Clinical Characteristics, Developmental Trajectory, and Caregiver Burden of Patients With Creatine Transporter Deficiency (SLC6A8).

BACKGROUND AND OBJECTIVES: Creatine transporter deficiency (CTD) is a rare X-linked genetic disorder characterized by intellectual disability (ID). We evaluated the clinical characteristics and trajectory of patients with CTD and the impact of the disease on caregivers to identify relevant endpoints for future therapeutic trials. METHODS: As part of a French National Research Program, patients with CTD were included based on (1) a pathogenic SLC6A8 variant and (2) ID and/or autism spectrum disorder. Families and patients were referred by the physician who ordered the genetic analysis through Reference Centers of ID from rare causes and inherited metabolic diseases. After we informed the patients and their parents/guardians about the study, all of them gave written consent and were included. A control group of age-matched and sex-matched patients with Fragile X syndrome was also included. Physical examination, neuropsychological assessments, and caregiver impact were assessed. All data were analyzed using R software. RESULTS: Thirty-one patients (27 male, 4 female) were included (25/31 aged 18 years or younger). Most of the patients (71%) had symptoms at <24 months of age. The mean age at diagnosis was 6.5 years. Epilepsy occurred in 45% (mean age at onset: 8 years). Early-onset behavioral disorder occurred in 82%. Developmental trajectory was consistently delayed (fine and gross motor skills, language, and communication/sociability). Half of the patients with CTD had axial hypotonia during the first year of life. All patients were able to walk without help, but 7/31 had ataxia and only 14/31 could walk tandem gait. Most of them had abnormal fine motor skills (27/31), and most of them had language impairment (30/31), but 12/23 male patients (52.2%) completed the Peabody Picture Vocabulary Test. Approximately half (14/31) had slender build. Most of them needed nursing care (20/31), generally 1-4 h/d. Adaptive assessment (Vineland) confirmed that male patients with CTD had moderate-to-severe ID. Most caregivers (79%) were at risk of burnout, as shown by Caregiver Burden Inventory (CBI) > 36 (significantly higher than for patients with Fragile X syndrome) with a high burden of time dependence. DISCUSSION: In addition to clinical endpoints, such as the assessment of epilepsy and the developmental trajectory of the patient, the Vineland scale, PPVT5, and CBI are of particular interest as outcome measures for future trials. TRIAL REGISTRATION INFORMATION: ANSM Registration Number 2010-A00327-32.

The French Version of the DABS: Adaptation Process and Preliminary Field Test.

The aim of this study was to develop a transcultural adaptation of the Diagnostic Adaptive Behavior Scale (DABS) in French and to perform a field evaluation of the adapted version of the tool (DABS-F). Eight experts in intellectual and developmental disabilities (IDD) and two professional translators formed two committees to translate the instrument. Thirty-four independent experts in IDD rated the clarity and relevance of the DABS-F. Results indicated complete agreement between the two translation committees and also demonstrated very satisfactory levels of clarity and relevance for the DABS-F. The latter result can be considered as evidence of the content validity of the adapted tool. Adjustments for the few items that presented less satisfactory results are discussed.

Neuropsychological and neuroanatomical phenotype in 17 patients with cystinosis.

