A Possible Genotype-Phenotype Correlation in Ashkenazi-Jewish Individuals With Aicardi-Goutières Syndrome Associated With SAMHD1 Mutation
Abstract
Aicardi-Goutières syndrome is a genetic neurodegenerative disorder with clinical symptoms mimicking a congenital viral infection. Mutations in six genes are known to cause the disease: 3 prime repair exonuclease I, ribonucleases H2A, B, and C, SAM domain and HD domain I, and most recently ADAR1. HD domain I mutations were previously reported in the Ashkenazi-Jewish community. We report an additional patient of Ashkenazi-Jewish descent and review the other three cases affected with Aicardi-Goutières syndrome due to SAM domain and HD domain I (SAMHD1) mutations described in Israel. We propose that there may be a phenotypic-genotypic correlation in accordance with the type of mutations inherited in the SAMHD1 genotype and suggest that Aicardi-Goutières syndrome may not be a rare disease in the Ashkenazi-Jewish population.
Keywords
Ashkenazi-Jewish, FTT, irritability, microcephaly, seizures, Aicardi-Goutières
Introduction
Aicardi-Goutières syndrome is a severe inflammatory encephalopathy of childhood, which also manifests in the skin and joints. Mutations in six genes are known to cause the disease: encoding the DNA exonuclease 1 (TREX1), the three nonallelic components of the RNase H2 endonuclease complex (RNASEH2B, RNASEH2C, and RNASEH2A), the SAM domain and HD domain 1 (SAMHD1), and a suppressor of type I interferon signal (ADAR1). All these genes play a putative role in the metabolism of nucleic acids. The accumulation of endogenous DNA or DNA-RNA hybrids, mistaken by the human host to be nucleic acids of viral origin, culminates in the induction of an interferon-alpha-mediated immune response.
There are known intergenic phenotypic variations in Aicardi-Goutières syndrome. In families with TREX1, RNASEH2A, and RNASEH2C mutations, the disease begins in utero, and patients manifest at birth with severe neurologic impairment, represented by progressive microcephaly, spasticity, and global developmental delay. In 35% of cases, death occurs in early childhood. On the other hand, patients who have SAMHD1, ADAR1, and RNASEH2B mutations exhibit a lesser degree of neurologic handicap with a later onset of presentation, sometimes after several months of normal development.
SAMHD1 mutations are found in specifically consanguineous subpopulations such as Ashkenazi Jews, Old Order Amish, and Maltese patients. We recently encountered a patient with the SAMHD1 gene Aicardi-Goutières syndrome phenotype, thus adding to the three patients who were previously diagnosed and described in Israel. All patients were of Ashkenazi-Jewish descent. Two patients harbored a homozygous deletion and showed a severe course, whereas the other two were compound heterozygotes of the same deletion associated with a missense or a frameshift insertion mutation. The latter two manifested a milder phenotype.
Our observations indicate a possible correlation between mutations and phenotypic presentation in SAMHD1-related disorders. We also suggest placing Aicardi-Goutières syndrome highly in the differential diagnosis when evaluating Ashkenazi-Jewish patients who present with pseudo-toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and syphilis clinical signs.
Case Reports
Patient 1
The proposita is a 4-month-old female infant born to nonconsanguineous Ashkenazi-Moroccan and Ashkenazi-Ashkenazi Jewish parents who are healthy. She was closely followed by several prenatal ultrasound scans because of intrauterine growth retardation. The scans showed a marked variance between approximate weight and age of gestation. Because of concern for intrauterine growth retardation, the mother underwent a cesarean section at 38 weeks. At birth, head circumference was 32.5 cm (half standard deviation below norm); weight was 2.100 kg. The infant’s postnatal social development was impaired: she did not fixate, follow, or make eye contact. At two months, she did not smile or laugh at three months. At the age of one month, she was hospitalized for further investigations because of severe failure to thrive and severe global developmental delay attributed to her swallowing and feeding difficulties. In addition, she was extremely irritable. Primary gastrointestinal disease was ruled out by various investigations, including gastroscopy, laryngoscopy, and pH metria, which were all normal.
