# 615224

ADVANCED SLEEP PHASE SYNDROME, FAMILIAL, 2; FASPS2


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
17q25.3 Advanced sleep-phase syndrome, familial, 2 615224 AD 3 CSNK1D 600864
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal dominant
NEUROLOGIC
Behavioral Psychiatric Manifestations
- Early sleep onset (almost 4 hours advanced over controls)
- Early sleep offset (almost 4 hours advanced over controls)
- Short circadian rhythm cycle (tau)
- Migraine, with or without aura
METABOLIC FEATURES
- Melatonin rhythm phase-advanced by 3-4 hours
- Temperature rhythm phase-advanced by 3-4 hours
MISCELLANEOUS
- Onset in childhood, but most noticeable in mid-teens and early adulthood
MOLECULAR BASIS
- Caused by mutation in the casein kinase 1, delta, gene (CSNK1D, 600864.0001)

TEXT

A number sign (#) is used with this entry because familial advanced sleep phase syndrome-2 (FASPS2) is caused by heterozygous mutation in the CSNK1D gene (600864) on chromosome 17q25.


Description

Advanced sleep phase syndrome is characterized by very early sleep onset and offset (summary by Jones et al., 1999).

For a discussion of genetic heterogeneity of advanced sleep phase syndrome, see FASPS1 (604348).


Clinical Features

Xu et al. (2005) reported a 3-generation family with autosomal dominant transmission of FASPS. Fifteen family members were interviewed for their typical work and vacation sleep-wake schedules, and 5 were identified with FASPS. In the absence of competing psychosocial demands, both the average sleep onset time (18:12 +/- 1.4 hours vs 23:24 +/- 1.1 hour) and final wake time (04:06 +/- 0.7 hour vs 08:00 +/- 1.6 hours) of these subjects were significantly earlier (p less than 0.0001) than those of the 9 unaffected family members. Affected individuals reported onset of FASPS between early childhood and the mid-teen years.

Brennan et al. (2013) found that 5 of the mutation carriers with FASPS2 in the family reported by Xu et al. (2005) had migraine with or without aura. One mutation carrier who did not have FASPS also had migraine. However, 3 family members who were offspring of carriers but did not carry the mutation also had migraine. A second unrelated family also segregated FASPS and migraine with or without aura.


Inheritance

The transmission pattern of FASPS2 in the families with or without migraine reported by Brennan et al. (2013) was consistent with autosomal dominant inheritance.


Molecular Genetics

Xu et al. (2005) identified a thr44-to-ala mutation in the CSNK1D gene (T44A; 600864.0001) that cosegregated with the FASPS phenotype in a 3-generation family.

In affected members of a family with FASPS2, Brennan et al. (2013) identified a heterozygous mutation in the CSNK1D gene (H46R; 600864.0002). In vitro functional expression studies showed that the T44A mutant enzyme had significantly reduced kinase activity compared to wildtype. Transgenic mice carrying the T44A mutation were more sensitive to pain after treatment with the migraine trigger nitroglycerin, and showed a reduced threshold for cortical spreading depression, which is believed to be the physiologic analog of migraine aura, as well as greater arterial dilation during cortical spreading depression. The mutant enzyme showed decreased phosphorylation of GJA1 (121014), which is a mediator of astrocyte signaling. Astrocytes derived from mutant mice showed increased spontaneous and evoked calcium signaling, which may underlie some of the vascular changes associated with cortical spreading depression. These results suggested that decreased CSNK1D activity can contribute to the pathogenesis of migraine.


REFERENCES

  1. Brennan, K. C., Bates, E. A., Shapiro, R. E., Zyuzin, J., Hallows, W. C., Huang, Y., Lee, H.-Y., Jones, C. R., Fu, Y.-H., Charles, A. C., Ptacek, L. J. Casein kinase 1-delta mutations in familial migraine and advanced sleep phase. Sci. Transl. Med. 5: 183ra56, 2013. Note: Electronic Article. [PubMed: 23636092, images, related citations] [Full Text]

  2. Jones, C. R., Campbell, S. S., Zone, S. E., Cooper, F., DeSano, A., Murphy, P. J., Jones, B., Czajkowski, L., Ptacek, L. J. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nature Med. 5: 1062-1065, 1999. [PubMed: 10470086, related citations] [Full Text]

  3. Xu, Y., Padiath, Q. S., Shapiro, R. E., Jones, C. R., Wu, S. C., Saigoh, N., Saigoh, K., Ptacek, L. J., Fu, Y.-H. Functional consequences of a CKI-delta mutation causing familial advanced sleep phase syndrome. Nature 434: 640-644, 2005. [PubMed: 15800623, related citations] [Full Text]


