Hard to swallow: Developmental biological insights into pediatric dysphagia

Abstract

Pediatric dysphagia—feeding and swallowing difficulties that begin at birth, last throughout childhood, and continue into maturity—is one of the most common, least understood complications in children with developmental disorders. We argue that a major cause of pediatric dysphagia is altered hindbrain patterning during pre-natal development. Such changes can compromise craniofacial structures including oropharyngeal muscles and skeletal elements as well as motor and sensory circuits necessary for normal feeding and swallowing. Animal models of developmental disorders that include pediatric dysphagia in their phenotypic spectrum can provide mechanistic insight into pathogenesis of feeding and swallowing difficulties. A fairly common human genetic developmental disorder, DiGeorge/22q11.2 Deletion Syndrome (22q11DS) includes a substantial incidence of pediatric dysphagia in its phenotypic spectrum. Infant mice carrying a parallel deletion to 22q11DS patients have feeding and swallowing difficulties. Altered hindbrain patterning, neural crest migration, craniofacial malformations, and changes in cranial nerve growth prefigure these difficulties. Thus, in addition to craniofacial and pharyngeal anomalies that arise independently of altered neural development, pediatric dysphagia may reflect disrupted hindbrain patterning and its impact on neural circuit development critical for feeding and swallowing. The mechanisms that disrupt hindbrain patterning and circuitry may provide a foundation to develop novel therapeutic approaches for improved clinical management of pediatric dysphagia.

Altered neurobiological function of brainstem hypoglossal neurons in DiGeorge/22q11.2 Deletion Syndrome

“…Dysphagia, difficulties with feeding and swallowing, is a major complication in infants with a broad range of neurodevelopmental disorders (LaMantia et al , 2016). There is a substantially increased frequency of perinatal and pediatric dysphagia associated with DiGeorge/22q11.2 Deletion Syndrome (22q11DS), a common genetic microdeletion syndrome that includes autism, attention deficit/hyperactivity disorder, and schizophrenia.…”

“…There is a substantially increased frequency of perinatal and pediatric dysphagia associated with DiGeorge/22q11.2 Deletion Syndrome (22q11DS), a common genetic microdeletion syndrome that includes autism, attention deficit/hyperactivity disorder, and schizophrenia. Disrupted feeding and swallowing from birth onward significantly compromises nutritional status, impairs appropriate weight gain, and can lead to life threatening aspiration-based infections of the nasal sinuses, middle ears, and lung in 22q11DS (LaMantia et al , 2016). Unfortunately, however, there are few, if any, therapeutic approaches to alleviate swallowing difficulties and the accompanying significant health problems.…”

“…Infant mice with a heterozygous deletion of 28 contiguous genes, orthologous to the minimal critical deletion in human 22q11DS, apparently have feeding and swallowing difficulties. These include reduced weight compared to age and sex matched wild type (WT) littermates from shortly after birth through early maturity, delayed milk emptying from mouth to esophagus, and aspiration of milk into the nasal pharynx and lungs (LaMantia et al , 2016). Thus, we compared the electrophysiological properties, synaptic neurotransmission and activation of postsynaptic receptors in hypoglossal motor neurons in LgDel and WT mouse pups to determine whether compromised patterning and early cranial nerve development is reflected in altered excitability in hypoglossal motor neurons or neurotransmission to these neurons.…”

Wired for eating: how is an active feeding circuitry established in the postnatal brain?

“…Postnatal feeding difficulties, such as dysphagia, are present in 80% of infants with neurodevelopmental disorders [55••]. They may reflect a disruption in the development of neural circuits critical for feeding.…”

The strengths of the genetic approach to understanding neural systems development and function: Ray Guillery's synthesis

“…Joined by our collaborator Larry Rothblat, we assessed how diminished 22q11 gene dosage compromises cortico‐cortical connectivity via layer 2/3 cortical projection neurons and interneurons, and how these changes contribute to disrupted cognitive behaviors in LgDel mice (Meechan et al., ; Meechan, Tucker, Maynard, & LaMantia, ; Meechan, Rutz et al., 2015; Paronett et al., ). In addition, with Sally Moody and David Mendelowitz, we characterized development and function of cranial sensory and brainstem motor circuits for feeding and swallowing (Karpinski et al., ; LaMantia et al., ; Wang, Bryan, LaMantia, & Mendelowitz, ). We related a 22q11 deletion‐dependent disruption of RA‐mediated hindbrain patterning (Karpinski et al., ; LaMantia et al., ; Figure , bottom panel ) to pediatric dysphagia—feeding and swallowing difficulty—that complicates early life for children with 22q11.2 DS (Eicher et al., ), thus establishing the LgDel mouse as the first genetically defined animal model for perinatal dysphagia in a neurodevelopmental disorder (reviewed by LaMantia et al., ).…”