Carnitine palmitoyltransferase II deficiency
Nov. 24, 2024
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Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
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Aicardi-Goutieres syndrome is a genetically heterogeneous multisystemic disorder due to defects in processing nucleic acids, often leading to progressive encephalopathy and cutaneous, hematological, and neurodevelopmental problems. Initially recognized as an early-onset leukoencephalopathy with intracranial calcifications, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia in the infancy period resembling a congenital infection, Aicardi-Goutieres syndrome is now recognized as a multisystem disorder with a highly variable disease progression and morbidity. Molecular studies have established at least nine genes that encode enzymes causative of Aicardi-Goutieres syndrome: TREX1 (3’ repair exonuclease 1), RNASEH2A (ribonuclease H2 subunit A), RNASEH2B, RNASEH2C, SAMHD1 (SAM-domain- and HD domain-containing protein 1), ADAR1 (adenosine deaminase acting on RNA 1), IFIH1 (interferon induced with helicase C domain 1), LSM11, and RNU71. Whereas IFIH1 is inherited in an autosomal dominant pattern, other genes are inherited in an autosomal recessive pattern, except specific variants in TREX1 and ADAR.
• Aicardi-Goutieres syndrome is a genetically heterogenous multisystemic disorder with a variable onset and phenotype. | |
• Subacute-onset encephalopathy, loss of motor and cognitive skills, paraparesis, epileptic seizures, microcephaly, dystonia, and non-neurologic manifestations, such as chilblain-like skin lesions, glaucoma, abnormal dentition, hypothyroidism, lupus-like disease, and arthropathy, can be seen in patients with Aicardi-Goutieres syndrome. | |
• Syndrome manifestations include hepatosplenomegaly, elevated liver enzymes, thrombocytopenia, sterile pyrexias, and basal ganglia calcifications. Therefore, Aicardi-Goutieres syndrome can mimic intrauterine TORCH infections and congenital HIV, both clinically and radiologically, in the absence of evidence of infection. | |
• Cerebrospinal fluid analysis reveals pleocytosis, suggesting a possible inflammatory reaction. | |
• Molecular genetic analysis and the establishment of causative genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1, LSM11, RNU71) that encode proteins in nucleic acid metabolism have marked an era in the pathogenesis and classification of clinical phenotypes. | |
• The identification of the molecular basis and subsequent progress in understanding disease pathogenesis have led to the first attempts in treatment, and further rationales for treatment modalities are expected to become available in the near future. |
In 1984, Jean Aicardi and Francoise Goutieres described eight children from five families presenting with early-onset encephalopathy characterized by basal ganglia calcifications, white matter abnormalities, cerebral atrophy, and CSF lymphocytosis (02). During the first year of life, spasticity, dystonia, and microcephaly were reported in these children. The consanguinity in families and recurrence of this clinical picture in siblings suggested a genetic basis for this phenotype, with an autosomal recessive trait. The authors identified nine previously reported, possibly similar cases of unclassified leukodystrophy in the literature that may have been the same clinical entity.
In 1988, Pierre Lebon identified the additional feature of this disease: elevation of CSF interferon alfa concentrations in the absence of demonstrable infection. This finding was a valuable marker in clinical diagnosis, and it also supported Aicardi and Goutieres’s suggestion that Aicardi-Goutieres syndrome was an inflammatory disease. Following publication by Aicardi and Goutieres, similar cases were subsequently reported (35; 34; 20; 26; 21; 22; 28). The term “congenital infection–like syndrome” was used, cutaneous features were described, and autoimmune disease features were noted.
The disorder was listed as “Aicardi-Goutieres syndrome” in 1992, and new cases were added to the disorder in the following years. There were probably many more cases of this early-onset hereditary encephalopathy characterized by microcephaly, leukodystrophy, diffuse cerebral atrophy, CSF lymphocytosis, and increased CSF levels of interferon alfa that were unrecognized. The phenotypic overlap of Aicardi-Goutieres syndrome with pseudo-TORCH syndrome was noted (07).
In 2005, Crow and colleagues hypothesized that abnormal regulation of interferon alfa causes the phenotypic similarities shared by systemic lupus erythematosus, congenital rubella, in utero HIV infection, and Aicardi-Goutieres syndrome. They emphasized that the identification and characterization of the Aicardi-Goutieres syndrome gene may provide new insights into the control of interferon alfa production and the disease pathogenesis (06).
Cree encephalitis, an early-onset progressive encephalopathy in Cree indigenous families in Canada (03), was originally considered a separate disorder, but subsequent genetic analysis revealed that it is the same as Aicardi-Goutieres syndrome 1 (08).
Dale and colleagues noted a congenital infection–like syndrome with clinical features similar to systemic lupus erythematosus (15). They described the disease as “familial systemic lupus erythematosus” and highlighted phenotypic similarities with Aicardi-Goutieres syndrome.
With the identification of the genetic basis of Aicardi-Goutieres syndrome, clinical phenotypes have been remarkably expanded. Mutations in the TREX1 (AGS1), RNASEH2A (AGS4), RNASEH2B (AGS2), RNASEH2C (AGS3), SAMHD1 (AGS5), ADAR1 (AGS6), and IFIH1 (AGS7) genes have been described as disease-causing mutations. Crow and colleagues suggested the term “type 1 interferonopathy” as the disease has various types of clinical manifestations, including neurologic and non-neurologic symptoms. In 2020, two new genes were described as a cause of disease. The LSM11 gene (AGS8) was described in two brothers, born of first-cousin parents, with Aicardi-Goutieres syndrome who died at 2 years of age. The RNU71 gene was described in 16 patients from 11 families with Aicardi-Goutieres syndrome with an autosomal recessive inheritance (28; 36).
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MedLink®, LLC
3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122
Toll Free (U.S. + Canada): 800-452-2400
US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125