**1. Introduction**

Huntington's disease (HD) is an autosomal-dominant hereditary neurodegenerative progressive disorder usually with a most common onset at the age of 30–50 years [1,2]. Nevertheless, motor onset can occur at every age and onsets ≤ 20 years of age are traditionally classified as juvenile HD (JHD) [3]. Recent research suggested the redefining of the term of younger HD patients and to use the term "pediatric" instead of juvenile Huntington's disease for those younger than 18 years, since the definition of juvenile HD (JHD) was found to be blurred and used in different ways [4]. The onset is

thereby defined as the presence of unequivocal clinical motor signs (>99% confidence with a diagnostic confidence level (DCL) of four on the "Unified Huntington's Disease Rating Scale" (UHDRS) [5]) caused by HD. Especially in younger patients, motor symptoms may present typically with bradykinesia, dystonia, but also with myoclonus or tremor. The cohort of JHD was described with varieties of motorand non-motor specific characteristics, thus demands were made for adapting common rating scales, usually to access disease-manifestation in adult HD, for use in children [6].

Case series reports on psychiatric and cognitive nonspecific deficits often accompanied a misdiagnosis or delays in HD diagnosis. JHD patients having an earlier onset also are described to have a longer delay between symptoms and diagnosis of HD [7]. Although the detectable genetic cause with an expansion of cytosine- adenine- guanine (CAG)-trinucleotide repeats in the huntingtin gene (HTT) on chromosome four is obvious to access [1,8], repeat expansions higher than 60–70 CAGs are described as causing a juvenile and more bradykinetic HD phenotype and were frequently detected in juvenile cases described in earlier research [7–10]. Although the genetic cause is unequivocal, characteristics of the clinical disease manifestation, especially in children, are manifold. HD is described as a complex disease with heterogeneous challenges and progressive loss of dependency and increasing disability. For the care of HD patients, several researchers recommend multidisciplinary approaches which are required and include the family, social workers, therapists and physicians to maintain quality of life and to decrease psychosocial problems [11]. For pediatric and juvenile HD, the support not only for children but also for parents or even the whole social system including schools, might be helpful. Psychosocial implications in these settings are described as wide ranged. Former research describes the role of the family and caregivers as burdensome due to disappointing experiences with social and health services, the dissatisfaction of being a caregiver, concern about children, and the loss of needed help from the social or family background due to increasing care for the HD patient and social withdrawal [12]. The unaffected family caregiver is thereby described to need the most support, attention, and help [12]. Many important aspects concerning these socio-medical and psychosocial backgrounds in HD are described [13]. Challenging ethical, social, and legal issues for HD patients, health care professionals, and caregivers are caused by the progressive disease [14]. Most published data consider HD patients and their influence on the social environment. However, further research is necessary regarding social aspects of support and the effects of the caregiver's behavior on the disease and the behavior of the patient and how these interactions affect relations in HD families [15].

The prevalence of HD varies between different geographical regions [16]. Systematic reviews indicated global variations, with an overall prevalence of 5.7 per 10,0000 persons, describing a lower incidence in Asia compared to Europe and North America [3,17]. However, more recently a substantial higher prevalence of HD in the UK (12.3 per 10,0000) and also in Germany was reported, with 9.3 per 10,0000 inhabitants using data of four million insured persons, probably caused by more accurate diagnoses and an improved life expectancy [18,19].The small cohort of juvenile HD patients is described with an equivocal estimated prevalence ranging between 1–9.6% of all HD cases in studies and meta-analyses estimating 4.92% to 6% of all HD patients being juvenile [4,20–23].

Although many important aspects about juvenile HD have been described, no case reports about the recently defined pediatric cohort or comparing research of pediatric and juvenile HD in the boundary of typical characteristics in adult HD were described [4]. Describing the different phenotypes of the clinical manifestation in HD and especially early-onset HD is not only important for the investigation of potential underlying and diverse mechanisms of pathophysiology but primarily for the adapting of different symptomatic therapeutic options. Hereby an exact assessment and rating of predominant symptoms can be crucial because the symptomatic therapy needs to be adapted to the type and extent of individual findings and adjusted frequently during the individual course of the disease [24]. Contrary to treatment of chorea, in a more bradykinetic phenotype, as described for JHD, dopamine agonists may be effective [24]. Case reports and small studies report on an improvement after the dopamine agonist pramipexole or after dosing of medication with L-dopa and amantadine [24,25]. Beside these

options for symptomatic therapies, there are no disease-modifying/slowing options or therapeutic options with neuroprotective effects available at the moment [26].

The aim of this case report series is to describe the rare group of early-onset patients, especially in regard to socio-medical aspects and individual or common treatment strategies. In addition, we differentiated between juvenile and the recently defined pediatric HD population (onset < 18 years).

#### **2. Patients and Methods**

To classify a cohort of the comparatively very rare pediatric and juvenile HD-patients in more detail, we investigated a retrospective analysis of data from our Huntington Centre North Rhine-Westphalia (NRW). Since its establishment in the year 1995, we have had 25 years of clinical and research experience concerning the treatment and care of adult and early-onset patients suffering from HD. A University Children's Hospital for Neuropaediatrics and Social Paediatrics is affiliated as a part of our institution. The affiliation of the department of Neuropaediatrics and Social Paediatrics to the Huntington Centre NRW for the diagnosis and treatment of HD children is well known among German pediatricians as a result of talks held at pediatric congresses and publications in pediatric journals. Moreover, this cooperation is well known among the German patient support organization, further admissions take place after molecular diagnostic testing in the department of human genetics as part of the Huntington Centre NRW. A rooming in together with a parent was possible when treating children as inpatients.

We analyzed data from our internal digital quality managemen<sup>t</sup> and hospital information system as well as archived medical letters and examination reports. Apart from this, additional data were collected from archived admission books of the outpatient and inpatient clinic and analyzed, (i) to receive information about a prevalence of juvenile and pediatric HD patients in our clinic, and (ii) to especially evaluate clinical patient-related information for presenting case reports and fundamental correlations of the heterogeneous clinical pictures in early-onset HD.

A special focus was set to describe challenging situations concerning the diagnosis and pharmaceutical treatment of affected patients compared to adult patients as well as challenging situations coming from the socio-medical environment of individual patients. Data concerning socio-medical information were anonymized, analyzed, and based on socio-medical anamnesis in the medical reports. No information was available coming from other sources, such as criminal reports or court proceedings. The investigation was confirmed by our local ethics committee (registration number 20-6892-BR) who agreed on the retrospective anonymized data analysis and publication of information coming from our clinical data managemen<sup>t</sup> system and medical letters.
