Cerebral Palsy, Spastic Quadriplegic, 1

A number sign (#) is used with this entry because of evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by homozygous mutation in the gene encoding glutamate decarboxylate-1 (GAD1; 605363) on chromosome 2q31. One such family has been reported.

Description

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). 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; Stanley, 1994). More rarely, familial clustering or absence of pre- or postpartum events indicate that there are genetic forms of the disorder (Lynex et al., 2004).

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, whereas other forms include athetoid/dyskinetic, ataxic (605388), and mixed (Gustavson et al., 1969).

Genetic Heterogeneity of Spastic Quadriplegic Cerebral Palsy

See also CPSQ2 (612900), caused by deletion of the ANKRD15 gene (KANK1; 607704) inherited on the paternal allele, and CPSQ3 (617008), caused by mutation in the ADD3 gene (601568) on 10q24.

Related phenotypes that were formerly classified in the CPSQ series include spastic paraplegia-47 (SPG47; 614066), spastic paraplegia-50 (SPG50; 612936), spastic paraplegia-51 (SPG51; 613744), and spastic paraplegia-52 (614067).

Clinical Features

Mitchell and Bundey (1997) and McHale et al. (1999) reported a consanguineous family of Pakistani origin in which 4 sibs had spastic cerebral palsy with onset in infancy. All had moderate to severe mental retardation. All had spasticity affecting predominantly the lower limbs, although 2 also had mild hypertonia and ataxia of the upper limbs. Spastic features included hypertonicity, hyperreflexia, and extensor plantar responses. Two older sibs had contractures. One patient had bilateral dislocated hips and another had microcephaly and scoliosis. Cranial nerve abnormalities, nystagmus, and seizures were not present.

Inheritance

Spastic cerebral palsy is the most common CP subtype and has a low overall recurrence risk. However, inherited spastic cerebral palsy has a recurrence risk in sibs of approximately 1 in 8 (Bundey and Griffiths, 1977). Most cases are autosomal recessive.

Population Genetics

The common forms of cerebral palsy have an incidence of 1 in 250 to 1,000 births (Pharoah et al., 1987; Bundey and Alam, 1993). However, approximately 2% of all CP cases in Swedish and English children are believed to be due to a genetic cause because most of these cases have no recognizable adverse pre- or postpartum events (Gustavson et al., 1969; Bundey and Griffiths, 1977).

Mapping

McHale et al. (1999) identified consanguineous families with multiple cases affected by symmetric spastic CP and performed a genomewide search for linkage using 290 polymorphic DNA markers. In 3 families, a region of homozygosity was identified on chromosome 2q21-q31 between markers D2S124 and D2S148 (maximum combined multipoint lod score for the 3 families was 5.75). The minimum region of homozygosity was approximately 5 cM between D2S124 and D2S2284.

Molecular Genetics

In 4 affected sibs of a consanguineous Pakistani family with autosomal recessive spastic cerebral palsy reported by Mitchell and Bundey (1997), Lynex et al. (2004) identified a homozygous mutation in the GAD1 gene (605363.0001).