This report describes cerebral palsy, spastic quadriplegic, 3 (CPSQ3), which is a subtype of cerebral palsy, spastic quadriplegic; CPSQ3 exhibits autosomal recessive inheritance. Based on data from one family, the human gene implicated in this disease is postulated to be ADD3 (adducin 3 or adducin gamma), a membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network; it also plays a role in actin filament capping, thus impacting actin filament length. There is a single orthologous gene in Drosophila, hts, for which loss-of-function mutations, RNAi targeting constructs, alleles caused by insertional mutagenesis, and an amorphic allele created by targeted recombination have been generated. Dmel\hts is also orthologous to two additional adducins in human, ADD1 and ADD3; ADD1 is implicated in essential hypertension (MIM:145500).
UAS constructs of Hsap\ADD3 and Hsap\ADD1 have been introduced into flies, including wild-type and a construct of Hsap\ADD3 carrying a disease-implicated variant. Partial heterologous rescue (functional complementation) is observed: neither the ADD3 nor the ADD1 wild-type gene alone is able to rescue the lethality observed for an amorphic allele of the fly hts gene; however, expression of both human genes results in partial suppression of the lethal phenotype. See the 'Disease-Implicated Variants' table below.
Animals homozygous for null or severe loss-of-function alleles of Dmel\hts typically die before reaching adult stage; in homozygous larvae the role and localization of the hts protein at neuromuscular junctions has been studied. Milder hypomorphic genotypes typically survive to adulthood, but exhibit progressive locomotor defects; females are sterile with severe abnormalities in oogenesis; progressive abnormalities in the adult brain are observed.
The observation of progressive locomotor defects in Dmel\hts mutant animals lends support to the identification of the human ADD3 gene as implicated in this form of spastic cerebral palsy.
[updated Apr.2024 by FlyBase; FBrf0222196]
Spastic cerebral palsy is the most common type of cerebral palsy. Spasticity is a form of hypertonia, or increased muscle tone, resulting in stiff muscles which can make movement difficult or impossible (https://www.cerebralpalsy.org.au/what-is-cerebral-palsy/types-of-cerebral-palsy/spastic-cerebral-palsy/).
Cerebral palsy (CP) is defined as a nonprogressive but not unchanging disorder of posture or movement, caused by an abnormality of the brain and first evident at the stage of rapid brain development (Hughes and Newton, 1992; pubmed:1544520). The most common forms result from factors surrounding difficulties before or at birth, such as severe perinatal asphyxia, congenital infection, prematurity, and multiple pregnancy (Blair and Stanley, 1988, pubmed:3351675; Stanley, 1994, pubmed:8200323). More rarely, familial clustering or absence of pre- or postpartum events indicate that there are genetic forms of the disorder (Lynex et al., 2004; pubmed:15571623). [from MIM:603513; 2017.1003]
Cerebral palsy can be classified according to the type of movement disorder: spastic cerebral palsy accounts for approximately 60% of cases and can be subdivided into hemiplegic, diplegic, quadriplegic, and monoplegic types (Gustavson et al., 1969; pubmed:5824822). [from MIM:603513; 2017.1003]
[CEREBRAL PALSY, SPASTIC QUADRIPLEGIC, 3; CPSQ3](https://omim.org/entry/617008)
[ADDUCIN 3; ADD3](https://omim.org/entry/601568)
Described in four siblings from one consanguineous family: Three patients developed severe spastic quadriplegia in the first months or years of life. All had cognitive impairment and poor speech. One patient developed seizures by age 2 (Kruer et al., 2013; pubmed:23836506; FBrf0223890). [from MIM:617008; 2017.10.03]
There is evidence that spastic quadriplegic cerebral palsy-3 (CPSQ3) is caused by homozygous mutation in the ADD3 gene; one such family has been reported. [from MIM:617008; 2017.10.03]
ADD3 encodes a membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network; plays a role in actin filament capping. [Gene Cards, ADD3; 2017.10.03]
The ADD3 gene encodes adducin-3, a member of a family of adducin proteins that have a physiologic actin-capping function, modulating the fast-growing end of actin filaments and controlling actin molecule length (summary by Kruer et al., 2013; pubmed:23836506; FBrf0223890). [from MIM:601568; 2017.10.03]
Many to one (3 human to 1 Drosophila); the human genes are ADD1, ADD2, and ADD3.
Moderate- to high-scoring ortholog of human ADD1, ADD2, and ADD3 (1 Drosophila to 3 human); Dmel\hts shares 33-35% identity and 49-53% similarity with the human genes.
