Purpose

To perform linkage analysis of candidate loci in a large Midwestern family with autosomal dominant essential tremor.

Methods

Thirty-eight members of a six-generation family were evaluated for essential tremor using consensus criteria. Linkage analysis was performed with microsatellite markers reported for three genetic loci associated with familial essential tremor.

Results

Patients exhibited a combination of postural and kinetic tremor involving primarily the arms and hands, with a mean age of onset of 31 years. Genetic studies excluded linkage to ETM1 and ETM2 loci, as well as a candidate locus for parkinsonism and postural tremor on chromosome 4p.

Conclusion

Familial essential tremor is a common hereditary movement disorder demonstrating phenotypic variability and genetic heterogeneity.

Inclusion body myopathy with Paget disease of the bone (PDB) and/or frontotemporal dementia (IBMPFD, OMIM 167320), is a progressive autosomal dominant disorder caused by mutations in the Valousin-containing protein (VCP, p97 or CDC48) gene. IBMPFD can be difficult to diagnose. We assembled data on a large set of families to illustrate the number and type of misdiagnoses that occurred. Clinical analysis of 49 affected individuals in nine families indicated that 42 (87%) of individuals had muscle disease. The majority were erroneously diagnosed with limb girdle muscular dystrophy (LGMD), facioscapular muscular dystrophy, peroneal muscular dystrophy, late adult onset distal myopathy, spinal muscular atrophy, scapuloperoneal muscular dystrophy, or amyotrophic lateral sclerosis (ALS) among others. Muscle biopsies showed rimmed vacuoles characteristic of an inclusion body myopathy in 7 of 18 patients (39%), however, inclusion body myopathy was correctly diagnosed among individuals in only families 5 and 15. Frontotemporal dementia (FTD) was diagnosed in 13 individuals (27%) at a mean age of 57 years (range 48.9-60.2 years); however, several individuals had been diagnosed with Alzheimer disease. Histopathological examination of brains of three affected individuals revealed a pattern of ubiquitin positive neuronal intranuclear inclusions and dystrophic neurites. These families expand the clinical phenotype in IBMPFD, a complex disorder caused by mutations in VCP. The presence of PDB in 28 (57%) individuals suggests that measuring serum alkaline phosphatase (ALP) activity may be a useful screen for IBMPFD in patients with myopathy.