INFLAMMATORY VASCULOPATHY - keywords
inflammatory vasculopathy
Aicardi J, Goutières F (1984) A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic spinal fluid lymphocytosis. Ann Neurol 15:49-54.
Barth PG, Walter A, Van Gelderen I (1999) Aicardi-Goutieres syndrome: a genetic microangiopathy? Acta Neuropathol (Berl) 98:212-216.
Barth, PG (2002) The neuropathology of Aicardi-Goutieres syndrome. Eur J Paediatr Neurol 6 Suppl A:A27-31; discussion A37-29, A77-86.
Billard C, Dulac O, Boulouche J, Echenne B, Lebon P, Motte J, Robain O, Santini JJ (1988) Encephalopathy with calcification of the basal ganglia in children. A reappraisal of Fahr’s syndrome with respect to 14 new cases. Neuropediatrics 20:12-19.
Bönnemann CG, Meinecke P (1992) 'Encephalopathy of infancy with intracerebral calcification and chronic spinal fluid lymphocytosis. Another case of the Aicardi-Goutières syndrome.' Neuropediatrics, 23, 157-161.
Burn J, Wickramasinghe HT, Harding B, Baraitser M (1986) A syndrome with intracranial calcification and microcephaly in two sibs, resembling intrauterine infection. Clin Genet 30: 112–116.
Campbell IL, Krucker T, Steffensen S et al. (1999) Structural and functional neuropathology in transgenic mice with CNS expression of IFN-alpha. Brain Res 835:46–61
Crow YJ, Hayward BE, Parmar R et al. (2006) Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi–Goutières syndrome at the AGS1 locus. Nat Genet 38:917–20
Crow YJ, Leitch A, Hayward BE et al. (2006) Mutations in genes encoding ribonuclease H2 subunits cause Aicardi–Goutières syndrome and mimic congenital viral brain infection. Nat Genet 38:910–16
du Plessis AJ, Kaufmann WE, Kupsky WJ (1993) Intrauterine-onset myoclonic encephalopathy associated with cerebral cortical dysgenesis. J Child Neurol8: 164–170.
Goldberg MF (1994) The blinding mechanisms of incontinentia pigmenti. Ophthalmic Genet 15(2): p. 69-76.
Goldberg MF, Custis PH (1993) Retinal and other manifestations of incontinentia pigmenti (Bloch-Sulzberger syndrome). Ophthalmology 100(11): p. 1645-54.
Goldstone DC, Ennis-Adeniran V, Hedden JJ et al. (2011) HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 480:379–82.
Goutières F, Aicardi J, Barth PG, Lebon P (1999) Aicardi- Goutières syndrome: an update and results of interferon studies. Ann Neurol 44:900–907.
Hauw JJ et al. (1977) [Neuropathological study of incontinentia pigmenti. Anatomical case report (author's transl)]. Acta Neuropathol (Berl) 38(2): p. 159-62.
Hennel SJ (2003) Insights into the pathogenesis of cerebral lesions in incontinentia pigmenti. Pediatr Neurol 29(2): p. 148-50.
Kasai T, Kato Z, Matsui E, Sakai A, Nishida T, Kondo N, Taga T (1997) Cerebral infarction in incontinentia pigmenti: the first report of a case evaluated by single photon emission computed tomography. Acta Paediatr 86(6): p. 665-7.
Knoblauch H, Tennstedt C, Brueck W, Hammer H, Vulliamy T, Dokal I, Lehmann R, Hanefeld F, Tinschert S (2003) Two brothers with findings resembling congenital intrauterine infection-like syndrome (pseudo-TORCH syndrome). Am J Med Genet 120: 261–265.
Lanzi G, D'Arrigo S, Drumbl G, Uggetti C, Fazzi E (2003) Aicardi-Goutières syndrome: differential diagnosis and aetiopathogenesis. Funct Neurol 18(2):71-5.
