Amyotrophic Lateral Sclerosis and Frontotemporal Dementia via the CHMP2B Gene
- Summary and Pricing
- Clinical Features and Genetics
|Test Code||Test Copy Genes||Individual Gene Price||CPT Code Copy CPT Codes|
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The great majority of tests are completed within 18 days.
Pathogenic variants in the CHMP2B gene account for ~ 1.3% of patients affected with FTD (van der Zee et al. 2008) and ~ 1% of patients affected with ALS (Cox et al. 2010).
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurons in the motor cortex, brain stem, and spinal cord (Tandan et al. 1985). The dysfunction and loss of these neurons results in rapid progressive muscle weakness, atrophy and ultimately paralysis of limb, bulbar and respiratory muscles. The mean age of onset of symptoms is about 55 years of age; most cases begin between 40 and 70 years of age. The annual incidence of ALS is 1-2 per 100,000 (Cleveland and Rothstein 2001).
The most common symptoms include twitching and cramping of muscles of the hands and feet, loss of motor control in the hands and arms, weakness and fatigue, tripping and falling. Symptoms usually begin with asymmetric involvement of the muscles. As the disease progresses, symptoms may include difficulty in talking, breathing and swallowing, shortness of breath, and paralysis.
Frontotemporal dementia (FTD), previously referred to as Pick’s disease, is a clinically heterogeneous syndrome due to the progressive degeneration and atrophy of various regions of the frontal and temporal lobes of the brain. Symptoms are insidious and begin usually during the fourth and sixth decades of life; although earlier and later onsets have been documented (Neary et al. 1998; Snowden et al. 2002; Bruni et al. 2007). The annual incidence of FTD is 3-4 per 100,000 (Onyike and Diehl-Schmid 2013).
Two major forms, the behavioral-variant (FTD-bv) and the primary progressive aphasia (PPA), are recognized based on the site of onset of degeneration and the associated symptoms.
In FTD-bv the degenerative process begins in the frontal lobes and results in personality changes and deterioration of social conducts. Most common behavioral changes are: disinhibition, apathy, deterioration of executive function, obsessive thoughts, compulsive behavior, and neglect of personal hygiene (Rascovsky et al. 2011).
In PPA the degenerative process begins in the temporal lobes. PPA is a language disorder that is further divided into two sub-forms: progressive non-fluent aphasia (PNFA) and semantic dementia (SD). PNFA is characterized by difficulty in verbal communications, word retrieval, and speech distortion. Reading, writing and spelling are also affected; while memory is relatively preserved. SD is characterized by the progressive impairment of word comprehension, object and face recognition, and loss of semantic memory. Reading and writing skills are relatively preserved (Gustafson et al. 1993).
Cognitive impairment was not initially associated with ALS. However, frontotemporal dementia (FTD) has been reported in several cases. Dementia has been documented in patients with ALS from different ethnic groups and affects both males and females (Wikström et al. 1982; Lipton et al. 2004; Mitsuyama and Inoue, 2009).
A more recent prospective study showed that FTD occurred in up to 14% of patients with ALS. Furthermore, cognitive impairment was detected in more than 40% of patients (Phukan et al. 2012).
Definite ALS has been reported in patients with a clinical diagnosis of FTD (Lomen-Hoerth et al. 2003).
In addition to pure ALS and pure FTD, a combination of ALS and FTD clinical features have been reported in both sporadic and familial cases (Morita et al. 2006; Ferrari et al. 2011).
About 10% of ALS cases are familial (Emery and Holloway 1982). In most of these families, ALS is inherited in an autosomal dominant manner (AD-ALS) and is age-dependent with high penetrance. In rare families, the disease is transmitted in an autosomal recessive or dominant X-linked pattern.
About 90% of patients with ALS are sporadic cases (SALS) with no known affected relatives. It is unclear how many of the apparently sporadic cases are inherited with low penetrance. The clinical presentations of familial ALS (FALS) and sporadic ALS (SALS) are similar. However, the onset of symptoms in FALS is usually earlier compared to that of SALS (Kinsley and Siddique 2015).
Autosomal Dominant ALS (AD-ALS) is a clinically and genetically heterogeneous disorder that affects all ethnic groups. Several genes have been implicated in the disease including CHMP2B (Parkinson et al. 2006).
To date, 8 different heterozygous pathogenic variants distributed along the entire coding region of the CHMP2B gene have been identified in patients with ALS. They are all of the missense type (Cox et al. 2010; van Blitterswijk et al. 2012).
FTD is inherited in about 40% of cases (Rosso et al. 2003). In these families, the disease is inherited in an autosomal dominant manner. The remaining cases appear to be simplex with no known affected relatives. Similar to ALS, it is unclear how many of the apparently sporadic cases of FTD are inherited with low penetrance (Cruts et al. 2006; Le Ber et al. 2007).
