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Clinical Features and Disease Haplotypes of Individuals With the N279K tau Gene Mutation
A Comparison of the Pallidopontonigral Degeneration Kindred and a French Family
Yoshio Tsuboi, MD;
Ryan J. Uitti, MD;
Marie-Bernadette Delisle, MD;
Joaquim J. Ferreira, MD;
Christine Brefel-Courbon, MD;
Olivier Rascol, MD, PhD;
Bernardino Ghetti, MD;
Jill R. Murrell, MD;
Michael Hutton, PhD;
Matthew Baker, BSc;
Zbigniew K. Wszolek, MD
Arch Neurol. 2002;59:943-950.
ABSTRACT
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Background An N279K missense mutation in exon 10 of the tau
gene reported in an American family with pallidopontonigral degeneration (PPND
family) was recently found in members of a French kindred with dementia and
supranuclear palsy.
Objectives To compare clinical phenotypes of both families and to perform genealogical
and molecular genetic studies to determine whether they are derived from a
common founder.
Design and Methods We performed clinical examinations of affected members of both families
and compared clinical phenotypes, existing genealogical family records, and
chromosome 17 microsatellite repeat markers in the vicinity of the tau gene.
Results The inheritance pattern is autosomal dominant in the PPND family and
appears so in the French family. Average age at onset of clinical symptoms
was 43 years in the PPND family and 41 years in the French family. Mean disease
duration was 8 years in the PPND family and 6 years in the French family.
Parkinsonism, personality changes, and dementia of the frontotemporal type
were seen in both kindreds. All affected patients exhibited rapidly progressive
parkinsonism characterized by bradykinesia, tremor, postural instability,
and rigidity. Some had a transient response to levodopa therapy during the
initial stages. Pyramidal signs and eye movement abnormalities, including
supranuclear gaze palsy, were common. Results of linkage studies of the tau region in chromosome 17 did not reveal a haplotype
common to both kindreds.
Conclusions Affected members from both families had more clinical similarities than
differences. Results of genealogical and molecular genetic studies determined
that the families were not related. The N279K mutations found in both families
have independent origins.
INTRODUCTION
PALLIDOPONTONIGRAL degeneration (PPND) is a hereditary neurodegenerative
syndrome that belongs to the group of disorders called frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).1-3 Pallidopontonigral degeneration
was found in an American family (the PPND family) that can be traced back
for more than 200 years. This kindred is the largest and most thoroughly investigated
of all families with FTDP-17. Pallidopontonigral degeneration is an autosomal
dominant disorder with early onset of rapidly progressive symptoms. Results
of molecular genetic studies in affected individuals have demonstrated the
presence of an N279K missense mutation in exon 10 of the tau gene in chromosome 17.4 This mutation
causes increased splicing-in of exon 10 and a corresponding increase in the
proportion of tau with 4 microtubule-binding repeats (4R tau), which is sufficient
to cause neurodegeneration.5
Recently, the same missense mutation was found in members of 1 French6-7 and 2 Japanese families.8-9
The objectives of the present study were to compare the clinical phenotypes
of the original PPND family with those of the French family and to determine
whether these 2 kindreds are genealogically and genetically related.
SUBJECTS, MATERIALS, AND METHODS
The pedigree of the PPND family has 311 members and spans 8 generations.
Of 39 affected individuals, 19 were examined by one of us (Z.K.W.). The pedigree
of the French family has 28 members. Of 3 affected individuals, 2 were examined
by one of us (O.R.). We based clinical comparisons of affected members from
the 2 families on the review of published reports and results of personal
examinations of individuals (from both kindreds) by one of us (Z.K.W.). We
used the Mini-Mental State Examination (MMSE)10
for evaluation of cognitive status.
Informed consent was obtained from all participants after the nature
of the procedures was fully explained.
We extracted DNA from blood samples drawn from 3 affected individuals
of the PPND family, from their 3 respective spouses, and from 8 unaffected
or at-risk family members; the samples had been systematically collected by
one of us (Z.K.W.) since 1987. The DNA was also extracted from brain tissue
of 1 affected individual from the French family.
