Clinical characteristics.

The spectrum of COL4A1-related disorders includes: small-vessel brain disease of varying severity including porencephaly, variably associated with eye defects (retinal arterial tortuosity, Axenfeld-Rieger anomaly, cataract) and systemic findings (kidney involvement, muscle cramps, cerebral aneurysms, Raynaud phenomenon, cardiac arrhythmia, and hemolytic anemia). On imaging studies, small-vessel brain disease is manifest as diffuse periventricular leukoencephalopathy, lacunar infarcts, microhemorrhage, dilated perivascular spaces, and deep intracerebral hemorrhages. Clinically, small-vessel brain disease manifests as infantile hemiparesis, seizures, single or recurrent hemorrhagic stroke, ischemic stroke, and isolated migraine with aura. Porencephaly (fluid-filled cavities in the brain detected by CT or MRI) is typically manifest as infantile hemiparesis, seizures, and intellectual disability; however, on occasion it can be an incidental finding. HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome usually associates asymptomatic small-vessel brain disease, cerebral large vessel involvement (i.e., aneurysms), and systemic findings involving the kidney, muscle, and small vessels of the eye. Two additional phenotypes include isolated retinal artery tortuosity and nonsyndromic autosomal dominant congenital cataract.

Diagnosis/testing.

Diagnosis is based on clinical findings and molecular genetic testing of COL4A1.

Management.

Treatment of manifestations: Supportive care tailored to the individual’s specific medical needs and including practical help and emotional support for affected individuals and their families. Hypertension should be treated to reduce the overall risk of stroke.

Prevention of primary and secondary complications: Avoiding head trauma and anticoagulant exposure may decrease the risk for intracerebral hemorrhage.

Surveillance: Depends on the severity and type of symptoms.

Agents/circumstances to avoid: Smoking and hypertension because these factors increase the risk for stroke; sustained head pressure or physical activities that may cause head trauma; anticoagulant use.

Genetic counseling.

COL4A1-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. The proportion of cases caused by a de novo pathogenic variant is estimated to be at least 27%. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant in the family is known.

Suggestive Findings

A COL4A1-related disorder should be suspected in individuals with any of the following phenotypes, which have overlapping features:

• Porencephaly type 1 [Gould et al 2005, Breedveld et al 2006, van der Knaap et al 2006, Yoneda et al 2013, Meuwissen et al 2015]
• Brain small-vessel disease with or without ocular anomalies [Gould et al 2006, Sibon et al 2007, Vahedi et al 2007, Coupry et al 2010, Shah et al 2012, Rødahl et al 2013, Meuwissen et al 2015]
• HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome [Plaisier et al 2007, Plaisier et al 2010]
• Tortuosity of retinal arteries [Zenteno et al 2014]
• Nonsyndromic autosomal dominant congenital cataract [Xia et al 2014]

Clinical features of COL4A1-related disorders vary widely and can include the following:

• Neurologic
  • Infantile hemiplegia
  • Developmental delay
  • Migraines with or without aura
  • Seizures
  • Dementia
  • Intellectual disability
  • Intracerebral hemorrhage at any age including antenatal, neonatal, and recurrent episodes
  • Ischemic stroke
  • Typically on neuroimaging: features of brain small-vessel disease (Figure 1)
• Ophthalmic
  • Transient visual loss caused by retinal hemorrhage
  • Cataract, glaucoma, microphthalmia/anophthalmia
• Other systemic findings
  • Hematuria
  • Raynaud phenomenon
  • Supraventricular arrhythmia
  • Muscle cramps

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]

Family history is consistent with autosomal dominant inheritance. Findings and age of onset vary within and between families.

Establishing the Diagnosis

The diagnosis of a COL4A1-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in COL4A1 identified by molecular testing (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of COL4A1 is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. 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 pathogenic missense variant that disrupts the collagen triple helix (see Molecular Genetics), a screening test for large duplications/deletions may have a very low yield.
• A multigene panel that includes COL4A1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes COL4A1) fails to confirm a diagnosis in an individual with features of a COL4A1-related disorder. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

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 (congenital cataract, retinal arterial tortuosity, eye anterior segment anomaly of Axenfeld-Rieger type) and systemic findings (muscle cramps and/or serum CK elevation, kidney involvement, cerebral aneurysms, Raynaud phenomenon, cardiac arrhythmia, hemolytic anemia).

HANAC Syndrome

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

The small-vessel brain disease of HANAC is usually clinically asymptomatic [Alamowitch et al 2009]. By contrast, the systemic symptoms usually observed in HANAC – including muscle cramps, renal involvement, retinal arterial tortuosity, and Raynaud phenomenon – are rarely reported in COL4A1-related porencephaly or small-vessel brain disease [Gould et al 2006, Meuwissen et al 2015].

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 intracerebral hemorrhage while on anticoagulants [Alamowitch et al 2009].
• 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 individuals after age 50 years.

Figure 2.

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

Muscle cramps involving a variety of muscles usually occur in 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, supraventricular arrhythmia, and liver cyst are variably reported.

