COL4A1- and COL4A2-Related Disorders (Gould Syndrome)

Multisystem spectrum of vascular basement membrane fragility caused by variants in the genes encoding the α1 and α2 chains of type IV collagen, with cerebral small vessel disease of predominantly haemorrhagic expression from the fetus to the adult, porencephaly, and ocular, renal and muscular anomalies

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. From familial porencephaly to type IV collagen

Porencephaly, a term applied to any cavity or cyst of cerebrospinal fluid within the brain parenchyma, was for decades regarded as an acquired sequel of fetal or perinatal vascular lesions. OMIM distinguishes encephaloclastic, or type 1, porencephaly, usually unilateral and resulting from focal destructive lesions due to fetal vascular occlusion or birth trauma, from “schizencephalic”, or type 2, porencephaly, usually symmetrical and interpreted as a primary defect of ventricular development; the encephaloclastic form is the more frequent [4]. Clinically, porencephalic cavities often present with hemiplegia, and de novo or inherited heterozygous variants of COL4A1 and COL4A2 account for a proportion of cases [30]. The first description of familial porencephaly is attributed to Berg and colleagues in 1983, and the following year Smit and colleagues described a Dutch family with vertical transmission of the disease [4]. In 2004, Aguglia and colleagues linked autosomal dominant type 1 porencephaly in an Italian family to the terminal region of 13q, with a maximum LOD score of 3.16 [4].

The gene was identified in 2005 by Gould and colleagues from a mutant mouse obtained by random mutagenesis, which developed porencephaly secondary to focal breaches of the vascular basement membranes: half of the animals died of cerebral haemorrhage on the first day of life and about 18% of survivors had porencephaly [31]. The cause was a semidominant Col4a1 mutation that inhibited secretion of both mutant and normal type IV collagen; in the same publications, COL4A1 variants cosegregated with porencephaly in the Smit and Aguglia families, the former with the substitution NM_001845.6:c.3706G>A p.(Gly1236Arg) (G1236R in the original publication) [4, 8, 31]. The authors proposed from the outset that the mutation acted together with environmental trauma, because not all mutant mice developed the lesion [31]. In 2006, Breedveld and colleagues confirmed the role of COL4A1 in three Dutch families, one of them with a variant abolishing the start codon that was present in an asymptomatic obligate carrier with white matter changes, the first demonstration of variable expressivity [32].

1.2. Broadening of the spectrum: small vessels, HANAC, COL4A2 and PADMAL

Also in 2006, Gould and colleagues showed that the murine mutation predisposed both newborn and adult animals to intracerebral haemorrhage (ICH), that caesarean delivery attenuated birth-related haemorrhage in mutant mice and that a human family with small vessel disease carried a COL4A1 variant; they concluded that these variants cause a spectrum of cerebrovascular phenotypes with a predisposition to haemorrhage, chiefly after environmental stress [33]. In 2007, Vahedi and colleagues described a normotensive man with infantile hemiparesis and recurrent deep ICH from the age of 17 years, all during sporting activity, with no family history, carrying COL4A1 NM_001845.6:c.2413G>A p.(Gly805Arg), adding sport to the known triggers (delivery, anticoagulation and head trauma) [8, 34].

The syndrome of hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC) was proposed by Plaisier and colleagues in 2007 from three families, one of them described in 2005 with autosomal dominant haematuria, retinal arterial tortuosity and muscle contractures; linkage to the COL4A1-COL4A2 locus and sequencing of complementary deoxyribonucleic acid (DNA) from skin fibroblasts revealed three nearby glycine substitutions in exons 24 and 25 of COL4A1 [14, 35]. In 2012, three groups extended the spectrum to COL4A2: Jeanne and colleagues identified rare variants in patients with adult ICH and demonstrated intracellular retention of both chains [36]; Verbeek and colleagues and Yoneda and colleagues described families with porencephaly and small vessel disease [5, 37].

Single-organ phenotypes followed: familial isolated retinal arterial tortuosity (Zenteno and colleagues, 2014), non-syndromic autosomal dominant congenital cataract in a large Chinese family (Xia and colleagues, 2014) and familial cystic kidney disease with haematuria and declining glomerular filtration rate (Gale and colleagues, 2016) [9, 15]. In 2011, Labelle-Dumais and colleagues described COL4A1 variants in infants with a Walker-Warburg syndrome and muscle-eye-brain disease phenotype, without variants in the α-dystroglycan glycosylation genes [24, 38].

In 2016, Verdura and colleagues showed that variants in a binding site for the microRNA miR-29, in the 3' untranslated region (3'UTR) of COL4A1, cause PADMAL, an ischaemic small vessel disease of young adults previously described in a Swedish family (Sourander and Wålinder, 1977) and a German family (Hagel and colleagues, 2004); the mechanism is overexpression of COL4A1, rather than the structural loss of function of the glycine variants [16, 39]. In 2024, Aloui and colleagues described an AluYa5 insertion in the same region with the same quantitative effect, and duplications encompassing COL4A1 and COL4A2 have been associated with early-onset recurrent ischaemic strokes [1, 40].

1.3. Nomenclature and reclassifications

The term “COL4A1-related disorders” became widespread with the review by Meuwissen and colleagues (2015), who also called them “COL4A1 mutation-related disorders”, and with GeneReviews, which grouped under that name autosomal dominant familial porencephaly, cerebral small vessel disease with haemorrhage, HANAC, retinal arterial tortuosity and non-syndromic congenital cataract [9, 10]. The 2025 international consensus adopted “COL4A1/A2-related disorders” and recognises six syndromes: familial type 1 porencephaly, cerebral small vessel disease with haemorrhage, HANAC, isolated retinal arterial tortuosity and/or congenital cataract, PADMAL, and duplications or triplications of COL4A1 and COL4A2 [1].

Patient organisations and family support groups united under the name Gould syndrome, in honour of the researcher who identified the gene [3, 41]. The term was taken up by the nephrology literature in 2025 (“Gould syndrome” for COL4A1/COL4A2 as opposed to Alport syndrome for COL4A3–COL4A5) and by OMIM, which now lists “Gould syndrome 1” as an alternative title for BSVD1 (175780) and “Gould syndrome 2” for BSVD2A (614483) [2, 4, 5]. In OMIM, the former names porencephaly 1 (POREN1) and porencephaly 2 (POREN2) became historical designations, and entry 607595 (small vessel disease with or without ocular anomalies) was removed and merged into 175780 [4, 9].

1.4. Definition of the entities covered

BSVD1 (COL4A1) and BSVD2A (COL4A2) denote autosomal dominant small vessel disease, with or without porencephaly, with onset from fetal life to adulthood, with or without ocular and systemic anomalies [4, 5]. Susceptibility to ICH (614519) refers to COL4A1 or COL4A2 variants identified in patients with adult haemorrhagic stroke, often without an evident familial phenotype [13]. HANAC is the form with retinal arteriolar tortuosity and constant cramps, cystic nephropathy or haematuria, carotid siphon aneurysms and usually silent cerebral disease, associated with glycine substitutions in exons 24 and 25 of COL4A1 [9, 14]. RATOR is isolated tortuosity of the second- and third-order retinal arteries with recurrent retinal haemorrhages [15]. PADMAL is the ischaemic small vessel disease of young adults due to overexpression of COL4A1, without haemorrhages [1, 39]. BSVD2B is the autosomal recessive form of COL4A2 [7]. COL4A1/COL4A2 duplications, isolated congenital cataract, isolated kidney disease, the congenital muscular dystrophy phenotype and the late cognitive and affective phenotype associated with exon 23 variants complete the spectrum [1, 24, 25].

2. Molecular Genetics and Pathophysiology

2.1. The genes and the α1α1α2(IV) heterotrimer

Type IV collagen is the main collagen of basement membranes, where it forms a network with laminins, proteoglycans and nidogen [9, 42]. Mammals have six α(IV) chains, encoded by COL4A1 to COL4A6, which assemble into only three heterotrimers: α1α1α2(IV), α3α4α5(IV) and α5α5α6(IV) [2, 9]. The α1α1α2(IV) heterotrimer is the oldest in evolution, exists throughout the animal kingdom and is present in almost all basement membranes of developing tissues and in most adult tissues, whereas the α3α4α5 and α5α5α6 networks have restricted tissue expression and are altered in Alport syndrome, which affects the kidney, ear and eye [2, 9]. This difference in distribution explains why COL4A1/COL4A2 disorders are mainly vascular and multisystemic, whereas those of COL4A3–COL4A5 are renal, auditory and ocular [2].

COL4A1 and COL4A2 are adjacent genes, tightly linked at a shared locus on 13q34; COL4A1 has 52 exons spanning about 158 kb [1, 6, 9]. Each chain has an amino-terminal 7S domain, a long collagenous domain with interrupted Gly-X-Y repeats and a carboxy-terminal non-collagenous NC1 domain [1, 9]. Intracellular assembly, in the endoplasmic reticulum (ER), begins with specific interactions between the NC1 domains of two α1 chains and one α2 chain, and the glycines of the Gly-X-Y repeats stabilise the triple-helical domain [9, 24]. NC1 fragments released by proteolysis have their own biological activity: arresten, derived from α1(IV), and canstatin, derived from α2(IV), are antiangiogenic [42, 43].

