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Sister and brother with Vici syndrome: Agenesis of the corpus callosum, albinism, and recurrent infections
Abstract
A sister and brother with Vici syndrome are described. They both had oculocutaneous albinism, agenesis of the corpus callosum, cataracts, and cardiomyopathy. They were born to healthy unrelated parents, and had postnatal growth retardation, profound developmental delay, hypotonia, and cataracts. The sister had recurrent infections, and died of progressive heart failure at age 19 months. The brother is alive at age six months with mild cardiomyopathy, and had a single episode of acute bronchitis at age three months. Review of the clinical manifestations of the sibs we described and six children reported in the literature indicates that Vici syndrome is a distinct clinical entity. Its main clinical manifestations include growth retardation, profound developmental delay, hypotonia, albinism, agenesis of the corpus callosum, cataracts, cardiomyopathy, and recurrent infections. The occurrence of the syndrome in three pairs of sibs of both sexes born to unaffected parents supports autosomal recessive inheritance.
... 20 Vici syndrome is a recessively inherited multisystem disorder, characterized by agenesis of the corpus callosum, cutaneous hypopigmentation, bilateral cataracts, cleft lip and palate, hypotonia and combined immunodeficiency. 21 Since the original report, nine other papers have described patients with Vici syndrome, [22][23][24][25][26][27][28][29][30] confirming it as a distinct clinical entity. ...
... Cataract is another common trait of Vici syndrome that is not obviously detected in Epg5 knockout mice (Fig. 1A). [21][22][23][25][26][27][28][29][30] Hypopigmentation has been reported in all Vici syndrome cases, variably involving the skin, hair and/or retina, 21-30 but epg5 −/− mice displayed the same skin and fur color as their control littermates (Fig. 1B). ...
... One invariable characteristic of Vici syndrome is agenesis of the corpus callosum, a failure to develop the large bundle of fibers that connect the cerebral hemispheres. [21][22][23][24][25][26][27][28][29][30] When we performed hematoxylin and eosin (H&E) staining of cerebral sections from 10 pairs of Epg5 +/− and epg5 −/− mice, we discovered that the corpus callosum was significantly thinner in mutant mice compared with controls, and was partially absent in three and completely absent in one of the knockout mice ( Fig. 1C and D). A reduced number of pyramidal neurons in layer 5 of the motor and sensory cortices may contribute to the loss of white matter. ...
Autophagy activity is essential for the survival of neural cells. Impairment of autophagy has been implicated in the pathogenesis of neurodegenerative disorders. Unlike the massive neuron loss in mice deficient for autophagy genes essential for autophagosome formation, we demonstrated that mice deficient for the metazoan-specific autophagy gene Epg5 develop selective neuronal damage and exhibit key characteristics of amyotrophic lateral sclerosis. Epg5 deficiency blocks the maturation of autophagosomes into degradative autolysosomes, slows endocytic degradation and also impairs endocytic recycling. Recessive mutations in human EPG5 have recently been causally associated with the multisystem disorder Vici syndrome. Here we show that while Epg5 knockout mice display some features of Vici syndrome, many phenotypes are absent.
... The underlying genetic defect remains unresolved. Following the initial report by Vici et al. [Dionisi Vici et al., 1988], a further eight cases with evocative features have been reported [del Campo et al., 1999;Chiyonobu et al., 2002;Miyata et al., 2007]. An associated neuromuscular phenotype as part of the syndrome has not been investigated in detail but is suggested by mild to moderate creatine kinase (CK) elevations in some cases [Chiyonobu et al., 2002;Miyata et al., 2007] and non-specific muscle biopsy abnormalities in one reported patient [del Campo et al., 1999]. ...
... Following the initial report by Vici et al. [Dionisi Vici et al., 1988], a further eight cases with evocative features have been reported [del Campo et al., 1999;Chiyonobu et al., 2002;Miyata et al., 2007]. An associated neuromuscular phenotype as part of the syndrome has not been investigated in detail but is suggested by mild to moderate creatine kinase (CK) elevations in some cases [Chiyonobu et al., 2002;Miyata et al., 2007] and non-specific muscle biopsy abnormalities in one reported patient [del Campo et al., 1999]. ...
... In 1988, Vici et al. described a malformation syndrome consisting of agenesis of the corpus callosum, combined immunodeficiency, bilateral cataracts, and hypopigmentation in two brothers [Dionisi Vici et al., 1988]; a further eight patients with similar evocative features have been reported subsequently, affected by the same condition [del Campo et al., 1999;Chiyonobu et al., 2002;Miyata et al., 2007]. The genetic cause of Vici syndrome is currently unknown and the diagnosis is based on a suggestive combination of clinical features. ...
Vici syndrome is a rare, genetically unresolved congenital multisystem disorder comprising agenesis of the corpus callosum, cataracts, immunodeficiency, cardiomyopathy, and hypopigmentation. An associated neuromuscular phenotype has not previously been described in detail. We report on an infant with clinical features suggestive of Vici syndrome and additional sensorineural hearing loss. Muscle biopsy revealed several changes including markedly increased variability in fiber size, increased internal nuclei, and abnormalities on Gomori trichrome and oxidative stains, raising a wide differential diagnosis including neurogenic atrophy, centronuclear myopathy (CNM) or a metabolic (mitochondrial) cytopathy. Respiratory chain enzyme studies, however, were normal and sequencing of common CNM-associated genes did not reveal any mutations. This case expands the clinical spectrum of Vici syndrome and indicates that muscle biopsy ought to be considered in infants presenting with suggestive clinical features. In addition, we suggest that Vici syndrome is considered in the differential diagnosis of infants presenting with congenital callosal agenesis and that additional investigation has to address the possibility of associated ocular, auditory, cardiac, and immunologic involvement when this radiologic finding is present. © 2010 Wiley-Liss, Inc.
... Dionisi Vici et al. [1988] first described two siblings with agenesis of the corpus callosum, cutaneous hypopigmentation, bilateral cataract, cleft lip and palate, and combined immunodeficiency. Thereafter other 10 similar cases have been reported, contributing to describe clinical and laboratory features of Vici syndrome [OMIM 242840] [Del Campo et al., 1999;Chiyonobu et al., 2002;Miyata et al., 2007;Al-Owain et al., 2010;McClelland et al., 2010]. All patients presented with recurrent infections and showed variable immunological abnormalities, however, their immune system has not been investigated in detail. ...
... Our patient is the 13th case with Vici syndrome [OMIM 242840], a rare congenital multisystem disorder characterized by agenesis of the corpus callosum, hypotonia, developmental delay, cataracts, cardiomyopathy, hypopigmentation, recurrent infections, and immunological abnormalities. It is likely to be inherited as an autosomal recessive trait [Del Campo et al., 1999;Chiyonobu et al., 2002;Miyata et al., 2007], although the genetic defect is still unknown. Phenotypical presentation is extremely variable and diagnosis is currently based on a suggestive combination of clinical features. ...
