Periventricular Nodular Heterotopia 7

A number sign (#) is used with this entry because of evidence that periventricular nodular heterotopia-7 (PVNH7) is caused by heterozygous mutation in the NEDD4L gene (606384) on chromosome 18q21.

Description

Periventricular nodular heterotopia-7 is a neurologic disorder characterized by abnormal neuronal migration during brain development resulting in delayed psychomotor development and intellectual disability; some patients may develop seizures. Other features include cleft palate and 2-3 toe syndactyly (summary by Broix et al., 2016).

For a phenotypic description and a discussion of genetic heterogeneity of periventricular heterotopia, see 300049.

Clinical Features

Broix et al. (2016) reported 6 unrelated children with delayed psychomotor development apparent since infancy, intellectual disability, and poor or absent speech. One patient had a similarly affected sib. Most patients had truncal hypotonia, and 1 patient was unable to sit or walk at age 6 years. Five patients had cleft palate, 1 had a bifid uvula, and all but 1 had 2-3 toe syndactyly. Four patients had seizures, including 2 with onset at 4 to 5 months of age. Brain imaging showed periventricular nodular heterotopia in all patients; 1 patient also had frontal cortical dysplasia, another had polymicrogyria, and 2 had a dysmorphic corpus callosum. Some patients had inconsistent dysmorphic facial features, such as micrognathia, deep-set eyes, and small nose. Additional variable features found in 1 or 2 patients included hearing impairment, optic atrophy, strabismus, myopia, cryptorchidism, and contractures.

Molecular Genetics

In 6 probands with PVNH7, Broix et al. (2016) identified de novo heterozygous missense mutations in the NEDD4L gene (606384.0001-606384.0004). The mutations were found by whole-exome sequencing or by direct screening of the NEDD4L gene in a cohort of patients with a similar phenotype. One of the patients had a similarly affected sib who also carried the mutation; their mother was found to be somatic mosaic for the mutation. Cellular transfection of the mutations showed that they resulted in unstable proteins that underwent proteasomal degradation, although ubiquitination activity was preserved for at least 1 mutation studied. In utero electroporation of 2 of the mutations and overexpression of wildtype NEDD4L into embryonic mouse brains resulted in an arrest of neuronal cells within the ventricular and periventricular zone, depletion of neurons in the cortical plate, and other abnormal neuronal distribution patterns. Further investigations showed differential disruption of certain signaling pathways: excess wildtype NEDD4L led to disruption of DAB1 (603448) and mTOR (601231) signaling pathways, while expression of the mutations was associated with deregulation of mTOR, AKT (164730), and SMAD2/3 (601366/603109) activities. Broix et al. (2016) hypothesized that the mutations, all of which occurred in the HECT domain, resulted in conformational changes and constitutive activation of the catalytic function of NEDD4L, which could trigger both autoubiquitination and degradation of the mutant proteins, as well as aberrant ubiquitination of other NEDD4L substrates.