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To date, 11 affected individuals have been described in the literature worldwide. The exact prevalence is not known.

The main clinical characteristics are global developmental delay and severe intellectual disability. Speech is usually absent or very limited. Motor development is moderately to severely delayed, with walking after 2 years or even inability to walk in some individuals. Muscular hypotonia, severe deficits in social interaction, and motor stereotypies are very common. Moreover, abnormal sleep-wake cycle, abnormality in breathing and chronic constipation may occur. Electroencephalogram abnormalities and seizures were observed in several individuals with variable onset between the first months of life and adolescence. Brain imaging is normal in the majority of cases, but may also show moderate cortical atrophy, cysts or asymmetry of the ventricular system. Additional features such as failure to thrive, pulmonary stenosis, valve or septal defects, hearing impairment, microcephaly, gastroesophageal reflux, early onset puberty and scoliosis are present in single or few cases. Mild but non-specific facial dysmorphisms, such as a broad mouth, strabismus or protruding tongue with drooling, have occasionally been described.

The disorder is caused by homozygous or compound heterozygous intragenic deletions or truncating variants in the NRXN1 gene (2p16.3). NRXN1 belongs to the evolutionarily conserved family of neurexins, presynaptic transmembrane proteins and has an important role in synaptic function.

Diagnosis is usually made by untargeted approaches such as chromosomal microarray analysis and/or multigene panel or exome sequencing. Detection of a heterozygous, deleterious variant in NRNX1 in an individual with a fitting phenotype should prompt careful investigation of the second allele.

Differential diagnosis includes other non-specific severe neurodevelopmental disorders with or without seizures.

Prenatal diagnosis and preimplantation-diagnostic are possible where the pathogenic variant(s) has/have been identified in an affected family member and/or carrier status in the parents has been confirmed.

Inheritance is autosomal recessive; genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. Heterozygous deletions or variants in NRXN1 are associated with an increased risk for variable neuropsychiatric abnormalities.

Ongoing developmental assessments are required to tailor educational services to individual needs, e.g. physical, occupational, speech therapies and behavioral management strategies. For patients with seizures, the appropriate seizure management is required.

There are patients living in their fourth decade. Usually severe cognitive impairment is present with dependence on others help for daily living.