COL4A1/COL4A2-related disorders

COL4A1 and COL4A2, both located on chromosome 13q34, encode the alpha1 and alpha 2 chains of type IV collagen, a key component of basement membranes in blood vessels and various soft organs in mammals [17]. Mutations in these genes can give rise to brain small vessel disease 1 (BSVD1, OMIM#175,780) and 2 (BSVD2, OMIM#614,483), respectively, and have been associated with a broad spectrum of cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities known as COL4A1/COL4A2–related disorders. They are inherited in an autosomal dominant (AD) fashion and have a high, de novo mutation rate. This complex of disorders is characterized by highly incomplete penetrance and a wide range of phenotypic variation even among family members [18] and manifest at any developmental stage, from the prenatal (fetal) to the adult stage.

Cerebrovascular manifestations occur in more than half of individuals harboring a COL4A1 mutation [14]. COL4A2 mutations are apparently associated with even less penetrance and a globally milder phenotype than COL4A1 mutations [19]. Seizures are the most prevalent clinical symptom associated with these variants. Motor dysfunction and developmental delay are highly prevalent [18].

Prenatal and neonatal intracerebral hemorrhage (ICH) and encephaloclastic porencephaly are frequently associated with mutations in both COL4A1 and COL4A2 [18, 20,21,22]. Their most common cause is a germinal matrix hemorrhage leading to deep venous infarction involving the basal ganglia and frontal lobe, tissue necrosis, and porencephalic cavitation (Fig. 1). Prenatal ICH size correlates clinically with motor outcomes [22]. Extensive bilateral porencephaly also resembles hydranencephaly.

Fig. 1

A 3-year-old, male patient with COL4A1-related disorder. a Axial non-contrast computed tomography demonstrated calcification along the bilateral occipital horns of the lateral ventricles (arrows) and asymmetrical ventricular enlargement. b-e Axial T2-weighted imaging and coronal FLAIR imaging revealed porencephaly in the bilateral frontal lobes, asymmetrical ventricular enlargement, hyperintensities in the bilateral basal ganglia, thalami, deep white matter, and cerebellar dysplasia. Note also the implanted intraocular lens for cataracts (arrows). f Axial T2*-weighted imaging demonstrated multiple microbleeds in the splenium of the corpus callosum and subcortical and deep white matter

Schizencephaly, also known as dysplastic porencephaly, is defined as a cleft extending from the pial surface to the lateral ventricle and lined by heterotopic gray matter. Schizencephaly is also associated with mutations in COL4A1 and COL4A2 [23, 24]. Niwa et al. reported susceptibility-weighted imaging (SWI) findings demonstrating hemorrhages in the peripheral portion of the schizencephalic and intraparenchymal region. Venous tortuosity may be helpful in assessing for a possible relationship between schizencephaly and COL4A1 mutations [25]. Other cortical malformations, ranging from polymicrogyria to subependymal and subcortical heterotopia without hemorrhage or calcification, have also been reported [24].

Other types of brain lesion related to prenatal hemorrhage have been reported in mutations in children, such as abnormal basal ganglia, dysplastic brain stem, cerebellar hemorrhage, cerebellar hypoplasia/atrophy, brain calcification, ventricular asymmetry, mild ventriculomegaly, and hydrocephalus (Figs. 1, 2) [18, 26, 27] while Dandy-Walker malformation may occur prenatally [28].

Fig. 2

COL4A2-related disorder in a 5-year-old, male patient with right hemiparesis. Axial T2-weighted imaging (a, b) and coronal FLAIR imaging (c, d) demonstrated cystic encephalomalacia in the left parietal lobe, ulegyria in the left insula and occipital lobe, and hyperintensities in the left posterior limb of the internal capsule and thalamus

Periventricular leukomalacia (PVL), defined as pre- or perinatal, post-hypoxic-ischemic leukoencephalopathy without porencephaly is reported in COL4A1 mutations [18]. In the absence of a remarkable family history, this PVL phenotype may elude diagnosis. In the absence of other prominent symptoms, such as porencephaly, a high creatine kinase (CK) concentration or microbleeds may be helpful in diagnosing this PVL phenotype in COL4A1 mutations.