... In eight of them, including our patient, other CNS abnormalities were found, such as cerebellar and cortical alterations [Dionisi Vici et al., 1988;Del Campo et al., 1999;Miyata et al., 2007;Al-Owain et al., 2010]. All children had variable hypopigmentation, ranging from complete albinism to an isolated mild depigmentation of retina [Chiyonobu et al., 2002], sometimes associated with facial dysmorphism. Our patient does not show dysmorphic facial features and his hair is slightly lighter than his parents. ...
Vici syndrome is a rare congenital multisystem disorder characterized by agenesis of the corpus callosum, hypotonia, developmental delay, hypopigmentation, cataract, cardiomyopathy, and immunological abnormalities. Recurrent infections, mainly affecting the respiratory tract, have been reported in the majority of cases, representing an important risk factor for morbidity and mortality. The immunological phenotype of patients is extremely variable, ranging from a combined immunodeficiency to nearly normal immunity. We report on a new patient with Vici syndrome, in whom we have extensively investigated immunological features. Despite a mild impairment of the cellular compartment, a defect of humoral immunity was found, requiring treatment with intravenous immunoglobulin. A wider knowledge of immune system abnormalities of Vici syndrome will help to plan strategies for treatment and prevention of infections, such as immunoglobulin replacement and antimicrobial prophylaxis, resulting in improved survival rates.
... This multisystem disorder is classically characterised by the five cardinal features of callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and oculocutaneous hypopigmentation (McClelland et al. 2010). Since its original description in 1988 (Vici et al. 1988), the phenotypic spectrum has continued to evolve with an increasing number of patients described and approximately 50 genetically confirmed cases reported to date (Vici et al. 1988;Al-Owain et al. 2010;Chiyonobu et al. 2002;Cullup et al. 2013;del Campo et al. 1999;Finocchi et al. 2012;McClelland et al. 2010;Miyata et al. 2007;Ozkale et al. 2012;Rogers et al. 2011;Said et al. 2012;Ehmke et al. 2014;Byrne et al. 2016a). These five manifestations in addition to three features recently described to occur almost universally in affected patients, namely, profound developmental delay, progressive failure to thrive and acquired microcephaly, are highly supportive of the diagnosis (Byrne et al. 2016a). ...
... Skeletal muscle myopathy, an important, less documented feature of Vici syndrome, had previously been suggested by the presence of profound hypotonia, generalised weakness, paucity of movements and variable eleva-tions of creatine kinase in early case reports (Chiyonobu et al. 2002;Miyata et al. 2007) and morphological abnormalities in muscle biopsy in one reported patient that were suggestive of a mitochondrial cytopathy but with normal respiratory chain enzyme analysis (del Campo et al. 1999). Histopathologically, the associated myopathic features were subsequently documented in detail in an infant with a neuromuscular phenotype, characterised by increased variability in fibre size with type 1 fibre hypotrophy and normally sized type 2 fibres (potentially fulfilling the criteria for fibre type disproportion), prominent centralised nuclei in atrophic fibres, increased glycogen storage and variable vacuoles on light microscopy. ...
Vici syndrome is a rare, under-recognised, relentlessly progressive congenital multisystem disorder characterised by five principal features of callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and oculocutaneous hypopigmentation. In addition, three equally consistent features (profound developmental delay, progressive failure to thrive and acquired microcephaly) are highly supportive of the diagnosis. Since its recognition as a distinct entity in 1988, an extended phenotype with sensorineural hearing loss, skeletal myopathy and variable involvement of virtually any organ system, including the lungs, thyroid, liver and kidneys, have been described.
... Human genetic studies showed that recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder characterized by agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy and combined immunodeficiency. [34][35][36][37] Epg5-deficient mice display some phenotypic similarities with Vici syndrome patients, including autophagy defects, corpus callosum changes and myopathy. 38 Nearly all Vici syndrome patients suffer recurrent infections and show combined immunodeficiency. ...
... 38 Nearly all Vici syndrome patients suffer recurrent infections and show combined immunodeficiency. [35][36][37] Epg5-deficient mice, however, exhibit elevated basal lung inflammation and influenza resistance. 39 Cataract is another common trait of Vici syndrome that is not obviously detected in Epg5-deficient mice. ...
Autophagy helps to maintain cellular homeostasis by removing misfolded proteins and damaged organelles, and generally acts as a cytoprotective mechanism for neuronal survival. Here we showed that mice deficient in the Vici syndrome gene Epg5, which is required for autophagosome maturation, show accumulation of ubiquitin-positive inclusions and SQSTM1 aggregates in various retinal cell types. In epg5−/− retinas, photoreceptor function is greatly impaired, and degenerative features including progressively reduced numbers of photoreceptor cells and increased numbers of apoptotic cells in the outer nuclear layer are observed, while the morphology of other parts of the retina is not severely affected. Downstream targets of the unfolded protein response (UPR), including the death inducer DDIT3/CHOP, and also levels of cleaved CASP3 (caspase 3), are elevated in epg5−/− retinas. Thus, apoptotic photoreceptor cell death in epg5−/− retinas may result from the elevated UPR. Our results reveal that Epg5-deficient mice recapitulate key characteristics of retinitis pigmentosa and thus may provide a valuable model for investigating the molecular mechanism of photoreceptor degeneration.
... Impairments of autophagy have been shown to be associated with hereditary disorders such as Danon, Parkinson, Alzheimer, and Huntington disease as well as amyotrophic lateral sclerosis [Aki et al., 2013]. Following the first description in 1988 in two brothers [2], 24 other cases of Vici syndrome have been published with variable expression of the defining features [Chiyonobu et al., 2002;Miyata et al., 2007;Al-Owain et al., 2010;McClelland et al., 2010;Rogers et al., 2011;Finocchi et al., 2012;Ozkale et al., 2012;Said et al., 2012;Cullup et al., 2013]. We report on a boy with Vici syndrome and a novel homozygous truncating mutation of EPG5. ...
... Following the first description in 1988 by Vici et al. [1988] in two brothers, 24 other cases of Vici syndrome have been published with variable expression of the clinical features [Al-Owain et al., 2010;Chiyonobu et al., 2002;Cullup et al., 2013;del Campo et al., 1999;Dionisi Vici et al., 1988;Finocchi et al., 2012;McClelland et al., 2010;Miyata et al., 2007;Ozkale et al., 2012;Rogers et al., 2011;Said et al., 2012]. We summarize the clinical features of the 26 previously reported cases, along with our own, in Table I. ...
Vici syndrome is a rare autosomal recessively inherited multisystem disorder characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, psychomotor delay, and hypopigmentation. Cullup et al. recently identified mutations in the gene EPG5 as the cause of Vici syndrome. EPG5 is involved in autophagy, an evolutionarily conserved lysosomal degradation process that is essential for cell homeostasis. Following the first description in 1988 by Vici et al., 24 other cases of Vici syndrome have been published with variable expression of the defining features. Here, we report on a further case of Vici syndrome with a homozygous truncating mutation of EPG5, identified by whole-exome sequencing. The mutation in our patient is the first reported affecting the penultimate exon of EPG5 and presenting with typical clinical manifestations of Vici syndrome. Additionally, we present a detailed clinical analysis of Vici syndrome comprising all cases previously described in the literature. © 2014 Wiley Periodicals, Inc.
