Vici syndrome is a rare autosomal recessive multisystem disorder caused by loss-of-function mutations in the EPG5 gene on the long arm of chromosome 18 (18q). Its five main features are congenital agenesis of the corpus callosum, bilateral cataracts, hypopigmentation of the skin and hair, cardiomyopathy, and immunodeficiency.
It was first reported in 1988 by Carlo Vici. The reported sibling cases had severe psychomotor developmental delay and recurrent lung infections, and died of bronchopneumonia at ages 2 and 3. Subsequently, in 1999, Del Campo et al. reported four additional cases, including male and female siblings born to unaffected parents, supporting autosomal recessive inheritance. From 2002 to 2017, another 26 cases were reported, and the total number of reported cases to date remains under 100 [1,2].
Although this disease is very rare, ophthalmologists who encounter bilateral cataracts with multiple organ abnormalities should consider it as a differential diagnosis.
The number of reported cases worldwide is extremely rare, with fewer than 100 cases. Since the first report in 1988, only about 30 cases have been reported over approximately 30 years. It is a rare hereditary multisystem disorder, and in ophthalmology, it may first be noticed as bilateral cataracts.
Onset is often within the first year of life. Visual impairment due to bilateral cataracts is the main ophthalmological complaint.
Ophthalmic Findings
Bilateral cataract: Present in 75%. One of the classic diagnostic features [1,4].
Optic nerve hypoplasia/atrophy: Optic nerve hypoplasia or optic atrophy may be observed [4].
Retinal hypopigmentation: Observed on fundus examination [4].
Foveal hypoplasia: OCT shows typical albinism-like reduction or absence of foveal depression [4].
Optic pathway misrouting: In some cases, VEP testing reveals optic pathway misrouting [4].
Systemic Findings
Brain abnormalities: Agenesis of the corpus callosum, pontine hypoplasia, delayed myelination.
Neurodevelopmental abnormalities: Severe developmental delay, microcephaly.
Cardiomyopathy: Cardiac dysfunction. Confirmed by echocardiography.
Hypopigmentation: Decreased pigmentation of the skin and hair (albinoid).
Immunodeficiency: Causes recurrent infections. Skeletal muscle myopathy also occurs.
Fundus examination may reveal decreased retinal pigmentation and optic atrophy. Optical coherence tomography (OCT) shows foveal hypoplasia and reduced foveal depression, similar to typical albinism patients.
Vici syndrome is caused by loss-of-function mutations in the EPG5 gene [3].
The EPG5 gene is located on the long arm of chromosome 18 (18q) and is involved in the autophagy pathway. Autophagy is a multistep pathway that functions as a waste disposal mechanism in the body and is particularly active in neural and muscle tissues [2,3].
Due to autosomal recessive inheritance, parents of affected children are usually carriers and asymptomatic. Consanguineous parents (related by blood) have an increased risk of having an affected child.
A definitive diagnosis of Vici syndrome requires clinical suggestive features plus confirmation of EPG5 mutation by genetic testing. The eight major features include “agenesis of the corpus callosum, cataract, hypopigmentation, cardiomyopathy, immunodeficiency, developmental delay, microcephaly, and growth failure” [1,2,5].
Initial screening tests:
Before considering Vici syndrome, the following more common diseases must be excluded.
| Disease | Similarities |
|---|---|
| Marinesco-Sjögren syndrome | Congenital cataract, cerebellar ataxia, intellectual disability |
| Chediak-Higashi syndrome | Hypopigmentation, immunodeficiency |
| Griscelli syndrome | Hypopigmentation, immunodeficiency |
| DiGeorge syndrome | Immunodeficiency, heart malformation |
Confirmation of corpus callosum agenesis by brain MRI and identification of EPG5 gene mutation by genetic testing are most important. Ophthalmic evaluation to confirm cataract, optic nerve abnormalities, and retinal hypopigmentation, along with echocardiography to assess cardiomyopathy, provides the basis for clinical diagnosis.