Additional Findings in COL4A1-Related Disorders

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

• Bilateral retinal arterial tortuosity is variably present in individuals with small-vessel brain disease with hemorrhage [Gould et al 2006] or with porencephaly [van der Knaap et al 2006], whereas all individuals with HANAC syndrome exhibited this finding [Plaisier et al 2007]. Additionally, one COL4A1 pathogenic variant has been characterized in individuals with familial retinal arteriolar tortuosity without cerebral or systemic symptoms [Zenteno et al 2014]. 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 hemorrhage occurring spontaneously or after minor stress or trauma. Visual prognosis has been excellent, without retinal sequelae.
• Congenital cataract is reported either as an isolated ocular feature [van der Knaap et al 2006, Shah et al 2010] or associated with other eye anterior segment abnormalities of Axenfeld-Rieger type in families with small-vessel brain disease and porencephaly [Sibon et al 2007, Coupry et al 2010, Rødahl et al 2013, Yoneda et al 2013, Meuwissen et al 2015]. Nonsyndromic congenital cataract has also been associated with a COL4A1 pathogenic variant in a large family [Xia et al 2014].
• Anterior segment anomaly of Axenfeld-Rieger type comprises a spectrum of ocular findings affecting the anterior chamber including congenital iris abnormalities, posterior embryotoxon, microcornea, increased intraocular pressure, and glaucoma. It has been described in families presenting with small-vessel brain disease and porencephaly [Sibon et al 2007, Meuwissen et al 2015].

Figure 3.

Fluorescein angiography showing typical retinal arteriolar tortuosity (arrows) in a patient with HANAC syndrome [Plaisier et al 2007]

Renal manifestations

• Bilateral renal cysts are very frequently observed in individuals with HANAC, and more rarely in affected individuals with small-vessel brain disease. In one family, renal cysts represent the main clinical manifestation, together with hematuria and glomerular filtration rate decrease [Gale et al 2016].
• Hematuria has been reported in individuals with porencephaly, small-vessel brain disease, and HANAC [Meuwissen et al 2015].
• Unilateral renal atrophy has been reported in two individuals [John et al 2015].
• Glomerular filtration rate decrease (usually affecting individuals age >40 years) has been observed in individuals with HANAC, as well as in affected individuals from one family presenting with renal cysts and hematuria without brain or extracerebral involvement [John et al 2015, Gale et al 2016].

Muscle manifestations. Serum CK elevation and painful muscle cramps, seen in all individuals with HANAC syndrome [Plaisier et al 2010], are only variably present in other affected individuals [Meuwissen et al 2015]. Muscle biopsy was performed in one affected individual with myopathic defects [Yoneda et al 2013].

Cardiac manifestations. Mitral valve prolapse and supraventricular arrythmia have been characterized in four patients [Plaisier et al 2010, Meuwissen et al 2015].

Ultrastructural basement membrane abnormalities have been demonstrated in skin vessels, at the dermo-epidermal junction, and in 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 [Plaisier et al 2010].
• 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 COL4A1 pathogenic variants is too small to explore genotype-phenotype relationships.

However, all six COL4A1 pathogenic variants 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 pathogenic variant responsible for more severe brain disease, including porencephaly and small-vessel brain disease, are mostly distributed through exons 25 to 51 [Meuwissen et al 2015].

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.

Prevalence

Prevalence of COL4A1-related disorders cannot be established as fewer than 100 families have been described.

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

To date pathogenic variants have been reported in individuals of Dutch, Italian, French, German, American, Chinese, Spanish, and Japanese origin.

Evaluations Following Initial Diagnosis

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

• Brain MRI including T₁-weighted saggital, T₂-weighted axial, and FLAIR axial images
• Brain angiographic CT scan
• Ophthalmologic examination including fundoscopic examination and slit-lamp examination
• Kidney and liver ultrasound examination or CT
• Measurement of serum CK concentration
• Measurement of serum creatinine concentration and estimation of the glomerular filtration rate
• Evaluation for the presence of hematuria
• Electrocardiogram (EKG); echocardiography and ambulatory EKG monitoring in individuals presenting with palpitations
• Consultation with a clinical geneticist and/or genetic counselor

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 >10.0 mm in diameter.

Prevention of Primary Manifestations

Avoidance of anticoagulant exposure and activities that involve an increased risk for head trauma may decrease the risk for intracerebral hemorrhage.

Prevention of Secondary Complications

See Prevention of Primary Manifestations.

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
• Hypertension because it increases the risk of stroke
• Sustained head pressure during birth or postnatal physical activities that may cause head trauma [Gould et al 2006]
• Anticoagulant use [Gould et al 2006]

Evaluation 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 in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• At least 50% of individuals diagnosed with a COL4A1-related disorder have an affected parent [Meuwissen et al 2015].
• A proband with a COL4A1-related disorder may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is estimated to be at least 27% [Meuwissen et al 2015].
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing for the pathogenic variant identified in the proband, medical record review, brain imaging by MRI, and ophthalmologic evaluation.
• If the COL4A1 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.
• The family history of some individuals diagnosed with a COL4A1-related disorder 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. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations and molecular genetic testing have been performed on the parents of the proband.

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.
• If the COL4A1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism.

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

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the COL4A1 pathogenic variant, other members of the parent's family may be at risk.

Related Genetic Counseling Issues

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

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the COL4A1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for a COL4A1-related disorder are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Revision History

• 7 July 2016 (ha) Comprehensive update posted live
• 8 March 2011 (me) Comprehensive update posted live
• 25 June 2009 (et) Review posted live
• 27 February 2009 (ep) Original submission

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