Genetics Basics

 

We all have billions of cells that make up our body. In each of those cells, we carry an instruction manual—called DNA— that guides our cells on how to function properly. Imagine that our DNA contains the instructions for building a house, where each chapter of the manual is a chromosome, and each paragraph in a chapter is a gene. When someone has a pathogenic variant (also known as a mutation), that gene might instruct you to place a kinked pipe in the plumbing, for example, which might cause the plumbing to fail when enough sediment backs up before the kink. This phenomenon explains why, in genetic adult-onset conditions, we might be born with a well-functioning house, but as we get older and use the house more, it might eventually fail us because it was not built right from the start.

 

PROGRANULIN (GRN) (PGRN) Basics1,2

The GRN gene provides instructions for making a protein called progranulin. This protein is primarily found in cellular structures called lysosomes, which are specialized compartments that digest and recycle materials. It is also emptied outside of cells and, therefore, can be measured in biofluids like blood and CSF.  When individuals have frontotemporal dementia (FTD)-causing pathogenic gene variation in GRN, they make a smaller amount of the normal progranulin protein, and this is believed to ultimately lead to the neurodegenerative process that results in FTD. Most progranulin mutations are “loss of function” variations, in that the protein does not do what it is supposed to do or does not get made in the first place. It is theorized that increasing progranulin levels in mutation carriers to be close to the normal amount will help to address or prevent the neurodegenerative process that leads to FTD. Indeed,  current experimental trials are testing approaches that increase progranulin levels. 

The onset of GRN FTD typically includes mild cognitive or behavioral impairments with relatively preserved functional independence. This is called the prodrome. Disease-associated biomarkers are elevated, indicating that brain cells are changing and these early symptoms represent the beginning of FTD. Understanding the factors associated with the onset of the prodrome and the progression from the prodrome into frank disease are active areas of research. Longitudinal studies of people with GRN pathogenic variants will help unlock ever finer mapping of how disease develops. 

 

 

Inheritance2 

We typically have two copies of most of our chromosomes, one coming from the sperm and one coming from the egg that joined to form you. GRN pathogenic variants linked to FTD are inherited in an autosomal dominant manner, meaning that the variant needs only to be present on one chromosome copy to create the disease. Autosomal dominant variants may cause disease in successive generations, and, as such, any child of a parent with the variant has a 50% chance of inheriting it. Though thought to be rare, it is possible that a person did not inherit their GRN pathogenic variant from a parent. This is called a de novo variant. The proportion of affected individuals with a de novo GRN variant is unknown, but is estimated to be 5% or fewer. Whether the mutation was inherited or de novo, children of a carrier have a 50% chance of inheriting the variant. 

 

Penetrance1,2

The proportion of people with a genetic mutation who develop the signs and symptoms of the disease associated with it is known as the gene’s penetrance. Even if one inherits a pathogenic GRN variant, it does not appear to be fully penetrant, meaning that not all people who carry a mutated gene will develop signs and symptoms of  FTD in their lifetime. Penetrance of GRN-FTD has been previously estimated to be close to 90% by age 70. It is likely our understanding of this issue is limited by the fact those with the mutation who do not develop symptoms are more rarely studied. Additional genetic variants- called genetic modifiers - that appear to make carriers more or less likely to develop symptoms have been identified. These additional genetic modifiers are not yet available for personal testing.  Unfortunately, the entire understanding of penetrance has not been determined, and it may not be settled for some time. It should be noted that many genes associated with adult-onset diseases, like the hereditary breast and ovarian cancer genes BRCA 1/2, also do not have complete (100%) penetrance; however, the presence of these genes is still understood to be a significant risk. 

 

Age of Onset/Diagnosis3

Pathogenic GRN variants cause disease in an age-dependent manner, meaning that disease occurs more often in older age. A large study of GRN-FTD cases arrived at an average age of diagnosis for a carrier of 61.3 years old.  Most cases are diagnosed approximately between the ages 53 and 69, with a smaller number of cases diagnosed earlier (as young as in the 30’s) and later (over 70 years of age). As disease manifests in an age-dependent manner, there are many more asymptomatic carriers at any one time than there are carriers with an active diagnosis.

 

Biomarkers

A biomarker is a term referring to biological measurements that provide information on a disease course. In some cases, biomarkers may be able to signal disease activity before there are serious symptoms. Some promising biomarkers in GRN-FTD are: 

 

• Plasma Progranulin2: Progranulin protein levels can be directly measured in the blood. Given that GRN-FTD disease is due to decreased levels of this protein, which in turn drives the neurodegenerative process, it is hypothesized that measuring plasma protein levels, specifically to see if there have been increases in GRN, would be a potential way of determining if a specific treatment is on target.   The amount of progranulin a mutation carrier produces (from their one healthy copy) is not associated with the age of onset or progression of disease. 

