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SALSA MLPA Probemix P033 CMT1

SALSA® MLPA® Probemix P033 CMT1 detects copy number variations in the PMP22 and KIF1b genes.

Specifications

Contents: 38 MLPA probes, including 16 probes for the common 17p12 deletion/duplication region, 2 probes for KIF1b, and flanking probes.

Tissue: genomic DNA isolated from human peripheral whole blood or buccal swabs.

Application: Charcot-Marie-Tooth disease (CMT) and hereditary neuropathy with liability to pressure palsies (HNPP).

CE-marked and registered for in vitro diagnostic (IVD) use in selected territories.

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List Prices Documentation

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MRC Holland has recently obtained the In Vitro Diagnostic Regulation (IVDR; EU 2017/746) certification for this product. The CE-IVDR version will be sold from early 2025, and will be accompanied by a change in the intended purpose. The probes targeting COX10, TEKT3 and KIF1B will no longer be intended for diagnostic use. The composition of this product remains unchanged.

Intended purpose

The SALSA MLPA Probemix P033 CMT1 is an in vitro diagnostic (IVD) or research use only (RUO) semi-quantitative assay for the detection of deletions or duplications in the human PMP22 and KIF1b genes in genomic DNA isolated from human peripheral whole blood specimens or buccal swabs. P033 CMT1 is intended to confirm a potential cause for and clinical diagnosis of Charcot-Marie-Tooth disease (CMT) or hereditary neuropathy with liability to pressure palsies (HNPP) and for molecular genetic testing of at-risk family members.

For the full intended purpose, see the product description.

Clinical background

Charcot-Marie-Tooth disease (CMT), with a worldwide incidence of 1 in 2500, is the most common hereditary sensorimotor neuropathy, comprising a group of clinically and genetically heterogeneous peripheral neuropathies. CMT is characterized by progressive distal muscle atrophy and weakness, sensory disturbance, the absence of deep tendon reflexes, and pes cavus deformity of the foot. More than 80 different genes are associated with CMT (http://www.ncbi.nlm.nih.gov/books/NBK1358/). Subtypes related to the genes PMP22, GJB1, MPZ and MFN2 are the most common ones, being responsible for up to 95% of CMT cases with a final diagnosis (Padilha et al. 2020). The disease can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. Table 1 provides an overview of the different genes involved in the CMT subtypes and the probemixes that cover these genes.

The most frequent form, CMT1A, accounts for as much as 50% of all CMT cases. CMT1A is a dominantly inherited, childhood-onset, slowly progressive motor and sensory neuropathy due to a duplication of PMP22 on chromosome 17. CMT type 2 is an axonal peripheral neuropathy which shows extensive clinical overlap with CMT1. However, in general, the phenotype of CMT2 patients is less severe. Until now, >15 subtypes of CMT2 have been described, each involving a different gene or chromosomal locus. Haploinsufficiency for the KIF1b gene is suggested to be responsible for CMT type 2A (Zhao et al. 2001; Drew et al. 2015).

Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by repeated focal pressure neuropathies such as carpal tunnel syndrome and peroneal palsy with foot drop. Recovery from acute neuropathy is often complete; when recovery is not complete, the resulting disability is usually mild. Some affected individuals also have signs of a mild to moderate peripheral neuropathy. The prevalence of HNPP is estimated at 7-16 in 100,000. The penetrance is 100% but expressivity is highly variable even within the same family. Approximately 6-23% of individuals diagnosed with HNPP have an asymptomatic affected parent. A contiguous gene deletion of chromosome 17p12 that includes PMP22 is present in approximately 80% of affected individuals; the remaining 20% have a pathogenic variant in PMP22 (https://www.ncbi.nlm.nih.gov/books/NBK1392/).

Table 1. Overview of the probemixes and genes related to CMT.
Probemix* Genes and coverage Condition Remarks
P033-B4 CMT1 (IVD)

PMP22: all exons

KIF1b: 2 probes

CMT1A and HNPP

CMT2A1

PMP22 probes in P033-B4 have the same ligation site as PMP22 probes in P405-B1 except for one exon 1 probe and one exon 4 probe. There is one additional PMP22 exon 5 probe present in P033-B4.
P405-B1 CMT1 (IVD)

PMP22: all exons

MPZ: all exons

GJB1: all exons

CMT1A and HNPP

CMT1B

CMTX

PMP22 probes in P405-B1 have the same ligation sites as PMP22 probes in P033-B4 except for one exon 1 probe and one exon 4 probe. There is one additional PMP22 exon 5 probe present in P033-B4.

MPZ probes in P405-B1 have the same ligation sites as MPZ probes in P143-C3.
P143-C3 MFN2-MPZ (RUO)

MFN2: all exons

MPZ: all exons

CMT2A

CMT1B

MPZ probes in P143-C3 have the same ligation sites as MPZ probes in P405-B1.

* IVD: in vitro diagnostic. RUO: research use only.