2.2. Molecular and cellular mechanisms

Glycine substitutions in the triple helix, the most common class, impair the formation and stability of the heterotrimer and act through a dominant-negative effect: in the mouse, the Col4a1 mutation inhibits secretion of both mutant and normal type IV collagen [9, 31, 42]. COL4A2 variants in patients with ICH cause intracellular accumulation of COL4A1 and COL4A2 with ER retention, at the expense of secretion, and two of three variants studied trigger ER stress and activate the unfolded protein response; Col4a2 mutant mice have ICH with complete penetrance [36]. A COL4A2 frameshift variant showed another mechanism, with increased fibroblast apoptosis without ER stress and fragmentation and duplication of epidermal basement membranes on electron microscopy, consistent with haploinsufficiency and an abnormal collagen network [37]. Splicing variants, premature stop codons and deletions have also been described, and the 2025 consensus accepts triple-helix glycine missense variants and premature stop codon variants as pathogenic, recommending caution with substitutions of other amino acids [1, 26].

In mouse models, intracellular accumulation of mutant collagen in endothelial cells and pericytes is a trigger for ICH; abnormal vascular development leads to small vessel disease, recurrent haemorrhagic strokes and age-related macroangiopathy [44]. A transient, generalised increase in blood–brain barrier permeability is associated with microbleeds, whereas focal loss of smooth muscle cells is associated with macrobleeds; increased TGFβ signalling impairs retinal vascularisation, and renal cysts result from alteration of Bowman's capsule, with activation of parietal epithelial cells, matrix remodelling and inflammation [24]. Structural brain lesions mainly reflect the timing of the vascular insult: haemorrhages before 26 weeks of gestation are associated with schizencephaly and polymicrogyria, periventricular or intraventricular haemorrhages between 22 and 34 weeks with porencephaly, and later lesions with periventricular leukoencephalopathy [24].

PADMAL has the opposite mechanism. COL4A1 3'UTR variants (NM_001845.6:c.*31G>T, c.*32G>A, c.*32G>T and c.*35C>A, classified as pathogenic in ClinVar) disrupt the miR-29 binding site and increase COL4A1 expression, with fibrosis and loss of smooth muscle cells in the small cerebral arteries [24, 39, 45]. The AluYa5 insertion in the 3'UTR increases COL4A1 messenger RNA (mRNA) 10.6-fold (95% confidence interval, CI, 1.4–17.1) and protein 2.8-fold (2.1–3.5) in fibroblasts, by altering the use of the canonical polyadenylation signals [40]. COL4A1/COL4A2 duplications and triplications likewise act through overexpression, and 6 of the 8 reported carriers had ischaemic stroke [1, 24]. Quantitative alterations of the cerebral vascular matrix thus constitute a second, ischaemic, pathogenic axis, distinct from the haemorrhagic axis of structural variants [39, 40].

2.3. Inheritance pattern

Inheritance is autosomal dominant in the great majority of families, with a 50% risk for each child of a carrier [1, 9]. The proportion of de novo variants depends on the population studied: at least 27% in GeneReviews, 40% (10/24) in the Erasmus MC diagnostic series, 60.7% (34/56) in a Japanese series with brain defects and 70% of fetuses with ICH with parental DNA available [9–12]. In the 2024 systematic review, variants were de novo in 148 individuals (136 COL4A1, 12 COL4A2) and inherited in 82 (66 COL4A1, 16 COL4A2); COL4A1 variants are more often de novo and associated with severe phenotypes, whereas several COL4A2 variants are inherited from asymptomatic or mildly affected parents [1, 24]. The 2025 consensus stresses that these estimates are subject to selection and test-access biases [1].

There are two inheritance patterns in the same gene. The autosomal recessive form of COL4A2 (BSVD2B, OMIM 621414) is established: two siblings of consanguineous Iranian parents with the homozygous variant NM_001846.4:c.3472G>C p.(Gly1158Arg) and a 7-year-old Italian boy with compound heterozygosity c.535C>T p.(Arg179Cys) and c.2069G>T p.(Gly690Val), both with unaffected heterozygous parents; the Italian family had leukoencephalopathy with punctate calcifications [7, 8, 46]. BSVD2B presents from infancy with global delay, intellectual disability with absent or poor speech, focal epilepsy that is often difficult to control and spastic tetraparesis, with colpocephaly, porencephaly, atrophy and leukoencephalopathy on MRI [47]. For COL4A1, recessive inheritance has been proposed in two Turkish siblings with the homozygous variant p.(Gly1278Ser), with small vessel disease, periventricular leukoencephalopathy, ocular defects, hemiparetic gait and seizures, and with heterozygous parents and five siblings without clinical or laboratory signs, and in a third patient with NM_001845.6:c.4078G>A p.(Gly1360Arg); OMIM classifies these associations as awaiting confirmation and the p.(Gly1278Ser) variant as of uncertain significance [6, 8, 48].

2.4. Variant spectrum and nomenclature

In August 2023, the Human Gene Mutation Database (HGMD) listed 269 pathogenic or likely pathogenic variants in COL4A1 and 42 in COL4A2, plus 64 and 25 variants of uncertain significance (VUS), respectively [24]. Most missense variants and in-frame duplications lie in the central part of the protein, between amino acids 600 and 1050 [24]. Glycine is usually replaced by a charged amino acid, and variant frequency is higher in COL4A1 than in COL4A2 [49]. The following table brings together variants described in the literature, in Human Genome Variation Society (HGVS) nomenclature, confirmed in VariantValidator on the MANE transcripts; historical notations that do not correspond to the current transcript are indicated [8].

The COL4A2 variant described as c.3206delC by Verbeek and colleagues has no unambiguous correspondence in the current MANE transcript (VariantValidator normalises this notation to an intronic position), and so it is not reproduced as current HGVS [8, 37]. Non-glycine variants of uncertain interpretation, such as COL4A1 NM_001845.6:c.2705C>G p.(Pro902Arg) (allele frequency of 0.00044 in gnomAD) and c.413C>G p.(Pro138Arg), described in newborns with ICH and inherited from the mother, illustrate the caution recommended by the consensus [1, 8, 51].

2.5. Genotype–phenotype correlations

Correlations are partial. Analysis of more than 100 human variants and a murine allelic series showed that the position of the substitution, rather than the properties of the substituting amino acid, has the greater influence on severity; the severity of cerebrovascular disease follows an amino→carboxy gradient for triple-helix glycine substitutions, whereas the penetrance and severity of myopathy and nephropathy depend on functional subdomains [49]. The six HANAC variants known in 2016 lay in exons 24 and 25 and affected glycines within a 30-amino-acid region of the CB3[IV] segment, which contains integrin-binding sites; porencephaly and small vessel disease variants were distributed mainly across exons 25 to 51 [9, 24, 26]. Missense variants affecting the NC1 domain appear to be associated with prenatal haemorrhage and porencephaly without kidney disease, and an NC1 frameshift caused familial kidney disease [1, 26]. In 2026, two nearby glycine substitutions in exon 23, at a major cell-binding site of the triple helix, were associated with a late phenotype of cognitive and mood changes with status cribrosum and diffuse white matter lesions, without haemorrhagic stroke [25]. 3'UTR variants and duplications produce ischaemic disease, and COL4A2 variants are more often associated with single-organ manifestations [24, 39]. In neurological cohorts, epilepsy-associated variants are distributed throughout COL4A1, with no clear correlation [52].

2.6. Penetrance, expressivity and modifiers

GeneReviews considered penetrance probably close to 100%, with variable expressivity in age at onset and severity, even within a family [9]. Population data contradict this estimate for some variants: in UK Biobank, 336 of 454,756 participants aged 40 to 69 years (1 in 1353) were heterozygous carriers of pathogenic COL4A1/2 variants identified in the literature, with 11 unique variants; the risk of any stroke was higher (odds ratio, OR 1.67; 95% CI 1.03–2.55), driven by ICH (OR 3.56; 95% CI 1.34–7.53), with no increase in ischaemic stroke (OR 1.16; 95% CI 0.54–2.15), and the associations were no longer significant after correction for multiple comparisons; carriers did not have more markers of small vessel disease on MRI (28 with imaging) or a higher risk of incident stroke (hazard ratio, HR 1.03; 95% CI 0.42–2.03) [23]. This cohort of adult volunteers under-represents severe forms and does not estimate the penetrance of paediatric de novo variants, but it shows that some published variants are associated with mild or absent phenotypes [23].

Expressivity varies within families: in the Italian cohort, intergenerational worsening was observed in 9 of 11 families, and analysis of 15 pedigrees in a European cohort suggested worsening in subsequent generations, especially with maternal transmission [24, 52]. In mice, allelic heterogeneity, genetic background and environmental factors such as intense exercise and anticoagulants modulate severity [44]. A modifier screen identified a locus (MoGS1) containing the fibronectin 1 gene that suppresses anterior segment dysgenesis and myopathy without altering ICH, indicating tissue-specific mechanisms [3].

