DO: 1572;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q25.1 | Hydrocephalus, normal pressure, 1 | 236690 | Autosomal dominant | 3 | CFAP43 | 617558 |
A number sign (#) is used with this entry because of evidence that normal-pressure hydrocephalus-1 (HYDNP1) is caused by heterozygous mutation in the CFAP43 gene (617558) on chromosome 10q25. One such family has been reported.
Normal-pressure hydrocephalus-1 (HYDNP1) is an autosomal dominant neurologic disorder characterized by the clinical triad of slowly progressive gait instability, urinary incontinence, and cognitive decline associated with ventricular enlargement on brain imaging with normal pressure of the cerebrospinal fluid (CSF). The onset of symptoms is usually in late adulthood; the symptoms are responsive to shunting. The disorder has been associated with recurrent respiratory infections and possible infertility issues, but the latter has not been confirmed (summary by Takahashi et al., 2011 and Morimoto et al., 2019).
Portenoy et al. (1984) described normal-pressure hydrocephalus in a 67-year-old man and his 74-year-old sister. Both had the classic triad of gait disturbance followed by mild dementia with psychomotor retardation and urinary or fecal incontinence. The authors knew of no other familial cases.
Cusimano et al. (2011) reported 2 Canadian sisters in their early seventies with HYDNP. They were unmarried and had no children. Both had typical symptoms and showed improvement with shunting. The report suggested a possible genetic predisposition to development of the disorder.
Takahashi et al. (2011) reported a 3-generation Japanese family in which 8 individuals had normal pressure hydrocephalus (NPH) in the absence of secondary causes: 4 living members were confirmed to have the disorder, and 3 deceased and 1 living member were suspected to have the disorder. Features included late-adult onset of gait disturbances, cognitive decline, and urinary incontinence. Brain imaging, when performed, showed enlarged ventricles and narrowing of the cortical sulci. CSF pressure was normal, and shunting relieved the symptoms. None of the patients had seizures or tremor. It was not noted whether the affected individuals had children.
Morimoto et al. (2019) reported a Japanese family in which 2 adult sibs and their deceased mother presented with the classic triad of NPH symptoms between 44 and 55 years of age. A third sib was similarly affected, but the age at onset was not reported and clinical details were limited. The patients had gait impairment, mild cognitive decline, and urinary incontinence. Brain imaging of 2 of the adult sibs showed a dilated ventricle and tightness of the Sylvian fissure, consistent with the diagnosis. Both also had recurrent respiratory infections and chronic sinusitis, but no bronchiectasis or situs abnormalities. None of the 3 affected adult sibs had children, but there was no detailed information about fertility. Two unaffected sibs did not have recurrent infections and had normal brain imaging.
The transmission pattern of HYDNP1 in the family reported by Morimoto et al. (2019) was consistent with autosomal dominant inheritance.
In 2 Japanese sibs with adult-onset HYDNP1, Morimoto et al. (2019) identified a heterozygous nonsense mutation in exon 35 of the CFAP43 gene (Y1502X; 617558.0012). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of the variant in patient cells were not performed, but it was predicted to result in a loss of function and haploinsufficiency. Nasal epithelial cells derived from 1 patient showed abnormal ciliary structure. There were 2 additional family members who were similarly affected, but DNA from those patients was not available. Morimoto et al. (2019) demonstrated that Cfap43-null mice developed hydrocephalus with ventricular dilatation observed on neuropathologic analysis (see ANIMAL MODEL).
Morimoto et al. (2019) found that Cfap43-null mice developed hydrocephalus with ventricular dilatation observed on neuropathologic analysis. Epithelial cells of the lateral ventricle, choroid plexus, and trachea from mutant mice showed no obvious differences, but testis and epididymal tissue showed distorted sperm flagella. Targeted immunofluorescent staining showed a decrease in acetylated tubulin in cilia of the choroid plexus, as well as other abnormalities in the ciliary protein composition. Transmission electron microscopy showed abnormal 8 or 10 + 2 peripheral microtubules. Complete knockout of the gene also increased embryonic lethality. Heterozygous Cfap43 +/- mice had normal hemotoxylin and eosin staining of the testis and epididymis.
Cusimano, M. D., Rewilak, D., Stuss, D. T., Barrera-Martinez, J. C., Salehi, F., Freedman, M. Normal-pressure hydrocephalus: is there a genetic predisposition? Canad. J. Neurol. Sci. 38: 274-281, 2011. [PubMed: 21320833] [Full Text: https://doi.org/10.1017/s031716710001146x]
Morimoto, Y., Yoshida, S., Kinoshita, A., Satoh, C., Mishima, H., Yamaguchi, N., Matsuda, K., Sakaguchi, M., Tanaka, T., Komohara, Y., Imamura, A., Ozawa, H., Nakashima, M., Kurotaki, N., Kishino, T., Yoshiura, K., Ono, S. Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities. Neurology 92: e2364-e2374, 2019. Note: Electronic Article. [PubMed: 31004071] [Full Text: https://doi.org/10.1212/WNL.0000000000007505]
Portenoy, R. K., Berger, A., Gross, E. Familial occurrence of idiopathic normal-pressure hydrocephalus. Arch. Neurol. 41: 335-337, 1984. [PubMed: 6696655] [Full Text: https://doi.org/10.1001/archneur.1984.04050150117029]
Takahashi, Y., Kawanami, T., Nagasawa, H., Iseki, C., Hanyu, H., Kato, T. Familial normal pressure hydrocephalus (NPH) with an autosomal-dominant inheritance: a novel subgroup of NPH. J. Neurol. Sci. 308: 149-151, 2011. [PubMed: 21704338] [Full Text: https://doi.org/10.1016/j.jns.2011.06.018]