John Christodoulou

Recent research has shed new light on a group of devastating conditions that cause progressive neurocognitive decline beginning in childhood or adolescence. Although pediatric neurologists have traditionally used the term neuroregressive or neurodegenerative to describe these conditions, such terms are nonspecific and employed across a range of neurological conditions, relative to their temporal progress or pathoetiology. Consequently, these conditions are increasingly recognized under the collective term childhood dementia, reflecting their clinical phenotype and drawing a parallel with adult-onset progressive cognitive decline. This terminology shift is raising public awareness and catalyzing systemic changes in research, health care delivery, and community support services. A scoping review published in the journal Brain identified 145 genetic conditions that meet the criteria for childhood dementia,1 whereas the “progressive intellectual and neurological deterioration” study in the United Kingdom, with broader inclusion criteria, identified 220 different disorders.2 Examples include lysosomal disorders such as Sanfilippo syndrome, Niemann-Pick disease type C and neuronal ceroid lipofuscinoses (or Batten disease), some mitochondrial diseases such as Leigh syndrome, and peroxisomal disorders such as X-linked adrenoleukodystrophy. Two-thirds of the cases can be attributed to inborn errors of metabolism.1,3 It was estimated that the overall incidence is around one in 2900 births, with childhood dementia leading to death before adulthood in 70% of individuals, and with a median life expectancy of just 9 years.1 Estimates of disease incidence are limited in low- and middle-income countries. Furthermore, in countries without newborn screening programs for treatable genetic conditions, such as phenylketonuria, and where access to specialist health care is limited, it is expected that there would be a substantial increase in childhood dementia burden.1 Additional disease burden due to preventable causes of childhood dementia such as infectious diseases and nutritional deficiencies is also of concern. To address this, comprehensive public health measures, including newborn screening and vaccination programs, and improved access to nutrition and antenatal care are needed. A systematic review highlighted the immense psychosocial toll childhood dementia takes on parents and caregivers.4 Overwhelming themes of social isolation, economic hardship, psychological distress, and difficulties navigating health care systems emerged, and a desperate lack of integrated, family-centered support services was identified as a key challenge faced by the carers of children with dementia. A cross-sectional study of 45 Australian children with 23 different dementia conditions highlighted the severe neurological disability experienced by these children and identified common areas of need.5 These areas included frequent and intense pain, behavioral and psychological symptoms, and sleep disturbances. Other major concerns were difficulty communicating, appetite changes, mobility problems, seizures, and hearing and vision impairment. All of these issues were compounded by the great delay in achieving an accurate diagnosis. In high-income countries, childhood dementia claims a comparable number of lives as childhood cancer each year.1 In these countries, thanks to medical research and better treatment, death rates from childhood cancer have almost halved in the past 20 years and more than 80% of children with cancer now survive.6-8 In contrast, there has been no notable improvement in survival rates for children with dementia, yet childhood dementia has received a tiny fraction of the research attention,9 funding,10 and public awareness. The disparity in available treatments is stark: whereas the National Institutes of Health National Cancer Institute lists 51 drugs approved by the US Food and Drug Administration for childhood cancer, only seven drugs are approved to treat childhood dementia in the United States. Even more concerning, these drugs are only applicable for ∼10% of diagnosed children, and many children receive their diagnosis too late for the medications to be beneficial. Although approaches to defining the burden of childhood neurocognitive disease are established, including the UK progressive intellectual and neurological deterioration study,2 Australia is the first country in the world to begin considering the collective group of childhood dementia disorders in a system-wide approach, including models of care and support, research funding, and policy. The Childhood Dementia Initiative, founded in 2020, is spearheading this work. This approach focuses on the presentation of childhood dementia—the symptoms and how children and their families are impacted—rather than the biological basis of each of the underlying diseases. Viewing childhood dementia as a collective enables the delivery of solutions with economies of scope and scale focused on the common health issues and social challenges that are faced. The easily understood language of “childhood dementia” also powerfully generates broader community understanding, with a notable increase in the use of the term in recent years by patient organizations, individual families, and the media. In consultations with families, support for using the term childhood dementia was strong.11 Families reported that they thought childhood dementia was the best term to explain what their child's condition was and that this term was the most effective term to communicate with all people involved in their network, including family members, health care professionals, service providers, and community. Improving brain health across the lifespan is emerging as a policy focus globally, and dementia in the elderly is no longer regarded as an inevitable consequence of aging.12,13 Consideration of dementia across the lifespan will encourage researchers focusing on different age groups to collaborate on studying shared mechanisms and biomarkers of disease and the development of precision medicine approaches. Increased awareness and understanding of childhood dementia, and recognition of dementia as a whole of life course disease,14 has already resulted in tangible steps forward including targeted research funding,15 the creation of resources for health professionals,16 and the extension of dementia services to children,17 but there is still much more to be done. In conclusion, the emerging body of evidence surrounding childhood dementia underscores the urgent need for greater awareness and education, earlier diagnosis, increased research, and coordinated action. The collective impact of these rare genetic disorders is very substantial, affecting not only the children diagnosed but also their families and health care systems. The unification of these conditions under the term childhood dementia represents a crucial step toward addressing the fragmentation in care, policy, and research. The next phase includes mobilizing the global clinical and research community to establish and implement a global research and policy agenda. As demonstrated by the progress made in childhood cancer outcomes, a concerted effort can lead to significant improvements in the identification and access to targeted therapies, service delivery, and consequently improved survival rates and quality of life.

