Ana Rodríguez-Muñoz1, Gema García-García1,2, Francisco Menor3, José M Millán1,2, Miguel Tomás-Vila4, Teresa Jaijo1,2,5. 1. Grupo de Investigación en Biomedicina Molecular, Celular y Genómica, Instituto de Investigación Sanitaria La Fe, Valencia, Spain. 2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain. 3. Radiología Infantil, Hospital Universitari i Politecnic La Fe, Valencia, Spain. 4. Neuropediatría, Hospital Universitari i Politecnic La Fe, Valencia, Spain. 5. Unidad de Genética y Diagnóstico Prenatal, Hospital Universitari i Politecnic La Fe, Valencia, Spain.
Abstract
BACKGROUND: Norrie disease (ND) is a rare X-linked disorder characterized by bilateral congenital blindness. ND is caused by a mutation in the Norrie disease pseudoglioma (NDP) gene, which encodes a 133-amino acid protein called norrin. Intragenic deletions including NDP and adjacent genes have been identified in ND patients with a more severe neurologic phenotype. We report the biochemical, molecular, clinical and radiological features of two unrelated affected males with a deletion including NDP and MAO genes. METHODS: Biochemical and genetic analyses were performed to understand the atypical phenotype and radiological findings. Biogenic amines in cerebrospinal fluid (CSF) were measured by high-performance liquid chromatography. The coding exons of NDP gene were amplified by polymerase chain reaction. Multiplex ligation-dependent probe amplification and chromosomal microarray were carried out on both affected males. Computed tomography and magnetic resonance imaging were performed on the two patients. RESULTS: In one patient, the serotonin and catecholamine metabolite levels in CSF were virtually undetectable. In both patients, genetic studies revealed microdeletions in the Xp11.3 region, involving the NDP, MAOA and MAOB genes. Radiological examination demonstrated brain and cerebellar atrophy. CONCLUSIONS: We suggest that alterations caused by MAO deficit may remain during the first years of life. Clinical phenotype, biochemical findings and neuroimaging can guide the genetic study in patients with atypical ND and help us to a better understanding of this disease.
BACKGROUND:Norrie disease (ND) is a rare X-linked disorder characterized by bilateral congenital blindness. ND is caused by a mutation in the Norrie disease pseudoglioma (NDP) gene, which encodes a 133-amino acid protein called norrin. Intragenic deletions including NDP and adjacent genes have been identified in NDpatients with a more severe neurologic phenotype. We report the biochemical, molecular, clinical and radiological features of two unrelated affected males with a deletion including NDP and MAO genes. METHODS: Biochemical and genetic analyses were performed to understand the atypical phenotype and radiological findings. Biogenic amines in cerebrospinal fluid (CSF) were measured by high-performance liquid chromatography. The coding exons of NDP gene were amplified by polymerase chain reaction. Multiplex ligation-dependent probe amplification and chromosomal microarray were carried out on both affected males. Computed tomography and magnetic resonance imaging were performed on the two patients. RESULTS: In one patient, the serotonin and catecholamine metabolite levels in CSF were virtually undetectable. In both patients, genetic studies revealed microdeletions in the Xp11.3 region, involving the NDP, MAOA and MAOB genes. Radiological examination demonstrated brain and cerebellar atrophy. CONCLUSIONS: We suggest that alterations caused by MAO deficit may remain during the first years of life. Clinical phenotype, biochemical findings and neuroimaging can guide the genetic study in patients with atypical ND and help us to a better understanding of this disease.
Authors: Andrey V Marakhonov; Irina A Mishina; Vitaly V Kadyshev; Svetlana A Repina; Maria F Shurygina; Olga A Shchagina; Natalya N Vasserman; Tatyana A Vasilyeva; Sergey I Kutsev; Rena A Zinchenko Journal: BMC Med Genet Date: 2020-10-22 Impact factor: 2.103