Introductory remarks:

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The HD mutation is present and active from the moment of conception, therefore there is no starting point for HD.

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The HD mutation may not cause health problems until late in life or even never during a normal lifespan.

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With increasing CAG repeats, the probability to develop symptoms increases, and the age of onset decreases.

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HD causes changes in brain structure and function that can be measured years before clinical symptoms appear. Symptoms appear, when the brain cannot compensate for these changes in brain structure and function any longer, this is usually a gradual process with fluctuating states over many years.

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The brain can compensate for these changes in brain function for many years (asymptomatic stage). This is the stage, in which disease-modifying therapies must start to prevent the appearance of symptoms.

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HD can cause motor, cognitive, emotional, and vegetative symptoms.

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No clinical symptom is specific to HD, so basing a diagnosis on a single symptom can be erroneous, even if the CAG expansion is present. Depression is the most frequent psychiatric symptom and appears in the majority of HD patients, but can be present in non-carriers including partners.

Even hyperkinetic movements are not necessarily symptoms of HD in persons at risk, as they can be present in non-carriers with other neurological and psychiatric disorders or as a consequence of medications.

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Since HD often does not start with motor symptoms, but with cognitive, emotional, behavioral, or vegetative symptoms with implications for function at home and/or at work and quality of life, diagnosis of HD must be based on a thorough diagnostic work-up (motor, cognitive, psychiatric, behavioral, and functional aspects). So relevant diagnostic procedures (brain scans of structure, function, or metabolism, tests of brain function, cognitive tests, biomarkers in blood) are essential and must be explained and offered.

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The diagnosis of HD is clinical-biological. Without the expanded repeat (> 27 CAG) HD is not the cause of the health issues in that patient.

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Diagnostic testing:

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(1) Any diagnostic procedure, either predictive or clinical, can only be administered with the fully informed consent of the person seeking that information. All meaningful diagnostic and supportive procedures must be offered and performed at the person's wish, but no unwanted tests or procedures must be forced upon that person.

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(2) It must be explained that the diagnosis of HD has far-reaching consequences for the entire family of the person requesting diagnostic information. It must also be explained that there is no specific moment of disease onset, but that HD is a continuous process from normal brain function to the clinical stage with gradually increasing disabilities.

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(3) It must be explained to the person requesting diagnostic information that the fundamental diagnostic test is the molecular-genetic test of the CAG-repeat in the Htt-gene. Without the repeat expansion beyond the normal range being documented, no diagnosis of HD is definitive. So, if the size of the CAG-repeat is not known, measuring it is the first logical step in diagnosing HD.

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Test results:

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(1) If the CAG-repeat-expansion beyond the normal range is not present, HD is excluded and other causes of symptoms demand thorough diagnostic work-up.

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(2) If the CAG-repeat-expansion beyond the normal range is documented, HD should be diagnosed and staged according to the presence of MRI findings or other biomarkers, and clinical signs of HD (see below under diagnosis).

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Diagnosis

 

(1) If - based on the entire clinical diagnostic workup (motor, cognitive, psychiatric, behavioral, vegetative, and functional components), preferentially supported by diagnostic tests relevant for HD or to exclude other causes of the symptoms - it is more likely than unlikely that this patient has symptoms or signs that have occurred (partly or completely) as a result of HD pathology, in the presence of the expanded CAG-repeat, a diagnosis of HD is the most likely and should be offered.

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(2) The stages of HD must be explained.

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(2.1) HD-mutation (CAG-repeat-expansion beyond normal range) not present: HD is excluded.

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(2.2) HD-mutation (CAG-repeat-expansion beyond normal range) present:

 

Stage 0 - Premanifest: no signs or symptoms on the neurological and psychiatric exam and no functional limitations normal findings in biomarkers.

Action:  It must be made completely clear to these individuals that they are healthy in regard to HD. No action beyond a healthy lifestyle and avoidance of chronic stress.

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Stage 1 - Presymptomatic: no signs or symptoms and no functional limitations, abnormal findings in biomarkers.

Action: It must be made completely clear to these individuals that they have not manifested HD. In this stage, disease-modifying therapies must start to prevent or delay the onset of overt symptoms.  Optimal medical care for other medical conditions (diabetes, heart, lung, liver), including dental care and nutrition is essential. A healthy lifestyle and avoidance of chronic stress will lead to a better prognosis.

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Stage 2 - Initial Phase: Symptoms or signs without significant distress or functional limitations, abnormal findings in relevant biomarkers.

Action: Adequate support for patient and family, optimal medical care for other medical conditions (diabetes, heart, lung,            liver), including dental care, and nutrition.  A healthy lifestyle and avoidance of chronic stress will help slow the progression of HD as much as possible.

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Stage 3 - Clinical Phase: Symptoms or signs with significant distress or functional limitations, abnormal findings in relevant biomarkers. Staging (early, middle, advanced) according to functional limitations.

Action: All of the above plus symptom-oriented therapies (medications & exercises).  Also, to include supportive therapies, and legal/financial/social advice.

 

Practical implications

At all stages, the following is essential for informed decisions and must be given in accordance with the needs and wishes of the patient, families, and/or their significant others:  Information about therapeutic interventions, including lifestyle - esp. drugs and alcohol, rehab and exercise, cognitive and behavioral management, therapeutic trials, family planning, social and health services, lay organization information, and HD support groups. Adequate medical, psychological, social, and legal supports must be available.