We analyzed 10 microsatellite repeat markers spanning 16 centimorgans
of chromosome 17 that included the tau gene region
in individuals from both families. The genotypes of these markers were generated
by means of analysis of fluorescently tagged polymerase chain reaction (PCR)
products using an automated sequencer with Genescan/Genotyper software (ABI
377; Perkin Elmer, Norwalk, Conn).
The PCR analysis included 25 ng of DNA in a 15-µL reaction mixture
containing 6 pmol of each primer, 0.2mM deoxyribonucleotide triphosphates,
1 U of Taq polymerase (QIAGEN, Valencia, Calif),
1x PCR buffer, and 10% PCR enhancer (Q-solution; QIAGEN). The oil-free
amplifications were performed in Touchdown thermal cyclers (ThermoHybaid,
Franklin, Mass), for 35 cycles of 94°C for 30 seconds, 58°C to 48°C
touchdown annealing for 30 seconds, and 72°C for 45 seconds, with a final
extension of 72°C for 10 minutes. Forward primers for each marker were
labeled at the 5' end with 6-carboxy-fluorescein (FAM)–, tetrachloro-6-carboxy-fluorescein
(TET)–, or hexachloro-6-carboxy-fluorescein (HEX)–fluorescent
dye; reverse markers were unlabeled.
Alleles were scored for fragment length (base pairs) using the Genotyper
software for the following markers: D17S798, D17S1294, D17S1293, D17S800, D17S1860, D17S791, D17S806, D17S1299, D17S1868, and ATC6A06. Centre
d'Etude du Polymorphisme Humain (CEPH) samples 1331-01 and 1331-02 were run
as standards (available at: http://www.cephb.fr/cephdb). Once the
genotypes were obtained for each marker, the PPND haplotype was compared with
marker information from the French family to investigate the possibility of
a common founder for the N279K mutation.
RESULTS
FINDINGS IN BOTH FAMILIES
The pedigrees of both families are presented in Figure 1, and the clinical features are given in Table 1. The inheritance pattern was autosomal dominant in the PPND
family and most likely in the French family. The average age at onset of clinical
symptoms was 43 years (range, 32-58 years) in the PPND family and 41 years
(range, 38-45 years) in the French family.
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Figure 1. Pedigrees of the family with pallidopontonigral
degeneration (PPND) and the French family. Squares represent male members;
circles, female members; diamonds, unknown sex; filled symbols, affected subjects;
a diagonal line through a symbol, deceased; a question mark inside a symbol,
unknown number of descendants; a dot in the center of a symbol, only historical
data are available; B:, year of birth; a number inside a symbol, age at death;
and short arrow, index case.
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Table 1. Characteristics, Symptoms, and Signs in the Family With Pallidopontonigral
Degeneration (PPND) and the French Family With the N279K Mutation of the tau Gene
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Parkinsonism, personality changes, and dementia of the frontotemporal
type were seen in both kindreds during the course of illness. Initial symptoms
almost always included parkinsonian features in both families. The parkinsonism
was characterized by the presence of bradykinesia, rigidity, and postural
instability. Resting tremor was sometimes encountered, usually at the initial
stages of the clinical manifestation and always as a transient feature. Response
to levodopa and dopamine agonist therapy was limited to the initial stages
of clinical presentation in both kindreds.
The personality changes often occurred at the onset of symptoms, sometimes
concomitantly with parkinsonism and sometimes a few weeks or months later.
These changes are characterized by relatively minor behavior aberrations,
such as irritability, excessive religiosity, or other minor changes in most
cases. However, violent behavior was present in 2 affected members of the
PPND family. Dementia of the frontotemporal type was seen in all affected
individuals of both families and was characterized by impairments in cognitive
processing and verbal and visual memory and by diminished cognitive flexibility.
Dementia almost always occurred in the later stages of the disease. However,
because of the profound motor impairment and mutism, full exploration of cognitive
functions in the later stages of the disease was not possible.
