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HelpTest ID: MSUDP Maple Syrup Urine Disease Gene Panel, Varies
Ordering Guidance
The recommended first-tier screening tests for maple syrup urine disease (MSUD) are a combination of biochemical tests including quantitative plasma amino acids and urine organic acids. Order AAQP / Amino Acids, Quantitative, Plasma and OAU / Organic Acids Screen, Urine.
Customization of this panel and single gene analysis for any gene present on this panel is available. For more information see CGPH/ Custom Gene Panel, Hereditary, Generation Sequencing, Varies.
Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.
Shipping Instructions
Specimen preferred to arrive within 96 hours of collection.
Specimen Required
Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. For instructions for testing patients who have received a bone marrow transplant, call 800-533-1710.
Submit only 1 of the following specimens:
Specimen Type: Whole blood
Container/Tube: Lavender top (EDTA) or yellow top (ACD)
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send whole blood specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 14 days
Specimen Type: Skin biopsy
Supplies: Fibroblast Biopsy Transport Media (T115)
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.
Specimen Volume: 4-mm punch
Specimen Stability Information: Refrigerated (preferred)/Ambient
Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.
Specimen Type: Cultured fibroblast
Container/Tube: T-25 flask
Specimen Volume: 2 Flasks
Collection Instructions: Submit confluent cultured fibroblast cells from a skin biopsy from another laboratory. Cultured cells from a prenatal specimen will not be accepted.
Specimen Stability Information: Ambient (preferred)/Refrigerated (<24 hours)
Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.
Specimen Type: Blood spot
Supplies: Card-Blood Spot Collection (Filter Paper) (T493)
Container/Tube:
Preferred: Collection card (Whatman Protein Saver 903 Paper)
Acceptable: PerkinElmer 226 (formerly Ahlstrom 226) filter paper or blood spot collection card
Specimen Volume: 5 Blood spots
Collection Instructions:
1. An alternative blood collection option for a patient older than 1 year is a fingerstick. For detailed instructions, see How to Collect Dried Blood Spot Samples.
2. Let blood dry on the filter paper at ambient temperature in a horizontal position for a minimum of 3 hours.
3. Do not expose specimen to heat or direct sunlight.
4. Do not stack wet specimens.
5. Keep specimen dry
Specimen Stability Information: Ambient (preferred)/Refrigerated
Additional Information:
1. Due to lower concentration of DNA yielded from blood spot, it is possible that additional specimen may be required to complete testing.
2. For collection instructions, see Blood Spot Collection Instructions
3. For collection instructions in Spanish, see Blood Spot Collection Card-Spanish Instructions (T777)
4. For collection instructions in Chinese, see Blood Spot Collection Card-Chinese Instructions (T800)
Specimen Type: Saliva
Patient Preparation: Patient should not eat, drink, smoke, or chew gum 30 minutes prior to collection.
Supplies: Saliva Swab Collection Kit (T786)
Specimen Volume: 1 Swab
Collection Instructions: Collect and send specimen per kit instructions.
Specimen Stability Information: Ambient 30 days
Additional Information: Due to lower concentration of DNA yielded from saliva, it is possible that additional specimen may be required to complete testing.
Forms
1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing (Spanish) (T826)
2. Molecular Genetics: Biochemical Disorders Patient Information (T527)
3. If not ordering electronically, complete, print, and send a Biochemical Genetics Test Request (T798) with the specimen.
Useful For
Follow up for abnormal biochemical results suggestive of maple syrup urine disease (MSUD)
Establishing a molecular diagnosis for patients with MSUD
Identifying variants within genes known to be associated with MSUD, allowing for predictive testing of at-risk family members
Genetics Test Information
This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 6 genes associated with maple syrup urine disease: BCKDHA, BCKDHB, BCKDK, DBT, DLD, PPM1K. See Targeted Genes and Methodology Details for Maple Syrup Urine Disease Gene Panel and Method Description for additional details.
Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, familial screening, and genetic counseling for maple syrup urine disease.
Method Name
Sequence Capture and Targeted Next-Generation Sequencing (NGS) followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing.
Reporting Name
MSUD Gene PanelSpecimen Type
VariesSpecimen Minimum Volume
See Specimen Required
Specimen Stability Information
| Specimen Type | Temperature | Time | Special Container |
|---|---|---|---|
| Varies | Varies | ||
Clinical Information
Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by the deficiency of the branched-chain ketoacid dehydrogenase (BCKDH) complex. The BCKDH complex is involved in the metabolism of the branched-chain amino acids (BCAA): isoleucine (Ile), leucine (Leu), and valine (Val).
