Pettigrew Syndrome

A number sign (#) is used with this entry because Pettigrew syndrome (PGS), known by several other names including Fried-type syndromic mental retardation, is caused by mutation in the AP1S2 gene (300629) on chromosome Xp22.

Description

Pettigrew syndrome is characterized by mental retardation and highly variable additional features, including choreoathetosis, hydrocephalus, Dandy-Walker malformation, seizures, and iron or calcium deposition in the brain, both between and within families (summary by Cacciagli et al., 2014).

See 311510 for another X-linked mental retardation syndrome associated with basal ganglia disease (Waisman syndrome).

See 220219 for another mental retardation syndrome with Dandy-Walker malformation.

Clinical Features

Fried (1972) reported a Scottish pedigree with X-linked mental retardation and/or hydrocephalus. The family included 6 affected males with IQs ranging from 20 to 50. Two patients had hydrocephalus, 1 of which was suspected to be the result of stenosis of the aqueduct of Sylvius. All had delayed motor development and difficulty walking as adults.

In a 4-generation family of Dutch descent, Pettigrew et al. (1991) described a distinct X-linked form of mental retardation involving 9 affected males and 5 obligate carrier females. Key manifestations included severe mental retardation, early hypotonia with progression to spasticity and contractures, choreoathetosis, seizures, a long, narrow face with coarse features, cystic enlargement of the fourth ventricle with cerebellar hypoplasia (Dandy-Walker malformation), and iron accumulation in the basal ganglia with neuroaxonal dystrophy similar to that in neurodegeneration with brain iron accumulation-1 (NBIA1; 234200). Of the 5 known heterozygotes, 3 were dull intellectually, and 1 of the 3 developed 'presenile dementia.' At autopsy, she had iron deposition and neuroaxonal dystrophy in the basal ganglia and atrophy of the cerebral cortex.

Cowles et al. (1993) described a family with Dandy-Walker malformation in 4 males in 4 separate sibships connected through presumably carrier females.

Carpenter et al. (1999) described a 4-generation family with nonspecific mental retardation, designated MRX59. The 5 affected males, ranging in age from 2 to 52 years, had a normal facial appearance and mild to severe mental retardation. Two of the affected males displayed aggressive behavior.

Wakeling et al. (2002) reported a family in which 2 sisters had 3 male fetuses with isolated Dandy-Walker variant; all 3 pregnancies were terminated.

Turner et al. (2003) described an X-linked recessive form of mental retardation in a family in which 10 males spanning 4 generations were affected. The main manifestations were severe to profound intellectual disability, muscular hypotonia in childhood, delayed walking, and in the adults, difficult and aggressive behavior. There was moderate reduction both in the occipitofrontal circumference and in height, and a similar facial appearance: triangular in shape with high forehead, prominent ears, and a small pointed chin.

Saillour et al. (2007) reported a French family in which 8 males spanning 4 generations had mental retardation. Four living patients were in specialized institutions. Other features included hypotonia, delayed motor development, and poor language skills. Among 5 patients, 2 who were examined had basal ganglia calcifications, and 2 had congenital hydrocephalus with stenosis of the aqueduct of Sylvius.

Mapping

Fried and Sanger (1973) found that the X-linked mental retardation syndrome in the Scottish family reported by Fried (1972) appeared to be linked to the blood group locus Xg with a most likely recombination fraction of 0.11.

Carpenter et al. (1999) performed linkage analysis on a 4-generation MRX59 family. A maximum lod score of 2.41 at theta = 0.00 was observed with microsatellite markers in Xp21.2, Xp22.1, and Xp22.2. Genetic localization of this familial condition made prenatal diagnosis informative for 1 of the obligate carriers.

Using linkage analysis in the 4-generation family with X-linked mental retardation that they studied, Turner et al. (2003) located the gene at Xp22 with maximum lod scores of 4.8 at theta = 0.0 for markers mapping between the closest recombination points at DXS7104 and DXS418.

Molecular Genetics

In a systematic sequencing screen of the coding exons of the X chromosome in 250 families with X-linked mental retardation (XLMR), Tarpey et al. (2006) identified 2 nonsense mutations and 1 consensus splice site mutation in the AP1S2 gene (300629) on Xp22 in 3 families, including those reported by Carpenter et al. (1999) and Turner et al. (2003). AP1S2 encodes an adaptin protein that constitutes part of the adaptor protein complex found at the cytoplasmic face of coated vesicles located at the Golgi complex. The complex mediates the recruitment of clathrin to the vesicle membrane. Tarpey et al. (2006) suggested that aberrant endocytic processing through disruption of adaptor protein complexes was likely to result from the AP1S2 mutations identified in the 3 XLMR-affected families. Such defects may plausibly cause abnormal synaptic development and function. AP1S2 was the first reported XLMR gene that encodes a protein directly involved in the assembly of endocytic vesicles.

Saillour et al. (2007) identified 2 pathogenic mutations in the AP1S2 gene (300629.0004 and 300629.0005, respectively) in affected members of 2 unrelated families with X-linked mental retardation. One of the families had been reported by Fried (1972).

Tarpey et al. (2009) sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation. They identified 3 mutations in the AP1S2 (300629) gene in 3 families.

In affected members of the family with MRXS reported by Pettigrew et al. (1991), Cacciagli et al. (2014) identified a hemizygous splice site mutation in the AP1S2 gene (300629.0006). The mutation was found by X-chromosome exome sequencing.

History

In extensive linkage studies in the family reported by Pettigrew et al. (1991), Huang et al. (1991) ruled out linkage with markers on Xp, proximal Xq, and Xq28. However, a new hypervariable short tandem repeat (STR) within the HPRT gene at Xq26 showed positive linkage to the disease locus, with a maximum lod score of 2.19 at a recombination fraction of 0.0.