Creation Date:
Cassandra L. Kniffin : 5/6/2013
carol : 06/14/2017
carol : 11/08/2013
carol : 5/16/2013
alopez : 5/10/2013
ckniffin : 5/6/2013

# 615224

ADVANCED SLEEP PHASE SYNDROME, FAMILIAL, 2; FASPS2


ORPHA: 164736;   DO: 0110012;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
17q25.3 Advanced sleep-phase syndrome, familial, 2 615224 Autosomal dominant 3 CSNK1D 600864

TEXT

A number sign (#) is used with this entry because familial advanced sleep phase syndrome-2 (FASPS2) is caused by heterozygous mutation in the CSNK1D gene (600864) on chromosome 17q25.


Description

Advanced sleep phase syndrome is characterized by very early sleep onset and offset (summary by Jones et al., 1999).

For a discussion of genetic heterogeneity of advanced sleep phase syndrome, see FASPS1 (604348).


Clinical Features

Xu et al. (2005) reported a 3-generation family with autosomal dominant transmission of FASPS. Fifteen family members were interviewed for their typical work and vacation sleep-wake schedules, and 5 were identified with FASPS. In the absence of competing psychosocial demands, both the average sleep onset time (18:12 +/- 1.4 hours vs 23:24 +/- 1.1 hour) and final wake time (04:06 +/- 0.7 hour vs 08:00 +/- 1.6 hours) of these subjects were significantly earlier (p less than 0.0001) than those of the 9 unaffected family members. Affected individuals reported onset of FASPS between early childhood and the mid-teen years.

Brennan et al. (2013) found that 5 of the mutation carriers with FASPS2 in the family reported by Xu et al. (2005) had migraine with or without aura. One mutation carrier who did not have FASPS also had migraine. However, 3 family members who were offspring of carriers but did not carry the mutation also had migraine. A second unrelated family also segregated FASPS and migraine with or without aura.


Inheritance

The transmission pattern of FASPS2 in the families with or without migraine reported by Brennan et al. (2013) was consistent with autosomal dominant inheritance.


Molecular Genetics

Xu et al. (2005) identified a thr44-to-ala mutation in the CSNK1D gene (T44A; 600864.0001) that cosegregated with the FASPS phenotype in a 3-generation family.

In affected members of a family with FASPS2, Brennan et al. (2013) identified a heterozygous mutation in the CSNK1D gene (H46R; 600864.0002). In vitro functional expression studies showed that the T44A mutant enzyme had significantly reduced kinase activity compared to wildtype. Transgenic mice carrying the T44A mutation were more sensitive to pain after treatment with the migraine trigger nitroglycerin, and showed a reduced threshold for cortical spreading depression, which is believed to be the physiologic analog of migraine aura, as well as greater arterial dilation during cortical spreading depression. The mutant enzyme showed decreased phosphorylation of GJA1 (121014), which is a mediator of astrocyte signaling. Astrocytes derived from mutant mice showed increased spontaneous and evoked calcium signaling, which may underlie some of the vascular changes associated with cortical spreading depression. These results suggested that decreased CSNK1D activity can contribute to the pathogenesis of migraine.


REFERENCES

  1. Brennan, K. C., Bates, E. A., Shapiro, R. E., Zyuzin, J., Hallows, W. C., Huang, Y., Lee, H.-Y., Jones, C. R., Fu, Y.-H., Charles, A. C., Ptacek, L. J. Casein kinase 1-delta mutations in familial migraine and advanced sleep phase. Sci. Transl. Med. 5: 183ra56, 2013. Note: Electronic Article. [PubMed: 23636092] [Full Text: https://doi.org/10.1126/scitranslmed.3005784]

  2. Jones, C. R., Campbell, S. S., Zone, S. E., Cooper, F., DeSano, A., Murphy, P. J., Jones, B., Czajkowski, L., Ptacek, L. J. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nature Med. 5: 1062-1065, 1999. [PubMed: 10470086] [Full Text: https://doi.org/10.1038/12502]

  3. Xu, Y., Padiath, Q. S., Shapiro, R. E., Jones, C. R., Wu, S. C., Saigoh, N., Saigoh, K., Ptacek, L. J., Fu, Y.-H. Functional consequences of a CKI-delta mutation causing familial advanced sleep phase syndrome. Nature 434: 640-644, 2005. [PubMed: 15800623] [Full Text: https://doi.org/10.1038/nature03453]


Creation Date:
Cassandra L. Kniffin : 5/6/2013

Edit History:
carol : 06/14/2017
carol : 11/08/2013
carol : 5/16/2013
alopez : 5/10/2013
ckniffin : 5/6/2013