MSUD can be divided into 5 phenotypes: classic, intermediate, intermittent, thiamine-responsive, and dihydrolipoyl dehydrogenase (E3)-deficient, depending on the clinical presentation and response to thiamine administration. Classic MSUD, the most common and most severe form, presents in newborns with feeding intolerance, failure to thrive, vomiting, lethargy, and maple syrup odor in urine and cerumen. If untreated, it progresses to irreversible intellectual disability, hyperactivity, failure to thrive, seizures, coma, cerebral edema, and possibly death.
Age of onset for individuals with non-classical forms of MSUD is variable, with some presenting with symptoms as early as 2 years of age. Symptoms include poor growth and feeding, irritability, and developmental delays. These patients can also experience severe metabolic intoxication and encephalopathy during periods of sufficient catabolic stress.
MSUD is a panethnic condition but is most prevalent in the Old Order Mennonite community in Lancaster, Pennsylvania with an incidence there of 1 in 760 live births. The incidence of MSUD is approximately 1 in 185,000 live births in the general population.
A comprehensive gene panel is a helpful tool to establish a diagnosis for patients with suggestive clinical and biochemical features given the broad clinical spectrum and genetic heterogeneity of MSUD. The BCKDH complex consists of 4 subunits (E1a, E1b, E2, E3), and this panel includes testing of the genes that encode each subunit (BCKDHA for E1a, BCKDHB for E1b, DBT for E2, and DLD for E3). In addition, BCKDK and PPM1K are also included, both of which impact the activity of the BCKDH complex. Disease-causing variants in both alleles of any of these genes result in disease.
The recommended first-tier tests to screen for MSUD is a combination of biochemical tests including quantitative plasma amino acids (AAQP / Amino Acids, Quantitative, Plasma) to measure BCAA levels and alloisoleucine and urine organic acids (OAU / Organic Acids Screen, Urine) to look for presence of toxic urine metabolites including 2-hydroxy-isovaleric acid and 2-oxo-isocaprioic acid.
Treatment of MSUD aims to normalize the concentration of BCAA by dietary restriction of these amino acids. Because BCAA belong to the essential amino acids, the dietary treatment requires frequent adjustment, which is accomplished by regular determination of BCAA and allo-isoleucine concentrations. Orthotopic liver transplantation has been successful and is an effective therapy for MSUD.
Reference Values
An interpretive report will be provided.
Interpretation
All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Clinical Reference
1. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.
2. Chuang DT, Shih VE, Wynn RM. Maple syrup urine disease (branched-chain ketoaciduria). In: Valle D, Antonarakis S, Ballabio A, Beaudet A, Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill Education; 2019. Accessed March 8, 2024. Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225084607&bookid=2709#225084691
3. Frazier DM, Allgeier C, Horner C, et al. Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach. Mol Genet Metab. 2014;112(3)210-217
4. Strauss KA, Puffenberger EG, Morton DH. Maple Syrup Urine Disease. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2006. Updated April 23, 2020. Accessed March 8, 2024. Available at www.ncbi.nlm.nih.gov/books/NBK1319
5. Diaz VM, Camarena C, de la Vega A, et al. Liver transplantation for classical maple syrup urine disease: long-term follow-up. J Pediatr Gastroenterol Nutr. 2014;59(5):636-639
Test Classification
This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.CPT Code Information
81405
81406 x 3
81479
88233-Tissue culture, skin, solid tissue biopsy (if appropriate)
88240-Cryopreservation (if appropriate)
81479 (if appropriate for government payers)
LOINC Code Information
| Test ID | Test Order Name | Order LOINC Value |
|---|---|---|
| MSUDP | MSUD Gene Panel | 105355-2 |
| Result ID | Test Result Name | Result LOINC Value |
|---|---|---|
| 608776 | Test Description | 62364-5 |
| 608777 | Specimen | 31208-2 |
| 608778 | Source | 31208-2 |
| 608779 | Result Summary | 50397-9 |
| 608780 | Result | 82939-0 |
| 608781 | Interpretation | 69047-9 |
| 608782 | Resources | 99622-3 |
| 608783 | Additional Information | 48767-8 |
| 608784 | Method | 85069-3 |
| 608785 | Genes Analyzed | 48018-6 |
| 608786 | Disclaimer | 62364-5 |
| 608787 | Released By | 18771-6 |
Day(s) Performed
Varies
Report Available
14 to 21 daysReflex Tests
| Test ID | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| CULFB | Fibroblast Culture for Genetic Test | Yes | No |
Testing Algorithm
For skin biopsy or cultured fibroblast specimens, fibroblast culture testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.
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