Clinical Diagnosis

The COL4A1-related disorders include the following phenotypes that have overlapping features:

• Autosomal dominant type 1 porencephaly [Gould et al 2005, Breedveld et al 2006, van der Knaap et al 2006, De Vries et al 2009]

• Brain small-vessel disease with hemorrhage [Vahedi et al 2003, Gould et al 2006, Vahedi et al 2007a, Vahedi et al 2007b]

• Brain small-vessel disease with Axenfeld-Rieger anomaly [Sibon et al 2007]

• Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome [Plaisier et al 2005, Plaisier et al 2007]

These four phenotypes were described before the molecular basis of COL4A1-related disorders was understood; however, it is now recognized that they are part of a continuum with overlapping features. Nonetheless, it is reasonable to continue to think of COL4A1-related disorders in terms of these phenotypes in order to provide affected individuals with information about the expected clinical course.

No diagnostic criteria have been established for COL4A1-related disorders. The findings and age of onset vary within and between families.

Clinical features of COL4A1-related disorders include:

• Infantile hemiplegia

• Migraines, with or without aura

• Seizures

• Dementia

• Intellectual disability

• Intracerebral hemorrhage, at various ages, including antenatal and recurrent episodes

• Ischemic stroke

• Transient visual loss caused by retinal hemorrhages

• Cataract, glaucoma, microcornea

• Hematuria

• Large bilateral renal cysts (size can vary from 10 to 200 mm)

• Raynaud phenomenon

• Paroxysmal supraventricular arrhythmia

• Muscle cramps

• Familial history consistent with autosomal dominant inheritance

Neuroimaging usually shows the following features of brain small-vessel disease (Figure 1):

Figure

Figure 1. Spectrum of brain imaging abnormalities in COL4A1-related disorders

A. Axial FLAIR showing right paraventricular porencephalic cyst and extensive white-matter abnormalities [van der Knaap et al 2006]
B. Axial FLAIR showing (more...)

• Porencephaly characterized by a fluid-filled cavity in the brain (Figure 1A) [Gould et al 2005, Breedveld et al 2006, van der Knaap et al 2006, De Vries et al 2009]

• Leukoencephalopathy with deep, usually bilateral and symmetric white-matter hyperintensities on T₂-weighted MRI, mainly located in supratentorial posterior periventricular areas (Figure 1B) [Vahedi et al 2007a, Vahedi et al 2007b]

• Cerebral microhemorrhages visualized with T₂-weighted gradient echo MRI [Vahedi et al 2007a, Vahedi et al 2007b]

• Lacunar infarcts

• Deep intracerebral hemorrhages (Figure 1C) [Vahedi et al 2007a, Vahedi et al 2007b]

• Dilated perivascular spaces [Vahedi et al 2007a, Vahedi et al 2007b]

• Single or multiple intracranial aneurysms, usually located in the intracranial portion of the internal carotid artery, rarely in the middle artery and the top of the basilar artery (Figure 1D) [Plaisier et al 2007]. Subarachnoid hemorrhage secondary to aneurysm rupture has not been reported to date.

Abdominal imaging inconstantly shows:

• Multiple bilateral large renal cysts in the cortex and medulla with normal kidney size (Figure 2) [Plaisier et al 2007, Plaisier et al 2010]

• Liver cysts [Plaisier et al 2007]

Figure

Figure 2. Abdominal MRI showing bilateral renal cysts in a patient with HANAC syndrome [Plaisier et al 2007]

Ophthalmologic examination (including funduscopic examination) inconstantly shows:

• Bilateral tortuosity of the second- and third-order arteries with normal first-order arteries and venous system (Figure 3) [Plaisier et al 2005, Gould et al 2006, Plaisier et al 2007]

• Hemorrhagic spots

• Microcornea [Sibon et al 2007]

• Congenital or juvenile cataract [Sibon et al 2007]

• Increased intraocular pressure [Sibon et al 2007]

• Iris hypoplasia [Sibon et al 2007]

• Retinal detachment [Sibon et al 2007]

• Optic nerve excavation [Sibon et al 2007]

Figure

Figure 3. Fluorescein angiography. Typical retinal arteriolar tortuosity (arrows) in a patient with HANAC syndrome [Plaisier et al 2007].

Testing

Urinalysis shows hematuria (dozen to hundreds of erythrocytes per high-power microscopic field) [Plaisier et al 2005, Plaisier et al 2007].

Blood testing shows:

• CK (creatine phosphokinase) increased concentration that is two- to fivefold upwards of the normal range [Plaisier et al 2005, Plaisier et al 2007];

• Mild decrease in glomerular filtration rate (GFR) [Plaisier et al 2005, Plaisier et al 2007].

Molecular Genetic Testing

Gene. COL4A1 encodes the alpha-1 chain of type IV collagen.