Lebon P, Badoual J, Ponsot G, Goutières F, Hémeury-CukierF, Aicardi J (1988) Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J Neurol Sci 84:201–208.
Lee AG, Goldberg MF, Gillard JH, Barker PB, Bryan RN (1995) Intracranial assessment of incontinentia pigmenti using magnetic resonance imaging, angiography, and spectroscopic imaging. Arch Pediatr Adolesc Med 149(5): p. 573-80.
Lim YW, Sanz LA, Xu X et al. (2015) Genome-wide DNA hypomethylation and RNA:DNA hybrid accumulation in Aicardi–Goutières syndrome. Elife. 2015 Jul 16;4. doi: 10.7554/eLife.08007
Maingay-de Groof F, Lequin M, Roofthooft DW, Oranje A, de Coo IF, Bok LA, Mancini GM, Govaert PP (2008) Extensive cerebral infarction in the newborn due to incontinentia pigmenti. Eur J Paediatr Neurol 12(4):284-9.
Meuwissen ME, Schot R, Buta S, Oudesluijs G, Tinschert S, Speer SD, Li Z, van Unen L, Heijsman D, Goldmann T, Lequin MH, Kros JM, Stam W, Hermann M, Willemsen R, Brouwer RW, Van IJcken WF, Martin-Fernandez M, de Coo I, Dudink J, de Vries FA, Bertoli Avella A, Prinz M, Crow YJ, Verheijen FW, Pellegrini S, Bogunovic D, Mancini GM (2016) Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. J Exp Med 213(7):1163-74
Mehta L, Trounce JQ, Moore JR, Young ID (1986) Familial calcification of the basal ganglia with cerebrospinal fluid pleocytosis.J Med Genet 23:157–160.
O'Doherty NJ, Norman RM (1968) Incontinentia pigmenti (Bloch-Sulzberger syndrome) with cerebral malformation. Dev Med Child Neurol 10(2): p. 168-74.
Pellegrino RJ, Shah AJ (1994) Vascular occlusion associated with incontinentia pigmenti. Pediatr Neurol 10(1): p. 73-4.
Razavi-Encha F, Larroche JC, Gaillard D (1988) Infantile familial encephalopathy with cerebral calcifications and leukodystrophy. Neuropediatrics 19:72-79.
Rice GI, Bond J, Asipu A et al. (2009) Mutations involved in Aicardi–Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet 41:829–32
Rice GI, del Toro Duany Y, Jenkinson EM et al. (2014) Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet 46:503–9
Sabatino G, Domizio S, Verrotti A, Ramenghi LA, Pelliccia P, Morgese G (1994) Fetal encephalopathy with cerebral calcifications: a case report. Child’s Nerv System 10:195-197.
Sanchis A, Cerveró L, Bataller A, Tortajada JL, Huguet J, Crow YJ, Ali M, Higuet LJ, Martínez-Frías ML (2005) Genetic syndromes mimic congenital infections. J Pediatr 146: 701–705.
Schwabenland M, Mossad O, Peres AG, Kessler F, Maron FJM, Harsan LA, Bienert T, von Elverfeldt D, Knobeloch KP, Staszewski O, Heppner FL, Meuwissen MEC, Mancini GMS, Prinz M, Blank T. Loss of USP18 in microglia induces white matter pathology. Acta Neuropathol Commun. 2019 Jul 4;7(1):106.
Shuper A, Bryan RN, Singer HS (1990) Destructive encephalopathy in incontinentia pigmenti: a primary disorder? Pediatr Neurol 6(2): p. 137-40.
Siemes H, Schneider H, Dening D, Hanefeld F (1978) Encephalitis in two members of a family with incontinentia pigmenti (Bloch-Sulzberger syndrome). The possible role of inflammation in the pathogenesis of CNS involvement. Eur J Pediatr 129(2): p. 103-15.
Slee J, Lam G, Walpole I (1999) Syndrome of microcephaly, microphthalmia, cataracts, and intracranial calcification. Am J Med Genet 84: 330–333.