On neurologic examination at four months, the head circumference curve was in the 2nd percentile. She did not make eye contact and did not follow, fixate, smile, or laugh. She presented with axial hypotonia with limb hypertonicity and brisk deep tendon reflexes. A brain ultrasound was then performed, disclosing symmetric dilation of the lateral ventricles, bilateral subependymal cysts, and frontal cortical and subcortical edema with calcifications of the basal ganglia (lenticulostriate vessels) and in the periventricular white matter. Diffuse edema and periventricular and basal ganglia calcifications were confirmed by computed tomography (CT).
Magnetic resonance imaging (MRI) showed signs of subacute infarcts in the territories of the right hemispheric vessels and, to a lesser degree, in the left hemisphere. The ventricular dilation suggested early development of concurrent leukomalacia. As differential diagnosis was relevant to intrauterine infection, the following investigations were made: toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and syphilis serology was negative, as was cytomegalovirus urine culture after birth. Ocular fundi revealed no chorioretinitis, and brain stem evoked response audiometry was normal. Cytomegalovirus polymerase chain reaction was negative. Magnetic resonance angiography was performed and showed intracerebral arteriopathy manifesting as multiple vessel stenosis.
In light of these findings, Aicardi-Goutières syndrome was suspected. Lumbar puncture revealed six cells, predominantly mononuclear. Cerebrospinal fluid interferon-alpha levels were 78 IU/mL (normal <2 IU/mL). At four months, the child developed focal and generalized convulsions. Molecular studies showed a large deletion (9 kb) involving the promoter, exon 1, and intron 1 in both alleles of the SAMHD1 gene.
Patient 2
The second patient was a previously reported 13-month-old boy who presented with global developmental delay and severe failure to thrive. His birth weight was 2300 g and head circumference 35 cm; general and neurologic examinations were normal.
At three weeks, he became irritable, began to feed poorly, developed diarrhea, and failed to gain weight. He also failed to attain developmental milestones. Eye contact was poor. Head circumference decreased to two standard deviations below the mean. Neurologic assessment revealed central hypotonia with brisk tendon reflexes and choreoathetoid movements. At 13 months, his weight, height, and head circumference were 4, 3, and 4 standard deviations below mean, respectively. He had profound mental retardation and severe irritability. MRI was notable for extensive white matter destruction, delayed myelination, hypoplasia of corpus callosum, severe cortical atrophy, and global brain destruction. He died of respiratory insufficiency at 15 months. Sequencing of the SAMHD1 gene revealed the same type of homozygous deletion (9 kb) spanning the promoter, exon 1, and intron 1 in both alleles.
Patient 3
The third patient is a 12-year-old boy with severe intellectual disability and microcephaly. He was born to nonconsanguineous Ashkenazi-Jewish parents after an uneventful pregnancy and delivery. At one month, head circumference measured 36.8 cm (one standard deviation above mean); at four months, 40 cm (1.5 standard deviations below mean); and at six months, 41.6 cm (two standard deviations below mean). At seven months, head ultrasound showed multiple bilateral periventricular calcifications, more on the right, and calcified thalamic blood vessels bilaterally. Computed tomography of the brain at nine months revealed multiple foci of calcifications in the subcortical white matter and periventricular areas. There were also frontal cortical hypodense areas. Toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and syphilis screen was negative. He was followed up in a child developmental center. His motor development was slow. At age three years, he began walking and spoke a few words at five years. At five years of age, he required a hamstring muscle release operation to relieve spasticity.