2.7. Allelic disorders and associations with common disease

Beyond the entities described, the sources associate COL4A1 variants with congenital muscular dystrophy phenotypes of the Walker-Warburg/muscle-eye-brain spectrum, familial cystic kidney disease, isolated congenital cataract, Peters anomaly with microphthalmia and, as a possible risk factor, primary open-angle glaucoma (27 likely pathogenic variants in 257 patients) [24, 38]. Three patients with spontaneous coronary artery dissection had de novo COL4A1 variants, a family with Marfan syndrome and thoracic aortic aneurysms had a COL4A1 variant and seven relatives with visceral aneurysms had a COL4A2 missense variant [24]. Common variants in COL4A1 and COL4A2 are among the genome-wide association study (GWAS) loci for coronary artery disease and myocardial infarction and for sporadic small vessel stroke, with small individual effects [53, 54].

3. Clinical Spectrum and Manifestations by System

3.1. Types within the class and distinguishing features

COL4A1/COL4A2-related disorders form a pleiotropic spectrum rather than separate syndromes; HANAC and PADMAL nevertheless have sufficiently distinct profiles to be treated as specific entities within the spectrum [24]. The available data describe natural history, because there is no disease-modifying therapy; differences between cohorts mainly reflect the mode of recruitment (paediatric, fetal, adult neurological or population-based) [23, 24].

3.2. Frequency of manifestations

The systematic review by Gasparini and colleagues (182 studies up to August 2023; 647 individuals from 485 families, of whom 546 had COL4A1 variants, 93 COL4A2 variants and 8 a duplication of both genes), combined with the Italian cohort of 43 individuals from 23 families, is the most extensive quantitative source [24]. With a denominator of 685 individuals, the most frequent manifestations were stroke (203/685; 29.6%), seizures or epilepsy (199/685; 29.0%), intellectual disability or developmental delay (168/685; 24.5%), porencephaly or schizencephaly (168/685; 24.5%), motor impairment (162/685; 23.6%), cataract (124/685; 18.1%), haematuria (63/685; 9.2%) and retinal arterial tortuosity (58/685; 8.5%) [24]. A second systematic review, published in 2026 (99 articles, 367 patients), found neurological symptoms in 78.5%, acute neurological deficits in 16.9%, abnormal MRI in most (leukoencephalopathy and porencephaly being the most frequent findings, even in patients with isolated non-neurological signs), lesion progression in 62.3% of cases with follow-up, ocular involvement in 71.3%, renal in 15.5%, muscular in 17.8% and cardiovascular in 7.9% [55]. Both reviews acknowledge publication bias towards severe phenotypes [24, 55].

Source: Gasparini and colleagues, 2024, Table 1 (systematic review plus Italian cohort) [24].

3.3. Fetal and neonatal period

Fetal presentation includes intracranial haemorrhage, hydrocephalus, hypoplasia or agenesis of the corpus callosum, schizencephaly and porencephalic cysts, detected on ultrasound or fetal MRI [1]. In the 2024 review, 89 of 195 strokes (45.6%) occurred before birth, mainly in the frontal lobes and basal ganglia, and 83 of those 89 (93.2%) were exclusively haemorrhagic [24]. In a Japanese series of 56 individuals with pathogenic variants, 32 of 47 with fetal information (68.1%) had at least one prenatal anomaly, detected at a median gestational age of 31 weeks; ventriculomegaly was the most common initial anomaly (20/32; 62.5%), there were posterior fossa malformations, including Dandy-Walker, in four, and fetal growth restriction in 16, eight of them with ventriculomegaly; only 14 had strongly suggestive prenatal findings [11]. On fetal MRI of eight cases with intraparenchymal haemorrhage, this was multifocal and bilateral in four, always involved the frontal lobes and, in six, the basal ganglia, with a median maximum diameter of 16 mm (6 to 65 mm); all had ventriculomegaly and four intraventricular haemorrhage, and haemorrhage size correlated with motor outcome [56].

In the newborn, typical presentations are seizures, multiple parenchymal, intraventricular and subdural ICH, congenital cataract and haemolytic anaemia with jaundice; 19 of the 25 reported cases of haemolytic anaemia (76%) were neonatal [1, 24, 50]. The 2025 consensus includes jaundice with haemolytic anaemia at birth among the indications for testing [1].

3.4. Neurological manifestations in childhood

Porencephaly is the second most frequent structural anomaly (124/647; 19.2%), ranging from small cavities to extensive cystic scars; depending on size and location, carriers are asymptomatic or have mainly motor impairment, seizures or both [24]. Schizencephaly, usually unilateral, is the most common cortical malformation (38/647; 5.9%), followed by polymicrogyria (1.7%), focal cortical dysplasia (0.9%) and one case of lissencephaly; these malformations result from early fetal cerebrovascular events [1, 24]. Intracranial calcifications (36/647; 5.6%) have a subependymal and peri-porencephalic pattern, and on MRI a pattern resembling periventricular leukomalacia, with subtle punctate calcification of the white matter or basal ganglia, is frequent [24, 57].

Epilepsy occurred in 183 of 647 individuals (28.3%): focal seizures in 29%, epileptic spasms in 16.4% and generalised seizures in 5.5%, with paediatric onset in 62.3% [24]. In a European cohort of 99 patients (44 new and 55 published), the most common phenotype was focal seizures with onset in childhood, often complicated by status epilepticus and antiseizure drug resistance; in 46.4% of the new patients with focal seizures the porencephalic cyst colocalised with the discharges, and a subgroup had epilepsy as the main manifestation, with non-specific MRI (periventricular leukoencephalopathy, ventricular asymmetry) [52]. In the Italian cohort, 18 of 43 individuals (41.9%) had epilepsy, always with onset in childhood (in the first year in seven), with two cases of West syndrome evolving into Lennox-Gastaut syndrome; this figure may be overestimated because it comes from an epilepsy referral centre [24]. In the Gould Syndrome Foundation global registry, almost half of the 35 children with seizures had had infantile spasms; among these children, 88.6% had developmental delay, 60.0% stroke, 65.7% a diagnosis of cerebral palsy, 57.1% constipation and 28.6% used a feeding tube [41].

Motor impairment (152/647; 23.5%) usually follows a prenatal stroke with porencephaly, and intellectual disability or delay (154/647; 23.8%) is associated in 87.1% of children (61/70) with porencephaly or other structural anomalies [24]. Children often present with a picture of hemiplegic or tetraparetic cerebral palsy, and the disease is recognised as a genetic cause of cerebral palsy mimics [46, 57, 58]. The consensus also describes language and learning disorders, autism spectrum disorder, extrapyramidal motor disturbances, behavioural changes and visual impairment of both central and peripheral origin, and stresses the frequent discrepancy between clinical status and the extent of the lesions [1].

3.5. Cerebrovascular manifestations in adults

In adults, the most common pattern is diffuse small vessel disease, with confluent or patchy periventricular hyperintensities, predominantly in the anterior circulation, deep microbleeds, lacunes, dilated perivascular spaces and deep intracerebral haemorrhages [1, 9]. ICH may be single or recurrent, spontaneous, post-traumatic, during sport or under anticoagulation, and some are fatal; it classically occurs in non-hypertensive adults before the age of 50 years, but has been described at 72 and 73 years [9, 13, 34]. In the 2024 review, 66 of 195 strokes (33.8%) occurred in adulthood, ischaemic in 47% and haemorrhagic in 42.4%; there was recurrence in 29 of these 66 patients (43.9%), 25 of them from nine families with PADMAL [24]. The European Academy of Neurology (EAN) reports a mean age at stroke of 30 to 40 years and haemorrhagic strokes twice as frequent as ischaemic ones in the forms due to structural variants [26]. A 29-year-old man with a de novo glycine variant in COL4A2 had recurrent deep ICH with mild hemisyndromes, diffuse leukoencephalopathy, multiple microbleeds, bilateral carotid siphon aneurysms, haematuria and raised CK, a phenotype overlapping that of COL4A1 [59].

Intracranial aneurysms mainly affect the internal carotid artery, at the siphon (11/647; 1.7%), and are constant in HANAC with no rupture reported; the consensus includes multiple carotid or vertebrobasilar aneurysms and dolichoectasia among the indications for testing in adults [1, 9, 24]. Mild cognitive impairment has been described in one family, all 29 adults with intellectual disability in the review had small vessel disease with haemorrhagic stroke, and the exon 23 phenotype presents with late cognitive decline with mood disorders [9, 24, 25].

3.6. HANAC

HANAC had been characterised in six families by 2016 [9]. Cerebral disease is usually asymptomatic: half of those affected have subcortical, periventricular or pontine leukoencephalopathy, dilated perivascular spaces, lacunes and microbleeds, none has porencephaly, and only 2 of 14 patients from three families had cerebrovascular symptoms (minor ischaemic stroke at 47 years and a small post-traumatic haemorrhage under anticoagulation at 48 years), although 8 of 9 adults studied with MRI had small vessel disease [9, 14]. Six individuals had single or multiple intracranial aneurysms, all at the carotid siphon, without rupture [9]. Bilateral retinal arteriolar tortuosity and persistently raised CK are present in all; cramps affect several muscles and begin before the age of 3 years, with strength only slightly affected in two patients and non-specific electromyography and biopsy [9]. One family had isolated microscopic haematuria with episodes of macroscopic haematuria, without proteinuria or hypertension, and three families had large bilateral cortical and medullary cysts, with kidneys of normal size; mild renal impairment may appear after the age of 50 years [9]. Raynaud phenomenon, supraventricular arrhythmia, hepatic cyst and tortuosity of the nail-bed capillaries complete the picture [9, 14].