Clinical testing

• Sequence analysis of genomic DNA. COL4A1 mutations are detected by sequence analysis of all exons and flanking intronic regions of COL4A1 genomic DNA (gDNA). Genomic DNA can be isolated from any tissue of the individual being tested. All the sequence alterations in COL4A1 are missense mutations except for a mutation that eliminates the ATG initiating codon and an insertion into the non-collagenous domain (see Molecular Genetics). The mutation detection frequency for sequence analysis has not been established.

• Deletion/duplication testing, which may employ a variety of methods, detects COL4A1 rearrangements not identifiable by sequence analysis of genomic DNA; these include exonic or whole-gene deletions. To date, no deletions or duplications involving COL4A1 as causative of COL4A1-related disorders have been reported. Because these disorders usually result from a COL4A1 missense mutation that disrupts the collagen triple helix (see Molecular Genetics), a screening test for large duplications/deletions may have a very low yield; as such, rearrangements would be predicted to affect collagen assembly in a different way.

Research testing

• Sequence analysis of cDNA. COL4A1 mutations may also be detected by complete sequence analysis of COL4A1 cDNA. The mRNA for complementary DNA (cDNA) sequencing is derived from dermal fibroblasts [Plaisier et al 2007].

Table 1. Summary of Molecular Genetic Testing Used in COL4A1-Related Disorders

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
COL4A1	Genomic DNA sequence analysis	Sequence variants 2	Unknown	Clinical
	Deletion / duplication analysis 3	None known	Unknown
	Complementary DNA sequence analysis	Sequence variants 2	Unknown	Research only

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array GH may be used.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

• In persons with porencephaly and/or small-vessel brain disease in whom the family history includes intracranial hemorrhage with or without hypertension before age 50 years, COL4A1 molecular genetic testing should consist of complete sequencing of the gDNA coding and flanking regions.

• In persons with HANAC syndrome, COL4A1 molecular genetic testing should begin with sequence analysis of exons 24 and 25, followed by complete sequencing of the gene.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in COL4A1.

Natural History

COL4A1-related disorders cover a spectrum of overlapping phenotypes characterized by a small-vessel brain disease of varying severity, including porencephaly, variably associated with eye defects (retinal arterial tortuosity, Axenfeld-Rieger anomaly) and systemic findings (muscle cramps, kidney involvement, cerebral aneurysms, Raynaud phenomenon, and cardiac arrhythmia).

Autosomal dominant familial porencephaly related to COL4A1 mutations has been reported in eight families [Gould et al 2005, Breedveld et al 2006, van der Knaap et al 2006, De Vries et al 2009]. This condition is characterized by the presence of fluid-filled cavities in the brain, caused by antenatal or perinatal parenchymal hemorrhage and detected by either CT or MRI (Figure 1A) [Mancini et al 2004, De Vries et al 2009]. In addition to porencephalic cysts, brain imaging shows various degrees of leukoencephalopathy, cerebral micro hemorrhage, and lacunar infarct.

The spectrum of neurologic symptoms varies in degree of severity and age of onset, with intrafamilial heterogeneity. Typically, affected individuals present with infantile hemiparesis, seizures, intellectual disability, dystonia, stroke, and migraine. First manifestations, including intracerebral hemorrhages, may occur in previously asymptomatic adults, and MRI brain anomalies can be clinically silent.

In one family, congenital cataract was observed in all affected individuals and associated with retinal arteriolar tortuosity in only one individual [van der Knaap et al 2006].

Autosomal dominant brain small-vessel disease with hemorrhage differs from the autosomal dominant familial porencephaly by the absence of porencephalic cavities, while brain imaging demonstrates characteristic brain small-vessel involvement, including diffuse periventricular leukoencephalopathy (Figure 1B), lacunar infarcts, microbleeds, dilated perivascular spaces, and deep intracerebral hemorrhages (Figure 1C) [Vahedi et al 2003, Gould et al 2006, Vahedi et al 2007a, Vahedi et al 2007b].

Neurologic manifestations are also heterogeneous within families, and vary from infantile hemiparesis with seizure to isolated migraine with aura, to absence of clinical symptoms. Single or recurrent intracerebral hemorrhages may occur in non-hypertensive adults who are younger than age 50 years. These hemorrhages can occur spontaneously, after trauma, or as result of anticoagulant use; sometimes they are fatal. Antenatal intracerebral and intraventricular hemorrhages have also been reported in two pairs of preterm sibs [de Vries et al 2009, Bilguvar et al 2009]. Mild cognitive impairment has also been reported in one family [Sibon et al 2007]; however, it is unclear if this is a separate finding or a manifestation of recurrent stroke.

