Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Panel

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 and Bradley. 1985. PubMed ID: 4051456). 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. PubMed ID: 11715057).

The most common ALS 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. PubMed ID: 9855500; Snowden et al. 2002. PubMed ID: 11823324; Bruni et al. 2007. PubMed ID: 17620546). The annual incidence of FTD is 3-4 per 100,000 (Onyike and Diehl-Schmid. 2013. PubMed ID: 23611343).

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. PubMed ID: 21810890).

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. 1993. PubMed ID: 8401782).

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. PubMed ID: 7125994; Lipton et al. 2004. PubMed ID: 15351890; Mitsuyama and Inoue. 2009. PubMed ID: 19780984).

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 ALS patients (Phukan et al. 2012. PubMed ID: 21836033).

Definite ALS has been reported in patients with a clinical diagnosis of FTD (Lomen-Hoerth et al. 2003. PubMed ID: 12682312).

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. PubMed ID: 16421333; Ferrari et al. 2011. PubMed ID: 21222600).

About 10% of ALS cases are familial (Emery and Holloway. 1982. PubMed ID: 7180680). 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. PubMed ID: 20301623).

Autosomal Dominant ALS (AD-ALS) is a clinically and genetically heterogeneous disorder that affects all ethnic groups. The following genes have been implicated in the disease: ANG, ARHGEF28, ANXA11, C9orf72, CDH3, CDH13, CHMP2B, FUS, GRN, HNRNPA1, HNRNP2B1, KIF5A, OPTN, PFN1, SOD1, SETX, SQSTM1, VAPB, VCP, PSEN1, TARDBP, TBK1, and UBQLN2.

FTD is inherited in about 40% of cases (Rosso et al. 2003. PubMed ID: 12876142). 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. PubMed ID: 16862115; Le Ber et al. 2007. PubMed ID: 17436289). FTD is genetically heterogeneous. Several genes have been implicated in the disorder: C9orf72, CHMP2B, FUS, GRN, SQSTM1, MAPT, PSEN1, PSEN2, TARDBP, TREM2 and UBQLN2.

The C9ORF72, GRN, and SQSTM1 genes have been implicated in patients with a combination of ALS and FTD (ALS-FTD).

Overall, the vast majority of pathogenic variants are missense. Few truncating variants were reported in SOD1, FUS, OPTN, CHMP2B, SQSTM1, ARHGEF28, GRN, PSEN1, PSEN2 and TREM2. Large pathogenic deletions appear to be rare. They were reported only in four genes: OPTN, GRN, MAPT and PSEN1 (Iida et al. 2012. PubMed ID: 22402017; Maruyama et al. 2010. PubMed ID: 20428114; Pickering-Brown et al. 2006. PubMed ID: 17071927; Rohrer et al. 2013. PubMed ID: 23904625; Rovelet-Lecrux et al. 2009. PubMed ID: 19263483; Evin et al. 2002. PubMed ID: 11997713).

With few exceptions, pathogenic variants in the genes included in this panel are inherited with an autosomal dominant manner or occurr de novo. The exceptions are:

One single variant, p.Asp90Ala, in SOD1 was reported at the homozygous state in patients with ALS (Andersen et al. 1995. PubMed ID: 7647793).

Recessive variants in OPTN were reported in Japanese cases (Maruyama et al. 2010. PubMed ID: 20428114; Iida et al. 2012. PubMed ID: 22402017).

UBQLN2-Related ALS and FTD are inherited in an X-linked dominant manner with reduced penetrance in females. The age of onset appears to be earlier in males with no difference in the duration of the disease (Deng et al. 2011. PubMed ID: 21857683).

See individual gene test descriptions for information on molecular biology of gene products.

Because a pathogenic expansion of the GGGGCC hexanucleotide repeat in a non-coding region of C9orf72 has been reported as the most common genetic cause of ALS, FTD, and ALS-FTD (Renton et al. 2011. PubMed ID: 21944779; DeJesus-Hernandez et al. 2011. PubMed ID: 21944778; Byrne et al. 2012. PubMed ID: 22305801), we will first screen the patients’ DNA for the presence or absence of this expansion. When we find a pathogenic expansion, we stop testing. When there is no evidence for the pathogenic expansion, we sequence all coding exons of the genes listed using Next Generation Sequencing (NGS).

The repeat-primed PCR test is used as a screening method for the presence or absence of a pathogenic GGGGCC hexanucleotide repeat expansion located in the first intron of C9orf72. Of note, this test is not designed to determine the number of GGGGCC repeats in alleles carrying the pathogenic expansion (Warner et al. 1996. PubMed ID: 9004136; Renton et al. 2011. PubMed ID: 21944779).

This panel provides 100% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

This NGS panel will detect pathogenic variants in at least 68% of patients with familial ALS and 11% of apparently sporadic cases of ALS (Renton et al. 2014. PubMed ID: 24369373). This panel will also detect pathogenic variants in up to 65% of patients with familial FTD. The following Table indicates sensitivity by gene and by phenotype.

Sensitivity corresponds to the percentage of all genotyped patients with a clinical diagnosis and a positive family history of either ALS or FTD. For genes with rare pathogenic variants, the numbers of reported simplex cases are listed.