Troost D, van Rossum A, Veiga Pires J, Willemse J (1984) Cerebral calcifications and cerebellar hypoplasia in two children: clinical, radiologic and neuropathological studies - A separate neurodevelopmental entity. Neuropediatrics 15:102-109.
Venkatesh S, Coulter DL, Kemper TD (1994) Neuroaxonal dystrophy at birth with hypertonia and basal ganglia mineralization. J Child Neurol 9:74-76.
Vivarellia R, Grossoa S, Cionia M, Galluzzib P, Montib L, Morgesea G, Balestria P (2001) Pseudo-TORCH syndrome or Baraitser-Reardon syndrome: diagnostic criteria. Brain Dev 23: 18–23.
Watts P, Kumar N, Ganesh A, Sastry P, Pilz D, Levin AV, Chitayat D (2008) Chorioretinal dysplasia, hydranencephaly, and intracranial calcifications: pseudo-TORCH or a new syndrome? Eye 22: 730–733.
Yoshikawa H, Uehara Y, Abe T, Oda Y (2000) Disappearance of a white matter lesion in incontinentia pigmenti. Pediatr Neurol 23(4): p. 364-7.
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references to inflammatory vasculopathy
NF1a mutation
Maternal exposure to pathogens [TORCH (toxoplasmosis, other [syphilis, varicella, mumps, parvovirus and HIV), rubella, cytomegalovirus, and herpes simplex] can cause severe fetal brain damage in utero. Characteristics of TORCH include microcephaly, white matter disease, cerebral atrophy and calcifications. Children are considered to have pseudo-TORCH syndrome (PTS) if they display a clinical phenotype indicative of in utero exposure to infection, but where the disorder has a non-infectious aetiology. Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, brain calcification and occasionally systemic features (like hepatocellular necrosis) at birth.
Baraitser-Reardon syndrome, reviewed by Vivarellia et al (2001) (11 families) changed in name to pseudo-TORCH syndrome later on, to emphasize the resemblance to congenital infections in instances of (familial) inflammation of brain vessels in the neonatal period.
To this review must be added the descriptions by du Plessis et al (1993), Slee et al (1999), and Watts et al (2008).) The cardinal features in 12 families were consanguinity in 5/12; congenital microcephaly in all; CNS calcification in all: in cerebral white matter 9/12 (periventricular in 6), in basal ganglia 5/12, in thalamus 5/12, in cerebellum 4/12, in caudate 2/12, in brainstem 2/12; ventriculomegaly in 12/12; (ponto)cerebellar hypoplasia in 6/12; seizures in 10/12; hepatomegaly in 6/12, with elevated liver enzymes; and thrombocytopenia in 5/12. Exceptional features were cloudy corneae (Burn et al 1986) and microphthalmia with cataract (Slee et al 1999). Polymicrogyria was mentioned by Burn et al (1986) and du Plessis et al (1993).
With advanced genetic options, at least three different subgroups of vascular inflammation have been described: incontinentia pigmenti, Aicardi-Goutières syndrome and USP18 mutation.
Aicardi-Goutières syndrome
inflammatory vasculopathy
incontinentia pigmenti
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term newborn with tetralogy of Fallot, falciform retinal dysplasia and elevated serum IgM of 1.58 g/L; intense periventricular calcification; rubella, CMV and toxoplasmosis were excluded
USP18 mutation
incontinentia pigmenti
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Incontinentia pigmenti is an X-linked dominant condition also known as Bloch-Sulzberger syndrome, which occurs in approximately 1 in 50.000 newborns (Pellegrino and Shah 1994, Maingay-de Groof et al. 2008). It is fatal in most males before the second trimester of pregnancy. The term is derived from the dislocation (incontinence) of melanin pigment from the basal-cell layer of the epidermis to the upper dermis. Skin lesions follow Blaschko lines with a distinct pattern of development in four stages: vesiculopapular, verrucous and hyperpigmented; finally there is a fourth stage of linear anhidrotic hypopigmented lesions. Other tissues involved are teeth, hair, nails, eyes and in 30-50% the central nervous system: epilepsy, mental retardation, hemiparesis, spasticity, microcephaly and cerebellar ataxia.