Other clinical features included pyramidal signs; dystonia (unrelated
to medications); eye movement abnormalities such as supranuclear gaze palsy,
eyelid opening and closing apraxia; perseverative vocalization; and urinary
incontinence (Table 1 and Figure 2).
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Figure 2. Clinical features of affected
members from the family with pallidopontonigral degeneration (PPND) and the
French family. A, Case 1 (V:26 of the PPND family [Figure 1]). Paucity of
facial expression and stooped posture are seen. Extraocular movements (EOM)
were preserved. B, Case 2 (VI:9 of the PPND family [Figure 1]). Masklike face,
vertical gaze palsy, and stooped posture are seen. C, Case 3 (III:6 of the
French family [Figure 1]). Similarities in clinical presentation with PPND
family cases are seen, ie, masklike face, vertical gaze palsy, and stooped
posture.
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The clinical course of the disease is relentlessly progressive and can
be delineated into 4 stages (Table 2).
The mean disease duration for affected individuals was 8 years (range, 5-19
years) for the PPND family and 6 years (range, 5-7 years) for the French family.
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Table 2. Clinical Features in Different Stages of the Disease*
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Genealogically, the PPND family is an American kindred traced back to
the Crown Colony of Virginia in the early 18th century. We were not able to
trace the origin of this family to France, and most settlers of this colony
were English. The French family has long resided in southern France. Available
family records and historical notes do not indicate that any family members
emigrated to the New World. Thus, we found no genealogical connections between
these 2 families.
Polymorphic marker analyses covering the tau
gene region in chromosome 17 did not reveal shared disease haplotypes between
the 2 families (Table 3). However,
a common mutation-bearing haplotype for the markers D17S1294, D17S1293, D17S800, D17S1860, D17S791, D17S806, and D17S1299 was shared in the 3
affected patients from the PPND family.
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Table 3. Linkage Analysis of 2 Families With the N279K Mutation of
the tau Gene*
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ILLUSTRATIVE CASE REPORTS
Case 1
Stooped posture became apparent in a 57-year-old right-handed man (V:26
of the PPND family [Figure 1]).
The change in posture was noted by his neighbors, who brought it to the attention
of his wife. Six months later, his supervisor at work sent him to the factory
physician. His movements had become slow, and the supervisor was concerned
that he would injure himself while operating electrical tools. The patient's
balance also deteriorated, and this led to occasional falls. He was examined
at his home by one of us (Z.K.W.) about a year after the onset of his symptoms.
At that time, features of parkinsonism, including rigidity, bradykinesia,
and postural instability, were documented. Resting tremor was absent, but
postural tremor was present in both upper extremities. He was excessively
emotional, crying easily and becoming withdrawn. His MMSE score was 25 of
30 points; he missed 4 points on the calculations and 1 point on the recall
scales. Shortly after this evaluation, he was treated with levodopa, without
any significant change in his parkinsonian features.
The patient was reexamined 18 months later, at 59 years of age. His
parkinsonism was noticeably worse. His posture was stooped and his head was
bent forward (Figure 2). His face
was masklike and his voice was hypophonic. Muscle rigidity was expressed more
in axial than in appendicular muscles. His speed in performing repetitive
movements was impaired. Resting tremor was again absent, but postural tremor
was still present. His family reported several episodes of violent behavior,
but at the time of examination, his behavior and mood were stable. He denied
having depression. On the MMSE test, he scored 22 of 30 points, missing points
on the orientation, calculations, and recall scales. He had frontal lobe release
signs, including glabellar and palmomental reflexes. His tendon reflexes were
brisk but symmetrical. He had equivocal Babinski sign bilaterally.
Case 2
This right-handed man (VI:9 of the PPND family [Figure 1]) reported that he first noticed a tremor in his right
leg at 40 years of age. When he was driving an automobile, his left leg would
sometimes feel stiff and occasionally shake. His wife noted that when he turned
his body, his turning had become en bloc. At 41 years of age, he had a shuffling
gait with reduced arm swing. His facial expression changed little, and he
had prominent drooling. He had resting tremor in both legs (the left more
than the right) and occasionally in his hands. His balance deteriorated steadily.
