Dr. Richard Bedlack shares his insights on ALS and genetic testing.
The newest gene for amyotrophic lateral sclerosis is found in both familial and sporadic ALS patients, as well as in patients with frontotemporal dementia, and is now the most common genetic cause of both diseases. New research presented at the 2012 annual meeting of the AAN highlighted not only the frequency of the gene, but also the emerging clinical picture associated with the gene, and the growing appreciation that a positive family history of ALS may include dementia and parkinsonism, as well as typical motor neuron disease.typical motor neuron disease.
The gene, called C9orf72, encodes a protein of unknown function. The first exon of the gene includes a GGGGCC hexanucleotide repeat, which in normal individuals does not exceed 23 repeats. In late 2011, two groups of researchers announced their discovery of ALS and FTD due to expansion lengths of greater than 40 units, and in some cases many hundreds of units. Multiple groups from across the globe have now reported finding the gene mutation in both familial and sporadic ALS patients. The C9orf72 repeat expansion mutation accounts for approximately 40 percent of all familial cases of European descent, according to several different groups examining patients in Europe and the United States. The expansion mutation is responsible for approximately 3 to 5 percent of sporadic cases as well.
The gene is autosomal dominantly inherited. De novo mutations are unlikely, according to Kevin Boylan, MD, of the Mayo Clinic in Jacksonville, FL. De novo cases, he suggested, are likely due to reduced penetrance in preceding generations. According to Adriano Chio, MD, of the University of Torino, Italy, there is some evidence emerging that the disease may show anticipation; that is, the mutation may cause disease at an earlier age in succeeding generations. The clinical features of ALS due to the C9orf72 repeat expansion are typical for the disease. There is some suggestion that the age of onset may be slightly lower than for other forms of the disease. In addition, cognitive involvement is more common, and may precede the development of motor symptoms. Preliminary analyses suggest that survival may be reduced in patients harboring the C9orf72 repeat expansion, although further studies are needed to confirm this finding. Orla Hardimann, MD, of Trinity College, Dublin, Ireland, suggested there may be a C9orf72-related “subphenotype” of ALS, characterized by younger age of onset, cognitive impairment, specific neuroimaging changes, and reduced survival.
Detailed medical and family histories of patients with the C9orf72 repeat expansion have turned up some surprising findings. Parkinsonism is present in a significant minority of patients, and is commonly reported in the family history. A family history of dementia is also common, consistent with the ability of the C9orf72 repeat expansion to cause frontotemporal dementia (FTD). “The classical definition of familial ALS is no longer acceptable, ”said Dr. Chio,“ and a new operative definition including presence of FTD in the patient or a family history should be included. In the clinical setting, the presence of comorbid FTD or a young onset should lead to genetic counseling.” Dr. Hardimann suggested that the Frontal Systems Behavior Scale (FrSBe) should be used as a screening tool. “If there is a strong family history of ALS, and the patient is behaviorally impaired, there is a very high likelihood, almost 70 percent, of having this variant,” she said.
Comment from Dr. Higgins
The pleiotropic effects of the C9orf72 gene repeat expansion require genotype-phenotype studies to clarify the range of phenotypes associated with C9orf72 mutations. The reasons why some of the repeat expansion carriers develop ALS whereas others develop FTD, progressive muscular atrophy (PMA), or primary lateral sclerosis (PLS) are unknown.1 Further studies including southern blot analyses are needed to determine the mutant allele length to clarify the minimal length of a pathogenic repeat expansion and the possibility of genetic anticipation.
Reference: 1. van Rheenen W, van Blitterswijk M, Huisman MH, Vlam L, van Doormaal PT, Seelen M, et al. Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases. Neurology. 2012. Epub 2012/07/31. doi: 10.1212/WNL.0b013e3182661d14. PubMed PMID: 22843265.