Why is this important: This paper is representative of an ongoing series of studies showing that frontotemporal dementias and motor neuron diseases (ALS being the prototype) are bookends on the opposite side of a continuum, which is one illness.
C9orf72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is characterized by:
Motor neuron disease, including upper or lower motor neuron dysfunction (or both) that may or may not fulfill criteria for the ALS phenotype;
Frontotemporal lobar degeneration (FTLD), including progressive changes in behavior, executive dysfunction, and/or language impairment; and
Some degree of parkinsonism (typically of the akinetic-rigid type without tremor that is levodopa unresponsive).
Age at onset is usually 30-70 years (range: 27 to 85 years) irrespective of the presenting symptoms. Initial manifestations may be pure FTLD or pure ALS; additional symptoms may appear during the disease course. Life expectancy is highly variable and mainly associated with the clinical manifestations.
Brain MRI typically shows symmetric bilateral frontal (most pronounced mesial frontal) ± temporal ± parietal ± cingulate cortex atrophy. FDG PET typically shows hypometabolism predominantly in fronto/temporal areas. The diagnosis of C9orf72-related ALS/FTLD is established by detection of a heterozygous C9orf72 pathogenic GGGGCC (G4C2) hexanucleotide repeat expansion on molecular genetic testing.
Treatment of manifestations: Motor neuron disease manifestations are treated as for ALS of other causes. Non-pharmacologic treatment options in FTLD include psychosocial support and education to reduce caregiver stress and burden as well as environmental, behavioral, and physical interventions designed to minimize the occurrence and consequences of undesired behaviors. Pharmacologic treatment should be considered when non-pharmacologic treatment options have failed or when behavioral and psychological signs and symptoms (as in FTLD) are dangerous or too stressful.
Surveillance: Clinical, neurologic, and neuropsychological follow up is necessary.
C9orf72-related ALS/FTD is inherited in an autosomal dominant manner, with age-dependent penetrance. Although most affected individuals have an affected parent, the parents may be unaffected because of either incomplete or age-dependent penetrance in the parent or de novomutation in the proband. Each child of an individual with C9orf72-related ALS/FTD has a 50% chance of inheriting the pathogenic C9orf72 G4C2 hexanucleotide repeat expansion. Prenatal testing for pregnancies at increased risk is possible if the pathogenic C9orf72 G4C2 hexanucleotide repeat expansion has been identified in an affected family member; however, requests for prenatal testing for adult-onset conditions such as C9orf72-related ALS/FTD are not common.