Frontotemporal Dementia Sponsored Testing Program

Symptoms of frontotemporal dementia, previously referred to as Pick’s disease, are insidious and begin usually during the fourth and sixth decades of life; although earlier and later onset have been documented (Snowden et al. 2002; Bruni et al. 2007 ). 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. 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). The clinical diagnosis of FTD is based on the combination of medical history, physical and neurological examination, brain imaging, and neuropsychological and psychiatric assessment (Neary et al. 1998; Snowden 2002; Rascovsky et al 2011; Mesulam 2001). FTD affects people worldwide, with a prevalence of up to 15 per 100,000 (Ratnavalli et al. 2002). It is the second most common dementia in people under the age of 65 years, after Alzheimer’s disease, accounting for up to 20% of presenile dementia cases (Snowden et al. 2002).

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. It is, however, unclear how many of the apparently sporadic cases are inherited with low penetrance (Cruts et al. 2006; Le Ber et al. 2007). FTD is genetically heterogeneous. Several genes have been implicated in the disorder: C9orf72, GRN, MAPT, CHMPEB, TARDBP, FUS and VCP. Pathogenic variants in the GRN gene account for up to 23 % of FTD familial cases and 5.8 % of simplex cases (Baker et al. 2006; Gass et al. 2006; Chen-Plotkin et al. 2011). About 120 different GRN pathogenic variants, distributed along the entire coding region of the gene, have been reported in patients with the various forms of FTD. Although the majority of variants are of the types that are expected to result in a truncated protein, missense variants that are predicted to result in amino acid substitutions have been documented (Human Gene Mutation Database; Cruts et al. 2006; van der Zee et al. 2007). There are no clear genotype-phenotype correlations. The same pathogenic variants result in various clinical presentations even within members of the same family, suggesting the involvement of genetic and environmental modifying factors (Hsiung and Feldman 2013). In addition to FTD, a homozygous truncating variant was reported to cause an adult form of neuronal ceroid lipofuscinosis (Smith et al. 2012). See also the description for Test #1909. The progranulin protein, also known as granulin, is a growth factor involved in various cellular functions, including neuronal survival (He and Bateman 2003). Its loss affects normal neurite outgrowth and branching (Gass et al. 2012).

The C9orf72 repeat expansion tests each utilize four unique assays: (1) a repeat primed PCR assay with the locus specific primer 5’ (upstream) of the repeat region (2) a repeat primed PCR assay with the locus specific primer 3’ (downstream) of the repeat region and (3,4) two unique fluorescent fragment length assays.

The sequencing panel typically provides 99.9% coverage of all coding exons of the genes listed plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.

This program is open to patients, who have a suspected clinical or clinical diagnosis of frontotemporal dementia.

SPECIMEN REQUIREMENTS

OCD-100 Buccal Swab

OCD-100 Buccal Swab used according to manufacturer instructions.

SHIPPING AND HANDLING INSTRUCTIONS

Label all specimen containers with the patient's name, date of birth, and/or ID number. At least two identifiers should be listed on specimen containers. Specimen deliveries are accepted Monday-Saturday for all specimen types. Holiday schedules will be posted on our website at least one week prior to major holidays.

Buccal

Specimens may be shipped at room temperature.

Specimen collection kits: Buccal specimen collection kits, which contain the TRF and the shipping label, may be requested through the kit order form or via the online order form.