Neuroanatomy of holoprosencephaly as predictor of function: beyond the face predicting the brain.

BACKGROUND: Despite advances in neuroimaging and molecular genetics of holoprosencephaly (HPE), the clinical spectrum of HPE has remained inadequately described. OBJECTIVE: To better characterize the clinical features of HPE and identify specific neuroanatomic abnormalities that may be useful predictors of neurodevelopmental function. METHODS: The authors evaluated 68 children with HPE in a multicenter, prospective study. Neuroimaging studies were assessed for the grade of HPE (lobar, semilobar, and alobar), the degree of nonseparation of the deep gray nuclei, and presence of dorsal cyst or cortical malformation. RESULTS: In general, the severity of clinical problems and neurologic dysfunctions correlated with the degree of hemispheric nonseparation (grade of HPE). Nearly three-quarters of the patients had endocrinopathies, with all having at least diabetes insipidus. The severity of endocrine abnormalities correlated with the degree of hypothalamic nonseparation (p = 0.029). Seizures occurred in approximately half of the children with HPE. The presence of cortical malformations was associated with difficult-to-control seizures. The presence and degree of dystonia correlated with the degree of nonseparation of the caudate and lentiform nuclei and the grade of HPE (p < 0.05). Hypotonia correlated with the grade of HPE (p < 0.05). Mobility, upper extremity function, and language correlated with the degree of nonseparation of the caudate, lentiform and thalamic nuclei, and grade of HPE (p < 0.01). CONCLUSIONS: Patients with HPE manifest a wide spectrum of clinical problems and neurologic dysfunction. The nature and severity of many of these problems can be predicted by specific neuroanatomic abnormalities found in HPE.

Holoprosencephaly: recent advances and new insights.

Holoprosencephaly is a relatively common brain malformation occurring in 5-12/100,000 live births. The astonishing growth in molecular genetic medicine has provided the field of developmental nervous system malformations with new perspectives and tools for unraveling its mysteries and offering better information for clinicians and families. This is particularly evident in the group of complex midline malformations known as holoprosencephaly. Although new molecular findings have shed light on some of the causes and manifestations of this malformation, there remains a need to build on the existing clinical knowledge so that we may develop more effective treatments and improve the quality of life of these patients.

Cell type-specific secretion of parathyroid hormone-related protein via the regulated versus the constitutive secretory pathway.

Parathyroid hormone-related protein (PTHrP) is endoproteolytically processed to yield a family of mature secretory forms. These include an amino-terminal, a mid-region, and a carboxyl-terminal form. Prior studies suggested that the mid-region form is secreted via the regulated secretory pathway, whereas the amino- and carboxyl-terminal forms are secreted via the constitutive pathway. Further, PTHrP is unusual in that it is produced under normal circumstances by neuroendocrine cell types as well as by prototypical constitutively secreting cell types. The potential for cell-specific secretory pathway use by PTHrP has not been explored. Using immunohistochemical and perifusion techniques, we demonstrate that all three PTHrP daughter peptides are secreted via the regulated pathway in neuroendocrine cells. In contrast, all three daughter peptides are secreted in a constitutive fashion by non-neuroendocrine cells. Thus, the secretion of PTHrP is unique in that it appears to be cell-specific. When it is expressed in neuroendocrine cells that contain the regulated pathway, it is secreted in a regulated fashion; when it is expressed in non-neuroendocrine cells, it defaults to the constitutive pathway. This phenomenon has not previously been described for a polypeptide hormone in naturally occurring cells.