Luckily, many HD centers participating in Enroll-HD have entered into the database HD patients without motor symptoms at the time of diagnosis.
In December 2017, I had the opportunity to analyze age-at-onset data in the Enroll-HD dataset available for research. Out of a total of 8714 participants, I found 4691 cases with both an age-at-onset of motor symptoms (the classical hallmark for diagnosing manifest HD) and an age-at-diagnosis.
Table 1 shows the descriptive statistics of the two variables.
Age-at-onset of motor symptoms has a mean of 45.5 years, with a range from age 2 to age 84! Usually, diagnosis is established a few years after the patient shows motor symptoms, so mean age-at-diagnosis is 2.7 years later, with a range from age 5 to age 90.
If one looks at the group of patients who were diagnosed when motor symptoms were present, the time gap between AaOM (age at onset of motor symptoms), and AaD (age at diagnosis), increases slightly to 3.3 years, which is good news compared to the historical data of a delay in diagnosis of about 8 years. But there are time gaps of more than 30 years.
See Figure 1.
Dots to the right of the line represent the patients who were diagnosed after onset of motor symptoms, to the left those patients who were diagnosed without showing motor symptoms.
Looking at the large number of patients with big delays in diagnosis (sad if true), a careful check of the database is necessary. Since AaO is an utmost important data in clinical research, we need robust data to start with.
The most puzzling finding in the dataset were the 371 (= 8%) cases, who were diagnosed years before they showed motor symptoms! Some of them were diagnosed as having HD more than 10 years before showing motor symptoms. Refer to the scatter diagram above.
These patients must have presented psychiatric and / or cognitive symptoms leading to a diagnosis of HD. Again, a careful check of the database is vital to come to reliable results and conclusions.
According to my clinical experience of over thirty-five years, there are HD patients who present psychiatric symptoms up to 2 decades before they show overt motor symptoms. But if one uses objective tests of motor performance in these patients, most of them will show subtle deficits and/or changes in brain metabolism, structure, or function.
I informed CHDI, the sponsor of Enroll-HD, about my findings in December 2017, and they quickly started to check the data for inconsistencies and discrepancies. So in the event that we cannot be sure that the all the data are correctly entered into the database, we have to be cautious about conclusions. But as of now, the data indicates that a number of HD patients show non-motor symptoms as first symptoms and they are indeed diagnosed as having HD. So the diagnostic criteria have to be updated in the way, Reilmann and colleagues suggested.