A number sign (#) is used with this entry because of evidence that a form of atypical supranuclear palsy is caused by mutation in the microtubule-associated protein tau gene (MAPT; 157140).Clinical Features
Mata et al. (1983) described 2 brothers and a sister with a 'new' Parkinson-dementia syndrome. The disorder, characterized also by ophthalmoparesis and pyramidal signs, came on in the third decade and progressed for several years. Kyphoscoliosis was present in all 3 sibs. Examination of the brain in the sister, who died at age 31 years, showed neurofibrillary degeneration of the hippocampus, basal ganglia and brainstem nuclei. The parents were not related. The authors suggested that the disorder most closely resembled the Parkinson-dementia complex of Guam (105500) but could be distinguished by the lack of Chamorro descent (a dubious argument) and the earlier age of onset. The legend for the pedigree presented as Figure 1 stated that the father and a cousin of his were 'neurologically affected' and the authors' concluding statement was as follows: 'Although the mode of inheritance of this disease appears to be autosomal dominant with low penetrance and expression, an autosomal recessive cannot be ruled out.' No information is in fact given on the father and his cousin.
Ohara et al. (1994) described 2 of 5 sibs of first-cousin parents of Japanese descent who developed vertical ophthalmoparesis, dementia, a parkinsonian syndrome, jaw tremor, and bradykinesia. Both sibs had a poor response to levodopa. The authors referred to this syndrome as a progressive supranuclear palsy-like syndrome. Progressive supranuclear palsy (PSP; 601104), also known as Steele-Richardson-Olszewski syndrome, is a sporadic disorder of adult onset with supranuclear palsy of vertical gaze, followed by proximal rigidity and dementia. There are no Lewy bodies as in Parkinson disease, but there are large numbers of neurofibrillary tangles. The sibs described by Ohara et al. (1994) had no Lewy bodies, but did have widespread distribution of neurofibrillary tangles in a pattern more reminiscent of Alzheimer disease than of classic Steele-Richardson-Olszewski syndrome. Unlike Alzheimer disease, however, there were no senile plaques either by conventional or by immunostaining procedures. Also unlike patients with classic Steele-Richardson-Olszewski syndrome, the affected sibs stooped forward rather than having their head in an opisthotonic position, a distinctive feature in the sporadic disorder.
Pastor et al. (2001) reported 2 Spanish brothers with atypical supranuclear palsy born from a third-degree consanguineous marriage with atypical PSP. The proband and his brother demonstrated a remarkably similar phenotype characterized by onset in the late thirties of mild cognitive decline, inappropriate behavior, ocular movement abnormalities, and asymmetric parkinsonism. Both were found to have a homozygous mutation in the MAPT gene (157140.0021).
Rossi et al. (2004) reported a patient who developed antecollis, dysarthria, postural instability with falls, slowing of ocular movements, and increased deep tendon reflexes at age 36 years, consistent with atypical PSP.Molecular Genetics
In a Spanish patient with atypical supranuclear palsy born from a third-degree consanguineous marriage, Pastor et al. (2001) identified a homozygous deletion of asn296 in the MAPT gene (157140.0021). Two uncles, who were heterozygous for the mutation, developed late-onset typical Parkinson disease (168600). However, there were several asymptomatic heterozygous individuals in the family over the age of 60, which the authors attributed to reduced penetrance.
In a family with a variable neurodegenerative phenotype, including a PSP-like syndrome and parkinsonism, Rossi et al. (2004) identified heterozygosity for a deletion of asn296 in the MAPT gene, which was caused by a different nucleotide change than that identified by Pastor et al. (2001); see 157140.0021. The mutation was also found in a paternal aunt with typical dopa-responsive Parkinson disease, in 2 asymptomatic sisters of the proband, and in 3 asymptomatic daughters of a deceased paternal uncle who had atypical dopa-unresponsive Parkinson disease with pyramidal signs and cognitive impairment. The authors suggested incomplete penetrance of the disorder.