... Our patient lacked the classic albinism of Vici syndrome, but his hair was much lighter than other family members, emphasizing that hypopigmentation is variable. Finally, our patient had Band T -cell lymphopenia with high CD4/CD8 ratio, and had infections caused by candida and pseudomonas; both of which were reported in five cases with Vici syndrome [Vici et al., 1988;del Campo et al., 1999;Chiyonobu et al., 2002;Miyata et al., 2007]. Immunological abnormalities in Vici syndrome include decreased C3þ T cells, reduced T-cell blastogenesis, absent delayed T-cell response to candida antigen, and decreased IgG2 [Vici et al., 1988;del Campo et al., 1999;Chiyonobu et al., 2002]. ...
... Finally, our patient had Band T -cell lymphopenia with high CD4/CD8 ratio, and had infections caused by candida and pseudomonas; both of which were reported in five cases with Vici syndrome [Vici et al., 1988;del Campo et al., 1999;Chiyonobu et al., 2002;Miyata et al., 2007]. Immunological abnormalities in Vici syndrome include decreased C3þ T cells, reduced T-cell blastogenesis, absent delayed T-cell response to candida antigen, and decreased IgG2 [Vici et al., 1988;del Campo et al., 1999;Chiyonobu et al., 2002]. ...
... Vici Syndrome (OMIM #242840) is a severe, rare neurodevelopmental/neurodegenerative disorder with multisystemic manifestations presenting in infancy, and characterized by profound global developmental delay (GDD), agenesis of the corpus callosum (ACC), hair and skin hypopigmentation and bilateral cataracts (Dionisi-Vici et al., 1988). Additional features include progressive microcephaly, failure to thrive, cardiomyopathy and varying degrees of immunodeficiency (del Campo et al., 1999;Chiyonobu et al., 2002;Byrne et al., 2016a;Abidi et al., 2020). The condition was first described by the Italian physician Carlo Dionisi-Vici and colleagues in 1988, in two Italian brothers who died at 2 and 3 years of age due to bronchopneumonia. ...
Introduction: Vici Syndrome is a rare, severe, neurodevelopmental/neurodegenerative disorder with multi-systemic manifestations presenting in infancy. It is mainly characterized by global developmental delay, seizures, agenesis of the corpus callosum, hair and skin hypopigmentation, bilateral cataract, and varying degrees of immunodeficiency, among other features. Vici Syndrome is caused by biallelic pathogenic variants in EPG5, resulting in impaired autophagy. Thus far, the condition has been reported in less than a hundred individuals.
Objective and Methods: We aimed to characterize the clinical and molecular findings in individuals harboring biallelic EPG5 variants, recruited from four medical centers in Israel. Furthermore, we aimed to utilize a machine learning-based tool to assess facial features of Vici syndrome.
Results: Eleven cases of Vici Syndrome from five unrelated families, one of which was diagnosed prenatally with subsequent termination of pregnancy, were recruited. A total of five disease causing variants were detected in EPG5: two novel: c.2554-5A>G and c.1461delC; and 3 previously reported: c.3447G>A, c.5993C>G, and c.1007A>G, the latter previously identified in several patients of Ashkenazi-Jewish (AJ) descent. Amongst 140,491 individuals screened by the Dor Yeshorim Program, we show that the c.1007A>G variant has an overall carrier frequency of 0.45% (1 in 224) among AJ individuals. Finally, based on two-dimensional facial photographs of individuals with Vici syndrome (n = 19), a composite facial mask was created using the DeepGestalt algorithm, illustrating facial features typical of this disorder.
Conclusion: We report on ten children and one fetus from five unrelated families, affected with Vici syndrome, and describe prenatal and postnatal characteristics. Our findings contribute to the current knowledge regarding the molecular basis and phenotypic features of this rare syndrome. Additionally, the deep learning-based facial gestalt adds to the clinician’s diagnostic toolbox and may aid in facilitating identification of affected individuals.
... Vici syndrome (also known as immunodeficiency with cleft lip/ palate, cataract, and hypopigmentation and absent corpus callosum, Dionisi Vici Sabetta Gambarara syndrome) is considered as a progressive neurodevelopmental multisystem disorder [1]. ...
Introduction. Vici syndrome (also known as immunodeficiency with cleft lip/palate, cataract, and hypopigmentation and absent corpus callosum) is considered as a progressive neurodevelopmental multisystem disorder. Till date, only 80 cases, including our patient, with this syndrome have been reported .This syndrome is characterized by agenesis of the corpus callosum, hypopigmentation of the eyes and hair, cataract, cardiomyopathy, combined immunodeficiency, hearing loss, seizures, and additional multisystem involvements which have been reported as case reports in the past. Clinical Manifestation. A 5-year-old girl, who is a product of consanguineous marriage, was referred to our center with developmental delay, optic atrophy, blindness, spasticity, seizure, movement disability, and spasticity. Her magnetic resonance imaging (MRI) test showed agenesis of the corpus callosum and her metabolic test reported normal. Materials and Methods. In our laboratory, blood sample was obtained from the patient. DNA was extracted from lymphocytes, and whole exome sequencing (WES) using next generation Illumina sequencing was performed. Result. A novel (private), homozygous, nonsynonymous mutation c.A3206G (p.Y1069C Het) in EPG5 gene was detected; in continuum, testing for this specific variant in her parents was carried out. DNA sequencing of the PCR-amplified product of the EPG5 exon 17 showed that her parents were heterozygote for this variant. These mutations have not been reported before and therefore classified as variation of unknown significance (VUS). Mutation in this gene is shown to cause autosomal recessive Vici syndrome. Conclusion. Since clinical features of Vici syndrome has overlap, its diagnosis is differential and developmental delay occurs in 98% of reported cases. Vici syndrome can be considered as one of the main causes of developmental delay, and this syndrome can be introduced as a novel group of inherited neurometabolic conditions and congenital disorders.
... [4] Since that original description of the disorder, an increasing number of cases have been reported with almost 78 confirmed cases published to the date. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] Editor: Maya Saranathan. ...
Rationale:
Vici syndrome (VICIS) is a rare, autosomal recessive neurodevelopmental disorder with multisystem involvement characterized by agenesis of the corpus callosum, congenital cataracts, cardiomyopathy, combined immunodeficiency, significant developmental delay, and hypopigmentation and in some cases loss of hearing. It is caused by mutations in Ectopic P-granules protein 5 gene, which is responsible for regulating autophagy activity.
Patient concern:
We report a 6-month-old Saudi female patient who was the second-born baby of first cousins. She was born by normal spontaneous vertex vaginal delivery. Parents noticed that she had global developmental delay and recurrent hospital admissions due to chest infections.