There is no curative treatment for Vici syndrome. Medical care is primarily supportive care, including management of specific symptoms affecting multiple organs [1,5].
Cataracts can be surgically repaired, but the severity of the systemic condition and expected prognosis must be carefully considered. In cases with severe central nervous system disorders or poor VEP response, visual function improvement is unlikely, so surgery may not be indicated.
In congenital cataracts, if visual function decline is progressive and surgery is expected to reliably improve visual function, surgery should be actively performed. Cases where family cooperation for postoperative amblyopia training is not available require careful judgment.
Disease progression is monitored through regular assessments as follows:
The EPG5 protein is responsible for transporting and fusing autophagosomes containing damaged or unnecessary cellular products to lysosomes that digest them [3].
When the autophagy pathway becomes dysfunctional due to EPG5 mutations, autophagosomes cannot fuse with lysosomes and accumulate within cells. This is thought to cause cellular dysfunction, but whether it is due to the accumulation of autophagosomes or other unknown downstream effects has not been fully elucidated [2,3].
The autophagy pathway is particularly active in neural and muscle tissues. This explains some of the skeletal muscle, cardiac muscle, and brain symptoms in Vici syndrome.
The EPG5 protein also plays a role in the immune system, which is thought to be the mechanism for increased susceptibility to viral and bacterial infections.
Autophagy also plays an important role in maintaining lens transparency. Lens fiber cells use autophagy to remove organelles during maturation. Autophagy impairment due to EPG5 mutations is thought to cause bilateral cataracts by disrupting the lens transparency maintenance mechanism.
In addition to hereditary causes (autosomal dominant, recessive, and X-linked recessive), congenital cataracts can be caused by intrauterine infections, metabolic disorders (galactosemia, hypocalcemia, homocystinuria, etc.), chromosomal abnormalities (Down syndrome, etc.), and systemic diseases or syndromes (bone diseases, central nervous system disorders, muscle diseases, etc.). Vici syndrome is classified under “congenital cataracts associated with systemic diseases or syndromes.”
Therapeutic approaches to correct autophagy defects caused by EPG5 mutations are being investigated at the basic research level. The search for compounds that promote activation of the autophagy pathway and gene therapy to restore EPG5 function are attracting attention as future therapeutic targets. However, they have not yet reached clinical application.
The widespread use of next-generation sequencing (NGS) has enabled faster and more accurate identification of EPG5 gene mutations. This is expected to reduce diagnostic delays and lead to earlier initiation of supportive therapy.
Through comparative studies with related diseases that share hypopigmentation and immunodeficiency, such as Chediak-Higashi syndrome and Griscelli syndrome, the pathophysiology of Vici syndrome is being elucidated.
Byrne S, Dionisi-Vici C, Smith L, Gautel M, Jungbluth H. Vici syndrome: a review. Orphanet J Rare Dis. 2016;11:21. PMID: 26927810. https://pubmed.ncbi.nlm.nih.gov/26927810/
Byrne S, Jansen L, U-King-Im JM, et al. EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy. Brain. 2016;139(Pt 3):765-781. PMID: 26917586. https://pubmed.ncbi.nlm.nih.gov/26917586/
Cullup T, Kho AL, Dionisi-Vici C, et al. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat Genet. 2013;45(1):83-87. PMID: 23222957. https://pubmed.ncbi.nlm.nih.gov/23222957/
Filloux FM, Hoffman RO, Viskochil DH, Jungbluth H, Creel DJ. Ophthalmologic features of Vici syndrome. J Pediatr Ophthalmol Strabismus. 2014;51(4):214-220. PMID: 24779424. https://pubmed.ncbi.nlm.nih.gov/24779424/
Abidi KT, Kamal NM, Bakkar AA, et al. Vici syndrome with pathogenic homozygous EPG5 gene mutation: A case report and literature review. Medicine (Baltimore). 2020;99(43):e22302. PMID: 33120733. https://pubmed.ncbi.nlm.nih.gov/33120733/
