"Spazio Huntington": Tracing the Early Motor, Cognitive and Behavioral Profiles of Kids with Proven Pediatric Huntington Disease and Expanded Mutations > 80 CAG Repeats

Abstract

The "Spazio Huntington-A Place for Children" program was launched in 2019. The aim was to contact at risk kids within Huntington disease (HD) families, to provide counseling to their parents and to start a prospective follow-up of kids suspicious to manifest pediatric HD (PHD). We met 25 at risk kids in two years, four of whom with PHD and highly expanded (HE) mutations beyond 80 CAG repeats. We rated motor, neuropsychological and behavioral changes in all PHD kids by the Unified HD Rating Scale (UHDRS)-total motor score (TMS) and additional measures of (1) cognitive level (Leiter International Performance Scale), (2) adaptive functioning (Adaptive Behavior Assessment Systems), (3) receptive language (Peabody Picture Vocabulary Test) and (4) behavioral abnormalities (Child Behavior Check List and Children's Yale-Brown Obsessive Compulsive Scale). All PHD kids showed a severe progression of neurological and psychiatric manifestations including motor, cognitive and behavioral changes. The magnetic resonance imaging contributed to confirm the suspicious clinical observation by highlighting very initial striatum abnormalities in PHD. Spazio Huntington is a program to prospectively study PHD, the most atypical face of HD, and may represent the basis to recruit PHD patients in future clinical trials.

Keywords: atypical Huntington disease; high CAG expansions; observational studies; pediatric Huntington disease; prospective studies.

Figure 1

Stratification of Spazio Huntington cohort. Flow chart showing the strategy of selection and stratification of the cohort, starting from a preliminary datasheet analysis of pedigrees and further interviews to families which were then met at “Spazio Huntington—A Place for Children”. The genetic test was only provided after a suspicious neurological exam highlighted a diagnosis which was suggestive of PHD (pediatric HD). All the confirmed PHD cases had a brain magnetic resonance imaging consistent with the diagnosis of PHD, according to the documented evidence, as described in [12]. In some cases the follow-up of children of expanded CAG homozygous patients may offer an opportunity to prospectively follow-up young subjects many years in advance before onset manifestations.

Figure 2

Longitudinal UHDRS-TMS progression. UHDRS: Unified Huntington’s Disease Rating Scale. TMS: total motor score. Each line refers to a single patient. Three out of four patients showed a remarkable yearly TMS change indicating a severe motor progression of the disease. TMS is reported within each circle. Orange = Patient 1, yellow = Patient 2, blue = Patient 4 and grey = Patient 3, the youngest patient, with only a basal assessment was available.

Figure 3

MRI (Magnetic Resonance Imaging) in a HE-PHD (highly expanded- pediatric Huntington disease) patient (Patient 3) and in a subject with suspicious motor manifestations of PHD. (a,b) Patient 3 with a pathological total motor score = 21 performed MRI at the very beginning of PHD (MRI age = 5, age at onset = 3.5). Atrophy and slight signal hyperintensity of the caudate nuclei and putamina (arrows). (c,d) At risk kid with total motor score = 20 and suspicious PHD. Normal appearance of basal ganglia, with no signs of atrophy or signal alterations.