To date, 4 different heterozygous pathogenic variants in the CHMP2B gene have been identified in patients with FTD. Two of these are truncating and the other two are missense variants (Skibinski al. 2005; van der Zee et al. 2008).
No pathogenic large copy number variations have been reported in the CHMP2B gene.
CHMP2B encodes a component of an endosomal sorting complex that is involved in degradation of surface receptor proteins and formation of endocytic multivesicular bodies (Tsang et al. 2006). Results obtained from functional studies suggest that accumulation of mutant CHMP2B proteins on endosomes prevent their interactions with lysosomes (Urwin et al. 2010).
In addition to CHMP2B, several other genes have been implicated in ALS, ALF/FTD and FTD (Robberecht and Philips 2013; Kinsley and Siddique 2015).
This test involves bidirectional Sanger sequencing of all coding exons and splice sites of the CHMP2B gene. The full coding sequence of each exon plus ~ 20 bp of flanking DNA on either side are sequenced. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.
Indications for Test
Patients with symptoms suggestive of ALS, FTD or ALS-FTD.
|Official Gene Symbol||OMIM ID|
|Amyotrophic Lateral Sclerosis Type 17||AD||614696|
|CHMP2B-Related Frontotemporal Dementia||AD||600795|
|Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Sequencing Panel|
- Genetic Counselor Team - email@example.com
- Khemissa Bejaoui, PhD - firstname.lastname@example.org
- Bruni A.C. et al. 2007. Neurology. 69: 140-7. PubMed ID: 17620546
- Cleveland D.W., Rothstein J.D. 2001. Nature Reviews. Neuroscience. 2: 806-19. PubMed ID: 11715057
- Cox L.E. et al. 2010. Plos One. 5: e9872. PubMed ID: 20352044
- Cruts M. et al. 2006. Nature. 442: 920-4. PubMed ID: 16862115
- Emery A.E., Holloway S. 1982. Advances in Neurology. 36: 139-47. PubMed ID: 7180680
- Ferrari R. et al. 2011. Current Alzheimer Research. 8: 273-94. PubMed ID: 21222600
- Gustafson L. 1993. Dementia. 4: 143-8. PubMed ID: 8401782
- Kinsley L, Siddique T. 2015 Amyotrophic Lateral Sclerosis Overview. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301623
- Le Ber I. et al. 2007. Human Mutation. 28: 846-55. PubMed ID: 17436289
- Lipton A.M. et al. 2004. Acta Neuropathologica. 108: 379-85. PubMed ID: 15351890
- Lomen-Hoerth C. et al. 2003. Neurology. 60: 1094-7. PubMed ID: 12682312
- Mitsuyama Y., Inoue T. 2009. Neuropathology. 29: 649-54. PubMed ID: 19780984
- Morita M. et al. 2006. Neurology. 66: 839-44. PubMed ID: 16421333
- Neary D. et al. 1998. Neurology. 51: 1546-54. PubMed ID: 9855500
- Onyike C.U., Diehl-Schmid J. 2013. International Review of Psychiatry. 25: 130-7. PubMed ID: 23611343
- Parkinson N. et al. 2006. Neurology. 67: 1074-7 PubMed ID: 16807408
- Phukan J. et al. 2012. Journal of Neurology, Neurosurgery, and Psychiatry. 83: 102-8. PubMed ID: 21836033
- Rascovsky K. et al. 2011. Brain. 134: 2456-77. PubMed ID: 21810890
- Robberecht W., Philips T. 2013. Nature Reviews. Neuroscience. 14: 248-64. PubMed ID: 23463272
- Rosso S.M. et al. 2003. Brain. 126: 2016-22. PubMed ID: 12876142
- Skibinski G. et al. 2005. Nature Genetics. 37: 806-8. PubMed ID: 16041373
- Snowden J.S. et al. 2002. The British Journal of Psychiatry. 180: 140-3. PubMed ID: 11823324
- Tandan R., Bradley W.G. 1985. Annals of Neurology. 18: 271-80. PubMed ID: 4051456
- Tsang H.T. et al. 2006. Genomics. 88: 333-46. PubMed ID: 16730941
- Urwin H. et al. 2010. Human Molecular Genetics. 19: 2228-38. PubMed ID: 20223751
- van Blitterswijk M. et al. 2012. Plos One. 7: e48983. PubMed ID: 23155438
- van der Zee J. et al. 2008. Human Molecular Genetics. 17: 313-22. PubMed ID: 17956895
- Wikström J. et al. 1982. Archives of Neurology. 39: 681-3. PubMed ID: 7125994
Bi-Directional Sanger Sequencing
Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org). 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 20 bases of non-coding DNA flanking the exon are sequenced.
As of March 2016, we compared 17.37 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 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.
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).
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 20 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.
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(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.
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- At room temperature, blood specimen is stable for up to 48 hours.
- If refrigerated, blood specimen is stable for up to one week.
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(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.
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- 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.
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- We strongly recommend maintaining a local back-up culture. We do not culture cells.