Biallelic mutations in human DCC cause developmental split-brain syndrome.

Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.

Endocrine disorders associated with holoprosencephaly.

OBJECTIVE: To investigate the incidence of endocrinopathies in holoprosencephaly (HPE) and correlate the severity of the endocrinopathies with the neuroanatomic abnormalities. STUDY DESIGN: We reviewed the histories and medical records of 117 children with HPE for endocrinopathies and related treatments. Neuroimaging studies were graded for severity of HPE, hypothalamus non-separation, and pituitary abnormalities. RESULTS: Diabetes insipidus (DI) occurred in 70% of patients with classic HPE. The severity of the DI correlated with the grade of HPE and hypothalamic non-separation (p < 0.0001). Anterior pituitary dysfunctions were much less common. Hypothyroidism was identified in 11% of patients, hypocorticism in 7%, and growth hormone deficiency in 5%. Only one patient with middle interhemispheric variant of holoprosencephaly (MIH) had any of these disorders. CONCLUSIONS: Patients with HPE have a high incidence of DI that may be related to the failure of cleavage of hypothalamic nuclei. Anterior pituitary dysfunctions are much less common than DI.

Electroencephalography in holoprosencephaly: findings in children without epilepsy.

OBJECTIVE: To evaluate the electroencephalographic characteristics of patients with holoprosencephaly (HPE) without epilepsy. METHODS: We evaluated the electroencephalograms (EEGs) of 18 children with HPE who lacked a history of seizures. Neuroimaging studies were assessed for severity of HPE and thalamic non-separation and the presence of dorsal cysts and cortical malformations. RESULTS: Hypersynchronous theta activity occurred in 50 and 60% of EEGs during wakefulness or drowsiness/sleep, respectively, and correlated with the grade of thalamic non-separation (p<0.05). Hypersynchronous beta activity during sleep occurred in 41% of EEGs. Posterior amplitude attenuation occurred in 33% of EEGs and correlated with the presence of a dorsal cyst (p

The middle interhemispheric variant of holoprosencephaly.

BACKGROUND AND PURPOSE: The middle interhemispheric variant of holoprosencephaly (MIH) is a rare malformation in which the cerebral hemispheres fail to divide in the posterior frontal and parietal regions. We herein describe the structural abnormalities of the brain in a large group of patients with MIH, compare these features with those of classic holoprosencephaly (HPE), and propose a developmental mechanism, based on current knowledge of developmental neurogenetics, by which MIH develops. METHODS: Brain images obtained in 21 patients with MIH (MR images in 16 patients and high-quality X-ray CT scans in five patients) were retrospectively reviewed to classify cerebral abnormalities. The cerebral parenchyma, hypothalami, caudate nuclei, lentiform nuclei, thalami, and mesencephalon were examined for the degree of midline separation (cleavage) of the two hemispheres. The orbits, olfactory apparati, and presence or absence of a dorsal cyst were also assessed. RESULTS: In all patients, by definition, midportions of the cerebral hemispheres were continuous across the midline, with an intervening interhemispheric fissure. The sylvian fissures were abnormally connected across the midline over the vertex in 18 (86%) of 21 patients. Two patients had relatively normal-appearing sylvian fissures; one had unilateral absence of a sylvian fissure owing to substantial subcortical heterotopia. Heterotopic gray matter or dysplastic cerebral cortex was also seen in 18 (86%) of 21 patients. MIH differed from classic HPE as follows. 1) In all subjects, the midline third ventricle separated the hypothalamus and lentiform nuclei. 2) The caudate nuclei were separated by the cerebral ventricles in 17 (89%) of the 19 [corrected] patients in whom they could be assessed. 3) The most commonly affected basal nucleus was the thalamus (non-cleavage in seven [33%] of 21 cases, abnormal alignment in 1 [5%]). 4) Three (18%) of the 17 [corrected] patients in whom the mesencephalon could be assessed showed some degree of mesencephalic non-cleavage. 5) No patients had hypotelorism (four had hypertelorism, the remainder manifested normal intraocular distances). Dorsal cysts were present in five (25%) of the 20 patients in whom they could be assessed (dorsal cysts could not be assessed after shunt surgery), and as in classic HPE, were associated with severe thalamic non-cleavage in three of these five patients. CONCLUSION: MIH appears to cause non-cleavage of midline structures in a completely different pattern than does classic HPE. In MIH, impaired induction or expression of genetic factors appears to influence the embryonic roof plate, whereas in classic HPE, induction or expression of the embryonic floor plate seems to be affected.