3.7. PADMAL and ischaemic forms

PADMAL begins between 30 and 45 years (35 to 45 years in the 2025 consensus; fourth and fifth decades in the Italian protocol and in OMIM), with recurrent small pontine infarcts, hemispheric lacunar infarcts, vascular leukoencephalopathy, cervical spinal cord ischaemic lesions and absence of haemorrhages; it progresses with cognitive and motor decline, consistent with multi-infarct dementia, and the EAN reports early death, with no manifestations described in children [1, 16, 24, 26]. In the original French family, four individuals had recurrent ischaemic strokes between 37 and 43 years (limb numbness, facial palsy, diplopia, imbalance); in the Swedish family, episodes began between 29 and 38 years with pyramidal, bulbar and cerebellar signs; in the German family, most began after the age of 30 years, but one patient at 12 [16]. In the families with the AluYa5 insertion, 17 of 19 patients (89.5%) had early-onset recurrent pontine ischaemic lesions [40]. Lacunes recur in PADMAL despite antiplatelet therapy [24, 54].

3.8. Ophthalmological manifestations

Ocular manifestations were described in 200 of 647 individuals (30.9%): cataract (18%), retinal arterial tortuosity (8.2%), corneal changes (4.0%), anterior segment changes (2.8%), microphthalmia (2.8%) and optic disc changes (2.2%) [24]. Cataract may be congenital or acquired, isolated (20/111 carriers of COL4A1 variants, 16 from one Chinese family) or associated with anterior segment anomalies; in children with bilateral congenital cataract, COL4A1 accounted for 10% of families with a monogenic aetiology in an exome series (2/20) and 1% in a Danish series of 211 children [1, 24]. Axenfeld-Rieger anomaly includes congenital iris malformations, posterior embryotoxon, microcornea, raised intraocular pressure and glaucoma [1, 9].

Retinal arterial tortuosity affects the second- and third-order arteries, with normal first-order arteries and veins and no leakage on fluorescein angiography; it causes episodes of transient visual loss due to retinal haemorrhage that is spontaneous or follows stress or minor trauma, with a generally excellent visual prognosis [1, 9]. In RATOR, two-thirds of patients have symptomatic transient visual loss; tortuosity may be absent in children with haemorrhages and become evident in adolescence, and there was one case of permanent visual impairment in one eye [15]. Tortuosity may progress to haemorrhage or retinal detachment, and anterior segment dysgenesis may lead to glaucoma with irreversible optic neuropathy [24]. In 13 oligosymptomatic or asymptomatic carriers, targeted examination found retinal tortuosity in 5 (38.5%), anterior segment dysgenesis in 4 (30.8%) and cataract in 2 (15.4%), and a family with p.(Gly1369Arg) had diffuse thinning of the peripapillary nerve fibre layer with normal intraocular pressure, suggestive of subclinical optic neuropathy [24]. Cerebral visual impairment, due to injury of the central visual pathways, frequently coexists with ocular changes in children [1].

3.9. Renal manifestations

Renal manifestations were described in 76 of 647 individuals (11.7%), mainly haematuria (9.3%), cysts (5.3%) and proteinuria (3.1%), the latter always with more severe neurological and ocular disease [24]. The cysts, of capsular origin, are bilateral and frequent in HANAC and rare in small vessel disease; in a Cypriot family of 20 individuals with a frameshift in the NC1 domain, the disease was mainly renal, ranging from microscopic haematuria to end-stage kidney disease, with one stroke and one aortic dissection [1, 24]. Congenital anomalies of the kidney and urinary tract, mainly vesicoureteral reflux, have been described in 14 individuals from 12 families, and unilateral renal atrophy in two [9, 24]. Declining glomerular filtration rate usually appears after the age of 40 years, and biopsy shows irregular thickening of the basement membranes of the tubules, Bowman's capsule and interstitial capillaries on electron microscopy, with normal light microscopy [1, 9].

3.10. Muscular, cardiovascular, haematological and other manifestations

CK is mildly raised in 7.9% of individuals described, with cramps in 41.2% of these; cramps are spontaneous and episodic, at rest or with cold, and there are rare cases of severe rhabdomyolysis with acute kidney injury [1, 24]. In the Italian cohort, biopsy showed mild myopathy in one patient and reduced dystrophin and α-dystroglycan in another [24]. Two infants had a congenital muscular dystrophy phenotype of the Walker-Warburg/muscle-eye-brain spectrum and died early, one at 6 months of respiratory failure [24, 38].

Cardiovascular manifestations include supraventricular arrhythmia, mitral valve prolapse with regurgitation, hypertension, septal defects, congenital heart disease (11 children with COL4A1; prevalence of 4.8% in the cohort compared with 0.8–1.2% in the paediatric population), coronary aneurysms or dissection, spontaneous coronary artery dissection and Raynaud phenomenon [1, 24]. The prevalence of arrhythmias (2.1%) does not differ from that of the general population (1.5–5%) [24]. In the Italian cohort, one woman had an acute coronary syndrome at 31 years without risk factors, and cardiac assessment of nine oligosymptomatic carriers was normal except for aortic sclerosis with mild mitral regurgitation and mild ectasia of the ascending aorta [24].

Haemolytic anaemia is mainly neonatal, with hyperbilirubinaemia and sometimes haemorrhagic stroke [1, 24]. Severe, repeated alveolar haemorrhage at 9 years in a child with schizencephaly and renovascular hypertension, gastrointestinal bleeding, intestinal pseudo-obstruction, vertebral dolichoectasia, varus or valgus foot and scoliosis have also been described [24]. In 2026, a 4-year-old girl had haematochezia with haemodynamic compromise due to submucosal colonic varices, without arteriovenous malformation or portal hypertension [60]. Natural history registries are studying gastrointestinal dysmotility, sleep apnoea and the lifetime risk of systemic aneurysms [1].

4. Clinical Recognition and Warning Signs

4.1. When to suspect: fetal and neonatal period

Suspicion arises in the face of unexplained fetal intraparenchymal or intraventricular haemorrhage, especially if multifocal, of different ages or associated with schizencephaly or porencephaly, and in the face of ventriculomegaly with fetal growth restriction [1, 11, 24]. In a Paris referral centre, 18 of 956 fetuses with brain anomalies (1.9%) had severe or multifocal haemorrhagic lesions or multifocal ischaemic-haemorrhagic lesions, and 5 of them (28%) had a pathogenic COL4A1 variant, four de novo; the median gestational age at diagnosis was 24 weeks (interquartile range 22–26) with a variant and 32 weeks (29.5–34.5) without a variant [61]. In 194 consecutive fetuses with ICH, 36 (19%) had pathogenic COL4A1/COL4A2 variants, and in two negative cases the cause lay in genes for inherited platelet disorders (MPL and MECOM) [12]. On fetal MRI, the haemorrhage typically involves the frontal lobes and basal ganglia [56]. In the term newborn, the combination of ICH without a risk factor with congenital cataract, jaundice with haemolytic anaemia or early seizures is particularly suggestive [1, 50]. Neonatal seizures without encephalopathy should not be attributed by default to a perinatal insult: in a study of 90 newborns of 36 or more weeks of gestation, with seizures in the first 72 hours of life and without criteria for neonatal encephalopathy, referred to a tertiary intensive care unit, MRI showed an evolving focal infarct, in an arterial territory or with a parasagittal distribution, in 69%, and 31% had a metabolic, neurocutaneous, vascular or developmental disorder of genetic or congenital origin (Cowan and colleagues, 2003) [62]. MRI changes suggesting an acute perinatal insult include acute and subacute parenchymal, intraventricular or extracerebral haemorrhages, so haemorrhage alone does not distinguish an acquired lesion from an inherited vasculopathy [62].

4.2. When to suspect: children

The disease should be considered in any child with a diagnosis of cerebral palsy whose MRI shows porencephaly or lesions resembling hypoxic-ischaemic injury without a compatible perinatal history; cerebral palsy affects about 1 in 400 births and perinatal asphyxia is a major factor in fewer than 5%, so genetic investigation is justified when risk factors are lacking [58]. In these children, ophthalmological examination (cataract, retinal arterial tortuosity) and testing for microscopic haematuria are direct clues to COL4A1 [58]. Other settings for suspicion are intracranial calcification with a family history of stroke or cataract, hydranencephaly, leukoencephalopathy with a “destructive” appearance mimicking an environmental cause, focal epilepsy or infantile spasms with a structural lesion, and unexplained episodic irritability with raised CK, which may reflect cramps in a child with severe neurological impairment [1, 57, 63–65].

