No abstract

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disabilities with various etiologies, but with a heritability estimate of more than 90%. Although the strong correlation between autism and genetic factors has been long established, the exact genetic background of ASD remains unclear. A number of genetic syndromes manifest ASD at higher than expected frequencies compared to the general population. These syndromes account for more than 10% of all ASD cases and include tuberous sclerosis, fragile X, Down, neurofibromatosis, Angelman, Prader-Willi, Williams, Duchenne, etc. Clinicians are increasingly required to recognize genetic disorders in individuals with ASD, in terms of providing proper care and prognosis to the patient, as well as genetic counseling to the family. Vice versa, it is equally essential to identify ASD in patients with genetic syndromes, in order to ensure correct management and appropriate educational placement. During investigation of genetic syndromes, a number of issues emerge: impact of intellectual disability in ASD diagnoses, identification of autistic subphenotypes and differences from idiopathic autism, validity of assessment tools designed for idiopathic autism, possible mechanisms for the association with ASD, etc. Findings from the study of genetic syndromes are incorporated into the ongoing research on autism etiology and pathogenesis; different syndromes converge upon common biological backgrounds (such as disrupted molecular pathways and brain circuitries), which probably account for their comorbidity with autism. This review paper critically examines the prevalence and characteristics of the main genetic syndromes, as well as the possible mechanisms for their association with ASD.

Autism is a severe childhood disorder already presenting in the first 3 years of life and, therefore, strongly correlated with neurodevelopmental alterations in prenatal, as well as postnatal period. Neurotransmitters hold a pivotal role in development by providing the stimulation needed for synapses and neuronal networks to be formed during the critical period of neuroplasticity. Aberrations of the serotonergic system modify key processes in the developing brain and are strongly implicated in the pathophysiology of developmental disorders. Evidence for the role of serotonin in autism emerges from neuropathological, imaging and genetic studies. Due to its developmental arrest, autism requires early intervention that would, among others, target the disrupted serotonergic system and utilize brain plasticity to elicit clinically important brain changes in children.

Background and AimsKIF1A-related disorders (KRD) were first described in 2011 and the phenotypic spectrum has subsequently expanded to encompass a range of central and peripheral nervous system involvement. Here we present a case series demonstrating the range of clinical, neurophysiological and radiological features which may occur in childhood-onset KRD. MethodsWe report on all the children and young people seen at a single large tertiary centre. Data was collected through a retrospective case-notes review. Results12 individuals from 10 families were identified. Eight different mutations were present, including four novel mutations. Two patients displayed a very severe phenotype including congenital contractures, severe spasticity and/or dystonia, dysautonomia, severe sensorimotor polyneuropathy and optic atrophy, significant white matter changes on brain MRI, respiratory insufficiency, and complete lack of neurodevelopmental progress. The remaining 10 patients represented a spectrum of severity with common features including a movement disorder with spasticity and/or dystonia, subtle features of dysautonomia, sensory axonal neuropathy, varying degrees of optic atrophy and of learning and/or behavioural difficulties, and subtle or absent -but sometimes progressive -changes in white matter on MRI. Epilepsy was common among the more severely-affected children. InterpretationThis case series demonstrates that KRD comprise a range of neurological disorders, with both the milder and the more severe forms combining central and peripheral (including autonomic) nervous system deficits.

Rare de novo mutations represent a significant cause of idiopathic developmental delay (DD). The use of next-generation sequencing (NGS) has boosted the identification of de novo mutations in an increasing number of novel genes. Here we present 3 unrelated children with de novo loss-of-function (LoF) mutations in QRICH1, diagnosed through trio-based exome sequencing. QRICH1 encodes the glutamine-rich protein 1, which contains 1 caspase activation recruitment domain and is likely to be involved in apoptosis and inflammation. All 3 children had speech delay, learning difficulties, a prominent nose and a thin upper lip. In addition, 2 of them had mildly raised creatine kinase (CK) and 1 of them had autism. Despite their small number, the patients had a relatively consistent pattern of clinical features suggesting the presence of a QRICH1-associated phenotype. LoF mutations in QRICH1 are suggested as a novel cause of DD.