There is increasing evidence that neuron loss precedes the phenotypic
expression of Huntington's disease (HD). As genes for late-onset neuro-
degenerative diseases are identified, the need for accurate assessment
of phenoconversion (i.e., the transition from health to the disease
phenotype) will be important.
Prospective longitudinal evaluation using the Unified Huntington's Disease
Rating Scale (UHDRS) was conducted by Huntington Study Group members
from 36 sites. There were 260 persons considered "at risk" for HD who
initially did not have manifest disease and had at least one subsequent
Repeat UHDRS data, obtained an average of 2 years later, showed that
70 persons were given a diagnosis of definite HD based on the quantified
Baseline cognitive performances were consistently worse for the at-risk
group who demonstrated conversion to a definitive diagnosis compared
with those who did not. Longitudinal change scores showed that the
at-risk group who did not demonstrate manifest disease during the
follow-up study period demonstrated improvements in all cognitive tests,
whereas performances in the at-risk group demonstrating conversion to
disease during the study declined across cognitive domains.
Neuropsychological measures show impairment 2 years before the
development of more manifest motor disease. Findings suggest that
these brief cognitive measures administered over time may capture
early striatal neural loss in HD.
Differences in duration of Huntington's disease based on age at onset=================================
Foroud, T., Gray, J., Ivashina, J., Conneally, P M. (1999).
J. Neurol. Neurosurg. Psychiatry 66: 52-56
Full Text: http://jnnp.bmjjournals.com/cgi/content/full/66/1/52
Conflicting reports in the literature have arisen regarding the relation
between age at onset and the progression and duration of illness in
patients with HD. Juvenile onset patients have been reported to have
shorter or similar disease duration than patients with adult onset.
Disease duration among those with onset beyond the age of 50 has
been shown in some studies to be longer than other patients with
adult onset; however, other reports have found a shorter duration
among late onset patients. Earlier onset patients have been found to
have a faster rate of basal ganglia atrophy than those with late onset ;
however, studies of disease progression have not consistently identified
an association between either age at onset or the number of
trinucleotide repeats and the rate of clinical decline.
Patients with juvenile HD had a median duration of 20.0 years.
Patients with juvenile HD had a 1 to 2 year shorter duration of illness
than patients with onset between 20 and 49 years. This finding would
support the contention that patients with juvenile HD have a different
clinical presentation with more rapid onset and progression of symptoms.
Estimating disease duration based on a more accurate estimate of
symptom onset may support our findings that disease duration is actually
longer than previously estimated.
Methods: The HD Roster, located at Indiana University
The HD Roster is the largest collection of families with HD available in
the world. By collecting detailed questionnaire data on the affected
patients in each family, it is possible to characterise early findings of
disease as well as to consider the relation between age at onset and
duration of illness in a large sample
Longitudinal change in basal ganglia volume in patients
caudate atrophy and symptom severity and duration of symptoms in
patients with Huntington's disease (HD) have been assumed to reflect
longitudinal changes in basal ganglia, but such neuropathologic
progression has never been directly demonstrated.
Subjects in the current study were 23 HD patients at various stages
of the disorder who had two MRI images at least 10 months apart
(mean interimage interval = 20.8 months). We measured volumes of
caudate, putamen, and globus pallidus blind to the order of the images.
For each structure, we calculated a change score by subtracting the
volume obtained on the follow-up imaging from that obtained on the
initial imaging. Results indicated significant decreases over time in caudate,
putamen, and total basal ganglia volume.
Age at onset and length of trinucleotide repeat correlated significantly
with amount of volume change in caudate and total basal ganglia, even
after controlling for length of interimage interval, duration of disease,
and measures of symptom severity. Amount of change in basal ganglia
structures was not significantly correlated with neurologic symptom severity
at the time of the initial imaging or duration of symptoms.