A diagnosis of Aicardi-Goutières syndrome was made at age nine years. Currently, he learns in a special education class. He is able to speak short sentences, recognizes his family, understands simple commands, can read a few words, and can count. He can barely write but can type on the computer keyboard. He is unable to dress himself but feeds himself and is toilet trained. He is known to be very social and has a pleasant habitus. He walks with a walker for short distances and is aided by a wheelchair for long distances. He had two seizures in early childhood/infancy but currently is not receiving any medications.
Molecular genetic testing revealed that he is a compound heterozygote for a c.1106T>C (L369S) mutation in exon 10 of SAMHD1 and a 9 kb deletion spanning the promoter, exon 1, and intron 1.
Patient 4
The fourth previously reported patient is a male infant born to nonconsanguineous parents of Ashkenazi-Jewish ancestry, delivered at term with normal growth parameters. During early infancy, he was thought to show delayed development. At age seven months, he developed acute left hemiparesis. At 11 months, he experienced another episode of left-sided weakness. A thrombosis of the right internal carotid artery was diagnosed on clinical and radiologic grounds. He was never able to walk; he obeyed simple commands and had basic reading and writing skills. His condition was stable until his current age of 28 years, at which time he was noted to be tetraplegic and could not speak, read, or write. However, he does hear well, laughs appropriately at certain jokes, and can communicate using a talking board.
His head circumference is less than three standard deviations below the mean. He is fed by gastrostomy, inserted at age 18 because of poor weight gain. Molecular analysis revealed a c649insG on one allele, and on the other allele, he carries the same 9 kb deletion spanning the promoter, exon 1, and intron 1 of the SAMHD1 gene, as described in the previous patients.
Discussion
Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous disorder, and mutations in the SAMHD1 gene have been increasingly recognized, particularly among individuals of Ashkenazi-Jewish descent. The four cases described here, all from this population, display a spectrum of clinical severity that appears to correlate with the underlying genotype.
Genotype-Phenotype Correlation:
Patients 1 and 2, who were homozygous for the large 9 kb deletion in SAMHD1, exhibited the most severe phenotype. Both presented in early infancy with profound developmental delay, microcephaly, failure to thrive, irritability, and early-onset seizures. Neuroimaging revealed extensive white matter destruction, calcifications, and vascular involvement. Both children had significant neurological impairment, and one died in infancy.
In contrast, Patients 3 and 4, who were compound heterozygotes for the 9 kb deletion and either a missense mutation (L369S) or a frameshift insertion (c649insG), demonstrated a milder course. While both had microcephaly and developmental delays, they achieved some developmental milestones, such as walking (albeit with assistance) and basic communication skills. Patient 4 survived into adulthood, albeit with significant physical disability, but retained some cognitive and social abilities.
These observations suggest that the presence of a missense or frameshift mutation in combination with the large deletion may allow for some residual SAMHD1 function, resulting in a less severe phenotype than that seen in individuals homozygous for the deletion.
Clinical Implications:
The clinical presentation of AGS due to SAMHD1 mutations can closely mimic congenital infections, with features such as microcephaly, intracranial calcifications, leukodystrophy, and early-onset neurological impairment. The diagnosis should be considered in Ashkenazi-Jewish patients presenting with these findings, especially when infectious causes have been excluded. Early recognition is crucial for genetic counseling and management.
Our findings also suggest that AGS due to SAMHD1 mutations may not be as rare in the Ashkenazi-Jewish population as previously thought. Given the apparent founder effect for the 9 kb deletion, carrier screening and awareness among clinicians and genetic counselors are warranted.
Conclusion
The four Ashkenazi-Jewish patients with AGS described here highlight a possible genotype-phenotype correlation associated with SAMHD1 mutations. Homozygosity for a large 9 kb deletion is associated with a severe, early-onset phenotype, while compound heterozygosity with a missense or frameshift mutation leads to a milder course. These findings emphasize the importance of considering AGS in the differential diagnosis of infants with neurodevelopmental impairment and suggest the need ZYS-1 for increased awareness and genetic counseling in at-risk populations.