| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q32.1 | Neurodevelopmental disorder with central and peripheral motor dysfunction | 618356 | Autosomal recessive | 3 | NFASC | 609145 |
A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with central and peripheral motor dysfunction (NEDCPMD) is caused by homozygous mutation in the NFASC gene (609145) on chromosome 1q32.
Neurodevelopmental disorder with central and peripheral motor dysfunction (NEDCPMD) is an autosomal recessive neurologic disorder with a highly variable phenotype. At the severe end of the spectrum, patients may have hypotonia apparent from birth, necessitating mechanical respiration and tube-feeding, and global developmental delay with absence of reaction to touch and no eye contact. At the mild end of the spectrum, patients may present with infantile-onset progressive ataxia and demyelinating peripheral neuropathy. The disorder is caused by mutation in the NFASC gene, which has several neuronal- and glial-specific transcripts. The variable clinical phenotype may be caused by several factors, including the severity of the mutation, the selective involvement of distinct isoforms by pathogenic variants, and the presence of genetic modifiers (summary by Monfrini et al., 2019).
Anazi et al. (2017) reported a consanguineous family (14DG0056) in which several patients had a similar neurodevelopmental disorder. Two patients were described in detail. One girl presented in the neonatal period with generalized hypertonia, stridor, and poor feeding necessitating tube placement. She had global developmental delay, no purposeful movements, hyperreflexia, poor overall growth with small head circumference, and no social smile, but she could babble. The other patient, a boy, presented at birth with hypotonia and respiratory insufficiency necessitating mechanical ventilation. He also had dysmorphic features, including hypertelorism, high and broad nasal bridge, micrognathia, glossoptosis, cleft palate, long thin hyperextensible fingers, and 11 pairs of ribs. Brain imaging showed diffuse white matter T2 hyperintensities. Several members of both families had a similar phenotype; at least 1 died at 3 months of age.
Smigiel et al. (2018) reported a girl, born of Polish parents who denied consanguinity, with a severe neurologic disorder. The pregnancy was complicated by polyhydramnios, suggesting fetal esophageal atresia, and decreased fetal movements. At birth, she showed respiratory insufficiency requiring mechanical ventilation and had severe hypotonia with no muscle tension or reflexes, as well as amimia and contractures of the hands and feet. Neurologic examination showed no reaction to touch or pain, absence of motor and oral automatisms, no eye contact, and narrow symmetric pupils with no response to light. She developed seizures at age 4 months. Brain and spinal cord imaging was essentially normal.
Monfrini et al. (2019) reported a brother and sister, born of consanguineous parents from northern Italy, with developmental delay and delayed walking at age 3 years with a wide-based ataxic gait. They had additional cerebellar signs, including dysarthria, intention tremor, dysmetria, saccadic pursuits, and dysdiadochokinesia. At age 11 years, the sister developed progressive spastic hypertonia with hyperreflexia, clonus, and extensor plantar responses. She later had to use a wheelchair and also developed myoclonic jerks of the upper limbs that disappeared during sleep. The brother did not develop spasticity, but reportedly had mild intellectual disability and developed aggression and anxiety during adolescence. Brain imaging showed cerebellar atrophy in the sister, and mild diffuse T2 hyperintensities suggesting hypomyelination in both patients. Electrophysiologic studies showed decreased central motor nerve conduction velocities, decreased somatosensory evoked potentials, and a length-dependent demyelinating sensorimotor peripheral neuropathy.
The transmission pattern of NEDCPMD in the family reported by Anazi et al. (2017) was consistent with autosomal recessive inheritance.
In multiple affected members of a consanguineous Middle Eastern family (14DG0056) with NEDCPMD, Anazi et al. (2017) identified a homozygous missense mutation in the NFASC gene (R370P; 609145.0001). The mutation, which was found by exome sequencing of 68 families with intellectual disability and confirmed by Sanger sequencing, segregated with the disorder in the family. It was filtered against the gnomAD database and classified as pathogenic according to ACMG guidelines; functional studies of the variant and studies of patient cells were not performed.
In a girl, born of likely remotely consanguineous Polish parents, with NEDCPMD, Smigiel et al. (2018) identified a homozygous nonsense mutation in the glial-specific transcript of the NFASC gene (NFASC155) (R846X; 609145.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Peripheral nerve biopsies from the patient showed absence of glial NFASC155 at the paranode of myelinated axons. CASPR (602346) was also not detected at the paranodes, confirming disruption of the axoglial complex. In contrast, patient tissue showed normal immunostaining for neuronal NFASC186.
In 2 sibs, born of consanguineous parents from northern Italy, with NEDCPMD, Monfrini et al. (2019) identified a homozygous missense mutation in the NFASC gene (V1122E; 609145.0003). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient-derived induced cells showed normal levels of NFASC transcript, but decreased protein expression with a loss of immunostaining in neuronal cell bodies and cell membranes.
Pillai et al. (2009) found that glia-specific Nfasc-155-null mice had severe ataxia, motor paresis, and death before the third postnatal week. Electrophysiologic studies of mutant mice showed dramatic reductions in nerve conduction velocities, and histologic studies of central and peripheral nerves showed loss of paranodal axoglial junctions and degeneration of myelinated axons. Loss of Nfasc-155 in myelinating glia of adult mice resulted in the gradual loss of axoglial junctions and failure to maintain segregated axonal domains.
Anazi, S., Maddirevula, S., Salpietro, V., Asi, Y. T., Alsahli, S., Alhashem, A., Shamseldin, H. E., AlZahrani, F., Patel, N., Ibrahim, N., Abdulwahab, F. M., Hashem, M., and 31 others. Expanding the genetic heterogeneity of intellectual disability. Hum. Genet. 136: 1419-1429, 2017. Note: Erratum: Hum. Genet. 137: 105-109, 2018. [PubMed: 28940097] [Full Text: https://doi.org/10.1007/s00439-017-1843-2]
Monfrini, E., Straniero, L., Bonato, S., Monzio Compagnoni, G., Bordoni, A., Dilena, R., Rinchetti, P., Silipigni, R., Ronchi, D., Corti, S., Comi, G. P., Bresolin, N., Duga, S., Di Fonzo, A. Neurofascin (NFASC) gene mutation causes autosomal recessive ataxia with demyelinating neuropathy. Parkinsonism Relat. Disord. 63: 66-72, 2019. [PubMed: 30850329] [Full Text: https://doi.org/10.1016/j.parkreldis.2019.02.045]
Pillai, A. M., Thaxton, C., Pribisko, A. L., Cheng, Jr-G., Dupree, J. L., Bhat, M. A. Spatiotemporal ablation of myelinating glia-specific neurofascin (Nfasc-NF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains. J. Neurosci. Res. 87: 1773-1793, 2009. [PubMed: 19185024] [Full Text: https://doi.org/10.1002/jnr.22015]
Smigiel, R., Sherman, D. L., Rydzanicz, M., Walczak, A., Mikolajkow, D., Krolak-Olejnik, B., Kosinska, J., Gasperowicz, P., Biernacka, A., Stawinski, P., Marciniak, M., Andrzejewski, W., Boczar, M., Krajewski, P., Sasiadek, M. M., Brophy, P. J., Ploski, R. Homozygous mutation in the neurofascin gene affecting the glial form of neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia. Hum. Molec. Genet. 27: 3669-3674, 2018. [PubMed: 30124836] [Full Text: https://doi.org/10.1093/hmg/ddy277]