He experienced many falls throughout the day and had difficulty standing up.
His balance was better in the morning than in the evening. Treatment with
a combination of carbidopa and levodopa did not benefit him.
At 44 years of age, the patient reported generalized stiffness in the
muscles of his neck, tongue, and extremities. The stiffness was more pronounced
in the afternoon and 3 hours after he had taken levodopa. The tremor in his
legs (particularly the left one) was also worse several hours after levodopa
administration. He reported frequent yawning and chewed gum constantly to
avoid yawning and to reduce excessive drooling. He was still independent in
almost all daily living activities, but his wife had to help him occasionally
with cutting food. On examination, his MMSE score was 30 of 30. His head and
neck were flexed (Figure 2). He
drooled and had obvious parkinsonian features, including a paucity of facial
expression and a severely reduced blinking rate. While walking, he needed
assistance to avoid falling as a result of postural instability. His muscle
tone was increased and characterized by a mixture of rigidity and spasticity;
hypertonicity was more pronounced in axial than in appendicular muscles. Muscle
strength was normal. Tendon reflexes were exaggerated, with bilateral ankle
clonus more pronounced on the right side. Equivocal Babinski sign was seen
bilaterally.
Case 3
This 41-year-old right-handed man (III:6 of the French family [Figure 1]) began to experience generalized
fatigue, forgetfulness, and slowness of movement. He was hospitalized shortly
after the onset of his illness. At that time, he complained of slowness of
movement and deterioration of motor skills. His family reported social withdrawal
and attention deficits, but he was still independent in all daily living activities.
Bradykinesia, rigidity, and apathy were noted. He was treated with selegiline
hydrochloride and a combination of carbidopa and levodopa. His symptoms improved
during the initial 6 months of treatment but then worsened; his work performance
also deteriorated. Eyelid-opening apraxia and frontal lobe release signs developed.
At 43 years of age, his MMSE score was 25 of 30 points, with difficulties
on the scales for orientation, calculations, and recall. His eyes were fixed
in a neutral position, with absent vertical gaze and slow horizontal gaze.
Oculocephalic maneuvers were normal. His posture was stooped and he had a
masklike face. His speech was soft and slow. He was able to say only a few
words. He was rigid, especially on the left side of the body. Frontal lobe
release signs, including glabellar and palmomental reflexes, were present.
He also had hyperreflexia and bilateral Babinski sign. He walked with assistance
from his wife. He shuffled, had gait ignition difficulties, and had postural
instability.
COMMENT
The course of disease in the French family with the N279K mutation appeared
similar to that of the PPND family, with a similar age at onset and duration
of disease. However, if differences existed, they would not have been detected
by means of statistical tests in this study because of the small number of
patients and the wide range of values.
Kindreds with FTDP-17 can be divided into the following 2 major clinical
groups on the basis of phenotype: dementia predominant and parkinsonism predominant.11 Families in which dementia predominates are more
common, but both types of presentation can occur with the same mutation and
even within a single family.12-13
Age at onset of disease varies, ranging approximately from 30 to 60 years.14-16 However, in some
families, symptomatic disease onset may occur at younger than 30 years or
at older than 60 years.13, 17 The
course of disease can be very aggressive, terminating in death within 5 years,
or it can be quite prolonged, lasting 20 years.15-16
The clinical picture is dominated by progressive dementia with personality
changes, although parkinsonian features are sometimes seen. If parkinsonism
does appear, it is usually in the form of rigidity during the final stages
of the disease.
