**4. Discussion**

Juvenile HD is described as a very rare manifestation of HD with an estimated prevalence of 1–9.6% of all HD cases in studies and meta-analyses estimate 4.92% to 6% of all HD patients being juvenile [4,12–15]. Out of 2593 individual HD patients treated within the last 25 years in the Huntington Centre NRW, 32 subjects were analyzed with an early onset younger than 21 years. This relates to a proportion of 1.23%. This is within the range of published data. Several problems arising from the terminology JHD are currently being discussed. Many patients seem to be called juvenile because of their more bradykinetic phenotype even if they are older than 21 [21,27,28]. Thus, in JHD the bradykinetic phenotype can be seen as being most characteristic, which is usually associated with a more dopaminergic therapy. However, there seems to be a large cohort of HD patients who are already adults su ffering from a more predominant bradykinetic-rigid clinical phenotype, called JHD. Some of them perhaps even had a motor onset beyond 20 years of age and are called JHD only because of their more bradykinetic symptoms [29]. This might explain the high range for estimation of prevalence of 1–9.6% and also explain why the prevalence in our cohort does not correspond with the higher mean described above and classified in the lower range since we used the strict definition of an age below 21 year for our collective. This di fference is even more obvious if the more recently definition of pediatric HD is used, with only 0.69% of all cases. This remarkably low rate might be caused due to fewer admissions of early-onset HD cases to our centre. However, as part of our institution, a university children's hospital for Neuropaediatrics and Social Paediatrics is a ffiliated and well known by the German pediatricians society and patient support organisation. Since to the best of our knowledge, this is the only known cooperation like this in Germany and the identified cases were submitted nationwide, we would expect a bias to even more JHD cases and not less in our cohort.

As a first aspect to discuss in our case report series we detected several findings concerning socio-medical aspects not only caused by HD pathology but also caused by early a ffected parents, instable family backgrounds, including drug abuse by a parent or multiple changes of partners. The results of our research are in line with earlier findings. Massive burdens for caregivers, HD families and especially for the patient arise from socio-medical problems in an observed mutual interplay of the social surrounding and the a ffected person [12].

That implements not only the pharmacological treatment of patients but also more socio-medical supports like the organization of a school accompaniment, support by a social worker and support of the non- a ffected parent including psychotherapy in order to reach and maintain a certain degree of education. Especially, problems in school were often described as initial symptoms in many cases, they were also accompanied by cognitive decline. In this context, the establishing of the diagnosis HD was extremely helpful for most cases in our experience since it was possible to reduce learning pressure in school and define new targets for education in discussion with the school. Children in most cases were not depressed or burdened by the establishing of the HD diagnosis, but relieved by finding an explanation for their di fficulties at school and by defining new, more social aspects of participating in school visits. This is even more important since a delay in diagnosis is described in our collective and also published data in many cases [30] as one reason for late diagnosis the resistance of parents was reported. Following our experience, we would rather recommend an earlier diagnosis than a delay in diagnosis to parents in order to reduce the burdens of their children in social-medical aspects. As another reason for late diagnosis, a lack of knowledge among health care professionals is discussed, possibly also caused by unsuspectingness about the heterogeneous motoric symptomatic with a more bradykinetic motor phenotype in early- onset HD. In many of our cases, expensive and stressful or even painful diagnostic interventions like lumbar punctures were performed even if family history of HD was positive. In addition, some cases were initially misdiagnosed and mistreated as attention deficit hyperactivity disorder or borderline disease. Thus, we can support former described findings of delayed diagnosis in this subgroup [30]. From our perspective it is decisive to enable HD patients and families a continuous care through a specialized centre. For this purpose, participating in a prospective registry study (e.g., ENROLL-HD) might enable annual visits, review of socio-medical aspects, and the family anamnesis. If an a ffected HD family member or caregiver is in contact with a specialized centre and reports di fficulties with a child, an investigation of this child should be offered. Additionally, index patients should be asked specifically about their own children and whether there are any abnormalities observed. A multidisciplinary setting including an early involvement of neurologists and neuropaediatricians is crucial and extremely helpful in our view. If there are typical HD symptoms, in most cases being investigated in a centre, diagnosis is not substantially delayed in our experience. However, if children are not initially investigated in a centre, we observed long delays and multiple unnecessary and stressful examinations including lumbar puncture and others in many cases. This might be due to several reasons: the lack of knowledge about more bradykinetic symptoms, concerns regarding performing genetic testing in a child with a lack of knowledge about the di fferential diagnostic-testing procedure, or concerns to make such a severe diagnosis as HD. Thus, the only way to avoid delays in diagnosis in these cases might be through the participation of professionals from a centre in meetings of patient-organisations, participation in congresses for professionals (e.g., neurologists or neuropaediatricians), public relations work about HD, and the o ffer of training courses for the specialized public. More important, from our experience, when making the diagnosis of HD in children is that almost all children were more relieved by the diagnosis than burdened. Regardless of the therapy with drugs, most children had a relief if their existing problems in school, in sports or with friends could be explained due to the HD diagnose. For example, subsequent changes or help in school setting reduced stress and declined fear of failure. Our impression is, that children, as in other severe diagnoses like cancer, seem to cope with the diagnosis well in most cases whereas diagnosis is often more di fficult for the parents.

