A Case of Dementia Parkinsonism Resembling Progressive Supranuclear Palsy Due to Mutation in the Tau Protein Gene FREE

PROGRESSIVE supranuclear palsy (PSP) is a sporadic neurodegenerative disease characterized by a tetrad of neurologic manifestations: supranuclear gaze palsy, pseudobulbar palsy, axial rigidity, and subcortical dementia.¹ Behavioral modifications and cognitive deficits are always present, especially in advanced disease.^{2 - 3} Pathologically, abundant neurofibrillary tangles, mostly of the globose type, consisting of abnormally hyperphosphorylated tau protein, are found in association with variable neuronal loss and gliosis. These alterations are typically present in the subthalamic nucleus, globus pallidus, striatum, thalamus, substantia nigra, superior colliculi, oculomotor nuclei, periaqueductal gray matter, locus ceruleus, pontine nuclei, and raphe nuclei.⁴ Neurofibrillary tangles may also be found in the prefrontal, premotor, and motor areas of the cortex.⁵ Tau-positive inclusions may also take the form of neuropil threads, tufted astrocytes, and coiled bodies.⁶

More recently, families with an apparently autosomal dominant form of PSP have been described.⁷ In addition, families with frontotemporal dementia parkinsonism (FTDP-17) due to mutations in exons 9, 10, 12, or 13, or the intron following exon 10 of the tau protein gene on chromosome 17, have been reported.⁸ The N279K mutation in exon 10 has been identified in 4 families^{9 - 12} ; its phenotype is one of dementia and parkinsonism, which in some cases resembles PSP. To our knowledge, this is the first Italian patient with a family history of dementia and parkinsonism clinically resembling PSP and with the exon 10 N279K mutation.

A 50-year-old woman was admitted to our institute in December 2000 for behavioral changes, motor slowness, and disturbance of balance. Three years earlier, at the age of 47 years, subtle personality changes, including personal neglect and lack of initiative, became apparent and were unresponsive to antidepressants. Motor slowness, poor balance, and a tendency to fall appeared later. Disinhibition, hyperorality, and irritability, along with cognitive dysfunction manifesting as lack of attention, impairment of judgment, and cognitive flexibility, appeared 1 year before admission. At the time of admission, she also had dysphagia and urinary urgency and had been taking levodopa (600 mg daily) and ropinirole (0.75 mg daily) for 10 months, with no apparent benefit.

One of the patient's 2 brothers died at the age of 45 years in 1995. He had been admitted to another hospital in 1991 for symptoms that had manifested 3 years earlier, and was diagnosed as having clinically probable PSP. A review of his medical record showed global cognitive impairment with marked apathy and abulia, psychomotor slowness, axial rigidity, vertical oculomotor paresis, and a tendency to fall backwards. The patient's other brother was described as healthy and declined to be examined. The patient's father died at age 46 years after 7 years of a progressive illness diagnosed as parkinsonism. None of the father's brothers or sisters had any neurologic condition, and all died in old age.

Neurologic examination of our patient revealed unstable gait, stooped posture, poor balance with tendency toward en bloc backward falls, blank facial expression, supranuclear upward gaze palsy involving pursuit and saccades, dysphagia, dysarthria, moderately increased limb and neck muscle tone, bradykinesia, slight postural hand tremor, brisk tendon reflexes, and positive Babinski sign. On interviewing the patient, anosognosia, apathy, reduced spontaneous speech production, memory dysfunction, and palilalia became apparent.

Results of routine blood tests, electrocardiogram, chest x-ray, and electroencephalogram were normal. Cerebral magnetic resonance imaging with a 0.5-Tesla machine showed slight mesencephalic atrophy, moderately increased third ventricle size, and slight signal hyperintensity in the periaqueductal region. Positron emission tomography with¹⁸fluorodeoxyglucose showed hypometabolism in the mesial and dorsolateral frontal cortex bilaterally. A perineal electromyogram revealed chronic denervation of the external anal sphincter.

Genetic analysis was performed on the proband's DNA, extracted from peripheral lymphocytes. Exon 10 of the tau gene was amplified by polymerase chain reaction with flanking primers 5′-CGAGCAAGCAGCGGGTCC-3′ and 5′-GTACGACTCACACCACTTCC-3′, using the following conditions: 95°C for 5 minutes; 95°C for 1 minute, 60°C for 1 minute, and 72°C for 1 minute, for 35 cycles. The polymerase chain reaction product was excised from 2.5% agarose gel after electrophoresis, purified with a silica matrix and sequenced in both directions by the dideoxy chain terminator method using an automated sequencer.

