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Communication

CTLA4 Alteration and Neurologic Manifestations: A New Family with Large Phenotypic Variability and Literature Review

by
Edoardo Genio
1,
Mauro Lecca
1,
Rachele Ciccocioppo
2 and
Edoardo Errichiello
1,3,*
1
Unit of Medical Genetics, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
2
Gastroenterology and Endoscopic Unit, Department of Medicine and Ageing, University Gabriele D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
3
IRCCS Mondino Foundation, 27100 Pavia, Italy
*
Author to whom correspondence should be addressed.
Genes 2025, 16(3), 306; https://doi.org/10.3390/genes16030306
Submission received: 30 January 2025 / Revised: 21 February 2025 / Accepted: 26 February 2025 / Published: 3 March 2025
(This article belongs to the Special Issue Genes and Variants in Human Rare Genetic Diseases)
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Abstract

Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4), a member of the immunoglobulin superfamily, is an essential negative regulator of immune responses that is constitutively expressed on both regulatory (Treg) and activated T cells. To date, heterozygous germline variants in CTLA4, leading to haploinsufficiency, have been associated with several immunological disorders, including hypogammaglobulinemia, multi-organ autoimmunity, lymphoproliferative disorders, and enlarged lymphoid organs. Indeed, CTLA4 carriers display highly heterogeneous clinical manifestations with a phenotypic spectrum ranging from asymptomatic carrier status to fatal autoimmunity. Here, we describe a family with autoimmune phenotypes (Hashimoto thyroiditis, psoriasiform dermatitis, celiac disease/inflammatory bowel disease, and rheumatoid arthritis), segregating across three different generations due to a recurrent missense variant [c.436G>A, p.(Gly146Arg)] in the CTLA4 gene. Interestingly, the proband showed prominent neurological manifestations, including seizures, hydrocephalus, and demyelination, which are less frequently reported in individuals with pathogenic variants in CTLA4. A detailed literature review of neurologic features that have been reported so far in CTLA4 carriers is also provided.

1. Introduction

CTLA4 (MIM *123890) encodes the cytotoxic T-lymphocyte antigen 4 (CTLA-4, also known as CD152), a transmembrane protein constitutively expressed on the surface of regulatory T cells (Treg) and activated T cells. It negatively modulates T cell activation and contributes to peripheral tolerance by competing with the stimulatory molecule CD28 for binding to CD80 and CD86 ligands on the surface of APCs (antigen-presenting cells) [1].
Homozygous variants of Ctla4 have been associated with fatal multi-organ lymphocytic infiltration and destruction in mice [2,3]. Biallelic variants have never been described in humans thus far, whereas pathogenic heterozygous variants, often showing incomplete penetrance and variable expression, are related to a rare primary immunodeficiency (prevalence <1/1,000,000; ORPHA:436159); this is characterized by a variable combination of enteropathy, hypogammaglobulinemia, recurrent respiratory infections, granulomatous lymphocytic interstitial lung disease, lymphocytic infiltration of non-lymphoid organs (i.e., intestine, lung, brain, bone marrow, and kidney), autoimmune thrombocytopenia or neutropenia, autoimmune hemolytic anemia, and lymphadenopathy [4,5,6,7]. Loss of function/haploinsufficiency is considered the main pathogenic mechanism, as reflected by gene predictive scores (pLI:1.00; LOEUF:0.21), although negative dominance has also been hypothesized [8]. In the Human Gene Mutation Database (HGMD; last access 18 February 2025) there are 140 CTLA4 variants listed (114 in coding and 26 in non-coding regions), with missense/nonsense, deletions, and splicing substitutions representing the most frequent classes of genetic alterations (72, 26 and 12 variants, respectively).
In a large cohort of CTLA4 carriers, neurologic manifestations were reported in about one third of individuals, mainly encephalitis/encephalomyelitis, seizures, headache, and nausea [6]. Here, we describe a three-generation family showing highly heterogeneous clinical phenotypes, including neurologic manifestations, caused by the recurrent c.436G>A (p.Gly146Arg) missense variant in CTLA4. A detailed literature review of neurologic phenotypes reported in CTLA4 carriers is also provided.

