Diagnosing Juvenile Huntington's Disease: An Explorative Study among Caregivers of Affected Children.

Objective: To investigate the reasons for the diagnostic delay of juvenile Huntington's disease patients in the Netherlands. Methods: This study uses interpretative phenomenological analysis. Eligible participants were parents and caregivers of juvenile Huntington's disease patients. Results: Eight parents were interviewed, who consulted up to four health care professionals. The diagnostic process lasted three to ten years. Parents believe that careful listening and follow-up would have improved the diagnostic process. Although they believe an earlier diagnosis would have benefited their child's wellbeing, they felt they would not have been able to cope with more grief at that time. Conclusion: The delay in diagnosis is caused by the lack of knowledge among health care professionals on the one hand, and the resistance of the parent on the other. For professionals, the advice is to personalize their advice in which a conscious doctor's delay is acceptable or even useful.

KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.

Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly 'pure' spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families. The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization. In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6-7%). The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia.