Loss of skills and onset patterns in neurodevelopmental disorders: Understanding the neurobiological mechanisms

Thurm, Audrey; Powell, Elizabeth M.; Neul, Jeffrey L.; Wagner, Ann E.; Zwaigenbaum, Lonnie

doi:10.1002/aur.1903

Cited by 27 publications

(25 citation statements)

References 116 publications

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“…Regression has long been recognized in neurodevelopmental disorders such as ASD [37], but the triggers and mechanisms are not well understood, and the literature focuses largely on early childhood regression, especially as it relates to Rett syndrome [37][38][39][40]. Significant cognitive and behavioral regression has been documented in PMS [5,6,9,15,16,18,41].…”

Section: Discussionmentioning

confidence: 99%

Psychiatric illness and regression in individuals with Phelan-McDermid syndrome

Kohlenberg

Trelles

McLarney

et al. 2020

J Neurodevelop Disord

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Background: Phelan-McDermid syndrome (PMS) is a genetic condition characterized by intellectual disability, speech and language deficits, hypotonia, autism spectrum disorder, and epilepsy. PMS is caused by 22q13.33 deletions or mutations affecting SHANK3, which codes for a critical scaffolding protein in excitatory synapses. SHANK3 variants are also known to be associated with an increased risk for regression, as well as for psychiatric disorders, including bipolar disorder and catatonia. This study aimed to further describe these phenomena in PMS and to explore any relationship between psychiatric illness and regression after early childhood. Methods: Thirty-eight people with PMS were recruited to this study through the Phelan-McDermid Syndrome Foundation based on caregiver report of distinct development of psychiatric symptoms. Caregivers completed a clinician-administered semi-structured interview focused on eliciting psychiatric symptomatology. Data from the PMS International Registry were used to confirm genetic diagnoses of participants and to provide a larger sample for comparison. Results: The mean age of the 38 participants was 24.7 years (range = 13 to 50; SD = 10.06). Females (31 of 38 cases; 82%) and sequence variants (15 of 38 cases; 39%) were over-represented in this sample, compared to base rates in the PMS International Registry. Onset of psychiatric symptoms occurred at a mean age of 15.4 years (range = 7 to 32), with presentations marked by prominent disturbances of mood. Enduring substantial loss of functional skills after onset of psychiatric changes was seen in 25 cases (66%). Symptomst indicative of catatonia occurred in 20 cases (53%). Triggers included infections, changes in hormonal status, and stressful life events. Conclusions: This study confirms that individuals with PMS are at risk of developing severe neuropsychiatric illness in adolescence or early adulthood, including bipolar disorder, catatonia, and lasting regression of skills. These findings should increase the awareness of these phenotypes and lead to earlier diagnosis and the implementation of appropriate interventions. Our findings also highlight the importance of genetic testing in the work-up of individuals with intellectual disability and acute psychiatric illness or regression. Future research is needed to clarify the prevalence and nature of psychiatric disorders and regression among larger unbiased samples of individuals with PMS.

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Section: Discussionmentioning

confidence: 99%

Psychiatric illness and regression in individuals with Phelan-McDermid syndrome

Kohlenberg

Trelles

McLarney

et al. 2020

J Neurodevelop Disord

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“…For example, loss of cognitive, social communication, and play skills following infantile spasms in children with TSC [Humphrey et al, ] suggests that subtypes of epilepsy have either a causal role or act as a marker of other neural abnormalities. Neuroimaging or neurogenetic studies in children with specific disorders such as TSC, CDD, or Rett Syndrome [Gupta et al, ; Thurm et al, ] might reveal genetic and neural correlates that could suggest possible causal mechanisms for regression in idiopathic ASD.…”

Section: Challenges For Future Researchmentioning

confidence: 99%

“…Autism with regression describes a pattern whereby children lose skills that they have previously acquired. Recently, there has been renewed interest in this group of children [Thurm, Powell, Neul, Wagner, & Zwaigenbaum, ]. The recognition of marked heterogeneity in ASD has led to the search for subgroups in which determining etiological factors might be more straightforward [Constantino & Charman, ].…”