4.3. When to suspect: adults

In adults, the main settings are deep or subcortical ICH of unknown cause in a young patient without hypertension or with controlled risk factors, ischaemic lesions in several territories or of different ages without risk factors, a pontine ischaemic lesion before the age of 65 years, markers of small vessel disease disproportionate to vascular risk factors, an incidentally discovered porencephalic cavity and multiple intracranial aneurysms or dolichoectasia [1]. The EAN recommends testing for COL4A1/COL4A2 in deep ICH, white matter hyperintensities or porencephaly of undetermined origin when a first- or second-degree relative has cerebral haemorrhage, porencephaly, retinal vessel tortuosity, haematuria, glomerular dysfunction, renal failure, renal cysts, infantile hemiparesis, early cataract, anterior segment anomalies, multiple intracranial aneurysms, cramps or hepatic cyst (mean score 4.78 out of 5; 100% agreement) [26]. Extraneurological signs (renal cysts, haematuria, proteinuria or unexplained renal failure; Axenfeld-Rieger, early cataract or glaucoma, retinal haemorrhage, retinal tortuosity; unexplained cramps, myalgia or rhabdomyolysis) and a strong family history reinforce suspicion [1].

4.4. Warning and emergency signs

The global patient registry showed that only 34.3% of families of children with seizures had received education on stroke recognition, even though more than half of these children had had a stroke [41]. There is no newborn screening for this disease.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria: consensus indications for genetic testing

There are no formal clinical diagnostic criteria; the diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic variant in COL4A1 or COL4A2 (or biallelic in COL4A2) [7, 9]. The 2025 international consensus recommends testing in the presence of two or more of the following signs, and considers it in the presence of a single sign in a fetus or newborn without an alternative cause [1].

Source: Tambala and colleagues, 2025 [1].

The 2024 Italian protocol lists similar indications: in the prenatal period, ventriculomegaly with fetal growth restriction, fetal intraparenchymal haemorrhage and schizencephaly; in the postnatal period, porencephaly, epilepsy due to suggestive structural anomalies, congenital cataract, a cerebral palsy picture with suggestive anomalies, retinal arterial tortuosity, anterior segment dysgenesis, raised CK with recurrent cramps, asymptomatic microscopic haematuria or renal cysts of apparently genetic cause and congenital anomalies of the kidney and urinary tract [24].

5.2. Tests in order

Genetic testing can be done by targeted sequencing, by panels that include COL4A1 and COL4A2 (small vessel disease, epilepsy, leukodystrophy) or by exome or genome; the consensus recommends that any panel for compatible symptoms include both genes and that genome sequencing be performed when the panel or exome is negative and suspicion is high, because pathogenic intronic variants exist [1]. If sequencing is negative, CNVs including COL4A1/COL4A2 should be sought [24]. In PADMAL, the analysis must cover the COL4A1 3'UTR, and the AluYa5 insertion was identified by linkage analysis with exome and genome sequencing [39, 40]. In fetal ICH without a COL4A1/COL4A2 variant, a panel of inherited platelet disorder genes should also be analysed and alloimmune thrombocytopenia excluded [12, 67].

The recommended initial assessment includes a detailed family history (early cerebrovascular disease, cerebral palsy, early dementia, ocular anomalies, cramps, haematuria, renal failure and recurrent miscarriages), brain MRI with intracranial and cervical MRA and ophthalmological assessment; after suspicion or confirmation, CK, coagulation tests, urinalysis, renal ultrasound, blood pressure measurement, electrocardiogram (ECG) and echocardiogram [1]. The EAN recommends a similar non-invasive multiorgan assessment, including liver ultrasound (mean score 4.93; 100% agreement) [26].

5.3. Neuroimaging

MRI should follow a stroke protocol with diffusion, susceptibility-weighted imaging (SWI) for microbleeds and calcifications, T2 FLAIR (fluid-attenuated inversion recovery) and MRA for aneurysms, interpreted according to the neuroimaging criteria for small vessel disease [1]. CT is the most sensitive method for calcification, and MRI, more often used as the first examination, may not detect it; gradient echo and SWI sequences are more sensitive for haemorrhage and mineralisation, and serial imaging may be needed to distinguish haemorrhage from calcification [57]. Typical findings are porencephaly, schizencephaly, polymicrogyria, periventricular leukoencephalopathy with anterior predominance, deep microbleeds, lacunes, dilated perivascular spaces, haemosiderin deposits, subependymal or peri-porencephalic calcifications and carotid siphon aneurysms [1, 4, 24]. In PADMAL, multiple pontine infarcts predominate, present in all symptomatic carriers in the original series [39]. In the neonatal period, unenhanced CT is reserved for suspected intra- or extracranial haemorrhage (falling haematocrit or coagulopathy) or birth trauma, because of irradiation; MRI and CT are more sensitive than cranial ultrasound for intraparenchymal haemorrhage, and, if CT is inconclusive, MRI between day 5 and day 14 defines the location and extent of the lesion, whereas conventional MRI before day 5 may underestimate the extent of hypoxic-ischaemic injury [62]. In pregnancy, fetal MRI is superior to ultrasound for detecting porencephaly and anomalies of the corpus callosum, gyration and posterior fossa [1, 67].

5.4. Other supporting investigations

Skin biopsy with electron microscopy shows duplication and fragmentation of the basement membranes of the dermoepidermal junction and dermal arterioles, with dissociation of smooth muscle cells, but it is neither necessary nor sufficient for diagnosis [9, 37, 43]. The consensus notes that analysis of skin fibroblasts may help interpret a VUS through COL4A1/COL4A2 expression levels, an approach relevant mainly for non-coding variants that increase expression [1, 40]. Targeted examination for subtle ocular signs (tortuosity, posterior embryotoxon, Axenfeld-Rieger) in asymptomatic relatives helps validate variants of uncertain significance [24].

5.5. Sensitivity and limitations of testing

GeneReviews stated that sequencing detects 100% of known variants in probands with a molecular diagnosis, which is the proportion of variants detectable by the method and not the clinical sensitivity of the test; in 2016 no causal deletion or duplication of COL4A1 had been described [9]. Since then, COL4A1/COL4A2 duplications and triplications, intronic variants, 3'UTR variants and an Alu element insertion have been described, so a negative exon panel does not exclude the diagnosis [1, 24, 40]. Yield depends on the population: 24 of 183 probands (13%) in a reference laboratory between 2005 and 2013, mainly children with porencephaly or parenchymal haemorrhage; 56 of 218 (25.7%) in Japanese individuals with suspected COL4A1/2-related brain defects; 28% in fetuses with severe or multifocal haemorrhagic lesions; and 19% in fetuses with ICH [10–12, 61]. Diagnostic rates by phenotype have not yet been established [1]. Parental mosaicism cannot be reliably detected in blood analysis, and testing of the parents of a proband with an apparently de novo variant should be complemented by MRI and ophthalmological examination [9, 50].

5.6. Variant interpretation and report content

The report should identify the gene, the reference transcript with version (NM_001845.6 for COL4A1 and NM_001846.4 for COL4A2), the variant in HGVS nomenclature at the complementary DNA and protein levels, zygosity, classification according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria and parental origin when studied [8, 50]. Triple-helix glycine missense variants and premature stop codon variants are considered pathogenic by the EAN (mean 4.78; 100%), and variants in the miR-29 site of the 3'UTR cause PADMAL (mean 4.86; 92.8%) [26]. Substitutions of other amino acids require caution and, preferably, family segregation, targeted examination of relatives and functional studies [1, 51]. The case of Yakabe and colleagues illustrates the classification as pathogenic of a novel, de novo glycine substitution, absent from population databases, with deleterious prediction and a typical phenotype (PS2, PM1, PM2, PP3, PP4) [50]. In the Italian cohort, carriers of VUS did not differ clinically from carriers of pathogenic variants, which reflects the pleiotropy of the disease and reinforces the usefulness of multiorgan phenotyping of relatives [24].

5.7. Practical algorithm

5.8. Prenatal and preimplantation diagnosis

Once the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible [9]. In India, single-cell sequencing analysis of trophectoderm biopsies from 12 embryos of a couple in which the father carried COL4A1 NM_001845.6:c.1537G>A p.(Gly513Ser) identified three embryos without the variant; transfer of one of them resulted in a pregnancy confirmed by chorionic villus sampling at 11 weeks and the birth of a non-carrier child [8, 68]. The Italian protocol recommends, in pregnant carriers, ultrasound scans according to an individualised protocol and fetal MRI after 20 weeks [24].

6. Differential Diagnosis

6.1. Comparative table

6.2. Acquired porencephaly and fetal haemorrhage

The most frequent differential diagnosis of a porencephalic cyst is an acquired lesion: pre- or neonatal parenchymal haemorrhagic infarction in the context of alloimmune thrombocytopenia, coagulopathy (von Willebrand disease, factor V or factor X deficiency), maternal warfarin exposure or thrombophilia, especially heterozygous factor V Leiden [9]. The prevalence of porencephaly of all causes at birth is 5.2 per 100,000 in Japan and 3.5 per 100,000 in the United States, and most of these cases are not genetic [76]. Severe fetal ventriculomegaly should be investigated for cytomegalovirus and toxoplasmosis (10–20% of cases), alloimmune thrombocytopenia and, with exposure, Zika virus [67]. Inherited platelet disorder genes account for some recurrent fetal ICH without a COL4A1/COL4A2 variant, which justifies studying both groups of genes [12]. In the first published Latin American case, the patient's mother had had a cerebral infarction with hemiplegia related to her daughter's delivery, a history that, in a family with the disease, may reflect the same vascular predisposition [77].