2. Subjects and Methods

2.1. Clinical Phenotype

The proband was a 45-year-old female born to non-consanguineous Italian parents. At 33 years of age, she came to our attention due to chronic diarrhea. Her family history was suggestive of autoimmune disorders, namely Hashimoto thyroiditis, psoriasiform dermatitis, celiac disease, and rheumatoid arthritis (Figure 1). At the age of 13, the proband was diagnosed with common variable immunodeficiency (CVID). Clinical records documented lymphopenia, postnatal growth retardation, interstitial pneumopathy and bronchiectasis (with a moderately decreased DLCO%), recurrent sinusitis, and other severe opportunistic infections. Six years later, she underwent treatment with cyclosporin, steroids, infliximab, and immunoglobulins, following a diagnosis of hemolytic anemia and autoimmune thrombocytopenia, along with a modest erythroid dysplasia diagnosed by bone marrow biopsy. At the age of 21, the proband was admitted to hospital following episodes of loss of consciousness. Head CT (Computed Tomography) highlighted pons hypodensity, likely suggestive of an ischemic stroke. One year later, she was admitted for an epileptic episode triggered by fever. At the age of 23, the proband underwent a splenectomy because of thrombocytopenia, and a cholecystectomy due to acute cholelithiasis. Afterwards, she began to manifest recurrent muco-hematic diarrheic episodes with dehydration; however, the diagnosis was uncertain (either inflammatory bowel disease (IBD), infective colitis, or autoimmune colitis.) At age 28 years, a brain MRI showed focal lesions of the vermis and left hemisphere, which were interpreted as autoimmune-related demyelination, and supratentorial hydrocephalus; this was treated with a ventriculoperitoneal shunt (VPS). The latest endoscopic follow-up revealed a colorectal polyposis. Laboratory investigations also confirmed hypogammaglobulinemia with almost undetectable values of IgA (<6 mg/dL; n.v.: 40–350 mg/dL), IgE (<2 kU/l; n.v.: 0–380 kIU/L), and IgM (5 mg/dL; n.v.: 54–300 mg/dL), but normal IgG (664 mg/dl; n.v.: 650–1600 mg/dL for adults) because of scheduled IgG therapeutic infusions. Further immunological assessments showed an almost complete absence of B lymphocytes (0.6%, n.v.>6%), reduced T cell proliferation in vitro, and significantly decreased circulating FOXP3+ regulatory T (Treg) cells. Anti-MuSK (Muscle-Specific Kinase) and anti-AChR (Acetylcholine Receptor) antibody tests were negative, as was a cerebrospinal fluid (CSF) analysis, an evoked potentials test, and other blood tests to rule out other conditions, such as infections (e.g., Lyme disease, syphilis, HIV, and Parvovirus), vitamin deficiencies (e.g., B12), and autoimmune diseases. Osteoporosis (t-score −2.8, z-score: −2.7) was also found by means of bone mineralometry.
The study was conducted in accordance with the local legislation and institutional requirements. Written informed consent for genetic analysis and publication of the clinical data was obtained from the participating subjects.

2.2. Genetic Analysis and In Silico Predictions

Whole-exome sequencing (WES) was performed on the proband and parental DNA samples (trio-WES), extracted from peripheral blood by standard procedures, using the Human Core Exome kit (Twist Bioscience, South San Francisco, CA, USA) on a NovaSeq 6000 system (Illumina, San Diego, CA, USA). The sequencing reads were aligned against the human reference genome (GRCh38/hg38). Variant calling was performed according to international guidelines using an in-house developed pipeline. In brief, the bioinformatic analysis was focused on variants with a frequency <5% in gnomAD v4.1.0 and an in-house database (~9500 samples), focusing on a virtual panel of 564 genes related to primary immunodeficiency and inflammatory bowel disease (PanelApp version 7.21). Variants were classified according to the ACMG-AMP and ACGS guidelines https://www.acgs.uk.com/quality/best-practice-guidelines/ accessed on 29 January 2025 and specific ClinGen recommendations (https://clinicalgenome.org/working-groups/sequence-variant-interpretation/) (last access 29 January 2025) [9]. The variant nomenclature was verified using Mutalyzer (https://mutalyzer.nl/ accessed on 29 January 2025) and VariantValidator (https://variantvalidator.org/ accessed on 29 January 2025).
Copy number variants (CNVs) were detected with Control-FREEC and EXCAVATOR tools [10,11]. Sanger sequencing was used for segregation analysis in the available family members and to search for known modifying/regulatory variants, particularly those located in non-coding regions uncovered by ES experiments, that could explain the observed intrafamilial phenotypic variability. A three-dimensional (3D) model of mutated protein structure was predicted using AlphaFold (https://alphafold.ebi.ac.uk/ accessed on 29 January 2025) and visualized with PyMOL 3.1 (https://pymol.org/ accessed on 29 January 2025). I-Mutant2.0 (https://folding.biofold.org/i-mutant/i-mutant2.0.html accessed on 29 January 2025) was used to predict the effect of the variant on protein stability. STRING v12.0 (https://string-db.org/ accessed on 29 January 2025) and Cytoscape v3.10.3 (https://cytoscape.org/ accessed on 29 January 2025) were used to investigate CTLA-4 interaction networks.