The sequence revealed a T to G substitution that resulted in the N279K mutation, giving rise to the substitution of lysine for asparagine (Figure 1). Analysis of exons 9, 12, and 13 showed normal sequences.

For neuropsychologic evaluation we used a battery of tests to assess global cognitive functioning (Mini-Mental State Examination and Raven test), verbal and spatial memory (short tale test, word association test, Corsi span, and supra-span), executive functions (semantic and phonemic fluency tests and the Nelson test for categorization and shifting ability), visuospatial abilities (Benton test), attention (visual search test), language comprehension (Token test), and apraxia (ideomotor, buccofacial, and constructive). The patient performed poorly on all tests.

A second examination 6 months later revealed urinary incontinence and worsened bradykinesia. There was also a marked deterioration in cognition, as revealed particularly by the appearance of spatiotemporal disorientation and a 7-point decrease in Mini-Mental State Examination score. Because of this deterioration, it was not possible to readminister many of the neuropsychologic tests (Table 1).

The characteristics of this patient are consistent with the diagnosis of probable PSP according to the clinical criteria of Litvan et al.¹ The alterations revealed by magnetic resonance imaging (mesencephalic atrophy) and positron emission tomography (frontal hypometabolism) also support the diagnosis of PSP.^{13 - 14} However, the early onset and rapid mental decay are uncommon in PSP, as are the upward rather than downward gaze palsy and the stooped posture rather than trunk hyperextension.

Four families with N279K mutations in exon 10 of the tau protein gene have been described so far, and in some cases, clinical phenotype and pathologic alterations were similar to those found in PSP, although the disease onset was early (around the fifth decade).^{9 - 12} Another case that was clinically and pathologically consistent with PSP and had a silent mutation (S305S) in exon 10 has been described.¹⁵ This mutation did not result in amino acid substitution in the tau protein, but rather, resulted in increased production of the 4 repeat isoform of the tau protein. In all of these families, age and clinical presentation varied; in some patients, the onset was marked by frontal dementia; others had mainly parkinsonism and subsequent cognitive decay.

In view of the heterogeneity of clinical signs, particularly at the onset, it appears inappropriate to classify these cases as familial PSP; we prefer the term FTDP-17, suggested by Wszolek et al.¹⁶ A hyperphosphorylated tau protein was found in neuronal and glial cytoplasmic inclusions in all cases from the above families, studied at autopsy. This alteration is also a hallmark of sporadic PSP, corticobasal degeneration, Pick disease, and some other parkinsonism-plus diseases. Exon 10 mutations (including the N279K mutation)^{17 - 18} resulting in 4 repeat tau overproduction seem to be associated with a mainly parkinsonian phenotype at disease onset, as in our family. However, more cases need to be described before generalizing, since FTDP-17 is clinically heterogeneous. Why this characteristic form of degeneration affects differing neuronal populations even in family members with the same gene mutation is unclear. Presumably, other genetic or environmental factors are involved the pathogenetic process.

Corresponding author and reprints: Floriano Girotti, MD, Division of Neurology I, Istituto Nazionale Neurologico Carlo Besta, Via Celoria 11, 20133 Milano, Italy (e-mail: soliveri@istituto-besta.it).

Accepted for publication March 14, 2003.

Author contributions: Study concept and design (Dr Girotti); acquisition of data (Drs Soliveri, Rossi, Monza, and Piacentini); analysis and interpretation of data (Drs Soliveri, Rossi, Monza, Tagliavini, Albaneseo, Bugiani, and Girotti); drafting of the manuscript (Dr Soliveri); critical revision of the manuscript for important intellectual content (Drs Rossi, Monza, Tagliavini, Piacentini, Albaneseo, Bugiani, and Girotti); obtained funding (Drs Tagliavini, Bugiani, and Girotti); administrative, technical, and material support (Drs Soliveri, Rossi, Monza, and Piacentini); study supervision (Drs Tagliavini, Albaneseo, Bugiani, and Girotti).

This work was supported by the Italian Ministry of Health, Department of Social Services.