The cause is mutation in the gene of nuclear factor kappa B (NF-kappaB) essential modulator (NEMO) currently known as IKBKG (inhibitor of kappa light polypeptide gene enhancer in B-cells), located on chromosome X, band q28. The gene product protects against tumour necrosis factor–induced apoptosis. CNS damage may cause neonatal seizures.
Ischaemic cerebrovascular accidents in the neonatal period are recognized as a complication of IP. There are no descriptions of documented large artery occlusion, although this has been documented in childhood. Striatal arteriopathy, detectable on ultrasound as an indicator of arteritis in middle sized MCA-derived perforator arteries, was recorded.
Hennel et al. 2003 indicated that the findings of microvascular haemorrhagic infarcts in the periventricular white matter and associated MRA changes of decreased branching and filling of intracerebral arteries are indicative of a microangiopathic arterial process. It is likely that IP affects middle and small sized arteries in the newborn brain, perhaps in addition to the postulated micro-arterial involvement. Kasai et al. 1997 reported infarction in multiple arterial regions of the brain: with SPECT sluggish blood flow was detected but there were no macrovascular occlusions on MRA. MRA was unremarkable in two infants studied by Lee et al. 1995. Pellegrino et al. 1994 did report MCA occlusion in a 4 year old girl with IP with acute onset of hemiparesis suggesting incontinentia pigmenti should be included in the differential diagnosis of ischaemic stroke in females. This suggests that large artery occlusion might be possible at any age, but is certainly uncommon in the newborn period.
Brain changes in IP are often bilateral and in the anterior circulation. There is the suggestion that venous lesions may be mixed together with lesions of small or middle-sized arteries.
O’Doherty and Norman 1968 reported a patient with polymicrogyria, unduly thickened cortical gray matter lacking normal lamination and unilateral pyramidal tract hypoplasia. They mentioned unexplained areas of focal necrosis within central white matter, loss of neurons within gyri and patchy loss of Purkinje cells and granule cells in the cerebellum.
Hauw et al. 1977 reported ulegyria together with a diffuse inflammatory process with perivascular infiltration of lymphocytes, histiocytes, eosinophils, mononuclear cells and macrophages.
Shuper et al. 1990 described an acute destructive encephalopathy with radiographic findings of haemorrhagic necrosis and brain edema.
Siemes et al. 1978 reported encephalitis with haemorrhagic necrosis of white matter and venous inflammation and they postulated a response to vaccination. Ocular manifestations included arteriolar occlusion and subsequent neovascularization and infarction (Goldberg and Custis 1993, Goldberg 1994).
Lee et al. 1995 postulated vascular occlusive phenomena seen in the retina and in the CNS.
Although highly associated with congenital CMV, anterior temporal lobe cysts in children can be seen in other diseases such as congenital muscular dystrophy, glutaric aciduria type II, megalencephalic leukoencephalopathy with subcortical cysts, non megalencephalic leukoencephalopathy with subcortical cysts and Aicardi-Goutières syndrome.
Aicardi-Goutières syndrome
Calcifications are both present as concretions and as perivascular cuffs of calcium surrounding small vessels. Small vessel involvement (microangiopathy) is apparent from a typical distribution of microinfarctions in at least one case studied.
Over time, atrophy develops, particularly of the periventricular regions, brainstem and cerebellum. Arteriopathy is a prominent feature of SAMHD1 mutations with aneurysms, stenoses and moyamoya pattern encountered.
