Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital central hypoventilation syndrome (CCHS) is a rare disorder of unknown etiology, characterized by failure of the autonomic control of respiration. The primary defect is believed to involve central respiratory control; however, no specific lesion has been identified. We report two cases of CCHS (one female, 3 mo of age and one male 2 yr of age) in which there was detailed examination of the neural, muscular, and chemoreceptor components of respiratory control. Although no specific abnormalities were identified in the central nervous system (CNS) or muscles of respiration, striking changes were observed in arterial chemoreceptors, carotid bodies (CB), and airway chemoreceptors, neuroepithelial bodies (NEB). In both cases, CB were small (< 50% of control), with a marked decrease in the number of glomus cells identified by immunostaining for tyrosine hydroxylase and serotonin. Ultrastructural analysis of glomus cells in Case 1 showed a marked decrease in the frequency of dense core vesicles (< 20% of control), the storage site of amine and peptide neurotransmitters. Immunostaining for S100 protein, a marker of sustentacular or Type II cells, was increased up to twofold compared with controls. In the lung, the frequency and size of NEB immunostained for bombesin was increased twofold in both cases, suggesting compensatory hyperplasia of airway chemoreceptors. Since intact peripheral chemoreceptors are essential for respiratory control, especially the response to hypoxia, abnormalities in CB and NEB may contribute to the pathophysiology of CCHS and related conditions such as sudden infant death syndrome (SIDS).
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PMID:Peripheral chemoreceptors in congenital central hypoventilation syndrome. 900 36

Congenital central hypoventilation syndrome (CCHS, Ondine's curse) is a rare disorder of the chemical control of breathing. It is frequently associated with a broad spectrum of dysautonomic symptoms, suggesting the involvement of genes widely expressed in the autonomic nervous system. In particular, the HASH-1-PHOX2A-PHOX2B developmental cascade was proposed as a candidate pathway because it controls the development of neurons with a definitive or transient noradrenergic phenotype, upstream from the RET receptor tyrosine kinase and tyrosine hydroxylase. We recently showed that PHOX2B is the major CCHS locus, whose mutation accounts for 60% of cases. We also studied the proneural HASH-1 gene and identified a heterozygous nucleotide substitution in three CCHS patients. To analyze the functional consequences of HASH-1 mutations, we developed an in vitro model of noradrenergic differentiation in neuronal progenitors derived from the mouse vagal neural crest, reproducing in vitro the HASH-PHOX-RET pathway. All HASH-1 mutant alleles impaired noradrenergic neuronal development, when overexpressed from adenoviral constructs. Thus, HASH-1 mutations may contribute to the CCHS phenotype in rare cases, consistent with the view that the abnormal chemical control of breathing observed in CCHS patients is due to the impairment of noradrenergic neurons during early steps of brainstem development.
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PMID:Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse). 1453 29

Haddad syndrome (congenital central hypoventilation syndrome and Hirschsprung's disease) is a rare disorder for which in-depth neuropathologic analysis is lacking. We report the brain findings in a full-term male infant with Haddad syndrome who died at 27 days of life. Bilateral hypoplasia of the superior temporal lobe and gyral anomalies in the frontal cortex were present. Immunohistochemistry with an antibody to tyrosine hydroxylase (noradrenaline synthesis) demonstrated hypoplasia of the locus coeruleus (implicated in chemoreception) and A5 region. Other findings included delayed maturation of the arcuate nucleus (putative human homologue of ventral medullary neurons in animals critical for chemoreception) and aberrant fascicles in the nucleus of the solitary tract. Efforts to determine the putative gene mutation were unsuccessful. This study implicates novel brain findings in Haddad syndrome mimicking those in murine Phox2b null mutants. This case suggests that abnormalities occur in CCHS in a network of sites critical to chemoreception.
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PMID:Novel neuropathologic findings in the Haddad syndrome. 1984 31