Diagnosis:
Brain magnetic resonance imaging showed brain atrophy with corpus callosum agenesis. Ophthalmology examination revealed bilateral congenital cataract. Molecular genetic testing identified the pathogenic homozygous variant c.4751T>A p. (Leu1584*) on exon 27 of the EPG5 gene and confirmed the diagnosis of Vici syndrome.
Interventions:
Supportive multidisciplinary care plan was initiated to this untreatable syndrome.
Outcomes:
The patient died at the age of 6 months due to sepsis with uncompensated septic shock.
Lessons:
VICIS is a rare untreatable disorder with worldwide distribution. High index of suspicion is needed to diagnose it and family genetic counselling is crucial.
... 2010; Alzahrani, Alghamdi, & Waggass, 2018;Balasubramaniam et al., 2018;Byrne et al., 2016c;Chiyonobu et al., 2002;Cullup et al., 2013;del Campo et al., 1999;Demiral, Sen, Esener, Ceylaner, & Tekedereli, 2018;El-Kersh, Jungbluth, Gringras, & Senthilvel, 2015;Hedberg-Oldfors, Darin, & Oldfors, 2017;Hori et al., 2017;Huenerberg et al., 2016;Maillard et al., 2017;McClelland et al., 2010;Miyata et al., 2007;Ozkale, Erol, Gümüs, Ozkale, & Alehan, 2012;Rogers, Aufmuth, & Monesson, 2011;Said, Soler, & Sewry, 2012;Shimada et al., 2018;Waldrop et al., 2018). The prognosis was found to be poor with a median survival of 42 months (Byrne, Dionisi-Vici, Smith, Gautel, & Jungbluth, 2016b). ...
We report on a sibling pair with the EPG5 c.1007A > G mutation who developed a severe form of Vici syndrome and died in infancy. The c.1007A > G (p.Gln336Arg) mutation, affecting the penultimate nucleotide and the splicing of exon 2 is the most common mutation of EPG5 and is typically associated with a less devastating prognosis: cardiomyopathy and cataract are less frequent consequences and the median survival time is 78 months compared to an overall median survival of 42 months. The less severe course related to c.1007A > G was formerly explained by the preserved canonical splicing in 25% of the transcripts. In contrast, we found the messenger RNA encoded by the c.1007A > G allele to be absent, explaining the severe course of the disease. This family provides another example of phenotypic variability related to a differential splicing.
... Since that original description of the disorder, an increasing number of cases have been reported, with almost 78 confirmed cases published to date [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]. The patients have presented, mostly in infancy, with characteristic features of VICIS together with other phenotypic features such as progressive failure to thrive, microcephaly, nystagmus, dysmorphic features, cardiomyopathy, hypotonia, and recurrent pulmonary infection, among others [4]. ...
INTRODUCTION: Vici syndrome, a rare autosomal recessive disorder, was first described in 1988 by Vici et al. Only 78 cases have been reported to date. The syndrome is characterised by agenesis of the corpus callosum, hypopigmentation, cardiomyopathy, progressive failure to thrive, dysmorphic features, immunodeficiency and cataracts. Mutations in the gene epg5 have been identified as the cause of Vici syndrome.
CASE DESCRIPTION: The parents are a consanguineous Saudi couple with two other children diagnosed with Gaucher disease. The patient was born at term and in the first 5 months had many hospital admissions for a recurrent chest infection. Physical examination, investigations and imaging studies revealed that the patient had agenesis of the corpus callosum, cataracts, psychomotor delay, immunodeficiency and hypopigmentation. The initial echocardiogram was normal. At 7 months, genetic testing confirmed the diagnosis of Vici syndrome with a c.3693G>Ap (Gln1231Gln) mutation in the gene EPG5. The patient developed a chest infection and was admitted to the pediatric intensive care unit. An echocardiogram was repeated and showed significant left ventricular dilation with a Z-score of 3.1, moderate mitral and tricuspid regurgitation, and depressed ventricular function with a fractional shortening of 17% and ejection fraction 37%. The patient’s condition deteriorated, and he died aged 8 months.
CONCLUSION: The symptoms of extensive system involvement in Vici syndrome have been present in the majority of reported cases and should prompt careful evaluation of this syndrome when such symptoms are present in an infant. In confirmed cases, close monitoring of the immune status and cardiac function, the two main causes of death among Vici syndrome patients, is vital to prevent rapid deterioration and improve life expectancy.
... We genetically identified nine patients (three males and six females) with VICIS, including two pairs of siblings, from seven Japanese families. Table 1 provides a summary of the clinical features of our nine patients and reported patients in the literature [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] . Typical clinical features are illustrated in Supplementary Fig. S1. ...
Vici syndrome (VICIS) is a rare, autosomal recessive neurodevelopmental disorder with multisystem involvement characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, developmental delay, and hypopigmentation. Mutations in EPG5, a gene that encodes a key autophagy regulator, have been shown to cause VICIS, however, the precise pathomechanism underlying VICIS is yet to be clarified. Here, we describe detailed clinical (including brain MRI and muscle biopsy) and genetic features of nine Japanese patients with VICIS. Genetic dissection of these nine patients from seven families identified 14 causative mutations in EPG5. These included five nonsense, two frameshift, three splicing, one missense, and one multi-exon deletion mutations, and two initiation codon variants. Furthermore, cultured skin fibroblasts (SFs) from two affected patients demonstrated partial autophagic dysfunction. To investigate the function of EPG5, siRNA based EPG5 knock-down, and CRISPR/Cas9 mediated EPG5 knock-out HeLa cells were generated. EPG5-depleted cells exhibited a complete block of autophagic flux caused by defective autophagosome-lysosome fusion. Unexpectedly, endocytic degradation was normal in both VICIS SFs and EPG5 depleted cells, suggesting that EPG5 function is limited to the regulation of autophagosome-lysosome fusion.
... While there have been scattered reports of ACC complicated with albinism in the past, the majority of these have been combined with abnormalities in the central nervous system [3]. In terms of the original underlying disease, the most frequently reported is Vici syndrome [4][5][6][7][8][9][10], with occasional reports of microcephalic osteodysplastic primordial dwarfism type I [11], hypomelanosis of Ito [12,13], Lowe syndrome [14], oculocerebrocutaneous syndrome [15], and other diseases. ...
Purpose:
To report a case of ocular albinism found in a newborn infant in whom agenesis of the corpus callosum (ACC) was indicated in utero.
Case report:
This study involved a female newborn who was delivered after a gestational period of 41 weeks. The patient was referred to the Obstetrics Department at Takatsuki Hospital, Takatsuki City, Japan, after the indication of ACC by magnetic resonance imaging (MRI) at a nearby clinic during the fetal period. At birth, the baby's weight was 2,590 g, and ACC and ventricular enlargement were found by cranial sonography and cranial MRI. While initial ophthalmic findings noted partial loss of pigmentation of the iris and hypopigmentation of broad areas of the fundus in both eyes, nystagmus was not observed. The patient's hair pigment was slightly diluted, and the color of her skin was slightly off-white. At 2 years after birth, obvious mental retardation was observed. With regard to other systemic findings, no apparent heart, kidney, or immune system abnormalities were found.