3. Results

3.1. Genetic Findings

Trio-WES identified a pathogenic heterozygous missense variant within exon 2 of CTLA4 (NM_005214.5:c.436G>A; p.Gly146Arg). The variant is reported in ClinVar (VCV000849622.11), HGMD (CM164030), and PubMed, and falls in a mutational hot-spot along with two other disease-causing variants (c.436G>T and c.437G>T) [6,12,13,14,15,16,17,18,19]. The variant was inherited from the affected father and co-segregated with the disease in the family (Figure 1).
The Gly146Arg variant in CTLA-4 is located within the ligand-binding domain [12], which includes the highly conserved ‘MYPPPY’ motif (aa 134–139). This motif is crucial for interactions with CD80 and CD86 and represents a mutational hot-spot, containing about one third of the disease-causing variants [20]. The missense change replaces glycine, which is neutral and non-polar, with arginine, which is basic and positively charged. A comparison between wild-type and mutant structures revealed significant 3D changes (RMSD = 2.18). GRAVY index scores of hydropathy (WT: 0.296; MUT: 0.278), indicated lower hydrophobicity of the mutant protein, while I-Mutant2.0 returned a negative ΔΔG value (−1.01 Kcal/mol), consistent with a loss of protein stability (Supplementary Figure S1). These in silico predictions are in line with previous functional studies showing significantly decreased levels of CTLA-4 protein in T cells of c.436G>A carriers compared with wild-type individuals [13,15].
To further investigate the observed intrafamilial variability, we searched for common CTLA4 variants that have been previously reported to modify penetrance, namely rs3087243 (CT60) and rs231775 (CTLA4+49); these are located within the 3′-UTR and first exon of CTLA4, respectively. The proband and an affected sister showed a G/G genotype for CT60, associated with a low expression of a soluble isoform of CTLA-4 lacking the third exon and a predisposition to autoimmune diseases, whereas the father was heterozygous A/G [21,22,23,24,25]. On the other hand, an A/A CTLA4+49 genotype was observed in all the affected family members. Because the inheritance pattern of such CTLA4 variants in the pedigree did not consistently explain the observed intrafamilial phenotypic variability, we searched for other potential genetic modifiers in genes encoding CTLA-4 interactors (Supplementary Table S1), under the hypothesis that additional ‘hits’ may worsen the proband’s clinical presentation. The only candidate variant, NM_175862.5:c.15-81C>A (rs915120854), detected in the proband but not in the relatives with milder clinical manifestations, was located in intron 1 of CD86. CD86 encodes the functional ligand of CTLA-4, which is required for inhibitory signals to prevent CD28-mediated T cell activation [26].