6.3. Cerebral palsy and congenital infection mimics

COL4A1 disease is one of the conditions with a specific test that have been mistaken for cerebral palsy, alongside molybdenum cofactor deficiency, Angelman syndrome, Rett syndrome, Batten disease, the lissencephalies and forms of X-linked intellectual disability [58]. “Destructive” leukoencephalopathy with calcification may also mimic congenital cytomegalovirus infection, the most common cause of calcification with polymicrogyria [57, 64]. JAM3, which causes haemorrhagic destruction of the brain, subependymal calcification and cataract, is the closest genetic phenocopy [70]. Isolated schizencephaly has a broad anatomoclinical spectrum, with focal epilepsy in most patients, and is associated with intrauterine cytomegalovirus infection and, in a small fraction of patients, with heterozygous EMX2 variants; familial occurrence is rare, and the cleft is usually lined by polymicrogyria [69]. Therefore, in the presence of schizencephaly, looking for old haemorrhage, cataract, retinal tortuosity and haematuria helps direct investigation towards COL4A1/COL4A2 [24, 69].

6.4. Monogenic small vessel diseases of adults

Among monogenic small vessel diseases, structural COL4A1/COL4A2 variants are distinguished by haemorrhagic predominance, the possibility of fetal or infantile onset and ocular, renal and muscular signs [1, 26]. CADASIL is mainly ischaemic, with migraine with aura and lesions of the anterior temporal pole and external capsule, and may be difficult to distinguish from PADMAL and from COL4A1/COL4A2 forms on imaging alone [54]. PADMAL is distinguished by recurrent pontine infarcts in young adults without haemorrhages, CARASIL by alopecia and low back pain, CARASAL by brainstem symptoms and RVCL-S by retinal vasculopathy and pseudotumoural lesions [26, 39]. In children, multisystemic smooth muscle dysfunction syndrome due to de novo variants at codon Arg179 of ACTA2 also combines periventricular white matter hyperintensities, intracranial arterial stenoses and ischaemic strokes, but is distinguished by neonatal patent ductus arteriosus, ascending aortic aneurysm in childhood, congenital mydriasis and an arteriopathy resembling moyamoya disease [75]. In adults with cognitive decline, stepwise progression and a history of stroke or transient ischaemic attacks point to a vascular cause, including CADASIL, rather than early-onset Alzheimer disease [78]; the late cognitive and affective phenotype of COL4A1 exon 23 should be included in this differential [25]. CADASIL and the other hereditary microangiopathies are part of the differential diagnosis.

6.5. Renal and ocular disorders

The haematuria with renal cysts of HANAC is distinguished from Alport syndrome by the absence of deafness, lenticonus and progressive proteinuria, and by the association with retinal tortuosity and cramps; Alport syndrome and the type IV collagen nephropathies of the α3α4α5 and α5α5α6 networks are part of the differential diagnosis [2, 9]. Autosomal dominant polycystic kidney disease has enlarged kidneys, unlike the cysts of HANAC, in kidneys of normal size [9]. In congenital cataract, anterior segment anomalies and microphthalmia, the presence of cerebrovascular lesions, retinal tortuosity or haematuria points to COL4A1, whereas isolated ocular defects have a broad genetic differential [9, 24]. Congenital cataract has an incidence of 1 to 15 per 10,000 births, 22% to 27% of cases are hereditary, and familial isolated cataract is mainly autosomal dominant, due to variants in the crystallins and other structural proteins of the lens [72]. About half of patients with anterior segment dysgenesis develop glaucoma, and, in the presence of childhood glaucoma, examination of the parents looks for minor signs of anterior segment dysgenesis [79]. Axenfeld-Rieger anomaly is called Axenfeld-Rieger syndrome only when accompanied by dental and systemic signs; PITX2 and FOXC1 account for 5–10% of isolated anterior segment dysgeneses, and FOXC1 variants may be associated with diffuse leukoencephalopathy suggestive of cerebral microangiopathy, a combination that mimics COL4A1 disease and is distinguished by hypodontia, redundant periumbilical skin, heart defects and deafness [73]. Peters anomaly is also genetically heterogeneous (PAX6, MAF, PITX2, CYP1B1), and bilateral involvement may only be detected on careful examination of the apparently normal eye [74].

7. Treatment and Risk Management Strategies

7.1. Principles and quality of evidence

There is no disease-modifying therapy, and recommendations rest on expert opinion, case series and animal models: the 2025 international consensus was obtained by a panel of 26 experts in a modified single-round eDelphi process, with a 70% agreement threshold; the EAN used a 1-to-5 Likert scale, with strong consensus when more than 70% of scores were ≥4 and the mean ≥4; the 2024 Italian protocol derives from a systematic review and a cohort of 43 individuals; and GeneReviews, updated in 2016, is based on case series [1, 9, 24, 26]. No recommendation derives from randomised trials [42]. Management is multidisciplinary (neurology, ophthalmology, nephrology, cardiology, genetics, anaesthesiology and rehabilitation), coordinated with the general practitioner or paediatrician to avoid redundant investigations, and participation in natural history registries and clinical studies is encouraged [1, 24]. The consensus does not apply to PADMAL, for which there is not yet a management consensus [1].

7.2. Guideline recommendations and divergences

Sources: [1, 9, 24, 26].

The main divergence concerns thrombolysis and delivery. The EAN and the Italian protocol advise against intravenous thrombolysis, whereas the 2025 consensus, supported by the guide by Guey and colleagues, allows reperfusion case by case in large artery occlusion in patients without prior ICH; both acknowledge that safety has never been studied in this population [1, 24, 26, 80]. Regarding delivery, the GeneReviews recommendation of routine caesarean section was based on the mouse model, in which surgical delivery reduced birth-related haemorrhage; the EAN softened it to “should be considered” and the 2025 consensus to “may be considered case by case”, identifying the relative safety of caesarean section and vaginal delivery as an area of active research [1, 9, 26, 33].

7.3. Haemorrhage prevention and control of vascular risk factors

Aggressive control of cerebrovascular risk factors is the central intervention: avoiding hypertension (target below 130/80 mmHg in adults and below the 95th percentile for age in children, with close monitoring), not smoking, avoiding sympathomimetics and treating hypercholesterolaemia, diabetes and obesity [1]. The Italian protocol proposes a target of ≤130/80 mmHg for all carriers, especially those with a history of haemorrhage or kidney disease, by extension of the American Heart Association (AHA) recommendations for the general population [24]. In UK Biobank, cardiovascular risk burden was associated with greater penetrance of NOTCH3 and HTRA1 variants, which supports the hypothesis that risk factor control improves prognosis in monogenic small vessel diseases; this association has not been shown specifically for COL4A1/2, because of the small number of events [23].

Prevention of head trauma includes avoiding contact sports, prolonged high-intensity activities and sustained cranial pressure, because ICH provoked by sport, trauma and exertion has been described [1, 9, 34]. In mice, intense exercise and anticoagulants worsened the disease [44]. Regular aerobic exercise, without prolonged strenuous exertion, is recommended [1].

Antiplatelets and anticoagulants are not recommended for primary or secondary cardiovascular or cerebrovascular prevention; in ischaemic stroke without prior ICH or with a strong indication, the decision should be made by a multidisciplinary team, weighing the history and bleeding risk, in both children and adults [1, 24]. By analogy with CADASIL, antiplatelet therapy is not indicated without prior ischaemic stroke, and lacunes recur in PADMAL despite antithrombotic therapy [24, 54]. The safety of medicines and supplements that interfere with platelet aggregation or coagulation has not been evaluated, but occasional use of non-steroidal anti-inflammatory drugs has been described as tolerated [1]. The Italian protocol advises against fluoroquinolones in collagen disorders unless there is no alternative, a recommendation extrapolated from other connective tissue disorders [24].

7.4. Acute stroke and intracerebral haemorrhage

When a carrier has a stroke, urgent imaging distinguishes haemorrhage from ischaemia. Intravenous thrombolysis is generally not recommended for small deep ischaemic lesions, and the decision on reperfusion in large artery occlusion should be individual, taking into account the absence of prior ICH; after prior ICH, reperfusion decisions follow the case-by-case analysis advocated by the AHA [1, 24]. ICH is treated according to general standards, and, according to the Italian protocol, the disease does not justify therapies aimed at reducing surgical bleeding risk, because there is no evidence of greater operative bleeding [24].

7.5. Intracranial and systemic aneurysms

GeneReviews recommended discussing surgical or endovascular treatment of asymptomatic intracranial aneurysms with a diameter greater than 10.0 mm [9]. The 2025 consensus warns that the safety of endovascular procedures has not been established and advises additional caution, as in other vascular collagen disorders; in the presence of intracranial aneurysms, it recommends screening the thoracic, abdominal and pelvic vasculature [1]. MRA surveillance is more frequent when an aneurysm is present [1].

