Two Thai families with Norrie disease (ND): Association of two novel missense mutations with severe ND phenotype, seizures, and a manifesting carrier

Abstract

We describe two Thai families with Norrie disease (ND) in three generations, including 10 affected males and one manifesting female. All affected males in each family had severely defective eye development with complete loss of vision. In addition, three male patients (one from family 1 and two from family 2) suffered from epilepsy, and one female carrier from one family manifested blindness with phthisis bulbi in her right eye. Mutation analysis of the ND gene (NDP) revealed two different novel missense mutations (L16P and S75P) that co-segregated with ND in each family, suggesting that the newly appearing proline at codon 16 or codon 75 alters the conformation of the ND protein and contributes to the severe phenotype of ND in each family. Other studies suggest that epileptic seizures or growth retardation that is associated with ND is the consequence of loss of contiguous genes, because most such patients had deletions extending beyond the Norrie locus. Our finding that the three affected males in the two families with the missense mutations had epilepsy does not support a contiguous gene effect, but favors the pleiotropism of NDP, at least as far as the epileptic manifestation is concerned. The unilateral blindness in the female carrier may have been due to non-random X-inactivation.

Deletion of MAOA and MAOB in a male patient causes severe developmental delay, intermittent hypotonia and stereotypical hand movements

“…23,24 Although seizures are uncommon in classical ND, there are examples of seizures in cases with NDP point mutations. 25,26 The occurrence of seizures in the family described here further supports a role for the disruption of several genes in this region being sufficient to cause epilepsy.…”

A novel missense mutation in the NDP gene in a child with Norrie disease and severe neurological involvement including infantile spasms

“…So far, there has only been one additional study that described two patients with a different type of epilepsy with a later onset. These patients had missense mutations at codons 16 and 75 at the NDP gene [Yamada et al, 2001].…”

“…Although Chen et al and Meindl et al have previously made the observation that mutations in the C‐terminal portion of the gene product appear to result in a less severe ND presentation, genotype–phenotype correlations were not evident due to the limited clinical data available. However, cases with large submicroscopic deletions were associated with a more severe neurologic syndrome [Bleeker‐Wagemakers et al, 1988; Chen et al, 1993, 1995; Schuback et al, 1995; Yamada et al, 2001]. Recently, Riveiro‐Alvarez et al described genotype–phenotype variation in relation to different mutations of the NDP gene and ophthalmologic findings in Spanish patients with ND or X‐linked familial exudative vitreoretinopathy (FEVR).…”

“…His clinical presentation includes blindness, epileptic seizures, hypotonia, and profound mental retardation. Although seizures have been rarely described in ND patients [Schuback et al, 1995; Yamada et al, 2001], to the best of our knowledge, such severe neurological involvement and hypsarrhythmia that were demonstrated in the EEG have not been previously reported in ND patients.…”

Molecular and clinical studies of X-linked deafness among Pakistani families

“…The incomplete penetrance of the clinical symptoms in the obligate carrier females has been documented in a few studies. 33–35 This unusual phenotype in a female has been attributed to Lyonization or an adverse effect of the mutant copy of the protein on the retina during development. 33–35 In family PKDF740 there were no obvious signs of mental retardation although this phenotype was not methodically pursued at the time family members were ascertained.…”