The phenotype of the 2 families described in this report was quite different
from that of the dementia-predominant kindreds and shares more similarities
with the parkinsonism-predominant group of kindreds. One family with a parkinsonism-predominant
phenotype has been described as having disinhibition-dementia-parkinsonism-amyotrophy
complex (DDPAC)18-19 and was the
first kindred with the disease that was linked to chromosome 17. A detailed
comparison of clinical, laboratory, and pathological features in the families
with PPND and DDPAC has been published elsewhere.20
In brief, the DDPAC kindred shares the presence of parkinsonian features and
dementia of the frontotemporal type with our PPND and French families. However,
in the PPND and French families, the clinical course is more aggressive, without
the prodromal stage seen in the DDPAC family. In addition, the amyotrophy
seen in the DDPAC family is not seen in our kindreds. The DDPAC kindred has
a mutation in the intron at position +14 of the intron following exon 10 (E10
+14) of the tau gene.21
The N279K mutation in our kindreds and the E10 +14 mutation seen in the DDPAC
family lead to similar biochemical abnormalities characterized by the excessive
production of 4R tau that in turn results in the selective accumulation of
these isoforms in insoluble form.
In another study, family A with familial progressive subcortical gliosis,
which had a mutation at position +16 of the intron following exon 10 (E10
+16) of the tau gene, was characterized by profound
dementia, but parkinsonism was seen in all cases relatively early in the disease
course.22-23 The response to levodopa
has not been reported. Patients from this family did not have supranuclear
gaze palsy. However, in multiple-system tauopathy with presenile dementia,
affected members had a mutation at intron +3 after exon 10 and presented with
parkinsonism and vertical gaze palsy accompanied by dementia and disinhibition.24-25 Recently, a family with a novel mutation
of S305S (E10 –1) was described.12 One
of the affected members presented with progressive parkinsonism associated
with vertical supranuclear gaze palsy and minimal dementia. This mutation
again affects alternative splicing of exon 10.
Other families with mutations in exons 9, 10, 12, and 13 of the tau gene have been studied. Families with a P301L mutation
in exon 10 have been described most frequently. The largest and best investigated
of these families was a Dutch family.26 In
this kindred, the most prominent behavioral changes included disinhibition,
loss of executive function, and language abnormalities. Parkinsonian features
may be present, but only in the late stage of the illness. Rigidity and bradykinesia
have been described. Results of biochemical studies in affected brain material
have shown that, as with the N279K mutation, the P301L mutation results in
selective accumulation of insoluble 4R tau. However, the P301L mutation does
not alter exon 10 alternative splicing and indeed is associated with a depletion
of soluble 4R tau in the brains of patients.27
Three kindreds with a P301S mutation have been described in Italy, Germany,
and Japan.17, 28-29
As a group, patients with this mutation have the youngest age at onset of
symptomatic disease (28 years in the Italian, third decade of life in the
German, and 37 years in the Japanese kindreds). Rapidly progressive courses
of dementia and parkinsonism have been seen in these families. The affected
individuals in the German kindred also have seizures, and some of them died
of status epilepticus.
One family with a G272V mutation in exon 9 (Dutch family II) has been
studied.26, 30 Affected family
members present with dementia of the frontotemporal type similar to that seen
in Pick disease. Some affected family members also have parkinsonism present,
but only in the late stage of the illness. A family with a V337M mutation
in exon 12 (the Seattle A family)31 has presented
with mood changes, social withdrawal, and behavioral abnormalities (schizophreniform
symptoms). Parkinsonism has not been observed in this family, except in 1
patient who experienced resting tremor. Two families with an R406W mutation
in exon 13 presented with memory loss like that seen in typical cases of Alzheimer
disease and personality changes.16, 32
Parkinsonism characterized by bradykinesia was present in 2 of 15 patients
in the late stage of the disease.16 Patients
with a G389R mutation in exon 13 presented with progressive aphasia and memory
problems followed by dementia.15 Parkinsonism
developed in the late stage.
Parkinsonism was also described recently in families harboring the E10
+12, delN296, and N296N mutations.33-35
Families with S305N (E10 -2), I260V, K257T, E342V, del280K, L284L, and
E10 +13 mutations are also known. However, the phenotypic description of these
families is somewhat limited and does not permit their clinical characterization.14
The findings from multiple families with tau
mutations, summarized above, suggest that exon 10 mutations that cause 4R
tau overproduction or accumulation, or both, may be more commonly associated
with a parkinsonism-predominant phenotypic presentation than other tau mutations in exons 9, 12, and 13. However, this correlation remains
uncertain because considerable phenotypic variability exists in families with
exon 10 mutations and because these families have not consistently been examined
by specialists in dementia and movement disorder.