Regulatory status

SALSA MLPA Probemix P033 CMT1 is CE-marked for in vitro diagnostic (IVD) use. This assay has also been registered for IVD use in Colombia, Costa Rica and Israel.

This assay is for research use only (RUO) in all other territories.

Product documentation

Version B4

Other versions

Contact us for earlier versions.

List prices

Product

Item no.
Description
Technology
Price
P033-025R
SALSA MLPA Probemix P033 CMT1 – 25 rxn
MLPA
€ 281.00
P033-050R
SALSA MLPA Probemix P033 CMT1 – 50 rxn
MLPA
€ 550.00
P033-100R
SALSA MLPA Probemix P033 CMT1 – 100 rxn
MLPA
€ 1075.00

Required reagents

A general SALSA MLPA Reagent Kit is required for MLPA experiments (to be ordered separately).

Item no.
Description
Technology
Price
EK1-FAM
SALSA MLPA Reagent Kit – 100 rxn – FAM (6 vials)
MLPA MS-MLPA
€ 341.00
EK1-Cy5
SALSA MLPA Reagent Kit – 100 rxn – Cy5 (6 vials)
MLPA MS-MLPA
€ 341.00
EK5-FAM
SALSA MLPA Reagent Kit – 500 rxn – FAM (5×6 vials)
MLPA MS-MLPA
€ 1571.00
EK5-Cy5
SALSA MLPA Reagent Kit – 500 rxn – Cy5 (5×6 vials)
MLPA MS-MLPA
€ 1571.00
EK20-FAM
SALSA MLPA Reagent Kit – 2000 rxn – FAM (5×6 vials)
MLPA MS-MLPA
€ 6037.00

Price details & ordering

The prices above are list prices for direct orders from MRC Holland. Contact us for a quote that takes discounts and additional costs (such as shipping costs) into account. Different prices apply for orders through one of our sales partners; contact your local supplier for a quote.

More information about ordering & prices

Positive samples

Inclusion of a positive sample is usually not required, but can be useful for the analysis of your experiments. MRC Holland has very limited access to positive samples and cannot supply such samples. We recommend using positive samples from your own collection. Alternatively, you can use positive samples from an online biorepository, such as the Coriell Institute.

The commercially available positive samples below have been tested with the current (B4) version of this product and have been shown to produce useful results.

  • Coriell NA05167: Heterozygous duplication affecting the probes for COX10, PMP22 and TEKT3.
  • Coriell NA12214: Heterozygous duplication affecting the probes for COX10, PMP22 and TEKT3.

Resources

General MLPA resources

MLPA education

Publications

Selected publications using P033 CMT1

  • Bergamin G et al. (2014). Mutation analysis of MFN2, GJB1, MPZ and PMP22 in Italian patients with axonal Charcot-Marie-Tooth disease. Neuromolecular Med. 16:540-50.
  • Brown SB et al. (2024). Point Mutation Analysis of PMP22 in Patients Referred for Hereditary Neuropathy with Liability to Pressure Palsies. Open J Genet. 4:426-33.
  • Chen CX et al. (2019). Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot-Marie-Tooth disease. Clin Genet. 96:439-48.
  • Cho SM et al. (2014). Partial Gene Deletions of PMP22 Causing Hereditary Neuropathy with Liability to Pressure Palsies. Case Rep Genet. 2014:946010.
  • DiVincenzo C et al. (2014). The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. 2:522-9.
  • Hung CC et al. (2008). Identification of deletion and duplication genotypes of the PMP22 gene using PCR-RFLP, competitive multiplex PCR, and multiplex ligation-dependent probe amplification: a comparison. Electrophoresis. 29:618-25.
  • Liu X et al. (2020). Clinical and Genetic Diversity of PMP22 Mutations in a Large Cohort of Chinese Patients With Charcot-Marie-Tooth Disease. Front Neurol. 11:630.
  • Miltenberger-Miltenyi G et al. (2009). Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene mutations. Eur J Hum Genet. 17:1154-9.
  • Slater H et al. (2004). Improved testing for CMT1A and HNPP using multiplex ligation-dependent probe amplification (MLPA) with rapid DNA preparations: comparison with the interphase FISH method. Hum Mutat. 24:164-71.
  • Strangler Herodež Š et al. (2005). MLPA Method for PMP22 Gene Analysis. Acta Chim Slov. 52:105-10.

References

  • Drew AP et al. (2015). Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing. Mol Genet Genomic Med. 3:143-54.
  • Padilha JPD et al. (2020). Diagnostic yield of targeted sequential and massive panel approaches for inherited neuropathies. Clin Genet. 98:185-90.
  • Zhao C et al. (2001). Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell. 105:587-97.
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CE

CE-marked products are for In Vitro Diagnostic (IVD) use only in EU (candidate) member states and members of the European Free Trade Association (EFTA), and the UK.

CO

IVD-registered in Colombia.

CR

IVD-registered in Costa Rica.

IL

IVD-registered in Israel.