ORPHA: 659975;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q21.1 | Neurodevelopmental disorder with hearing loss and spasticity | 619616 | Autosomal recessive | 3 | AFG2B | 619578 |
A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with hearing loss and spasticity (NEDHLS) is caused by homozygous or compound heterozygous mutation in the SPATA5L1 gene (AFG2B; 619578) on chromosome 15q21.
Biallelic mutation in the SPATA5L1 gene can also cause nonsyndromic hearing loss (DFNB119; 619615).
Neurodevelopmental disorder with hearing loss and spasticity (NEDHLS) is characterized by hearing loss, global developmental delay/impaired intellectual development, spastic-dystonic cerebral palsy, focal or generalized epilepsy, and microcephaly. Some children present with hypotonia (Richard et al., 2021).
Richard et al. (2021) described 25 individuals from 18 families with mild to severe hearing loss and global developmental delay/impaired intellectual development. Cognitive impairment ranged from severe to profound. Sixteen of the patients had spastic-dystonic cerebral palsy, and 15 had cortical visual impairment. Most patients had movement disorders, including spasticity (17/25), dystonia (15/25), or a combination of the two (13/25). Seizures were diagnosed in 13 of 18 patients, and seizure types included infantile spasms, absence focal, and generalized. Microcephaly was present in 13 of 25 patients. Facial dysmorphisms included downslanting palpebral fissures, low frontal hairline, large ears, tooth malformations, bitemporal narrowing, depressed nasal bridge, and micrognathia, among other findings. Common neuroimaging findings included diminished cerebral volume, periventricular leukomalacia, widened sylvian fissures, anterior temporal hypoplasia, and hypoplastic corpus callosum. Quantitative volumetric analysis of brain MRIs revealed a significant decrease in white matter volume compared to controls.
The transmission pattern of neurodevelopmental disorder with hearing loss and spasticity in the families reported by Richard et al. (2021) was consistent with autosomal recessive inheritance.
In 25 individuals from 18 families with neurodevelopmental disorder with hearing loss and spasticity, Richard et al. (2021) identified homozygous or compound heterozygous mutations in the SPATA5L1 gene (see, e.g., 619578.0001-619578.0002; 619578.0005-619578.0010). None of the identified variants were found in homozygous state in the gnomAD database.
Richard, E. M., Bakhtiari, S., Marsh, A. P. L., Kaiyrzhanov, R., Wagner, M., Shetty, S., Pagnozzi, A., Nordlie, S. M., Guida, B. S., Cornejo, P., Magee, H., Liu, J., and 93 others. Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss. Am. J. Hum. Genet. 108: 2006-2016, 2021. [PubMed: 34626583] [Full Text: https://doi.org/10.1016/j.ajhg.2021.08.003]