MR angiography can also detect asymptomatic, intracranial aneurysms, dolichoectasia, and vascular tortuosity. These most frequently occur in the internal carotid arteries, specifically in the C4 and C5 segments. In certain instances, they can affect the basilar artery as well [29].

A distinct phenotype known as hereditary angiopathy, nephropathy, aneurysms, and cramps (HANAC) stems from COL4A1 mutations at exons 24 and 25 [30]. The cerebrovascular phenotype is characterized by cSVD with a low risk of hemorrhagic stroke and the presence of aneurysms around the carotid siphon. Bilateral retinal arteriolar tortuosity is persistent and frequently accompanied by multiple, retinal hemorrhages in the absence of any other ocular abnormality. Patients with HANAC may also experience muscle spasms and kidney lesions, which can contribute to renal cyst formation, chronic kidney failure, and occasionally hematuria.

There is no effective treatment. However, patients and their physicians should be informed that the fragility of the vascular wall may lead to a cerebral or retinal hemorrhage, which can cause the vascular wall to rupture in response to trauma (shock, vigorous physical movement, vaginal delivery) or anticoagulant use, which individuals with this condition should avoid [31]. In pregnant patients with this condition, cesarean delivery has been proposed as a method of avoiding birth trauma to prevent cerebral vascular injury [32].

Similarly, dysfunction of the tight junction components, such as occludin (OCLN) and junctional adhesion molecules (JAMs), is associated with overlapping clinical presentations. In particular, JAM3 mutations are known to cause congenital cataracts and hemorrhagic destruction of the brain [33, 34]. JAM3 screening should be requested in prenatal diagnostic screening for congenital cataracts.

COLGALT1-related disorders

COLGALT1-related disorders (BSVD3, OMIM #618,360) are autosomal recessive disorders caused by mutations in the COLGALT1 gene on chromosome 19p13, which encodes the collagen beta galactosyltransferase 1 (ColGalT1) protein. ColGalT1 initiates glycosylation of CoL4a1 (and possibly Col4a2), a crucial step in the formation of the triple helix of collagen IV. Miyatake et al. [35] described two patients with a compound heterozygous variant of the COLGALT1 gene and demonstrated that decreased ColGalT1 activity leads to decreased synthesis of CoL4a1 protein, thereby reducing type IV collagen secretion. Additionally, Teunissen et al. reported a more severe phenotype with a homozygous essential splice site variant of the COLGALT1 gene [36].

The resulting phenotype varies highly in terms of the timing and location of intracranial hemorrhages. Some patients may have in utero or early infantile onset accompanied by severe, global, developmental delay, spasticity, and seizures and require full support for daily living. Other patients may exhibit normal or mildly delayed development accompanied by a sudden onset of intracranial hemorrhage resulting in acute, neurological decline. Environmental stress (either in utero stress or an infection) might trigger its onset, as is the case in COL4A1/COL4A2-related disease.

The radiographic features of COLGALT1-related disorders are also comparable to those of COL4A1/COL4A2-related disease [35, 36]. MRI findings typical of COL4A1/COL4A2-related disease include porencephaly, parenchymal/intraventricular hemorrhage, hydrocephalus, cerebral calcification, microbleeds, vascular leukoencephalopathy, lacunar infarcts, dilated perivascular spaces, and intracranial aneurysms (Figs. 3, 4).