Conclusion:
Although the patient in question is presently growing without any major systemic problems, it will be necessary in the future to pay attention to any changes in systemic and ophthalmic findings.
... The incidence of Vici syndrome is unknown. Since the original description of the disorder by Dionisi-Vici and colleagues in 1988 [1], an exponentially increasing number of patients has been reported, with around 50 genetically confirmed cases published to date [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Vici syndrome is likely to be rare but probably underdiagnosed. ...
Vici syndrome [OMIM242840] is a severe, recessively inherited congenital disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency. Profound developmental delay, progressive failure to thrive and acquired microcephaly are almost universal, suggesting an evolving (neuro) degenerative component. In most patients there is additional variable multisystem involvement that may affect virtually any organ system, including lungs, thyroid, liver and kidneys. A skeletal myopathy is consistently associated, and characterized by marked fibre type disproportion, increase in internal nuclei, numerous vacuoles, abnormal mitochondria and glycogen storage. Life expectancy is markedly reduced.
Vici syndrome is due to recessive mutations in EPG5 on chromosome 18q12.3, encoding ectopic P granules protein 5 (EPG5), a key autophagy regulator in higher organisms. Autophagy is a fundamental cellular degradative pathway conserved throughout evolution with important roles in the removal of defective proteins and organelles, defence against infections and adaptation to changing metabolic demands. Almost 40 EPG mutations have been identified to date, most of them truncating and private to individual families.
The differential diagnosis of Vici syndrome includes a number of syndromes with overlapping clinical features, neurological and metabolic disorders with shared CNS abnormalities (in particular callosal agenesis), and primary neuromuscular disorders with a similar muscle biopsy appearance. Vici syndrome is also the most typical example of a novel group of inherited neurometabolic conditions, congenital disorders of autophagy.
Management is currently largely supportive and symptomatic but better understanding of the underlying autophagy defect will hopefully inform the development of targeted therapies in future.
... Vici syndrome (OMIM 242840) is a severe, early-onset neurodevelopmental disorder characterized by the key features of callosal agenesis, cataracts, cardiomyopathy, generalized hypopigmentation, and combined immunodeficiency. Since its recognition as a distinct entity (Vici et al., 1988), additional case reports have suggested an extended phenotype including sensorineural hearing loss, a skeletal myopathy, and other, more variable multi-systemic features (del Campo et al., 1999;Chiyonobu et al., 2002;Miyata et al., 2007Miyata et al., , 2014Al-Owain et al., 2010;Rogers et al., 2011;Finocchi et al., 2012;Ozkale et al., 2012;Said et al., 2012;Cullup et al., 2013;Ehmke et al., 2014;Filloux et al., 2014). ...
Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs∗5, p.Arg417∗, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.
... Vici syndrome: EPG5 mutations First described by Dionisi-Vici et al. (1988), Vici syndrome (OMIM #242840) is a rare autosomal recessive multisystem disease with 50 published cases to date (Dionisi Vici et al., 1988;del Campo et al., 1999;Chiyonobu et al., 2002;Miyata et al., 2007;Al-Owain et al., 2010;McClelland et al., 2010;Rogers et al., 2011;Finocchi et al., 2012;Ozkale et al., 2012;Said et al., 2012;Cullup et al., 2013Cullup et al., , 2014Ehmke et al., 2014;Filloux et al., 2014;Tasdemir et al., 2015;Byrne et al., in press). Vici syndrome is classically characterized by a set of five cardinal features that include agenesis of the corpus callosum, bilateral cataracts, hypertrophic and/or dilated cardiomyopathy, combined immunodeficiency, and skin, hair and retinal hypopigmentation (Fig. 3). ...
Single gene disorders of the autophagy pathway are an emerging, novel and diverse group of multisystem diseases in children. Clinically, these disorders prominently affect the central nervous system at various stages of development, leading to brain mal- formations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration, among others. Frequent early and severe involvement of the central nervous system puts the paediatric neurologist, neurogeneticist, and neuro- metabolic specialist at the forefront of recognizing and treating these rare conditions. On a molecular level, mutations in key autophagy genes map to different stages of this highly conserved pathway and thus lead to impairment in isolation membrane (or phagophore) and autophagosome formation, maturation, or autophagosome-lysosome fusion. Here we discuss ‘congenital dis- orders of autophagy’ as an emerging subclass of inborn errors of metabolism by using the examples of six recently identified monogenic diseases: EPG5-related Vici syndrome, beta-propeller protein-associated neurodegeneration due to mutations in WDR45, SNX14-associated autosomal-recessive cerebellar ataxia and intellectual disability syndrome, and three forms of heredi- tary spastic paraplegia, SPG11, SPG15 and SPG49 caused by SPG11, ZFYVE26 and TECPR2 mutations, respectively. We also highlight associations between defective autophagy and other inborn errors of metabolism such as lysosomal storage diseases and neurodevelopmental diseases associated with the mTOR pathway, which may be included in the wider spectrum of autophagy- related diseases from a pathobiological point of view. By exploring these emerging themes in disease pathogenesis and underlying pathophysiological mechanisms, we discuss how congenital disorders of autophagy inform our understanding of the importance of this fascinating cellular pathway for central nervous system biology and disease. Finally, we review the concept of modulating autophagy as a therapeutic target and argue that congenital disorders of autophagy provide a unique genetic perspective on the possibilities and challenges of pathway-specific drug development.
... A recent study by Cullup et al. showed that recessive mutations in EPG5, a key factor implicated in the maturation of autolysosomes, play a causative role in Vici syndrome [27]. Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, psychomotor retardation, and immunodeficiency with cleft lip and palate [28][29][30][31]. ...
Autophagy is a major intracellular degradative process that delivers cytoplasmic materials to the lysosome for degradation. Since the discovery of autophagy-related (Atg) genes in the 1990s, there has been a proliferation of studies on the physiological and pathological roles of autophagy in a variety of autophagy knockout models. However, direct evidence of the connections between ATG gene dysfunction and human diseases has emerged only recently. There are an increasing number of reports showing that mutations in the ATG genes were identified in various human diseases such as neurodegenerative diseases, infectious diseases, and cancers. Here, we review the major advances in identification of mutations or polymorphisms of the ATG genes in human diseases. Current autophagy-modulating compounds in clinical trials are also summarized.Cell Research advance online publication 10 December 2013; doi:10.1038/cr.2013.161.
... Sequence variants affecting the canonical donor and acceptor splice sites were observed in four families (2,3,4,10) and are predicted to abolish splicing according to the prediction tools in Alamut, namely SpliceSiteFinder-like, MaxEntScan, NNSPLICE and Human Splicing Finder. The homozygous variant c.1007A>G (p.Gln336Arg) detected in patient 7 affects the penultimate base of exon 2 and is predicted by SpliceSiteFinder-like and NNSPLICE to abolish the donor splice site; scores for MaxEntScan and Human Splicing Finder are also reduced. ...
Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle and fibroblasts from individuals with mutant EPG5, resulting in the accumulation of autophagic cargo in autophagosomes. These findings position Vici syndrome as a paradigm of human multisystem disorders associated with defective autophagy and suggest a fundamental role of the autophagy pathway in the immune system and the anatomical and functional formation of organs such as the brain and heart.
... A third report in the literature by Chiyonobu et al. [3] presented two additional siblings, a brother and a sister, with Vici syndrome. The sister died at age 19 months, possibly due to progressive myocardial failure, while the brother was still living at age 6 months. ...
Purpose. The objective of this study was to present and describe two additional patients diagnosed with Vici syndrome. Methods. Clinical, laboratory, and imaging findings of the two siblings are discussed in detail. The two patients' descriptions are compared with the other eleven patients reported in the literature. We also presented detailed autopsy results on the male sibling, which demonstrated cytoplasmic vacuoles of the cardiomyocytes and confirmed the clinical findings. Results. The patients reported here include the 13th and 14th patients reported with Vici syndrome. The summary of findings present in these patients includes postnatal growth retardation, developmental delay, bilateral cataracts, agenesis of the corpus callosum, cerebellar anomalies, gyral abnormalities, seizures, hypotonia, and cardiomyopathy. Conclusion. Vici syndrome should be suspected in any child with agenesis of the corpus callosum and one of the following findings: cardiomyopathy, cataracts, immune deficiency, or cutaneous hypopigmentation.
The first sign of a primary immunodeficiency is often infection. Understanding the infections that are specific to an immunodeficiency is critical to an early and often lifesaving diagnosis. In severe combined immunodeficiencies affecting both cellular and humoral immunity, onset is often in infancy and includes bacterial, viral, and fungal infections, including opportunistic infections. Slightly less severe combined immunodeficiencies (such as primary T-cell disorders, some defects of NF-κB signaling, disorders primarily affecting only CD4+ or CD8+ T cells, and disorders of B cells) may lead to later onset of symptoms or a hallmark diagnostic specific infection. Due to the syndromic features, many patients with combined immunodeficiencies with syndromic features are diagnosed by birth, and before their first infectious episode. The onset of infections is also often in infancy and early childhood and infections can be caused by viral, bacterial, and fungal pathogens and can be fatal. Other immunodeficiencies are less severe, including those that affect specific antibody responses, and some defects in innate immunity, phagocyte function, or the complement cascade. These less severe defects may present with only a subset of infectious organisms and/or may present later in life, but there are still a number of examples of significant infections. Diseases of immune dysregulation and autoimmunity are only occasionally also associated with infection, but infections can still be life-threatening. Last, a growing number of novel therapeutics act to phenocopy states of primary immunodeficiency, and many are associated with similar infections to those seen in patients with mutations in the therapeutic targets.
Background:
Vici syndrome is a rare autosomal recessive disease with phenotypically heterogeneous presentation. Characteristic features of the disease are oculocutaneous albinism, corpus callosum agenesis, cataract, cardiomyopathy, and immunodeficiency.
Case:
Here we report two Turkish patients with Vici syndrome. One of these patients had a novel mutation in EPG5 and presented with idiopathic thrombocytopenic purpura (ITP) and maculopapular rashes similar to Stevens-Johnson syndrome, which has been previously reported in only a few cases in the literature.
Conclusion:
Vici syndrome presents with a typical phenotype which may facilitate diagnosis for infants with multisystemic disorders. ITP and maculopapular rashes might be added to the spectrum of findings of patients with Vici syndrome.
Primary immune deficiencies are a heterogeneous group of inherited disorders generally caused by specific gene mutations affecting the immune system and leading to various clinical manifestations, including severe infections, autoimmunity, and malignancies. In this chapter, general considerations on primary immune deficiency as well as the various circumstances in which a primary immune deficiency is evoked are described. This chapter serves as a roadmap to understand the layout of this book and it mirrors the clinical approach taken by immunologists.
Vici syndrome is a multisystem disorder characterized by agenesis of the corpus callosum, oculocutaneous hypopigmentation, cataracts, cardiomyopathy, combined immunodeficiency, failure to thrive, profound developmental delay, and acquired microcephaly. Most individuals are severely affected and have a markedly reduced life span. Here we describe an 8‐year‐old boy with a history of developmental delay, agenesis of the corpus callosum, failure to thrive, myopathy, and well‐controlled epilepsy. He was initially diagnosed with a mitochondrial disorder, based in part upon nonspecific muscle biopsy findings, but mitochondrial DNA mutation analysis revealed no mutations. Whole exome sequencing revealed compound heterozygosity for two EPG5 variants, inherited in trans. One was a known pathogenic mutation in exon 13 (c.2461C > T, p.Arg821X). The second was reported as a variant of unknown significance found within intron 16, six nucleotides before the exon 17 splice acceptor site (c.3099‐6C > G). Reverse transcription‐polymerase chain reaction of the EPG5 mRNA showed skipping of exon 17—which maintains an open reading frame—in 77% of the transcript, along with 23% expression of wild‐type mRNA suggesting that intronic mutations may affect splicing of the EPG5 gene and result in symptoms. However, the expression of 23% wild‐type mRNA may result in a significantly attenuated Vici syndrome phenotype.
EPG5-related Vici syndrome is a rare multisystem autosomal recessive disorder characterized by corpus callosum agenesis (ACC), hypopigmentation, cataracts, acquired microcephaly, failure to thrive, cardiomyopathy and profound developmental delay, and immunodeficiency. We report here the first case of prenatally diagnosed Vici syndrome with delayed gyration associated with ACC. Trio based exome sequencing allowed the identification of a compound heterozygous mutation in the EPG5 gene. Our patient subsequently demonstrated severe developmental delay, hypopigmentation, progressive microcephaly, and failure to thrive which led to suspicion of the diagnosis. Her MRI demonstrated ACC with frontoparietal polymicrogyria, severe hypomyelination, and pontocerebellar atrophy. This prenatal presentation of malformations of cortical development in combination with ACC expands the EPG5-related phenotypic spectrum. Our report supports the idea that EPG5-related Vici syndrome is both a neurodevelopmental and neurodegenerative disorder.
The common forms of pediatric nystagmus differ clinically and pathophysiologically from adult-onset nystagmus. Acquired nystagmus in any age group may be associated with neurological lesions involving the vestibular and ocular motor pathways in the brainstem and/or cerebellum. The type of the nystagmus and the associated neurological signs and symptoms usually permit a clinical localization that can then be confirmed by neuroimaging.