As a second aspect, it is important to distinguish between the heterogeneous movement disorders in early- onset HD, with bradykinesia, dystonia, tremor or myoclonic hyperkinesia in order to achieve a beneficial pharmacological treatment [31–33]. Many of our cases were treated with dopaminergic drugs or amantadine for an improvement of bradykinesia, benzodiazepines or tetrabenazine was used for treatment of dystonia with beneficial effects. In single severe cases, cannabinoids and deep brain stimulation (DBS) was used for more generalized dystonia or botulinum toxin- injection for focal dystonia. For DBS only, intermittent positive effects and only mild beneficial effects after treatment with trihexyphenidyl were observed [33]. A relatively high amount of 37.5% of the pediatric cohort and 11.1% of the juvenile cohort, respectively, suffered from tremor. In most cases tremor was treated with dopa-agonists like pramipexole, in one case an excellent benefit was observed after treatment with clozapine with an initial indication of dopa-induced hallucination [34]. Valproic acid was used for treatment of epilepsy, as a mood stabilizer but also for treatment of myoclonic hyperkinesia in two cases [31]. As listed in our reports, in many cases a combination of medication or changes in medication in the course of the disease was necessary.

The occurrence of epilepsy with seizures in JHD is described as an additional important clinical feature [7,10,35]. Although not much is known about why epilepsy occurs more in JHD than in adultonset HD, retrospective studies report on a very frequent occurrence of 38% in a collective of juvenile HD patients, which corresponds to a rate of 37.5% in our collective [36]. Valproic acid was used for treatment in many cases but also levetiracetam, lamotrigine and benzodiazepines. No case of increased irritability as a known side-effect was observed regarding treatment with levetiracetam.

As another clinical feature, a delay of speech development was observed in five cases and therewith present in 25% of the pediatric cohort. Remarkably, the speech development delay and a consequent logopaedic therapeutic trial was even described in advance of other clinical symptoms or diagnosis of HD. As family anamnesis revealed a younger and older brother without any suspected speech development delay, we assumed a potential organic cause due to HD.

Finally, we observed a very high amount of different psychiatric disturbances like aggression and irritability in 62.5% of the pediatric and 33.3% of the juvenile cohort, respectively. Substantial aggressive and criminal behavior causing serious problems for the family and social network as well as for the patient was observed in case 6 in particular. His mother was suffering from HD and already severely affected at the time of first admission. Besides the potential organic burdens due to the disease, we observed challenging situations for the patient constituted by a socially disadvantaged family situation possibly leading to delinquent behavior due to missing corrective behavior of the father. He was burdened also as the caregiver for the affected mother during that time. Disease-related missing impulse control, an additional impact of the social surrounding, or even further developments of the common puberty-age with a personal-development process can be discussed as being decisive for his behavior. Remarkably, older and younger siblings of this case did not show any delinquent behavior, that is why we assume the described multifactorial reasons including HD related brain changes and not solely the influence of his social background on the described behavior. Suicidal ideations or attempts were described in 31.2% of the pediatric and 33.3% of the juvenile cohort, as well as other psychiatric symptoms, with apathy in two pediatric cases and obsessive behavior in one juvenile and pediatric case [37]. Treatment was effective for most of these cases following guidelines and common psychiatric treatment strategies [27]. Serotonin-selective-reuptake inhibitors (SSRI) and mirtazapine, especially if sleep problems occurred, were the most common medication for treatment of depression. Quetiapine and risperidone were used for the treatment of irritability and aggressive behavior, whereas in single cases zuclopenthixole for the treatment of severe aggressive behavior was also effective [38]. As potential side- effects, bradykinesia and rigidity worsened especially after treatment with risperidone. As a relevant side-effect of therapies with L-dopa or dopa- agonists, hallucinations, especially optical hallucinations, might occur. In five of our 25 cases with complete records, optical, and in one case acoustic, hallucinations were caused due to the dopaminergic treatment and improved after reduction of dosage or with additional neuroleptic treatment [34].

As a limitation, our case reports are based on a retrospective analysis of medical reports and not on standardized implemented scales for accessing of symptoms. Moreover, in seven cases, no additional detailed medical reports were available anymore. However, this more descriptive research approach enabled the depiction of heterogeneous and manifold aspects in early-onset HD which might not be captured in standardized scales, such as the described socio-medical aspects. More in general this is a very rare subgroup of HD, which might limit power for further research in many aspects.