7.6. Epilepsy

Epilepsy is treated according to the electroclinical presentation, because there is no specific antiseizure regimen of proven efficacy [1, 24]. The consensus recommends anticipatory guidance on seizures, counselling about infantile spasms, given their frequency in infants, immediate treatment and a low threshold for electroencephalogram (EEG) in the presence of regression or paroxysmal episodes [1]. Focal seizures with onset in childhood are often drug-resistant and complicated by status epilepticus, and in almost half of cases the epileptogenic zone colocalises with a porencephalic cyst, a finding relevant to presurgical evaluation [52]. Adherence and efficacy of therapy should be checked at each visit [24]. The global registry recommends that all families receive information materials on infantile spasms and stroke recognition [41].

7.7. Eye, kidney, muscle and heart

Cataract with significant opacities requires surgery, and glaucoma is initially treated with topical medication, reserving surgery for refractory cases [9]. Ophthalmological complications are managed according to standard practice, and transient visual loss requires urgent assessment to identify retinal haemorrhage [1]. Cerebral visual impairment benefits from early multidisciplinary assessment, continuous monitoring, visual habilitation and environmental adaptation strategies shared with caregivers [1].

In the presence of albuminuria, proteinuria should be quantified (urine protein/creatinine ratio in children; ratio or 24-hour urine in adults); proteinuria justifies referral to nephrology to consider renin–angiotensin–aldosterone system blockade, and reduced renal function, cystic disease or hypertension also justify referral; in children, microscopic or macroscopic haematuria, cysts or blood pressure ≥95th percentile justify paediatric nephrology referral [1]. The Italian protocol uses as a referral threshold proteinuria above 0.3 g/day or a protein/creatinine ratio above 0.3 [24].

For muscular manifestations, it is recommended to maintain aerobic exercise while avoiding prolonged strenuous exertion, to advise about cramps worsening with cold and to suspect cramps in the presence of irritability, unexplained crying or sleep disturbance in children with severe neurological impairment; there is only anecdotal evidence of benefit from drugs that increase nitric oxide [1]. Symptomatic paroxysmal supraventricular arrhythmia is treated with antiarrhythmics, namely beta-blockers [9].

7.8. Doses

There is no targeted therapy whose dosage needs to be stated: the medicines used (antiseizure drugs, antihypertensives, renin–angiotensin–aldosterone system blockers, beta-blockers, treatment of infantile spasms) are prescribed according to the standards and labels of their respective general indications, with no specific dose adjustment described for this disease [1, 9, 24].

7.9. Anaesthesia, surgery and perioperative situations

Prolonged recovery from anaesthesia and anaesthetic complications have been described; the consensus recommends an anaesthesiology consultation before any procedure, with information about the variant, and strict peri-procedural blood pressure support to avoid hypotension [1]. In 2026, the first description of anaesthetic management in a child with Gould syndrome undergoing bilateral adductor and gracilis tenotomy was published, discussing perioperative considerations (neurological deficits, seizures, ophthalmological changes and supraventricular arrhythmias) [66]. There is no evidence of increased surgical bleeding risk [24].

7.10. Pregnancy, delivery and neonatal period

The pregnancy of a carrier or of a carrier fetus requires high-risk obstetric follow-up, with ultrasound scans according to an individualised protocol and fetal MRI after 20 weeks to exclude brain malformations, fetal vascular events and malformations of other organs, and delivery in a tertiary centre may be considered [1, 24]. The mode of delivery is decided case by case, and sustained cranial pressure during delivery should be avoided [1, 24]. When fetal disease is suspected, a fetal or neonatal neurology consultation is recommended [1]. In the Mexican case, the patient had been born preterm by caesarean section and her two pregnancies were complicated by severe pre-eclampsia with early termination [77].

7.11. Rehabilitation, support and transition

Motor rehabilitation, speech therapy, visual habilitation and feeding support (gastrostomy in severe cases) follow individual needs [1, 51]. Emotional support and family counselling are part of care, and psychological support may improve quality of life [1, 24]. Transition to adult care should ensure continuity of vascular, renal and ophthalmological surveillance, because the risk of ICH, aneurysms and kidney disease persists or appears in adulthood [1, 9].

7.12. Regulatory status

Sources: [27, 44, 81].

7.13. Clinical studies and preclinical evidence

Sources: [27, 44, 81].

Preclinical results cannot be transposed into practice. Sodium 4-phenylbutyrate reduced ICH in mice, including in established disease, but did not alter the ocular and renal defects and, although it reduced ER stress and increased incorporation of type IV collagen into the basement membrane, the structure of the latter remained abnormal and less resistant to mechanical stress, which led the authors to regard it as potentially contraindicated for manifestations caused by matrix defects [81]. Treatment of the disease will probably require approaches that simultaneously restore ER homeostasis and the matrix, with patient stratification by presentation and variant mechanism [81]. Gene editing is regarded as promising for type IV collagen disorders, with no human studies [2]. No negative, suspended or withdrawn trials were identified, which reflects the absence of therapeutic trials and does not demonstrate the non-existence of unregistered studies [27].

7.14. Developments in the last 12 months

None of these developments changes the management established by the 2025 consensus; the exon 23 series broadens the clinical spectrum and the indication for testing in adults with cognitive decline and small vessel disease without proportionate risk factors [1, 25].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by scenario

In the autosomal dominant forms, each child of a carrier has a 50% probability of inheriting the variant [1, 9]. According to GeneReviews, most diagnosed individuals have an affected parent, but paediatric and fetal series show de novo proportions of 40% to 70%, and the 2025 consensus considers these estimates biased by test access [1, 9–12]. Risks to siblings depend on the parents' status:

An apparently negative family history does not exclude transmission, owing to failure to recognise the disease, early death or late onset in a parent; assessment of the parents of a proband with an apparently de novo variant includes testing for the variant, clinical review, brain MRI and ophthalmological examination [9]. Non-medical explanations, such as paternity or maternity other than reported or undisclosed adoption, should be considered [9].

8.2. Cascade and presymptomatic testing

The EAN recommends presymptomatic testing of relatives, except in PADMAL, because of the benefit of preventive measures, including avoiding delivery complications (mean 4.71; 100%), and the 2025 consensus recommends testing and counselling of at-risk relatives [1, 26]. In practice, screening of carriers and first-degree relatives includes neurological, ophthalmological, renal and cardiac assessment, and targeted ophthalmological assessment detects retinal tortuosity, anterior segment dysgenesis or cataract in some oligosymptomatic carriers [4, 24]. The consensus accepts testing of first-degree relatives with high CK, haematuria, early small vessel disease, glaucoma or Axenfeld-Rieger, respecting personal preferences, local legislation and, if necessary, ethical approval [1].

When testing asymptomatic minors, the potential benefits noted by the EAN (prevention of delivery complications) and the preventive measures of the consensus (trauma prevention, blood pressure control, screening for aneurysms and ocular signs) should be discussed with the family in the light of the general principles of counselling [1, 26]. PADMAL was excluded from the EAN recommendation for presymptomatic testing, because of the absence of proven preventive measures [26].

8.3. Reproductive options

The ideal time for risk assessment and discussion of reproductive options is before pregnancy, and counselling should be offered to affected or at-risk young adults [9]. Once the variant is known, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible, with the published example of the birth of a non-carrier child after embryo selection [9, 68]. The pregnancy of a carrier, or with an at-risk fetus, requires high-risk follow-up, a genetics clinic consultation and, when fetal disease is suspected, fetal or neonatal neurology [1]. Use of prenatal diagnosis is a personal decision, and views may differ between professionals and within families [9].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What is known about frequency

The prevalence of the disease has not been established [1, 9]. Orphanet assigns familial porencephaly a point prevalence class of <1/1,000,000 in Europe (not validated), and the same class to HANAC (six families), PADMAL (11 cases) and familial isolated retinal arteriolar tortuosity (about 100 cases), estimates based on counts of published cases and not on population studies [19–22]. The number of published cases has grown steadily: a 2015 review gathered 174 individuals (157 with COL4A1 variants and 17 with COL4A2 variants), GeneReviews considered in 2016 that prevalence could not be established because fewer than 100 families had been described, and the 2024 systematic review gathered 647 individuals from 485 families up to August 2023 [9, 10, 24]. In UK Biobank, 1 in 1353 adults aged 40 to 69 years carries a published pathogenic COL4A1/2 variant, mainly p.(Gly332Arg), and 0.04% of strokes in the cohort were attributed to these variants; this carrier frequency, much higher than the frequency of clinical disease, reflects the reduced penetrance of some variants and the recruitment of healthy volunteers [23]. Porencephaly of all causes has a birth prevalence of 5.2/100,000 in Japan and 3.5/100,000 in the United States, figures that cannot be attributed to COL4A1/2 [76].