BACKGROUND: Cystinosis is a rare autosomal recessive disorder caused by intracellular cystine accumulation. Proximal tubulopathy (Fanconi syndrome) is one of the first signs, leading to end-stage renal disease between the age of 12 and 16. Other symptoms occur later and encompass endocrinopathies, distal myopathy and deterioration of the central nervous system. Treatment with cysteamine if started early can delay the progression of the disease. Little is known about the neurological impairment which occurs later. The goal of the present study was to find a possible neuroanatomical dysmorphic pattern that could help to explain the cognitive profile of cystinosis patients. We also performed a detailed review of the literature on neurocognitive complications associated with cystinosis. METHODS: 17 patients (mean age = 17.6 years, [5.4-33.3]) with cystinosis were included in the study. Neuropsychological assessment was performed including intelligence (Intelligence Quotient (IQ) with Wechsler's scale), memory (Children Memory Scale and Wechsler Memory Scale), visuo-spatial (Rey's figure test) and visuo-perceptual skills assessments. Structural brain MRI (3 T) was also performed in 16 out of 17 patients, with high resolution 3D T1-weighted, 3D FLAIR and spectroscopy sequences. RESULTS: Intellectual efficiency was normal in patients with cystinosis (mean Total IQ = 93). However the Perceptual Reasoning Index (mean = 87, [63-109]) was significantly lower than the Verbal Comprehension Index (mean = 100, [59-138], p = 0.003). Memory assessment showed no difference between visual and verbal memory. But the working memory was significantly impaired in comparison with the general memory skills (p = 0.003). Visuospatial skills assessment revealed copy and reproduction scores below the 50th percentile rank in more than 70% of the patients. Brain MRI showed cortical and sub-cortical cerebral atrophy, especially in the parieto-occipital region and FLAIR hypersignals in parietal, occipital and brain stem/cerebellum. Patients with atrophic brain had lower Total IQ scores compared to non-atrophic cystinosis patients. CONCLUSIONS: Patients with cystinosis have a specific neuropsychological and neuroanatomical profile. We suggest performing a systematic neuropsychological assessment in such children aiming at considering adequate management.

Prisms adaptation improves haptic object discrimination in hemispatial neglect.

Neglect manifestations are typically explored in the visual modality. Although they are less commonly investigated tactile deficits also exist, and the aim of this study was to explore neglect in this modality. A haptic object discrimination task was designed to assess whether or not shape perception is impaired in seven right brain damaged patients with or without neglect. Each patient's performance on the object discrimination task was assessed before and after a brief period of prism adaptation, a bottom-up rehabilitation technique known to improve neglect symptoms. The results suggest that a haptic deficit - in the form of substantially more left errors - is present only in patients with neglect. Following prism adaptation, the left bias error rates in neglect patients were substantially reduced, and were similar to those observed in patients without neglect. Moreover, the haptic processing of the right side of objects also improved slightly. This finding suggests an expansion of the effects of prism adaptation to the unexposed, tactile modality supporting the cross-modal central effect hypothesis.

Involving children and young people in clinical research through the forum of a European Young Persons' Advisory Group: needs and challenges.

Children and young people are seen as fundamental to the design and delivery of clinical research as active and reflective participants. In Europe, involvement of children and young people in clinical research is promoted extensively in order to engage young people in research as partners and to give them a voice to raise their own issues or opinions and for their involvement in planning and decision making in addition to learning research skills. Children and young people can be trained in clinical research through participation in young person advisory groups (YPAGs). Members of YPAGs assist other children and young people to learn about clinical research and share their experience and point of view with researchers, thereby possibly influencing all phases of research including the development and prioritization of research questions, design and methods, recruitment plans, and strategies for results dissemination. In the long term, the expansion of YPAGs in Europe will serve as a driving force for refining pediatric clinical research. It will help in a better definition of research projects according to the patients' needs. Furthermore, direct engagement of children and young people in research will be favorable to both researchers and young people.

The manual haptic perception of orientations and the oblique effect in patients with left visuo-spatial neglect.

This study addresses the limits of haptic orientation deficit observed in patients with left visuo-spatial neglect (VSN) in the fronto-parallel plane. We concentrated on two aspects of the haptic perception of vertical, horizontal and oblique orientations: first, the global level of performances compared with normal subjects and, second, the occurrence of the oblique effect (i.e. lower performances in oblique orientations than in vertical-horizontal orientations). Subjects were asked to position a rod, presented in the fronto-parallel plane, to one of four orientations: vertical, horizontal, left 45 degrees oblique and right 45 degrees oblique. First, we found a haptic orientation deficit in neglect patients: The precision was lower in the neglect patients than in the normal (young adults and seniors) subjects. Second, we observed in both neglect patients and control subjects the occurrence of a similar haptic oblique effect and there were no differences between the results in the left and right hemispaces. Taken together, this means that, in spite of the global haptic orientation production deficit observed in VSN patients, no specific pattern was observed in the haptic production of different orientations in these subjects as compared to the two other groups. The haptic orientation deficit of neglect patients seems to affect in the same way all values and spatial positions of orientations.