Characterizing Common Phenotypes Across the Childhood Dementia Disorders: A Cross-sectional Study From Two Australian Centers.

BACKGROUND: Childhood dementias are a group of rare pediatric conditions characterized by progressive neurocognitive decline. Quantifying and characterising phenotypes to identify similarities between specific conditions is critical to inform opportunities to optimize care and advance research. METHODS: This cross-sectional study recruited primary caregivers of children (<18 years) living with a dementia syndrome from neurology and metabolic clinics in Sydney and Adelaide, Australia. Sociodemographic and clinical data were collated. Behavior, eating, sleep, pain, and neurological disability were assessed using validated tools, including Strengths and Difficulties, Child Eating Behaviour, and Children's Sleep Habits questionnaires and visual analog of pain and modified Rankin scales. Data were analyzed with descriptive statistics. RESULTS: Among 45 children with 23 different dementia syndromes, the modified Rankin Scale demonstrated at least moderate neurological disability and functional dependence in 82% (37/45). Families reported delays in receiving an accurate diagnosis following initial symptoms (mean: 1.6 ± 1.4 years, range: 0-5 years). The most prevalent phenotypes included communication, comprehension, or recall difficulties (87%, 39/45); disturbances in sleep (80%, 36/45); appetite changes (74%, 29/39); mobility issues (53%, 24/45); and hyperactive behavior (53%, 21/40). Behavioral problems had a "high" or "very high" impact on everyday family life in 73% (24/33). CONCLUSIONS: Childhood dementia disorders share substantial behavioral, motor, sensory, and socioemotional symptoms, resulting in high care needs, despite their vast heterogeneity in age of onset and progression. Considering their unifying characteristics under one collective term is an opportunity to improve treatment, provide quality care, and accelerate research.

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.