Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.2 | Neurodevelopmental disorder with hypotonia, neuropathy, and deafness | 617519 | Autosomal recessive | 3 | SPTBN4 | 606214 |
A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND) is caused by homozygous or compound heterozygous mutation in the SPTBN4 gene (606214) on chromosome 19q13.
Knierim et al. (2017) reported a boy, born of consanguineous Kurdish parents, with NEDHND. He presented soon after birth with hypotonia, facial weakness, and areflexia. He had delayed motor development and feeding difficulties, and he never achieved head control. At age 10 years, he had myopathic facies, high-arched palate, severe distal muscle weakness, generalized muscle atrophy, scoliosis, ankle contractures, and severely delayed motor and mental development with inability to stand, sit, eat, or speak. Muscle biopsy showed type 1 fiber atrophy, but serum creatine kinase was normal. He also had central deafness with absent brainstem-evoked potentials and a combined axonal and demyelinating motor neuropathy.
Wang et al. (2018) reported 6 patients from 5 unrelated families with a severe neurodevelopmental disorder apparent from birth. The patients had congenital hypotonia, profound weakness with areflexia, respiratory and feeding difficulties, and profound developmental delay with no language development. They were unable to sit unsupported and were nonambulatory. Electrophysiologic studies in 3 patients showed a motor neuronopathy/axonopathy that was documented to be progressive in 1 patient. Muscle biopsy showed denervated and atrophic muscle, consistent with a neurogenic disease. Three patients had seizures, including 2 with severe intractable epilepsy. Additional features included cortical visual impairment and deafness due to auditory neuropathy. Wang et al. (2018) concluded that the muscle weakness in these patients was primarily due to severe motor axonal neuropathy and neuronopathy as opposed to a myopathy.
The transmission pattern of NEDHND in the family reported by Knierim et al. (2017) was consistent with autosomal recessive inheritance.
In a boy, born of consanguineous Kurdish parents, with NEDHND, Knierim et al. (2017) identified a homozygous truncating mutation in the SPTBN4 gene (Q533X; 606214.0001). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. Western blot analysis of patient fibroblasts showed absence of the SPTBN4 protein, and immunostaining of patient muscle sample showed absence of SPTBN4 at the sarcolemma. The phenotype was similar to that of the 'quivering' mouse, which results from a homozygous loss-of-function mutation in the Sptnb4 gene.
In 6 patients from 5 unrelated families with NEDHND, Wang et al. (2018) identified homozygous or compound heterozygous mutations in the SPTBN4 gene (see, e.g., 606214.0002-606214.0006). The mutations were found by exome sequencing; confirmed segregation of the mutations with the disorder was only possible in 1 family (family A). All patients except 1 (patient from family C) carried biallelic nonsense or frameshift mutations predicted to result in a complete loss of function. The patient from family C carried compound heterozygous missense mutations (R504Q, 606214.0004 and R2435C, 606214.0005). Five of the 7 variants were located N-terminal to SR10 and were predicted to affect only the longer sigma-1 splice variant; SR15 mediates the interaction with ankyrin-G (ANK3; 600465). The equivalent human variants in mouse Sptbn4 were expressed in cultured rat hippocampal neurons. Most of the truncating variants failed to localize to the axon initial segments (AIS) due to an inability to interact with ANK3, whereas the 2 missense variants and 1 C-terminal frameshift mutation (c.7453delG; 606214.0006) were able to interact with ANK3 and localized properly to the AIS. The c.7453delG mutant was abnormally present in small intracellular puncta rather than normal diffuse distribution, suggesting that the mutation disrupted the PH domain and altered the distribution of SPTBN4 in membrane compartments. The mutant protein was also unable to bind phosphoinositides, further demonstrating an adverse effect on PH domain function. Examination of the nodes of Ranvier was possible for 2 patients. Sural nerve biopsy from the patient with a homozygous truncating mutation (W903X; 606214.0003) that affected only the sigma-1 variant showed significantly reduced neurofascin labeling at the nodes of Ranvier as well as decreased immunostaining for certain sodium and potassium channels and nearly undetectable nodal immunoreactivity for the shorter SPTBN4 isoform (sigma-6). The findings indicated that sigma-6 is not sufficient to rescue nodal abnormalities. Sural nerve biopsy from the patient with compound heterozygous missense mutations showed fairly normal structure at the nodes of Ranvier, with a small reduction in potassium channels. Wang et al. (2018) concluded that SPTBN4 mutations disrupt the cytoskeletal machinery that controls proper localization of ion channels and function of axonal domains mainly at the AIS and the nodes of Ranvier, resulting in severe neurologic dysfunction.
The autosomal recessive mouse mutation 'quivering' (qv), described by Yoon and Les (1957), produces progressive ataxia with hindlimb paralysis, deafness, and tremor. Ear twitch responses (Preyer reflex) to sound are absent in homozygous qv/qv mice, although cochlear morphology seems normal and cochlear potentials recorded at the round window are no different from those of control mice. However, responses from brainstem auditory nuclei show abnormal transmission of auditory inflammation, indicating that in contrast to the many mutations causing deafness originating in the cochlea, deafness in qv is central in origin (Deol et al., 1983; Bock et al., 1983). Parkinson et al. (2001) reported that qv mice carry loss-of-function mutations in the Sptnb4 gene that cause alterations in ion channel localization in myelinated nerves. They concluded that this finding provides a rationale for the auditory and motor neuropathies of these mice. Knierim et al. (2017) found absence of Sptbn4 immunostaining at the sarcolemma of muscle from the qv mouse, as well as complete absence of type 1 muscle fibers.
Bock, G. R., Frank, M. P., Steel, K. P., Deol, M. S. The quivering mutant mouse: hereditary deafness of central origin. Acta Otolaryng. 96: 371-377, 1983. [PubMed: 6637453] [Full Text: https://doi.org/10.3109/00016488309132722]
Deol, M. S., Frank, M. P., Steel, K. P., Bock, G. R. Genetic deafness of central origin. Brain Res. 258: 177-179, 1983. [PubMed: 24010186] [Full Text: https://doi.org/10.1016/0006-8993(83)91248-9]
Knierim, E., Gill, E., Seifert, F., Morales-Gonzalez, S., Unudurthi, S. D., Hund, T. J., Stenzel, W., Schuelke, M. A recessive mutation in beta-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness. Hum. Genet. 136: 903-910, 2017. [PubMed: 28540413] [Full Text: https://doi.org/10.1007/s00439-017-1814-7]
Parkinson, N. J., Olsson, C. L., Hallows, J. L., McKee-Johnson, J., Keogh, B. P., Noben-Trauth, K., Kujawa, S. G., Tempel, B. L. Mutant beta-spectrin 4 causes auditory and motor neuropathies in quivering mice. Nature Genet. 29: 61-65, 2001. [PubMed: 11528393] [Full Text: https://doi.org/10.1038/ng710]
Wang, C.-C., Ortiz-Gonzalez, S. R., Yum, S. W., Gill, S. M., White, A., Kelter, E., Seaver, L. H., Lee, S., Wiley, G., Gaffney, P. M., Wierenga, K. J., Rasband, M. N. Beta-IV spectrinopathies cause profound intellectual disability, congenital hypotonia, and motor axonal neuropathy. Am. J. Hum. Genet. 102: 1158-1168, 2018. [PubMed: 29861105] [Full Text: https://doi.org/10.1016/j.ajhg.2018.04.012]
Yoon, C. H., Les, E. P. Quivering, a new first chromosome mutation in mice. J. Hered. 48: 176-180, 1957.