This is the first longitudinal MRI study to document progressive basal
ganglia atrophy in HD, and suggests that quantitative neuroimaging with
serial MRI may be useful in monitoring effectiveness of potential
In addition, demonstration of greater rate of basal ganglia atrophy in
patients with earlier symptom onset suggests that treatment effects
may be more quickly observed in this subgroup of patients than in the
general HD population.
==========================================Duration of illness in Huntington's disease
is not related to age at onset
1993 JNNP http://jnnp.bmjjournals.com/cgi/content/abstract/56/1/98
The age at onset and duration of illness were studied in patients
with Huntington's disease in the Leiden Roster which at 1 July 1990
contained 2787 patients. Of 1106 patients, 800 deceased and 306
alive, the age at onset was known. The median duration was 16.2
(range 2-45) years.
In contrast to the current opinion, the median duration was independent
of the age of onset. The median duration in juvenile Huntington's disease
was 17.1 years, which is much longer than reported in the literature,
and comparable with the categories for the age of onset of 20-34 and
Only in the group where onset was over 50 years of age was the median
duration somewhat shorter (15.6 years), which can be ascribed to unrelated
causes of death. As age of onset and duration of illness are not related,
at least two mechanisms to determine the clinical course have to be
postulated: one for age of onset and another for duration of illness.
Duration was shorter for males, especially for those with an affected father.
Factors related to onset age in Huntington's disease
1982 Source NIH:
Ages of manifestation varying from 4 to 65 years are found in a
sample of 95 HD pedigrees compiled since 1968 from the
Southeastern United States.
Significant parent-child correlations of age of onset indicate
consistency of onset age within nuclear families. However, an
average intrafamily range of 9 years and an average intrapedigree
range of 12 years reveal substantial variability of onset age
within these groups.
Of the nine cases of juvenile-onset HD identified in this sample,
seven were of paternal descent. The preponderance of juvenile
patients inheriting the HD gene from a father confirms similar
findings from other studies.
In addition, a trend toward earlier onset in all offspring of paternal
transmission suggests that the juvenile-onset phenomenon is only
the tail of a shift in the curve of onset ages for this group. A trend
toward earlier onset in successive generations was noted.
This "anticipation" may reflect the finding that persons of early onset
in prior generations are selectively nonreproductive as a result of
manifestation of the disorder. By identifying familial factors influencing
onset age of HD, it may be possible to more effectively evaluate
environmental factors that influence the onset of the disorder.
Clinical and neuropathologic assessment of severity in
patients in whom postmortem brain specimens had been graded
for degree of neuropathologic involvement in the striatum.
Juvenile/adolescent onset (4 to 19 years of age) was associated
with very severe neuropathologic involvement produced by an
apparent rapid degenerative process.
Cases of early (20 to 34 years) and midlife (35 to 49 years) onset
had respectively less severe striatal involvement, suggesting a
slower degenerative progression.
High correlations among the grade of neuropathologic involvement,
cell counts of neurons, and a rating of physical disability suggest
that each represents a common underlying degenerative process
of the disease.
The relationship between the age at onset and the extent of neuro-
pathologic involvement suggests that a single mechanism may
determine both onset and rate of degenerative disease progression.
Trinucleotide repeat length instability and age of onset
in Huntington's disease. Source NIH. date unknown
The initial observation of an expanded and unstable trinucleotide
repeat in the Huntington's disease gene has now been confirmed
and extended in 150 independent Huntington's disease families.
HD chromosomes contained 37-86 repeat units, whereas normal
chromosomes displayed 11-34 repeats.
The HD repeat length was inversely correlated with the age of onset
of the disorder. The HD repeat was unstable in more than 80% of
meiotic transmissions showing both increases and decreases in size
with the largest increases occurring in paternal transmissions.
The targeting of spermatogenesis as a particular source of repeat
instability is reflected in the repeat distribution of HD sperm DNA.
The analysis of the length and instability of individual repeats in
members of these families has profound implications for pre-