Mutations are identified in approximately 90% of individuals with characteristic clinical and radiologic findings of AGS. It is established that the disorder may result from a defect in the degradation of RNA–DNA heteroduplexes, causing them to accumulate at high levels. Mutations in the following genes are responsible for the disorder: TREX1 (3′ to 5′ single-stranded DNA exonuclease, AGS1); RNASEH2A, RNASEH2B, and RNASEH2C (RNase H2AGS2-4); SAMHD1 (3′ to 5′ exonuclease and dNTP hydrolase, AGS5); ADAR1 (RNA adenosine deaminase, AGS6); and gain of function mutations in the cytosolic double-stranded RNA receptor gene IFIH1, mimicking the intracellular response to a viral infection. Most AGS is inherited in an autosomal recessive manner; in a few instances AGS can result from de novo autosomal dominant mutations in TREX1.
Brain inflammation involving astrocyte pathology has been reported with: Aicardi-Goutières syndrome, Alexander disease, autoimmune GFAP astrocytopathy, CIC-2-related disease, megalencephalic leukoencephalopathy with subcortical cysts, oculo-dento-digital dysplasia, vanishing white matter disease. An example is presented here of pseudo-Torch syndrome associated with NF1A (nuclear factor 1 a in astrocytes) mutation.
Aicardi-Goutières syndrome (AGS) is an early-onset encephalopathy that results in intellectual and physical handicap. A portion of infants with AGS present at birth with abnormal neurologic findings, progressive microcephaly, hepatosplenomegaly, elevated liver enzymes and thrombocytopenia, similar to congenital infection. Affected infants present at variable times after the first few days of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by irritability, intermittent sterile pyrexia, loss of skills and slowing of head growth. As many as 40% have chilblain lesions on the fingers, toes and ears. There can be prominent eye disease: microphthalmia, opaque anterior eye chamber, blindness, glaucoma, abnormal VEPs. The general condition of the patient is poor, there is marked hypotonia interrupted by opisthotonic episodes, failure to develop, febrile episodes, and death in a state of decerebration within a few years, although some children survive for several years (Aicardi and Goutières 1984).
However, cases of later onset after the age of 6–12 months may run a less severe course (Rice et al. 2009). Most individuals with AGS do not reproduce.
The diagnosis can be made with confidence in individuals with typical findings, characteristic abnormalities on imaging (calcification of the basal ganglia and white matter, leukodystrophic changes) and mutation in one of five known related genes. Generalized patchy cerebral demyelination and a chronic low-grade CSF lymphocytosis, without evidence of infection, are characteristic. The persistent mild CSF lymphocytosis (10–80 cells/mm3) is not constant and tends to decrease with time. Moderately elevated levels of interferon alpha are present in CSF in most cases, at least in the first years of the disease (Lebon et al. 1988) and to a lesser extent in the blood. Cases have been reported as ‘Cree encephalitis’ from highly inbred Indian communities of Northern Quebec.
a postmortem brain with massive haemorrhagic destruction
prenatal ultrasound (22nd gestational week with hyperechoic change in cortex and deep grey matter
lesion in deep grey matter and cortex on T2 neonatal MRI
Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. Loss-of-function recessive mutations of USP18 were identified in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune reaction with haemorrhagic destruction, calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. This proposes USP18 as a therapeutic target not only for genetic but also acquired IFN-mediated CNS disorders. The mechanism may be decreased control of IFN in microglia (Schwabenland et al. 2019)
NFIA-related disorder is defined as heterozygous inactivation or disruption of only NFIA without involvement of adjacent or surrounding genes. It comprises CNS abnormalities (most commonly of the corpus callosum) with or without urinary tract defects, such as unilateral or bilateral vesicoureteral reflux and hydronephrosis. Additional features include macrocephaly, seizures, developmental delay and/or cognitive impairment, nonspecific dysmorphic features, ventriculomegaly, and hypotonia, which can exacerbate motor delay and feeding issues in infancy. Rarer features may include strabismus, cutis marmorata, or craniosynostosis of the metopic, lambdoid, or sagittal suture.
https://www.ncbi.nlm.nih.gov/books/NBK542336/
NF1A mutation
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