Fig. 3

COLGALT1-related disorder in a 12-year-old, male patient with severe developmental delay, epilepsy, spastic quadriplegia. Axial T2-weighted imaging (a) and FLAIR imaging (b) demonstrated porencephaly in the left hemisphere with destructive changes of the basal ganglia and bilateral leukoencephalopathy with mild atrophy. Hyperintense lesions were also observed in the right basal ganglia, posterior limb of the internal capsule, and bilateral thalami (reprinted with permission from Reference [35])

Fig. 4

COLGALT1-related disorder. Axial T2-weighted imaging (a) at the age of 9 years demonstrated hyperintense lesions in the bilateral basal ganglia, thalami, deep cerebral white matter, and internal and external capsules. Axial diffusion-weighted imaging (DWI) (b) revealed susceptibility effects of microbleeds in the right basal ganglia and left temporal white matter. After 1 day, axial FLAIR imaging (c) and computed tomography (d) after the patient lost consciousness owing to an influenza virus infection demonstrated acute, massive, bilateral, parenchymal and intraventricular hemorrhages (reprinted with permission from Reference [35])

Neonatal and infantile stagesIncontinentia pigmenti

Incontinentia pigmenti (IP, also called Bloch-Sulzberger syndrome, OMIM #308,300) is an X-linked, neurocutaneous disorder caused by a mutation in the IKK-gamma gene (IKBKG), also called NEMO, on chromosome Xq28. IKBKG is essential for the activation of the nuclear factor-kappa B (NF- κB) transcription factor, which is involved in preventing tumor necrosis factor-alpha (TNF-α)-induced apoptosis and in regulating the immune and inflammatory responses [37]. Thus, IKBKG-deficient cells are probably more prone to inflammation and apoptosis. IP is characterized by congenital skin lesions, dental and skeletal dysplasia, and ocular and central nervous system (CNS) abnormalities. IP is almost exclusively seen in females. The mutations appear to be lethal in males; postzygotic mosaicism related to IKBKG has been reported in only a few male patients [38].

The skin lesions characteristic of IP progress through the bullous stage (birth to age 4 months); the verrucous stage (for several months); the hyperpigmentation stage (age 6 months to adulthood); to the atretic stage. The skin abnormalities characterizing each stage occur along the lines of embryonic and fetal skin development known as the Blaschko lines [39, 40] (Fig. 5), which correspond to cell migration or growth pathways established during embryogenesis. Similar to dermatomes, they are linear at the extremities and circumferential at the trunk.

Fig. 5

Incontinentia pigmenti in a female neonate with a decreased level of consciousness and weak sucking reflex. a A clinical photograph of skin lesions on day 15 shows an erythematous and vesiculobullous rash on her arms and trunk spreading in along the Blaschko lines (reprinted with permission from Reference [40]). b, c Axial DWI demonstrated multiple areas of ischemic change with scattered foci of restricted diffusion in the bilateral cerebral cortices, basal ganglia, thalami, splenium of the corpus callosum, and midbrain. (d) Axial susceptibility-weighted imaging (SWI) demonstrated multiple microhemorrhages in the bilateral cerebral cortices and thalami. e, f Axial T2-weighted imaging and FLAIR imaging (g) found multiple, cavitary lesions in the bilateral, cerebral subcortical white matter

Neurological manifestations occur in 30% of IP patients, constituting one of the major causes of morbidity and mortality associated with the condition. Symptoms, such as seizures, intellectual disability, developmental delay, spastic paresis, cerebellar ataxia, and microcephaly, may also be observed. Most neurological features occur from the neonatal through the early infantile period and only rarely in late childhood [41, 42]. Inflammatory mechanisms, vascular injury, and possibly disturbed apoptosis during development are apparently at the root of the cerebral manifestations [43].

Brain MRI can visualize tissue damage resulting from disease in small vessels as well as also medium-sized cerebral arteries [44]. Such tissue damage may include periventricular and subcortical white matter disease, hemorrhagic changes, corpus callosum hypoplasia, polymicrogyria, cortical dysplasia, cerebral atrophy, cerebellar hypoplasia, myelination delays or ventricular dilatation [43, 45]. DWI abnormalities are characteristic, with multifocal and punctate lesions distributed throughout the white matter in a speckled pattern often associated with changes in the corpus callosum. Reduced diffusion is also observed in the basal ganglia, thalami, cerebellum, and cerebral peduncles [40, 46] (Fig. 5). Sequential scans in affected infants demonstrate progressive cortical and white matter cavitation/atrophy, ventricular enlargement, and thinning of the corpus callosum.

