C9orf72 Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis

Clinical characteristics: C9orf72 frontotemporal dementia and/or amyotrophic lateral sclerosis (C9orf72-FTD/ALS) is characterized most often by frontotemporal dementia (FTD) and upper and lower motor neuron disease (MND); however, atypical presentations also occur. Age at onset is usually between 50 and 64 years (range: 20-91 years) irrespective of the presenting manifestations, which may be pure FTD, pure amyotrophic lateral sclerosis (ALS), or a combination of the two phenotypes. The clinical presentation is highly heterogeneous and may differ between and within families, causing an unpredictable pattern and age of onset of clinical manifestations. The presence of MND correlates with an earlier age of onset and a worse overall prognosis.

Diagnosis/testing: The diagnosis of C9orf72-FTD/ALS is established in a proband with suggestive findings and a heterozygous abnormal G₄C₂ (GGGGCC) hexanucleotide repeat expansion in C9orf72 identified by molecular genetic testing.

Management: Treatment of manifestations: Care is often provided by a multidisciplinary team that includes a neurologist, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and genetic counselor.

Surveillance: Routine follow up by multidisciplinary specialists to monitor neurologic findings, mobility and activities of daily living, psychiatric/behavioral manifestations, nutrition and safety of oral feeding, respiratory and bladder function, and needs of affected individuals and care providers for psychosocial support.

Genetic counseling: C9orf72-FTD/ALS is inherited in an autosomal dominant manner. Almost all individuals diagnosed with C9orf72-FTD/ALS inherited a C9orf72 G₄C₂ repeat expansion from a heterozygous parent. In most families the heterozygous parent is affected; however, a heterozygous parent may not have clinical manifestations of the disorder due to age-dependent reduced penetrance. Each child of an individual with C9orf72-FTD/ALS has a 50% chance of inheriting the C9orf72 G₄C₂ repeat expansion. Once a C9orf72 G₄C₂ repeat expansion has been identified in an affected family member, prenatal and preimplantation genetic testing for the presence of the C9orf72 G₄C₂ repeat expansion are possible. (Note: The presence of a C9orf72 G₄C₂ repeat expansion cannot predict the disease course in any given individual.)