KIF1A-associated neurological disorder (KAND) is a genetic condition characterised by motor, cognitive and ophthalmologic features. The speech and language phenotype have not been systematically analysed. Here, we assess speech and language using observer- and clinician-reported outcomes, and performance outcome measures. 44 individuals (25 female) with KAND (median age 7 years, range 1-60 years) participated. Median age at diagnosis was 4 years (range 0.5-58 years). KIF1A variants were missense (41/44 individuals, 93%), intragenic deletion (2/44, 5%) and splice site (1/44, 2%). Age at first words was delayed (>12 months) in 38/44 (86%) individuals. At assessment, 28/44 (64%) combined words into sentences and all of the 20 individuals assessed had dysarthria. Apraxic speech features and phonological impairments occurred in children aged under 8 years. 36/37 (97%) participants had language impairment, with expressive language skills stronger than receptive (p = 0.02) and written (p = 0.03) language on the Vineland Adaptive Behaviour Scales. 7/32 (22%) caregivers reported speech and language regression. Mild to severe intellectual disability occurred in 31/33 (94%) individuals. 22/44 (50%) participants had used augmentative and alternative communication, such as key word sign or speech generating devices. Individuals had average social motivation skills in contrast to moderately impaired social cognition, communication and awareness on the Social Responsiveness Scale (p < 0.05). 16/44 (36%) had epilepsy and 40/44 (91%) had visual impairment, namely nystagmus (16/44, 36%), optic nerve atrophy and strabismus (both 12/44, 27%). Individuals with KAND frequently have speech and language disorders necessitating early and targeted speech and language interventions.

Rett syndrome (RTT) is a rare, X-linked, severe neurodevelopmental disorder, predominantly associated with pathogenic variants in the methyl-CpG-binding protein-2 (MECP2) gene, with an increasing number of atypical RTT or RTT-like individuals having pathogenic variants in other genes, such as cyclin-dependent kinase-like 5 (CDKL5) or forkhead box G1 (FOXG1). However, ~20% of individuals with a clinical diagnosis of RTT remain genetically undiagnosed, highlighting the importance of ongoing genomic and functional studies to expand the genetic spectrum of RTT. We present a female who was born to healthy nonconsanguineous parents and presented with severe intellectual disability, macrocephaly, ataxia, absent speech, and poor eye contact. The affected individual was clinically diagnosed with atypical RTT, but genetic testing showed no pathogenic variants in MECP2, CDKL5, or FOXG1. Singleton whole genome sequencing was conducted, which identified a heterozygous stop-gain variant [NM_001170629.2: c.5017C>T, p.(Arg1673⁣∗)], in the chromodomain-helicase-DNA-binding protein 8 (CHD8) gene. Variant curation revealed its absence in unaffected populations, in silico predictions of pathogenicity, and an existing association with intellectual developmental disorder with autism and macrocephaly (IDDAM) (OMIM #615032). In vitro functional analyses, including Western blots, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and proteomic analyses, demonstrated a significant reduction of the CHD8 transcript and two CHD8 protein isoforms in the proband's skin fibroblasts relative to control fibroblasts. Additionally, proteomic analysis indicated a significant reduction of the MeCP2 protein, indicating a possible molecular link between CHD8 and MeCP2 and thus clinically between IDDAM and RTT. As the affected individual's phenotype is consistent with atypical RTT, our results suggest that CHD8 could be considered in the expanding genetic spectrum of atypical RTT, which may assist the diagnosis of other MECP2-negative RTT individuals.

