Aicardi-Goutieres Syndrome 5

A number sign (#) is used with this entry because Aicardi-Goutieres syndrome-5 (AGS5) is caused by homozygous or compound heterozygous mutation in the SAMHD1 gene (606754) on chromosome 20q11.

For a phenotypic description and a discussion of genetic heterogeneity of Aicardi-Goutieres syndrome, see AGS1 (225750).

Rice et al. (2009) reported 13 probands with Aicardi-Goutieres syndrome. The families were of diverse ethnic backgrounds, including Hungarian, Maltese, Indian, French, Canadian, Moroccan, and Pakistani. Several of the families were consanguineous. Clinical features included onset in infancy of severe developmental delay, poor feeding, irritability, or abnormal neurologic signs. Many patients had white blood cells and interferon-gamma in CSF. Almost all had leukodystrophy and calcifications in the basal ganglia or periventricular regions.

Clinical Variability

Dale et al. (2010) reported a brother and sister with AGS5 who were born of unrelated and unaffected parents. The father was of Maltese origin. The 13-year-old older sister had normal development until age 6 months when she showed mildly delayed psychomotor development. She had postnatal microcephaly, and chronically dry, scaly skin with intermittent rash and intermittent appearance of chilblains of the toes. Her skin became gradually tight, particularly on the distal extremities, and biopsy showed an inflammatory reaction. Since age 3 years, she experienced stiffness and pain in the joints, resulting in secondary contractures, reduced hand function, and intermittent use of a wheelchair. Imaging studies were noncontributory. She had mild learning difficulties, but the neurologic examination was otherwise normal. In contrast, her brother developed a stiff gait with scissoring and toe walking at age 3 years. He had lower limb spasticity and hyperreflexia, but no learning disabilities and no microcephaly. He had a similar chronic skin condition as his sister. He never had joint problems. Both children also had recurrent mouth ulcers. Family history revealed 2 family members with mild skin involvement only, and a third deceased relative with skin lesions and a progressive arthropathy related to immune dysregulation. Dale et al. (2010) noted that the diagnosis of AGS can be made even when some of the original diagnostic features, such as progressive neurologic dysfunction and intracranial calcifications, are absent. The 2 sibs they described represented the milder end of the phenotypic spectrum, with the presence of chilblains alerting to the diagnosis.

Leshinsky-Silver et al. (2011) reported a boy, born of unrelated Ashkenazi Jewish parents, who presented at age 3 weeks with failure to thrive, poor growth, and lack of development. He had central hypotonia with brisk tendon reflexes and choreoathetoid movements. Brain MRI showed extensive white matter destruction, delayed myelination, hypoplasia of the corpus callosum, severe cortical atrophy, destructive lesions of the aqueductal body and pons, and pathologic lesions in the frontal lobe and basal ganglia. Blood samples showed increased serum lactate, anemia, and thrombocytosis. He had profound mental retardation, poor growth, and severe irritability, and died at age 15 months. Two subsequent pregnancies were terminated after studies showed periventricular white matter lesions and hyperechogenic foci in the basal ganglia between 28 and 34 weeks' gestation. Southern blot analysis of patient skeletal muscle and liver tissue showed multiple mitochondrial DNA deletions, which were not found in blood and fibroblasts, and there were similar findings in fetal autopsy tissues.

Rice et al. (2009) demonstrated that AGS5 is an autosomal recessive disorder.

By genomewide linkage analysis and candidate gene sequencing of multiple families with Aicardi-Goutieres syndrome, Rice et al. (2009) identified homozygous or compound heterozygous mutations in the SAMHD1 gene (see, e.g., 606754.0001-606754.0007). All of the mutations involved highly conserved residues, segregated with the disease, and all unaffected parents tested were heterozygous for the mutations.

In 2 sibs with variable manifestations of AGS5, Dale et al. (2010) identified compound heterozygosity for 2 mutations in the SAMHD1 gene (606754.0002 and 606754.0008).

Leshinsky-Silver et al. (2011) identified a homozygous 9.1-kb deletion in the SAMHD1 gene (606754.0009) in affected members of a family with atypical AGS5 associated with in utero onset of white matter abnormalities and mitochondrial DNA deletions in muscle and liver. Leshinsky-Silver et al. (2011) suggested that mutant SAMHD1 causes an induction of the cell intrinsic antiviral response, apoptosis, and mitochondrial DNA destruction.