Retinal arteriolar tortuosity is constantly associated with the brain disease in affected individuals in one family [Vahedi et al 2003, Gould et al 2006], whereas in another family, the eye findings are characterized by various anterior segment anomalies of the Axenfeld-Rieger type [Sibon et al 2007].

Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome has been well characterized in six families [Plaisier et al 2005, Plaisier et al 2007, Plaisier et al 2010].

The small-vessel brain disease of HANAC is usually asymptomatic. By contrast, the systemic symptoms of HANAC (muscle cramps, renal involvement, and Raynaud phenomenon) are not usually observed in COL4A1-related porencephaly or small-vessel brain disease. Although retinal tortuosity has only been reported in one family with small-vessel brain disease [Vahedi et al 2003, Gould et al 2006], it is consistently observed in families with HANAC.

• Brain involvement

  • Half of affected individuals have cerebral small-vessel disease characterized by leukoencephalopathy affecting subcortical, periventricular, or pontine regions; dilated perivascular spaces; lacunar infarcts, and microbleeds. None have porencephaly. Only two of the 14 affected individuals have clinical cerebrovascular symptoms: a minor ischemic stroke and a mild post-traumatic hemorrhage while on anticoagulants.

  • Single or multiple intracranial aneurysms, all located on the carotid siphon, have been observed in six individuals, with no rupture episode (Figure 1D).

• Renal manifestations

  • One family presented with isolated microscopic hematuria (i.e., without proteinuria or hypertension) and intermittent episodes of gross hematuria. Kidney biopsy was normal by light microscopy, but ultrastructural examination disclosed irregular and abnormal thickening of the basement membranes of the tubules, Bowman’s capsule, and interstitial capillaries. Small renal cysts were variably observed.

  • Three families had renal findings of bilateral cortical and medullary renal cysts without hematuria. Cysts were large, but the overall kidney size was normal (Figure 2). Mild renal failure without proteinuria or hypertension may develop in older individuals.

• Muscle cramps involving a variety of muscles are present in most affected individuals, with first episodes occurring before age three years. Muscle strength was slightly affected in only two individuals. Electromyography does not show a specific abnormality, and muscle biopsy, available in one person only, is normal. All affected individuals have persistent elevation of serum CK concentration.

• Bilateral retinal arteriolar tortuosity is observed in all individuals with HANAC syndrome (see Ocular manifestations below).

• Other manifestations. Raynaud phenomenon and supraventricular arrhythmia are variably reported.

Ocular manifestations are variably observed in COL4A1-related disorders. Three distinct ocular features have been reported:

• Bilateral retinal arteriolar tortuosity is present in one family with small-vessel brain disease with hemorrhages [Vahedi et al 2003, Gould et al 2006], in one individual with porencephaly [van der Knaap et al 2006], and in all individuals with HANAC syndrome [Plaisier et al 2005, Plaisier et al 2007]. Fundus examination shows marked tortuosity of second- and third-order retinal arteries, with normal first-order arteries and retinal veins (Figure 3). No leakage or staining is observed on fluorescein angiography. Affected individuals experience episodic transient visual loss as a result of retinal hemorrhages, occurring spontaneously or after minor stress or trauma. To date, visual prognosis has been excellent, without retinal sequelae.

• Congenital cataract is reported as an isolated ocular feature in two families [van der Knaap et al 2006, Shah et al 2010] and is associated with other eye anterior segment abnormalities of Axenfeld-Rieger type in a family with small-vessel brain disease [Sibon et al 2007].

• Axenfeld-Rieger anomaly with congenital cataract, microcornea, retinal detachment, increased intraocular pressure, and optic nerve excavation has been described in one family presenting with small-vessel brain disease including diffuse leukoencephalopathy, stroke-like episodes, and mild cognitive impairment in adults [Sibon et al 2007]. Additionally, one individual had infantile hemiparesis with porencephaly. Retinal vascular tortuosity is not detected in this family.

Ultrastructural basement membrane abnormalities have been demonstrated in skin vessels, at the dermo-epidermal junction, and in the kidney.

• In individuals with HANAC syndrome with hematuria, ultrastructural examination disclosed irregular and abnormal thickening of the basement membranes of the tubules, Bowman’s capsule, and interstitial capillaries [Plaisier et al 2007]. In the skin, similar alterations including duplication of the basement membrane are seen at the dermo-epidermal junction and in dermal arterioles; vascular smooth muscle cells are dissociated due to abnormal spreading of basement membrane.

• In one individual with autosomal dominant porencephaly, focal disruption and a major increase in thickness of the basement membrane of skin capillaries were found [van der Knaap et al 2006].

Genotype-Phenotype Correlations

The number of pathogenic COL4A1 mutations is too small to explore genotype-phenotype relationships.