9.2. Geographical distribution and populations studied

By 2016, variants had been described in individuals of Dutch, Italian, French, German, American, Chinese, Spanish and Japanese origin [9]. The main quantitative series are European (Erasmus MC in the Netherlands; French cohorts from Paris; Italian cohort from Florence; multicentre European epilepsy cohort; British population of UK Biobank), Japanese and from the international global registry of the Gould Syndrome Foundation (70 families from 12 countries) [10–12, 23, 24, 41, 52, 61]. A Cypriot family with mainly renal disease, consanguineous Turkish and Iranian families with recessive forms and the first Latin American case, a Mexican woman with recurrent ischaemic strokes, published in 2023, have also been described [7, 24, 48, 77]. No founder variants have been described; the p.(Gly332Arg) variant, the most frequent in UK Biobank, was not associated with a risk different from the others [23]. The sources consulted do not include data from Portugal or Brazil, which does not mean that there are no patients or publications in those countries.

9.3. Special populations

In children with severe neurological impairment, cramps and seizures may present only as irritability, crying or sleep disturbance [1]. In pregnancy, the risk falls on the carrier fetus (prenatal and perinatal haemorrhage) and on the pregnant carrier, in whom pre-eclampsia and vascular complications have been described in isolated reports [1, 77]. Athletes and patients anticoagulated for another reason constitute groups at risk of provoked ICH [1, 34]. In older people, variants may present for the first time as late ICH or cognitive decline [13, 25].

9.4. European networks and patient organisations

The centres that published the Italian protocol are members of the European Reference Networks EpiCARE and ITHACA, suited to the follow-up of paediatric forms with epilepsy, malformations and intellectual disability [24]. The Gould Syndrome Foundation (https://www.gouldsyndromefoundation.org/) maintains the global patient registry, and the Associazione Famiglie COL4A1-A2 (https://www.col4a1.net/) co-organised the first European conference on the disease, in Rome, in February 2024 [1, 28, 29, 41]. GeneReviews also lists general resources from the National Institute of Neurological Disorders and Stroke (porencephaly page), the National Eye Institute, the Epilepsy Foundation, the National Kidney Foundation and the French rare kidney disease network (filière) ORKiD [9].

10. Illustrative Clinical Case

10.1. Newborn with multiple intracranial haemorrhages and bilateral congenital cataract

Yakabe and colleagues described, in 2022, a male newborn, the first child of non-consanguineous parents with no family history of cerebral haemorrhage, seizures or cataract, born at 36 weeks and 4 days by normal vaginal delivery, weighing 2606 g (+0.14 standard deviations) and measuring 46.6 cm (−0.11 standard deviations) [50]. On the second day of life he had a generalised clonic seizure; cranial ultrasound and CT showed multiple intracranial haemorrhages with intraventricular extension, and he was transferred to a university hospital in Tokyo [50]. MRI showed multiple parenchymal and subdural haemorrhages and dilated vessels in the centrum semiovale, without tumour, dissection or venous thrombosis (Figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC9187765/figure/Fig1/) [50]. Ophthalmological examination revealed bilateral congenital cataract, and the combination of cerebrovascular disease with cataract led to suspicion of COL4A1/A2 disease [50].

The karyotype was 46,XY. Capture-based targeted sequencing identified the heterozygous variant COL4A1 NM_001845.6:c.2291G>A, p.(Gly764Asp), a glycine substitution in the Gly-X-Y repeats of the triple helix, confirmed in VariantValidator; Sanger sequencing showed that it was absent from the blood of both parents (Figure 2 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC9187765/figure/Fig2/) [8, 50]. The variant was not present in gnomAD or in the Japanese jMorp database, bioinformatic predictions were deleterious and it was classified as pathogenic by the ACMG/AMP criteria (PS2, PM1, PM2, PP3, PP4) [50].

10.2. Lessons

The case brings together the neonatal warning signs defined by the consensus: ICH without vascular malformation or coagulopathy in a near-term newborn, congenital cataract and no family history, consistent with a de novo variant [1, 50]. The authors considered the risk for future siblings to be low, but advised monitoring of future pregnancies because only the parents' blood had been analysed, which corresponds to the empirical risk of about 1% due to germline mosaicism [9, 50]. After diagnosis, current recommendations provide for baseline ophthalmological (including retinal tortuosity and intraocular pressure), renal, cardiac and CK assessment, MRA, anticipatory guidance on infantile spasms and prevention of head trauma; the report does not describe the long-term course [1, 50].

Two other reports complete the spectrum: a Latin American case of recurrent ischaemic strokes in a young adult with leukodystrophy, whose mother had had a delivery-related cerebral infarction, and two term newborns with ICH and maternally inherited non-glycine variants, whose interpretation illustrates the caution required with variants of uncertain significance [51, 77].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Overall prognosis is uncertain, because clinical heterogeneity is extreme and natural history studies with prospective follow-up are lacking [1]. Forms with fetal or neonatal onset and extensive haemorrhage, porencephaly or schizencephaly are associated with motor impairment, intellectual disability and epilepsy, often drug-resistant; in fetuses with intraparenchymal haemorrhage, lesion size correlated with motor outcome, and none of the five with follow-up had symptomatic recurrent haemorrhage [24, 52, 56]. In the global registry, 28.6% of children with epilepsy used a feeding tube and 88.6% had developmental delay [41]. Adult forms range from asymptomatic white matter changes to recurrent ICH with severe disability or death; in PADMAL, the course is towards progressive cognitive and motor impairment, with early death reported by the EAN [9, 16, 26, 34]. MRI lesions progress in 62.3% of patients with reported serial imaging [55]. The visual prognosis of retinal haemorrhage is generally excellent, mild renal impairment appears after 40 to 50 years in HANAC and in familial kidney disease, and HANAC aneurysms did not rupture in the series described [1, 9]. In UK Biobank, adult carriers of published variants did not have a higher risk of incident stroke over a median follow-up of 12.6 years, up to 2021 (HR 1.03), indicating that many carriers identified in adulthood have a benign course [23].

11.2. Baseline assessment after diagnosis

The recommended baseline assessment includes neurological assessment (signs of previous stroke, seizures, motor, language and cognitive deficits), MRI and MRA of the head and neck with SWI, ophthalmological examination with dilated indirect ophthalmoscopy and slit lamp (and, depending on age and cooperation, visual acuity, intraocular pressure and optical coherence tomography, OCT), ECG and transthoracic echocardiogram, blood pressure measurement, urinalysis, creatinine with estimated glomerular filtration rate, renal and bladder ultrasound, CK, full blood count and coagulation tests, and a genetics clinic consultation [1, 9, 24]. The EAN and GeneReviews also include liver ultrasound, and the Italian protocol proposes abdominal MRI (or ultrasound if MRI is not feasible) to detect malformations or vascular changes [9, 24, 26].

11.3. Surveillance

Surveillance intervals have not been validated in outcome studies; the frequency of MRI, in particular, has not been established, and the consensus proposes it as reasonable [1]. Follow-up of the renal and ocular forms extends to oligosymptomatic and asymptomatic carriers, because retinal tortuosity and anterior segment dysgenesis may progress to complications [24].

12. Summary and Final Considerations

COL4A1- and COL4A2-related disorders, now also called Gould syndrome, result from alterations of the α1α1α2(IV) heterotrimer, the basement membrane collagen of almost all tissues. Glycine substitutions in the triple helix and variants that reduce the amount of protein weaken the small vessels and produce a predominantly haemorrhagic disease, which may begin in the fetus, with porencephaly, schizencephaly and intraventricular haemorrhage, or in adulthood, with deep ICH, leukoencephalopathy, microbleeds and lacunes. Variants that increase COL4A1 expression, in the 3'UTR or through duplication, produce a distinct ischaemic picture, PADMAL, with recurrent pontine infarcts in young adults.

The spectrum is multisystemic: congenital cataract, retinal arterial tortuosity with retinal haemorrhages, anterior segment dysgenesis and glaucoma; haematuria, renal cysts and late decline in renal function; cramps with raised CK; intracranial and systemic aneurysms; congenital heart disease, arrhythmias and arterial dissections; neonatal haemolytic anaemia. HANAC, associated with exons 24 and 25, combines constant retinal tortuosity and cramps with nephropathy and aneurysms and often silent cerebral disease. Inheritance is autosomal dominant, with a high proportion of de novo variants in severe forms, incomplete penetrance and variable expressivity within families; there are recessive forms of COL4A2 and, possibly, of COL4A1.

Diagnosis rests on clinical suspicion in the presence of unexplained fetal or neonatal haemorrhage, cerebral palsy mimics with porencephaly, epilepsy with a structural lesion, ICH or ischaemic lesions disproportionate to risk factors in adults and associated ocular, renal or muscular signs, followed by sequencing of COL4A1 and COL4A2; a negative panel does not exclude the diagnosis, which may require genome sequencing, CNV analysis and 3'UTR analysis. Management, without targeted therapy, is preventive and multidisciplinary: strict blood pressure control, abstention from antithrombotics unless there is a strong indication discussed by the team, prevention of head trauma and high-risk sports, caution with thrombolysis and endovascular procedures, anaesthetic preparation, planned delivery in a specialised centre and neurological, ophthalmological, renal and cardiac surveillance. The 2025 international consensus and the 2024 Italian protocol are the current references, with divergences noted regarding thrombolysis and caesarean section. Animal models have identified targets (endoplasmic reticulum stress, matrix modifiers), but no treatment has yet reached clinical trials, and natural history registries are the necessary step to define prognosis and prepare those trials.

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