TREX1 RVCL-S

HERNS (Hereditary Endotheliopathy, Retinopathy, Nephropathy, and Stroke), HVR (Hereditary Vascular Retinopathy), and CRV (CerebroRetinal Vasculopathy) are terms for the same autosomal dominant condition responsible for retinal vascular involvement and damage to the cerebral white matter. This condition is associated with mutations in the TREX1 gene, located on the short arm of chromosome 3. Since the identification of the implicated gene, the common term RVCL (Retinal Vasculopathy with Cerebral Leukoencephalopathy and systemic manifestations) has been proposed.

Definition

HERNS (Hereditary Endotheliopathy, Retinopathy, Nephropathy, and Stroke), HVR (Hereditary Vascular Retinopathy), and CRV (CerebroRetinal Vasculopathy) are terms for the same autosomal dominant condition characterized by retinal vascular involvement and damage to the cerebral white matter. This condition is associated with mutations in the TREX1 gene, located on the short arm of chromosome 3. Since the identification of the implicated gene, the common term RVCL (Retinal Vasculopathy with Cerebral Leukoencephalopathy and systemic manifestations) has been proposed.

Epidemiology

The involvement of the TREX1 gene in the occurrence of RVCL is recent. The prevalence is unknown, with only a few families reported to date.

Clinical Description and Prognosis

The clinical spectrum and natural history of this condition are not yet fully understood. The diagnosis of HERNS should be considered when an adult of middle age presents with retinal and/or cerebral involvement.
In this condition, visual symptoms may precede neurological deficits, often manifesting as a decline in visual acuity that begins centrally, associated with vascular retinopathy characterized by capillary occlusions, telangiectasias, and microaneurysms predominantly in the macular area, sometimes extending to the juxtafoveal region. Occasionally, retinal lesions may begin peripherally, with less severe visual symptoms. In the absence of an identified cause, these abnormalities warrant brain imaging to investigate potential silent white matter lesions.
Cerebral lesions may range from white matter hyperintensities and small infarcts to more severe cases resembling a pseudotumor with contrast enhancement on MRI. These lesions, which can cause a mass effect, are often symptomatic, leading to focal neurological deficits, intracranial hypertension, and/or seizures. Other neurological symptoms, such as migraines (with or without aura), depression, and psychiatric disorders, may also be observed. In most cases, the condition progresses negatively, resulting in patient death within 5 to 10 years.
In some patients, retinal or cerebroretinal involvement is associated with glomerular nephropathy, leading to renal insufficiency and proteinuria. Raynaud’s phenomena have also been reported in certain families.

Etiology – Pathophysiology

TREX1 is involved in remodelling the ends of DNA, reducing the number of aberrant DNA fragments within cells. Mutations associated with HERNS cause a frameshift after the protein’s active sites, resulting in the production of a truncated TREX1 protein. This alteration does not affect the protein’s activity but changes its subcellular distribution. In microscopy… (the text seems to be cut off here; please provide the continuation if needed)

Microscopic Findings

In electron microscopy, the ultrastructural examination reveals a duplication of the basement membrane into multiple layers at the level of the capillaries and arterioles of the brain, kidneys, skin, and certain mucous membranes. TREX1 is also involved in other very different conditions. Both homozygous and heterozygous mutations of this gene are responsible for Aicardi-Goutières syndromes, which are associated with severe infantile encephalopathy, cerebral calcifications, and lymphocytosis in the cerebrospinal fluid (CSF). TREX1 mutations have also been identified in an autosomal dominant form of cutaneous lupus characterized by chilblains and in approximately 2% of patients with systemic lupus erythematosus.

Diagnosis (Criteria-Methods)

The mode of transmission of the disease is autosomal dominant (affecting males and females equally, with a 50% chance of inheritance in children of affected individuals). A thorough family history is essential, looking for any suggestive antecedents in other family members. A history of retinopathy or neurological symptoms of a central nature in a first- or second-degree relative may suggest the diagnosis.
The diagnosis is most often considered in the presence of characteristic cerebral or retinal involvement.
Cerebral involvement is best visualized via MRI, which should at a minimum include T1, T2, FLAIR, and gradient echo sequences. This examination allows for the identification of the anomalies described in the syndrome:

• White matter lesions
• Small cerebral infarcts
• Pseudotumor-like lesions that take up contrast

Vascular retinopathy is diagnosed during a fundus examination by an ophthalmologist, revealing capillary occlusions, telangiectasias, and/or microaneurysms predominantly in the macular area. Retinal photographs (using a device called a retinal camera), sometimes supplemented by angiography (injecting a contrast agent through a vein in the arm to visualize the retinal vessels), help analyse these anomalies more thoroughly.

Genetic testing is essential for definitively diagnosing RVCL. Mutations in the C-terminal part of the single exon of the TREX1 gene (3-5 Repair Exonuclease 1) located on the short arm of chromosome 3 are investigated. Genetic diagnosis is possible before the appearance of symptoms for members of an affected family. However, conducting genetic testing on a healthy individual without any clinical manifestations of the disease and no prior examinations is only done within a specialized and multidisciplinary consultation framework. After neurological (neurologist), psychological (interview with a psychologist), and genetic (geneticist) evaluations, the patient’s request is assessed collectively, and a reflection period is proposed before blood sampling. Clinical and psychological follow-up is always offered after the results are announced.

Management

As of now, no specific preventive treatment is known. The use of oral or parenteral corticosteroids may prove transiently effective for the perilesional oedema associated with pseudotumour-like lesions. However, neither corticosteroid therapy nor surgical excision can halt the progression of the disease

Figure: RVCL: Retinal Artery Anomalies on Angiography and Cerebral Lesions Visualized by MRI.

Legend:

• A: Fluorescein angiography during the venous phase conducted due to visual symptoms evolving since the age of 31, revealing areas of non-capillary perfusion in the macular region, dilated and tortuous vessels associated with telangiectasias and capillary shunts.
• B: MRI (FLAIR) performed at age 31 in the absence of neurological symptoms, showing punctate hyperintensities in the white matter.
• C: MRI (T1 post-gadolinium injection) conducted at age 36 due to clumsiness in the left upper and lower limbs, revealing a pseudotumour-like lesion.
• D: MRI (Proton Density) performed one month later due to symptoms of intracranial hypertension, confirming an increase in size of the pseudotumour-like lesion and associated perilesional oedema with significant mass effect.

Source: Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), J. Jen et al., Neurology 1997; 49:1322-1330.

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