 

• NfL (neurofilament light chain)4: A marker of neuronal damage that can be found in both spinal fluid and in blood. Although NfL levels increase across the lifespan in everyone, in GRN mutation carriers, NfL levels start to rise even more a few years before clinical symptoms appear. Although NfL levels may show promise to predict the onset of disease, there is a lot of variability in individuals independent of disease, which complicates interpretation. This is a very active area of research. NfL tests have recently become commercially available in the United States via LabCorp. 

 

• Brain MRI (magnetic resonance imaging of the brain)4: Studies have shown that GRN  carriers show changes in volume in specific brain regions on MRI prior to diagnosis. MRI machines are available in most major medical centers, but when used for clinical care, they tend to have high costs for patients to access them, and these data have only been evaluated in a research setting. 

 

• TDP-43 Biomarkers2: TDP-43 is a protein that is found in all cells. Normally it is diffusely distributed inside a cell’s nucleus, but disease processes cause TDP-43 aggregates in the brain in GRN FTD. There are currently no validated tests for measuring TDP-43 aggregates in living people. Recently, attention has been paid to the possibility that the loss of the full function of TDP-43 is part of the disease process and may precede TDP-43 aggregation. 

 

Research

Many people would like to study carriers of pathogenic GRN variants both pre-symptomatically and when diagnosed with the disease! 

 

A list of studies looking to observe us (and provide access to free and often anonymous genetic counseling and time with genetic FTD experts) is here. *Please note that while we make every effort to be sure the status of clinical trials and studies is accurate and up-to-date, we cannot make guarantees. You will need to go to the websites directly in order to be informed of all current studies and trials.

 

The four interventional trials currently recruiting symptomatic GRN carriers are also listed in the above document. 

 

References

 

1. Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, Crook R, Melquist S, Kuntz K, Petersen R, Josephs K, Pickering-Brown SM, Graff-Radford N, Uitti R, Dickson D, Wszolek Z, Gonzalez J, Beach TG, Bigio E, Johnson N, Weintraub S, Mesulam M, White CL 3rd, Woodruff B, Caselli R, Hsiung GY, Feldman H, Knopman D, Hutton M, Rademakers R. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet. 2006 Oct 15;15(20):2988-3001. doi: 10.1093/hmg/ddl241. Epub 2006 Sep 1. PMID: 16950801.

2. Greaves CV, Rohrer JD. An update on genetic frontotemporal dementia. J Neurol. 2019 Aug;266(8):2075-2086. doi: 10.1007/s00415-019-09363-4. Epub 2019 May 22. PMID: 31119452; PMCID: PMC6647117.

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4. Staffaroni AM, Quintana M, Wendelberger B, Heuer HW, Russell LL, Cobigo Y, Wolf A, Goh SM, Petrucelli L, Gendron TF, Heller C, Clark AL, Taylor JC, Wise A, Ong E, Forsberg L, Brushaber D, Rojas JC, VandeVrede L, Ljubenkov P, Kramer J, Casaletto KB, Appleby B, Bordelon Y, Botha H, Dickerson BC, Domoto-Reilly K, Fields JA, Foroud T, Gavrilova R, Geschwind D, Ghoshal N, Goldman J, Graff-Radford J, Graff-Radford N, Grossman M, Hall MGH, Hsiung GY, Huey ED, Irwin D, Jones DT, Kantarci K, Kaufer D, Knopman D, Kremers W, Lago AL, Lapid MI, Litvan I, Lucente D, Mackenzie IR, Mendez MF, Mester C, Miller BL, Onyike CU, Rademakers R, Ramanan VK, Ramos EM, Rao M, Rascovsky K, Rankin KP, Roberson ED, Savica R, Tartaglia MC, Weintraub S, Wong B, Cash DM, Bouzigues A, Swift IJ, Peakman G, Bocchetta M, Todd EG, Convery RS, Rowe JB, Borroni B, Galimberti D, Tiraboschi P, Masellis M, Finger E, van Swieten JC, Seelaar H, Jiskoot LC, Sorbi S, Butler CR, Graff C, Gerhard A, Langheinrich T, Laforce R, Sanchez-Valle R, de Mendonça A, Moreno F, Synofzik M, Vandenberghe R, Ducharme S, Le Ber I, Levin J, Danek A, Otto M, Pasquier F, Santana I, Kornak J, Boeve BF, Rosen HJ, Rohrer JD, Boxer AL; Frontotemporal Dementia Prevention Initiative (FPI) Investigators. Temporal order of clinical and biomarker changes in familial frontotemporal dementia. Nat Med. 2022 Oct;28(10):2194-2206. doi: 10.1038/s41591-022-01942-9. Epub 2022 Sep 22. PMID: 36138153; PMCID: PMC9951811.