In addition to the families we studied, 2 families of Japanese origin
have been shown to have the N279K mutation and presented with a parkinsonism-predominant
phenotype.8-9 Disease onset and
duration and clinical course are similar to those observed in our 2 families.
Collaboration with Japanese researchers on genealogical, genetic, and clinical
aspects of these kindreds is planned. The findings at present strongly suggest
that the N279K mutation produces a consistent phenotype, even in markedly
different genetic backgrounds. This is in contrast to other exon 10 mutations
(P301L and E10 +16 splice site) that have been associated with markedly variable
clinical presentations (dementia predominant and parkinsonism predominant),
even in the same family.
Direct comparison of available pathological material from the PPND and
the French families is in progress. Widespread neuronal loss and gliosis are
known to be present in both kindreds. On the basis of published reports,36 the cortical abnormalities appear to be slightly
more pronounced in the French family. The substantia nigra, globus pallidus,
and pontine and mesencephalic tegmenta appear to be equally affected in both
kindreds. The distribution and severity of other abnormalities, including
the presence of ballooned neurons and neuronal and glial tau inclusions, appear
to be similar in both kindreds.
The PPND and French families share more similarities than differences
in clinical features. The N279K mutation can develop independently in different
parts of the world. Further understanding of the pathogenesis of the FTDP-17
disorders continues to hinge on study of their clinical and pathological presentation
and the presence of common founder effects.
AUTHOR INFORMATION
Accepted for publication December 17, 2001.
Author contributions: Study concept and design (Drs Tsuboi, Ghetti, Hutton, and Wszolek); acquisition
of data (Drs Tsuboi, Delisle, Ferreira, Brefel-Courbon,
Rascol, Ghetti, Murrell, and Wszolek and Mr Baker); analysis and interpretation
of data (Drs Tsuboi, Uitti, Ghetti, Hutton, and Wszolek); drafting of the manuscript (Drs Tsuboi, Rascol,
and Hutton and Mr Baker); critical revision of the manuscript for important
intellectual content (Drs Uitti, Delisle, Ferreira, Brefel-Courbon,
Rascol, Ghetti, Murrell, Hutton, and Wszolek); statistical expertise (Mr Baker); obtained funding (Drs Ghetti,
Hutton, and Wszolek); administrative, technical, and material support (Drs Tsuboi, Ferreira, Brefel-Courbon, Rascol, and Ghetti and
Mr Baker); study supervision (Drs Uitti, Delisle,
Hutton, and Wszolek).
We thank all members of the PPND and French families we studied for
their cooperation, patience, and understanding.
This study was supported in part by the Morris K. Udall National Institutes
of Health Parkinson's Disease Center of Excellence at Mayo Clinic, Jacksonville,
Fla; a National Institute on Aging program grant, Mayo Clinic, Jacksonville
(Dr Hutton); and grant PHS D30 AG10133 from the Indiana Alzheimer Disease
Center, Indianapolis.
Corresponding author and reprints: Zbigniew K. Wszolek, MD, Department
of Neurology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224 (e-mail: wszolek.zbigniew{at}mayo.edu).
From the Departments of Neurology (Drs Tsuboi, Uitti, and Wszolek)
and Research (Dr Hutton and Mr Baker), Mayo Clinic, Jacksonville, Fla; Service
d'Anatomie et de Cytologie Pathologiques and Institut National de la Santé
et de la Récherche Médicale U466, Centre Hospitalier Universitaire
Rangueil (Dr Delisle), and the Clinical Investigation Centre and Neuropharmacology
Unit, Centre Hospitalier Universitaire Purpan (Drs Ferreira, Brefel-Courbon,
and Rascol), Toulouse, France; and the Department of Pathology, Indiana University
School of Medicine, Indianapolis (Drs Ghetti and Murrell).
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