Lafora Disease via the NHLRC1 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
635 NHLRC1$540.00 81403 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

Mutations in the NHLRC1 gene account for ~30% of LD cases (Gomez-Abad et al. 2005).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 NHLRC1$990.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Features

Lafora disease (LD) is a form of progressive myoclonic epilepsy. During adolescence, LD patients present with myoclonic seizures, headaches, dysarthria, ataxia and hallucinations (Turnbull et al. 2012). Seizures, though at first controlled by anticonvulsants, soon become drug resistant and increase in frequency and severity. Rapid neurodegeneration occurs within 10 years of seizure onset resulting in dementia (Gomez-Abad et al. 2005). Patients are eventually reduced to a vegetative state due to severe myoclonus. LD can be distinguished from other progressive myoclonic epilepsies by the presence of intracellular Lafora bodies, insoluble glycogen aggregates, in neurons and other cells. Lafora bodies can be detected via axillary skin biopsy.


Lafora disease is inherited in an autosomal recessive manner and is caused by loss-of-function mutations in the NHLRC1/EPM2B or EPM2A genes. Mutations in either NHLRC1 or EPM2A result in similar LD phenotypes, with NHLRC1 mutations resulting in a slower clinical progression (Criado et al. 2011; Franceschetti et al. 2006). Missense, nonsense and frameshift mutations in NHLRC1 as well as deletions encompassing the entire NHLRC1 gene have been reported in LD patients (Singh and Ganesh 2009; Kecmanovic et al. 2013; Lohi et al. 2007).

Under normal cellular conditions, glycogen assembles into soluble, spherical polyglucosan structures. In LD patients, polyglucosan structure is disrupted, resulting in the formation of insoluble aggregates, known as Lafora bodies. Whether Lafora bodies are the cause of LD or a symptom is unclear, though the number of Lafora bodies in neurons correlates with increased neurodegeneration (Criado et al. 2011).

EPM2A encodes the phosphatase, laforin. NHLRC1 encodes malin, a ubiquitin ligase. Laforin and malin localize to the endoplasmic reticulum where they physically interact. Laforin and malin normally prevent the accumulation of Lafora bodies by regulating enzymes involved in glycogen metabolism and by promoting autophagy and the degradation of Laflora bodies (Liu et al. 2013). Studies in mouse models demonstrate that loss of either laforin or malin results in an accumulation of Lafora bodies in neurons and subsequent neurodegeneration (Turnbull et al. 2011).

Testing Strategy

Testing involves PCR amplification from genomic DNA and bidirectional Sanger sequencing of the single coding exon and ~10bp of adjacent noncoding sequences. This testing strategy will reveal coding sequence changes, splice site mutations and small insertions or deletions in the NHLRC1 gene, but will not detect large deletions in the NHLRC1 locus. We will also sequence any single portion (Test #100) or portions of the exon (Test #200) in family members of patients with known mutations or to confirm research results.

Indications for Test

Candidates for NHLRC1 testing include patients with symptoms of Lafora disease and for which mutations in EPM2A were not found.


Official Gene Symbol OMIM ID
NHLRC1 608072
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Lafora Disease 254780


Genetic Counselors
  • Criado O, Aguado C, Gayarre J, Duran-Trio L, Garcia-Cabrero AM, Vernia S, San Millan B, Heredia M, Roma-Mateo C, Mouron S, Juana-Lopez L, Dominguez M, et al. 2011. Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy. Human Molecular Genetics 21: 1521–1533. PubMed ID: 22186026
  • Franceschetti S, Gambardella A, Canafoglia L, Striano P, Lohi H, Gennaro E, Ianzano L, Veggiotti P, Sofia V, Biondi R. 2006. Clinical and genetic findings in 26 Italian patients with Lafora disease. Epilepsia 47: 640–643. PubMed ID: 16529633
  • Gomez-Abad C, Gomez-Garre P, Gutierrez-Delicado E, Saygi S, Michelucci R, Tassinari CA, Rodriguez de Cordoba S, Serratosa JM. 2005. Lafora disease due to EPM2B mutations: A clinical and genetic study. Neurology 64: 982–986. PubMed ID: 8651643
  • Kecmanovic M, Jovic N, Čukic M, Keckarevic-Markovic M, Keckarevic D, Stevanovic G, Romac S. 2013. Lafora disease: Severe phenotype associated with homozygous deletion of the NHLRC1 gene. Journal of the Neurological Sciences 325: 170–173. PubMed ID: 23317923
  • Liu Y, Zeng L, Ma K, Baba O, Zheng P, Liu Y, Wang Y. 2013. Laforin–Malin Complex Degrades Polyglucosan Bodies in Concert with Glycogen Debranching Enzyme and Brain Isoform Glycogen Phosphorylase. Molecular Neurobiology. PubMed ID: 24068615
  • Lohi H, Turnbull J, Zhao XC, Pullenayegum S, Ianzano L, Yahyaoui M, Mikati MA, Quinn NP, Franceschetti S, Zara F, Minassian BA. 2007. Genetic diagnosis in Lafora disease: Genotype-phenotype correlations and diagnostic pitfalls. Neurology 68: 996–1001. PubMed ID: 17389303
  • Singh S, Ganesh S. 2009. Lafora progressive myoclonus epilepsy: A meta-analysis of reported mutations in the first decade following the discovery of the EPM2A and NHLRC1 genes. Human Mutation 30: 715–723. PubMed ID: 19267391
  • Turnbull J, DePaoli-Roach AA, Zhao X, Cortez MA, Pencea N, Tiberia E, Piliguian M, Roach PJ, Wang P, Ackerley CA, Minassian BA. 2011. PTG Depletion Removes Lafora Bodies and Rescues the Fatal Epilepsy of Lafora Disease. PLoS Genetics 7: e1002037. PubMed ID: 21552327
  • Turnbull J, Girard J-M, Lohi H, Chan EM, Wang P, Tiberia E, Omer S, Ahmed M, Bennett C, Chakrabarty A, Tyagi A, Liu Y, et al. 2012. Early-onset Lafora body disease. Brain 135: 2684–2698. PubMed ID: 22961547
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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