Section: Introductionmentioning

confidence: 99%

Regression in autism spectrum disorder: Reconciling findings from retrospective and prospective research

et al. 2018

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The way in which the behavioral manifestations of autism spectrum disorder (ASD) emerge in infancy is variable. Regression-loss of previously acquired skills-occurs in a subset of children. However, the etiology and significance of regression remains unclear. Until recently, investigation of regression relied on retrospective report by parents or examination of home videos from early in life. However, home videos and retrospective report of the nature and timing of regression, and association with factors such as illness or immunization, is potentially subject to bias. The advent of prospective studies of infant siblings at familial high-risk of ASD has the potential to document regression as it occurs. Recent research has suggested that subtle loss of skills occurs in a larger proportion of children with ASD than previously assumed; however, there are few reports of clear-cut regressions, such as that involving dramatic loss of language and other established skills, in the prospective literature. This could be because of the following: clear-cut regression occurs less commonly than parent report suggests, study design limits the potential to detect regression, or there are differences between multiplex and simplex families in the rate of de novo genetic mutations and therefore regression risk. This review will bring together literature from retrospective and prospective research and attempt to reconcile diverging findings, with a specific focus on methodological issues. Changing conceptualizations of regression will be discussed, as well as etiological factors that may be associated with regression. The main challenges that need to be addressed to measure regression in prospective studies will be set out.Lay Summary: Regression-a loss of previously established skills-occurs in a subset of children with ASD. Parental recall is not always accurate but studying younger siblings of children with ASD, 10-20% of whom will develop ASD, should make it possible to measure regression as it occurs. Clear-cut regression, like loss of language, has not often been reported in infant sibling studies, but recent research suggests that gradual loss of social engagement might be more common. This review looks at the evidence for regression from infant sibling studies and asks how study design affects the likelihood of capturing regression.

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“…About 32% of children with ASD undergo an enigmatic developmental regression (DR) during the second year of life 17,18 . Following apparently normal development, DR involves loss of the child’s previously acquired milestones followed by the emergence of ASD symptoms 17,19–23 . DR most often appears clinically after childhood illness, often with fever 24,25 .…”

Section: Introductionmentioning

confidence: 99%

Developmental regression and mitochondrial function in children with autism

Singh

Diggins

et al. 2020

Ann Clin Transl Neurol

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Background: Developmental regression (DR) occurs in about one-third of children with Autism Spectrum Disorder (ASD) yet it is poorly understood. Current evidence suggests that mitochondrial function in not normal in many children with ASD. However, the relationship between mitochondrial function and DR has not been well-studied in ASD. Methods: This cross-sectional study of 32 children, 2 to 8 years old with ASD, with (n = 11) and without (n = 12) DR, and non-ASD controls (n = 9) compared mitochondrial respiration and mtDNA damage and copy number between groups and their relation to standardized measures of ASD severity. Results: Individuals with ASD demonstrated lower ND1, ND4, and CYTB copy number (Ps < 0.01) as compared to controls. Children with ASD and DR had higher maximal oxygen consumption rate (Ps < 0.02), maximal respiratory capacity (P < 0.05), and reserve capacity (P = 0.01) than those with ASD without DR. Coupling Efficiency and Maximal Respiratory Capacity were associated with disruptive behaviors but these relationships were different for those with and without DR. Higher ND1 copy number was associated with better behavior. Conclusions: This study suggests that individuals with ASD and DR may represent a unique metabolic endophenotype with distinct abnormalities in respiratory function that may put their mitochondria in a state of vulnerability. This may allow physiological stress to trigger mitochondrial decompensation as is seen clinically as DR. Since mitochondrial function was found to be related to ASD symptoms, the mitochondria could be a potential target for novel therapeutics. Additionally, identifying those with vulnerable mitochondrial before DR could result in prevention of ASD.

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Loss of skills and onset patterns in neurodevelopmental disorders: Understanding the neurobiological mechanisms

Cited by 27 publications

References 116 publications

Psychiatric illness and regression in individuals with Phelan-McDermid syndrome

Psychiatric illness and regression in individuals with Phelan-McDermid syndrome

Regression in autism spectrum disorder: Reconciling findings from retrospective and prospective research

Developmental regression and mitochondrial function in children with autism

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