Ocular abnormalities are another major cause of disability in IP patients. Approximately 20–37% of IP patients have an ocular defect, such as strabismus, retinopathy, congenital cataract or microphthalmia [47, 48].

Previous studies have reported retinal lesions and perivascular and intravascular eosinophilic infiltration of the CNS and skin in IP. Maingay-de Groof et al. reported that NEMO mutation activates eotaxin, a potent, eosinophil-selective chemokine that is highly expressed by endothelial cells in IP and correlates with perivascular and intravascular eosinophilic infiltration [44].

Aicardi-Goutieres syndrome

Aicardi-Goutieres syndrome (AGS) typically manifests as an early-onset, subacute encephalopathy usually resulting in profound intellectual and physical disability. AGS presents at birth or in the first few weeks of life with abnormal neurological findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia. Although AGS is phenotypically similar to congenital toxoplasmosis, other, rubella, cytomegalovirus, herpes simplex (TORCH) infections, serological tests for common prenatal infections return negative. Over time, chilblain skin lesions on the fingers, toes, and ears develop in up to 40% of individuals. Severe, neurological dysfunction becomes clinically apparent in infancy, manifesting as progressive microcephaly, spasticity, dystonic posturing, and profound psychomotor retardation, often leading to death in early childhood. Recently, atypical, sometimes milder, cases of AGS have come to light [49].

Many, previous studies have advocated the use of the more generic term, type I interferonopathy (IFN), to refer to this group of monogenic diseases because the upregulation of type I interferon is a crucial aspect of its pathogenesis [50]. Mutations in any of the following nine genes may result in the AGS phenotype: TREX1 (AGS1, OMIM #225,750), RNASEH2B (AGS2, OMIM #610,181), RNASEH2C (AGS3, OMIM #610,329), RNASEH2A (AGS4, OMIM #606,034), SAMHD1 (AGS5, OMIM #612,952), ADAR (AGS6, OMIM #615,010), IFIH1 (AGS7, OMIM #615,846), LSM11 (AGS8, OMIM #619,486), and RNU7-1 (AGS9, OMIM #619,487). The encoded proteins are involved in nucleic acid metabolism and/or signaling. Spinal fluid and serum analysis reveals elevated levels of interferon activity stemming from increased expression of interferon-stimulated genes in the peripheral blood [51]. TREX1 mutations are associated with a true neonatal presentation [52]. Most patients present symptoms at a slighter later age. Mutations most frequently occur in RNASEH2B [53].

Computed tomography (CT) demonstrates multiple, punctate or globular calcifications of the basal ganglia, particularly the putamina, thalami, deep and subcortical white matter, and cerebellar dentate nuclei (Fig. 6). TREX1 mutations tend to produce particularly severe calcification [53]. T2-weighted imaging demonstrates hyperintensity in the subcortical and deep white matter, especially in the frontal and temporal lobes [49]. White matter rarefaction and anterior temporal lobe cysts are strongly associated with TREX1 mutations and early age at onset [53, 54].

Fig. 6

Aicardi-Goutieres syndrome with IFIH1 mutations in a 15-year-old, female patient with quadriplegia and chilblain skin lesion of the big toe. a–c Axial non-contrast computed tomography found multiple calcifications of the bilateral, right frontal, subcortical white matter, bilateral deep white matter, basal ganglia, and cerebellar dentate nuclei. d Axial T2-weighted imaging demonstrated mild cerebral atrophy. The bilateral basal ganglia demonstrated a few, punctate hypointensities secondary to calcification (arrows). e MR angiography revealed mild stenosis of the major cerebral arteries

Cerebral atrophy is usually progressive, and cerebellar atrophy and brain stem atrophy are prevalent. Delayed myelination is associated with RNASEH2B mutations and early age at onset [53]. Intracerebral vasculopathy, including intracranial stenosis, moyamoya syndrome, and aneurysms, is associated with SAMHD1 mutations [55] while bilateral striatal necrosis is associated with ADAR mutations [56]. RNASET2-deficient leukoencephalopathy mimics AGS and congenital cytomegalovirus infection clinically and radiologically [57].