When investigating whether a variant identified by diagnostic genetic testing is causal for disease, applied genetics professionals evaluate all available evidence to assign a clinical classification. Functional assays of higher and higher throughput are increasingly being generated and, when appropriate, can provide strong functional evidence for or against pathogenicity in variant classification. Despite functional assay data representing unprecedented value for genomic diagnostics, challenges remain around the application of functional evidence in variant curation. To investigate a growing gap articulated in recent international studies, we surveyed genetic diagnostic professionals in Australasia to assess their application of functional evidence in clinical practice. The survey results echo the universal difficulty in evaluating functional evidence but expand on this by indicating that even self-proclaimed expert respondents are not confident to apply functional evidence, mainly due to uncertainty around practice recommendations. Respondents also identified the need for support resources and educational opportunities, and in particular requested expert recommendations and updated practice guidelines to improve translation of experimental data to curation evidence. We then collated a list of 226 functional assays and the evidence strength recommended by 19 ClinGen Variant Curation Expert Panels. Specific assays for more than 45,000 variants were evaluated, but evidence recommendations were generally limited to lower throughput and strength. As an initial step, we provide our collated list of assay evidence as a source of international expert opinion on the evaluation of functional- evidence and conclude that these results highlight an opportunity to develop additional support resources to fully utilize functional evidence in clinical practice.

Methods: Consecutive infants with hypotonia were identified from research and clinical databases across 5 teaching hospitals in United States, Canada, United Kingdom, and Australia. Inclusion criteria included NICU admission and genetic evaluation. Infants with a known explanation for hypotonia were excluded. Data regarding infant characteristics, genetic testing, and diagnoses were collected. The primary outcome was identification of a molecular diagnosis. Impact on care was a secondary outcome. The Fisher exact and Wilcoxon rank-sum tests were used for statistical analysis. Results: We identified 147 infants with unexplained hypotonia. The median gestational age was 39 weeks (interquartile range [IQR] 36-42 weeks), 77 (52%) were female, and the median age was 8 days at the time of evaluation (IQR 2-19 days). Eighty (54%) had hypotonia as the main clinical feature while 67 (46%) had additional multisystem involvement. Seventy-five (51%) underwent rapid ES, 44 (30%) rapid GS, 2 (1%) both ES and GS, and 26 (18%) were admitted before ES or GS became available. Of the 121 infants who underwent ES and/or GS, 72 (60%) had the primary outcome of a molecular diagnosis. In addition, 2 infants with mitochondrial genome variants were diagnosed by mitochondrial GS after negative ES, and one infant needed targeted testing to identify a short tandem repeat expansion missed by GS. The proportion diagnosed by ES and GS was not different between infants with hypotonia as the primary finding (37/56, 66%) and infants with multisystemic symptoms (35/65, 54%, odds ratio [OR] 1.7, CI 0.8-3.7, p value = 0.20). Testing was more likely to have an impact on care for infants receiving a genetic diagnosis (57/66 vs 14/33, OR 8.4, CI 2.9-26.1, p = 1.0E-05). Conclusions: Rapid ES and GS provided a molecular diagnosis for most of the infants with unexplained hypotonia who underwent testing. Further studies are needed to assess the generalizability of these findings as increased access to genetic testing becomes available. Methods: This study provides Class IV evidence that in unexplained neonatal hypotonia, rapid ES or GS adds diagnostic specificity.