However, all six COL4A1 mutations associated with hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (i.e., HANAC syndrome) are localized in exons 24 and 25 [Plaisier et al 2007, Plaisier et al 2010]. They affect glycine residues localized in a short 30-amino acid region of the protein, whereas all but one mutation responsible for more severe brain disease, including porencephaly and small-vessel brain disease, are distributed through exons 25 to 51 [Gould et al 2005, Breedveld et al 2006, van der Knaap et al 2006, De Vries et al 2009].

Penetrance

Penetrance of COL4A1-related disorders is probably close to 100%, with expression varying in age of onset and severity of the clinical symptoms, even in the same family; however, these data need verification in larger cohort studies.

Anticipation

No convincing evidence of anticipation has been documented

Prevalence

Prevalence of COL4A1-related disorders cannot be established as only 17 families (65 affected individuals) have been described.

No data are available on the prevalence of COL4A1 mutations in persons with microscopic hematuria or renal cysts.

Mutations reported so far have been found in individuals of Dutch, Italian, French, German, and American origin.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with COL4A1-related disorders, the following are recommended:

• Brain MRI

• Brain angio CT

• Ophthalmologic examination

• Kidney and liver ultrasound examination or CT

• Serum CK concentration

• Measurement of serum creatinine concentration and estimation of the glomerular filtration rate

• Evaluation for the presence of hematuria

Treatment of Manifestations

Hypertensive individuals must be treated to reduce the global risk of stroke.

Supportive care including practical help, emotional support, and counseling are appropriate for affected individuals and their families.

No specific support exists for individuals with COL4A1-related disorders.

• Seizures are managed using standard protocols.

• Cataract surgery may be required for individuals with severe lens opacities.

• Glaucoma is initially treated with topical anti-glaucoma medication. Surgery is reserved for eyes that do not respond to medical therapy.

• Symptomatic paroxysmal supraventricular arrhythmia should be treated with antiarrhythmic drugs (beta blockers).

• Surgical or endovascular treatment should be discussed for asymptomatic intracranial aneurysms larger than 10.0 mm in diameter.

Surveillance

The interval at which individuals with COL4A1-related disorders should be seen for follow-up depends on the severity and type of symptoms.

Annual clinical evaluation is reasonable.

Regular brain imaging can be proposed, especially to evaluate the size of asymptomatic cerebral aneurysms.

Agents/Circumstances to Avoid

The following should be avoided:

• Smoking because it increases the global risk of stroke

• Sustained or physical activities that may cause head trauma [Gould et al 2006]

• Anticoagulant use [Gould et al 2006]

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Cesarean delivery for pregnancies in which the fetus is at risk for a COL4A1-related disorder is recommended to prevent brain vascular injury attributable to birth trauma in newborns [Gould et al 2006].

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

COL4A1-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with a COL4A1-related disorder have an affected parent.

• A proband with a COL4A1-related disorder may have the disorder as the result of a new mutation. The proportion of cases caused by de novo mutations is currently unknown.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include medical record review, brain imaging by MRI, and ophthalmologic evaluation. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although most individuals diagnosed with a COL4A1-related disorder have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.

• Although penetrance of COL4A1-related disorders is probably close to 100%, age of onset and severity of the clinical symptoms vary, even in the same family.

• The sibs of a proband with clinically unaffected parents are still at increased risk (for the disorder) because of the possibility of reduced penetrance in a parent.

Offspring of a proband. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo mutation or the parent has reduced penetrance. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed. Although this testing can determine whether or not the fetus has inherited the COL4A1 mutation, it cannot predict the appearance or severity of clinical manifestations.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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Suggested Reading

1. Flossmann E. Genetics of ischaemic stroke; single gene disorders. Int J Stroke. 2006;1:131–9. [PubMed: 18706033]
2. Hara K, Shiga A, Fukutake T, Nozaki H, Miyashita A, Yokoseki A, Kawata H, Koyama A, Arima K, Takahashi T, Ikeda M, Shiota H, Tamura M, Shimoe Y, Hirayama M, Arisato T, Yanagawa S, Tanaka A, Nakano I, Ikeda S, Yoshida Y, Yamamoto T, Ikeuchi T, Kuwano R, Nishizawa M, Tsuji S, Onodera O. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med. 2009;360:1729–39. [PubMed: 19387015]
3. Mine M, Tournier-Lasserve E. Intracerebral hemorrhage and COL4A1 mutations, from preterm infants to adult patients. Ann Neurol. 2009;65:1–2. [PubMed: 19194872]
4. Lanfranconi S, Markus HS. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Stroke. 2010;41:e513–8. [PubMed: 20558831]

Author Notes

www.eunefron.org

Revision History

• 8 March 2011 (me) Comprehensive update posted live

• 25 June 2009 (et) Review posted live

• 27 February 2009 (ep) Original submission