Despite the lack of an established treatment, immune modulation (such as corticosteroid therapy) during the active phase may be beneficial [49]. Janus kinase (JAK) inhibitors are reportedly beneficial in controlling inflammation and preventing the progression of end-organ damage by blocking interferon activation in type 1 interferonopathies, including AGS [58, 59].

Childhood and adolescenceMitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS, OMIM #540,000) refers to a heterogeneous group of disorders caused by point mutations in mitochondrial DNA. The majority of patients have in common the pathogenic variant m.3243A > G in the mitochondrial DNA tRNA-leucine (MT-TL1) [60] and may experience the onset of symptoms, including headache, nausea, seizures, episodic vomiting, and permanent or reversible stroke-like episodes as well as some symptoms of generalized mitochondrial disease, at any age (the second decade is the most common). Compared to strokes of vascular origin, there is a higher incidence of clinical symptoms, such as cortical blindness and auditory agnosia [31]. Serum and CSF lactate are usually elevated at the time of presentation.

Although the underlying, pathophysiological mechanism of the stroke-like episodes remains unclear, the cytopathic and angiopathic theories are two, prevailing hypotheses of their etiology [61]. The cytopathic theory proposes that defects in oxidative phosphorylation resulting from mitochondrial mutation cause neuronal and glial cellular dysfunction, potentially resulting in cell death during periods of increased metabolic activity. The angiopathic theory proposes that abnormal mitochondrial function in the arteriolar endothelium leads to impaired autoregulation and ischemia.

Brain CT demonstrates symmetrical calcification in the basal ganglia more prominently in older patients [62]. MRI findings of stroke-like lesions do not correspond to vascular territories, involve the cortex and juxtacortical white matter, and primarily affect the parietal and occipital lobes and basal ganglia (Fig. 7). Some studies have reported decreased diffusion in some affected areas [63, 64] while other studies have reported the opposite [65]. Sequential scans may reveal the resolution and subsequent reappearance of abnormal areas or the development of new lesions. Most of the severe lesions progress to cortical laminar necrosis, gliosis, and atrophy [66].

Fig. 7

MELAS with point mutations of m.3243A > G in the mitochondrial DNA tRNA-leucine (MT-TL1) in a 10-year-old, female patient with transient visual impairment. Axial T2-weighted imaging (a) demonstrated mild swelling and hyperintensity in the left temporal and posterior cortices (arrows). Axial DWI (b) demonstrated hyperintensity in the left temporal and posterior regions, and an ADC map (c) demonstrated corresponding, increased diffusion (arrows). MR angiography (d) revealed dilation of the left middle and posterior cerebral arteries. 1H-MRS (PRESS, TE/TR 35/2,000 ms) (e) of the left occipital lobe revealed a prominent doublet peak of lactate and decreased NAA/Cr ratio. MELAS mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, PRESS point-resolved spectroscopy, NAA N-acetyl aspartate

1H-MR spectroscopy (MRS) demonstrates a high lactate level in the affected areas of the brain (Fig. 7). The presence of lactate in areas of the brain that are not visibly abnormal on T2 or diffusion imaging is more suggestive of mitochondrial disease [67, 68]. MR angiography reveals prominent dilatation of the arteries (Fig. 7), and perfusion-weighted imaging (PWI) and arterial spin labeling (ASL) demonstrate hyperperfusion in the affected areas in the acute stage, which may be useful in differentiating MELAS from acute ischemic stroke [