This chapter provides dedicated discussion on the intracranial disorders of neuro-ophthalmologic consequence in children. An integrated approach to these diseases has emerged from the proliferation of multidisciplinary clinics and programs combining expertise in pediatric neurology, neurosurgery, neuropathology, neuroradiology, neuro-oncology, and neuro-ophthalmology. The molecular and genetic aberrations involved in the pathogenesis of many of these disorders have only recently been elucidated. Refinement in neurosurgical management continues to advance the treatment of these disorders, while preventative and therapeutic measures will arise from molecular genetic research. Advances in neuroimaging have revolutionized the diagnosis of intracranial disease in children, while recent documentation of increased cancer risk in children exposed to multiple computed tomographic (CT) scans has emphasized the need to order diagnostic magnetic resonance (MR) imaging when neuroimaging is warranted [167].
Primary immune deficiencies are a heterogeneous group of inherited disorders caused by specific gene mutations affecting the immune system and leading to various clinical manifestations, including severe infections, autoimmunity, and malignancies. In this chapter, general considerations on primary immune deficiency as well as the various circumstances in which a primary immune deficiency has to be evoked are described.
Vici syndrome (OMIM 242840) is a rare syndrome and since its initial description by Vici et al. [1988], only 29 cases have been reported. We describe two brothers from healthy consanguineous Turkish parents with psychomotor delay, congenital bilateral cataracts, high palate, long philtrum, micrognathia, fair hair, and skin. They both had general hypotonia and elevated muscle enzymes. Magnetic resonance imaging (MRI) of the brain confirmed agenesis of corpus callosum in both patients. Secundum type atrial septal defect (in Patient 1) and mild mitral, tricuspid, and pulmonary insufficiency (in Patient 2) were detected by echocardiographic examination. Immunological studies were normal, as were chromosome karyotype analyses (46, XY). Both children had bilateral cutaneous syndactyly between second and third toes and also bilateral sensorineural hearing loss. Patient 1 had poor feeding and regurgitation necessitating a feeding tube; mild laryngomalacia was subsequently detected by bronchoscopy. Mutation analysis in patient 2 showed a homozygous p.R2483* (c.7447C > T) mutation in EPG5 gene. We report a summary of the clinical findings in our patients and 29 cases from the literature. © 2015 Wiley Periodicals, Inc.
To report and compile the ophthalmological features critical to diagnosis of Vici syndrome, a rare congenital disorder characterized principally by agenesis of the corpus callosum, cataracts, cardiomyopathy, immune defects, and hypopigmentation.
A child with Vici syndrome (OMIM 242840) is reported with emphasis on the ophthalmologic evaluation. Ophthalmologic assessments including fundus examination, visual evoked potentials (VEPs), and ocular coherence tomography are presented. These findings are compared with those identified in other published cases of children with Vici syndrome.
Ophthalmologic findings included bilateral nuclear and anterior polar cataracts, bilateral optic nerve atrophy, and mild fundus hypopigmentation. Evoked potentials recorded across the mid-occipital scalp demonstrated misrouting of optic pathways typical of albinism. Optical coherence tomography exhibited a poorly defined fovea demonstrating a lesser degree of foveal depression also consistent with ocular albinism. Review of reported children with Vici syndrome identifies bilateral cataracts, nystagmus, fundus hypopigmentation, visual impairment, and optic nerve hypoplasia as common ophthalmologic features.
Ophthalmologic findings are critical to the diagnosis of Vici syndrome. Most common are bilateral cataracts and relative fundus hypopigmentation. VEPs can identify misrouting of optic pathways typical of ocular albinism, thereby establishing the diagnosis in challenging cases. [J Pediatr Ophthalmol Strabismus 20XX;XX(X):XX-XX.].
The most common forms of nystagmus in infancy and childhood differ clinically and pathophysiologically from adult-onset nystagmus.
Acquired nystagmus in both childhood and adulthood may often be associated with neurological lesions involving the vestibular
and ocular motor pathways in the brainstem and/or cerebellum. On the basis of the clinical and electrophysiological characteristics
of the nystagmus and any associated neurological signs or symptoms, neurotopical localization can often be inferred and then
confirmed by neuroimaging.
The European Journal of Human Genetics is the official Journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports, News and Commentary articles and reviews in the rapidly expanding field of human genetics and genomics.
The phenotypically heterogeneous, autosomal recessive Vici syndrome was first described in 1988 in a sister and brother with oculocutaneous albinism, agenesis of the corpus callosum, cataract, cardiomyopathy, cleft lip, and immunodeficiency. Only 14 cases of Vici syndrome have yet been reported, several involving morphologic and functional defects in addition to those described in the initial case. We report on a 3-month-old Turkish girl with Vici syndrome associated with laryngomalacia, further expanding the clinical spectrum. We also review clinical features in all 15 Vici syndrome patients, to distinguish general from less common signs. To the best of our knowledge, this report is the first of a Turkish patient with Vici syndrome.
Advances in genetics and neuroimaging have revolutionized the diagnosis of intracranial disease in children. An integrated
approach to these diseases has also emerged from the proliferation of multidisciplinary clinics and programs combining expertise
in pediatric neurology, neurosurgery, neuropathology, neuroradiology, neuro-oncology, and neuro-ophthalmology. The role of
genetic defects is increasingly recognized in many intracranial disorders, and basic research elucidates their pathogenesis
at the molecular level. Refinement in neurosurgical management continues to advance the treatment of these disorders, while
preventative and therapeutic measures will arise from molecular genetic research.
Dilated cardiomyopathy (DCM) is a primary heart muscle disease characterized by ventricular dilatation and impaired systolic function. DCM is the most common form of cardiomyopathy, and is also the commonest cause for heart failure and cardiac transplantation in adults and children. The frequency of familial occurrence of DCM had been significantly underestimated in the past, but extensive family studies showed that 35–45% of cases are familial. This recognition led to molecular genetic investigations that have further enhanced the understanding of the molecular pathogenesis of DCM. In this review, we discuss these new insights into the genetics of DCM which will have important implications for the diagnosis, risk stratification and treatment of DCM.
Since its first description by Vici et al. [1988], further reports have continued to broaden the clinical phenotype of this rare multisystem disorder. Main features of agenesis of corpus callosum (ACC), hypopigmentation, immunodeficiency/recurrent infections, cataracts, severe failure to thrive, and profound psychomotor delay have been reported in all cases. An additional feature is the recent evidence for neuromuscular involvement. We describe a female infant with the above core features in whom an initial rapid neurological deterioration and associated transient left ventricular hypertrophy and liver dysfunction was followed by relative clinical stability after ten months of age. This case further underlines the clinical phenotype of Vici syndrome as an early onset neurodegenerative disorder with hypopimentation, recurrent infections and muscle findings indicating myopathic and neurogenic features.
Macular dystrophy is a cause of childhood and adult visual handicap and has been associated with multiple gene defects. Syndromic macular dystrophy is rare and a novel congenital form of syndromic macular dystrophy is presented. The authors report on a consanguineous family in which the 5-year-old female proband presented with nystagmus and low vision due to congenital macular dystrophy visible on fundus examination associated with complete corpus callosum agenesis, hippocampi hypoplasia and recurrent illnesses.
