within 96 hours of collection.
Submit only 1 of the following specimens:
Preferred:
Specimen Type: Whole blood
Container/Tube:
Preferred: Lavender top (EDTA) or yellow top (ACD)
Acceptable: Any anticoagulant
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send specimen in original tube.
Specimen Stability Information: Ambient (preferred)/Refrigerated
Specimen Type: Cultured fibroblasts
Container/Tube: T-75 or T-25 flask
Specimen Volume: 1 full T-75 or 2 full T-25 flasks
Specimen Stability Information: Ambient (preferred)/Refrigerated <24 hours
Specimen Type: Skin biopsy
Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin. Tubes can be supplied upon request (Eagle's minimum essential medium with 1% penicillin and streptomycin [Supply T115]).
Specimen Volume: 4-mm punch
Specimen Stability Information: Refrigerated (preferred)/Ambient
Acceptable:
Specimen Type: Blood spot
Container/Tube: Whatman Protein Saver 903 Paper
Specimen Volume: 5 blood spots
Collection Instructions:
1. Let blood dry on the filter paper at ambient temperature in a horizontal position for 3 hours.
2. Do not expose specimen to heat or direct sunlight.
3. Do not stack wet specimens.
4. Keep specimen dry.
Specimen Stability Information: Ambient (preferred)/Refrigerated
Specimen Minimum Volume Defines the amount of specimen required to perform an assay once, including instrument and container dead space. Submitting the minimum specimen volume makes it impossible to repeat the test or perform confirmatory or perform reflex testing. In some situations, a minimum specimen volume may result in a QNS (quantity not sufficient) result, requiring a second specimen to be collected.
Reject Due To Identifies specimen types and conditions that may cause the specimen to be rejected
| Hemolysis | NA |
| Lipemia | NA |
| Icterus | NA |
| Other | Formalin or fixative preservative |
Specimen Stability Information Provides a description of the temperatures required to transport a specimen to the laboratory. Alternate acceptable temperature(s) are also included.
| Specimen Type | Temperature | Time |
|---|---|---|
| Varies | Varies | |
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Multiple causes of inborn errors of cobalamin (cbl; better known as vitamin B12) metabolism have been identified. These disorders have been classified into 9 distinct complementation classes (cblA-cblH and mut, caused by mutations in the gene encoding methylmalonyl coenzyme A mutase). Complementation analysis utilizes cells from the patient to determine at what stage of the cbl metabolism pathway an error is occurring, and uses this information to differentiate between the various complementation class disorders.
Depending on the complementation class involved, errors in cbl metabolism can result in methylmalonic aciduria, homocystinuria, or both. The most common disorder in this group is methylmalonic aciduria and homocystinuria, cblC (cobalamin C) type, which results in both methylmalonic aciduria and homocystinuria.
cblC type is an autosomal recessive disorder with a variable age of onset. In the early onset form, symptoms appear in the first several years of life and include failure to thrive, developmental delay, seizures, metabolic crisis, and hydrocephalus. Patients may also have hemolytic uremic syndrome. Adults can present with confusion or other changes in mental status, cognitive decline, and megaloblastic anemia. Biochemical presentation includes methylmalonic aciduria and homocystinuria in urine organic acid or plasma amino acid analysis.
Other complementation class disorders, such as cblD and cblF, can result in a similar biochemical phenotype, and complementation testing or molecular testing is utilized to distinguish between these different types.
Mutations in the MMACHC gene are responsible for the cblC type disorder. The most common mutation (identified in approximately 40% of mutant alleles) is 271dupA. This multi-ethnic mutation is most frequently associated with early-onset disease, especially when present in the homozygous state. Another early-onset mutation is R111X, which is common in the Cajun and French Canadian populations. R132X is a late-onset mutation that has been identified in individuals of Indian, Pakistani, and Middle Eastern ethnicity. Although these genotype-phenotype correlations are well-established, there is often considerable variability in age of onset and expression of symptoms, even within families.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Interpretation Provides information to assist in interpretation of the test results
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
A small percentage of individuals who are carriers or have a diagnosis of methylmalonic aciduria and homocystinuria, cblC type (MMACHC) may have a mutation that is not identified by this method (eg, large genomic deletions, promoter mutations). The absence of a mutation(s), therefore, does not eliminate the possibility of positive carrier status or the diagnosis of MMACHC. For carrier testing, it is important to first document the presence of a MMACHC gene mutation in an affected family member.
In some cases, DNA alterations of undetermined significance may be identified.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical and biochemical findings, additional testing should be considered.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Lerner-Ellis JP, Tirone JC, Pawelek PD, et al: Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet 2006;38:93-100
2. Morel CF, Lerner-Ellis JP, Rosenblatt DS: Combined methylmalonic aciduria and homocystinuria (cblC): Phenotype-genotype correlations and ethnic-specific observations. Mol Genet Metab 2006;88:315-321
3. Martinelli D, Deodato F, Dionisi-Vici C: Cobalamin C defect: natural history, pathophysiology, and treatment. J Inherit Metab Dis 2011;34(1):127-135
Method Description Describes how the test is performed and provides a method-specific reference
DNA sequencing is utilized to test for the presence of a mutation in all 4 coding exons of the MMACHC gene. (Unpublished Mayo method)
Day(s) and Time(s) Test Performed Outlines the days and times the test is performed. This field reflects the day and time the sample must be in the testing laboratory to begin the testing process and includes any specimen preparation and processing time required before the test is performed. Some tests are listed as continuously performed, which means assays are performed several times during the day.
Monday; 10 a.m
Analytic Time Defines the amount of time it takes the laboratory to setup and perform the test. This is defined in number of days. The shortest interval of time expressed is "same day/1 day," which means the results may be available the same day that the sample is received in the testing laboratory. One day means results are available 1 day after the sample is received in the laboratory.
Maximum Laboratory Time Defines the maximum time from specimen receipt at Mayo Medical Laboratories until the release of the test result
Specimen Retention Time Outlines the length of time after testing that a specimen is kept in the laboratory before it is discarded
Performing Laboratory Location The location of the laboratory that performs the test
Test Classification Provides information regarding the medical device classification for laboratory test kits and reagents. Tests may be classified as cleared or approved by the US Food and Drug Administration (FDA) and used per manufacturer's instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR), Investigation Use Only (IUO) product, or a Research Use Only (RUO) product.
CPT Code Information Provides guidance in determining the appropriate Current Procedural Terminology (CPT) code(s) information for each test or profile. The listed CPT codes reflect Mayo Medical Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing.
81479-Unlisted molecular pathology procedure
LOINC® Code Information Provides guidance in determining the Logical Observation Identifiers Names and Codes (LOINC) values for the result codes returned for this test or profile.
| Result ID | Reporting Name | LOINC Code |
|---|---|---|
| 50504 | Specimen | 31208-2 |
| 50505 | Specimen ID | N/A |
| 50506 | Source | N/A |
| 50507 | Order Date | N/A |
| 50508 | Reason For Referral | 42349-1 |
| 50509 | Method | In Process |
| 50510 | Result | In Process |
| 50511 | Interpretation | 69047-9 |
| 50512 | Extraction Performed? | N/A |
| 50513 | Amendment | In Process |
| 50514 | Reviewed By | N/A |
| 50515 | Release Date | N/A |
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