Patients signed informed consent forms to participate in the research. Proband was screened for 18 recessive macular dystrophy genes and ABCA4 and had a G banded karyotype on peripheral blood lymphocytes. Patients were evaluated using ocular biomicrosopy, fluorescein retinal angiograms, electroretinograms, visual evoked potentials, retinal optical coherence tomography, brain MRI and multifocal electroretinograms.
The older brother presented with subclinical findings of bilateral absence of foveal macular peak on multifocal electroretinograms and minimal corpus callosum hypoplasia. The younger sister was recently discovered to have a similar macular dystrophy. The father showed subclinical unilateral decreased foveal macular peak and the mother showed a granular-appearing fundus. No mutations were identified in the RP and macular dystrophy genes screened.
A review of the literature confirms that this is the first report of a congenital and possibly developmental macular dystrophy, with neurologic syndromic features and possible autosomal recessive inheritance but varying penetrance.
A 45-day-old male baby presented with a leaking myelomeningocele and signs of meningitis. A computerised tomographic scan of brain revealed gross supratentorial ventriculomegaly with inflammatory exudates suggestive of intracranial infection. An unexpected association of complete agenesis of corpus callosum was discovered, however it is an incidental finding, a rare combination indeed.
In syndromic immunodeficiencies, clinical features not directly associated with the immune defect are prominent. Patients may present with either infectious complications or extra-immune medical issues. In addition to the immunologic abnormality, a wide range of organ systems may be affected. Patients may present with disturbances in skeletal, neurologic, dermatologic, or gastrointestinal function or development. These conditions can be caused by developmental abnormalities, chromosomal aberrations, metabolic disorders, or teratogens. For a number of these conditions, recent advances have resulted in an enhanced understanding of their genetic basis. The finding of immune deficits in a number of defined syndromes with congenital anomalies suggests that an underlying genetic syndrome should be considered in those patients in whom a significant non-immune feature is present.
The development of the corpus callosum depends on a large number of different cellular and molecular mechanisms. These include the formation of midline glial populations, and the expression of specific molecules required to guide callosal axons as they cross the midline. An additional mechanism used by callosal axons from neurons in the neocortex is to grow within the pathway formed by pioneering axons derived from neurons in the cingulate cortex. Data in humans and in mice suggest the possibility that different mechanisms may regulate the development of the corpus callosum across its rostrocaudal and dorsoventral axes. The complex developmental processes required for formation of the corpus callosum may provide some insight into why such a large number of human congenital syndromes are associated with agenesis of this structure.
Vici syndrome is a rare congenital disorder characterized by albinism, agenesis of the corpus callosum, and developmental delays. Cardiac complications usually cause poor prognosis. We report sibling cases of Vici syndrome, and address complications of renal tubular acidosis. We also demonstrate the significance of serial examinations of brain natriuretic peptides, and discuss the possible early use of a beta-blocker to control cardiomyopathy. A sleep study including polysomnography indicated functional brainstem involvement, in which muscle atonia during non-rapid sleeping eye movements, and bursts of rapid eye movements increased. These findings provide new clues for medical care of patients with Vici syndrome.
We report on two sibs and two other unrelated patients with agenesis of corpus callosum, oculocutaneous albinism, repeated infections, and cardiomyopathy. All manifested postnatal growth retardation, microcephaly, and profound developmental delay. Additional central nervous system anomalies present in at least one patient included hypoplasia of the cerebellar vermis, white matter neuronal heterotopia, or bilateral schizencephaly. Repeated viral, bacterial, and fungal infections were consistent with a primary immunodeficiency. However, immunological studies showed variable, nonspecific findings. Cardiomyopathy with progressive heart failure or infection led to death before age 2 years in three of the patients. This syndrome was first described by Vici et al. [1988: Am. J. Med. Genet. 29:1-8]. The four patients reported herein confirm this unique disorder. Affected sibs of both sexes born to unaffected parents provide evidence for autosomal recessive inheritance.
We report on two sibs and two other unrelated patients with agenesis of corpus callosum, oculocutaneous albinism, repeated infections, and cardiomyopathy. All manifested postnatal growth retardation, microcephaly, and profound developmental delay. Additional central nervous system anomalies present in at least one patient included hypoplasia of the cerebellar vermis, white matter neuronal heterotopia, or bilateral schizencephaly. Repeated viral, bacterial, and fungal infections were consistent with a primary immunodeficiency. However, immunological studies showed variable, nonspecific findings. Cardiomyopathy with progressive heart failure or infection led to death before age 2 years in three of the patients. This syndrome was first described by Vici et al. [1988: Am. J. Med. Genet. 29:1–8]. The four patients reported herein confirm this unique disorder. Affected sibs of both sexes born to unaffected parents provide evidence for autosomal recessive inheritance. Am. J. Med. Genet. 85:479–485, 1999. © 1999 Wiley-Liss, Inc.
We describe 2 brothers with a malformation syndrome consisting of agenesis of the corpus callosum, cutaneous hypopigmentation, bilateral cataract, cleft lip and palate, and combined immunodeficiency. The clinical history of both patients was characterized by severe psychomotor retardation, seizures, recurrent severe respiratory infections, and chronic mucocutaneous candidiasis. The children died of bronchopneumonia at age 2 and 3 years, respectively. Immunological investigations showed, in one sib studied, skin anergy to recall antigens, profound depletion of T4+ lymphocytes, and serum IgG2 deficiency. Necropsy showed agenesis of the corpus callosum, hypoplasia of the cerebellar vermis, and profound hypoplasia of the thymus and of the peripheral lymphoid tissue.
The distinctive features of these sibs appear to define a previously undescribed hereditarty MCA/MR syndrome. The clinical and pathological findings seem to indicate, as a pathogenetic mechanism, a defect involving the embryonic organization of the central nervous system and of the immune system.
Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common autosomal recessive disorders in Japan (incidence is 0.7-1.2 per 10,000 births), is characterized by congenital muscular dystrophy associated with brain malformation (micropolygria) due to a defect in the migration of neurons. We previously mapped the FCMD gene to a region of less than 100 kilobases which included the marker locus D9S2107 on chromosome 9q31. We have also described a haplotype that is shared by more than 80% of FCMD chromosomes, indicating that most chromosomes bearing the FCMD mutation could be derived from a single ancestor. Here we report that there is a retrotransposal insertion of tandemly repeated sequences within this candidate-gene interval in all FCMD chromosomes carrying the founder haplotype (87%). The inserted sequence is about 3 kilobases long and is located in the 3' untranslated region of a gene encoding a new 461-amino-acid protein. This gene is expressed in various tissues in normal individuals, but not in FCMD patients who carry the insertion. Two independent point mutations confirm that mutation of this gene is responsible for FCMD. The predicted protein, which we term fukutin, contains an amino-terminal signal sequence, which together with results from transfection experiments suggests that fukutin is a secreted protein. To our knowledge, FCMD is the first human disease to be caused by an ancient retrotransposal integration.
An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy Agenesis of the corpus callosum, combined immunode®ciency, bilateral cataract, and hypopigmentation in two brothers
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