3.2. Phenotypic Constellation in CTLA4 c.436G>A Carriers

Neurologic and neuroradiologic features are described in a minor and variable portion of CTLA4 carriers. In a large study where 133 individuals were enrolled, a broad spectrum of neurologic manifestations, ranging from nausea and headache to aphasia and encephalitis, were reported in 25 of them (~19%) [6].
According to HGMD, the c.436G>A variant (CM164030) detected in our family has been reported in only 10 other individuals (Table 1). Gastrointestinal features, including Crohn’s disease, gastritis, and enteropathy, were reported in 8 out of 10 subjects; respiratory anomalies, including pneumopathy and recurrent pulmonary infections, in 6/10; hematological alterations, including autoimmune hemolytic anemia, iron deficiency anemia, immune thrombocytopenic purpura, and Evans syndrome, in 6/10; skin and skeletal anomalies in 4/10 each; endocrine manifestations (type 1 diabetes) in 2/10; renal involvement was observed in 1/10. Neurologic symptoms were detected in four of the subjects, including recurrent paralysis of limbs, abnormality of vision, anxiety, seizures, recurrent headache, paraparesis, nausea, and fecal incontinence (Table 1); one showed intramedullary lesions on a brain MRI scan.
Our proband showed seizures, hydrocephalus, vermis lesions, and demyelination as the main neurological/neuroradiological symptoms. As far as we know, such neuroradiological lesions have never been reported in CTLA4 heterozygotes. We ruled out the presence of other disease-causing variants in genes associated with brain malformations, especially hydrocephalus, vermian anomalies and demyelination, and epilepsy, that might be involved in the neurophenotype observed in the proband.

4. Discussion

CTLA-4 is a key regulator of immune homeostasis whose alterations have been observed in many autoimmune disorders. The clinical history of our family emphasizes the broad phenotypic variability and incomplete penetrance associated with CTLA4 variants, estimated to be between 55% and 70% [6,8,27]. To the best of our knowledge, such a large intrafamilial variability has never been reported before, at least for the c.436G>A variant, and underlines the pleiotropy of CTLA4.
The extremely variable spectrum of neurologic characteristics reported in up to 30% of CTLA4 carriers from childhood to late adulthood, includes headache and seizures (as leading symptoms), encephalitis/encephalomyelitis with cerebral perivascular lymphocytic infiltration, nausea, aphasia, visual impairment, ventriculomegaly, and slowly progressive cognitive deterioration (Table 1) [5,14,15,28,29,30]. Our proband showed lesions of the cerebellar vermis, seizures, hydrocephaly, and demyelination. The latter is commonly observed in multiple sclerosis (MS), where CTLA4 downregulation has also been reported, while certain polymorphic variants in CTLA4 are linked to reduced remyelination in MS, suggesting potential common underlying immunologic mechanisms between CTLA4 deficiency and ‘genuine’ MS [31,32,33,34,35,36]. Interestingly, tumefactive demyelinating lesions on a brain MRI that were suggestive of MS have been reported previously in a 14-year-old girl carrying a different pathogenic CTLA4 variant (c.208C>T, p.(Arg70Trp)) [37]. CTLA4 alterations have also been associated with an increased susceptibility to myasthenia gravis (MG). Further, functionally abnormal Treg cells have been found in MG individuals with a low expression of CTLA4 [38,39]. In a previous cross-sectional observational study, cerebellar lesions were identified in 75% of CTLA4 subjects, while demyelination was reported in a 48-year-old female proband carrying a heterozygous frameshift variant in CTLA4 exon 1 (c.81dup; p.Leu28Serfs*32) [40,41]. Several systemic autoimmune disorders, such as systemic lupus erythematosus, display hydrocephaly as a symptom, likely as the result of direct damage to the small-sized venous structures, or immune complex deposition within the arachnoid villi leading to a lack of reabsorption of the cerebral spinal fluid [42]. The emergence of these lesions in CTLA4 carriers can be explained by the lack of CTLA4-mediated inhibitory signals for T cell activation, caused by an altered ability of CTLA-4 to bind the costimulatory ligands CD80 and CD86. This causes T cell infiltration of the brain and loss of blood-brain barrier integrity, which in turn induces a state of persistent neuroinflammation leading to demyelination, periventricular, cerebellar, and spinal cord injury.
Interestingly, the neurological manifestations observed in the proband, especially demyelination, recapitulate some of the side effects of cancer immunotherapy using immune checkpoint inhibitors (ICIs), such as the CTLA4-blocking monoclonal antibodies ipilimumab and tremelimumab [43,44,45,46,47,48,49]. This evidence suggests caution when using ICIs in CTLA4 carriers, as well as the potential risk of administering ICIs to subjects with clinically silent CTLA4 haploinsufficiency.
In conclusion, neurologic involvement may be underestimated in CTLA4 deficiency because of the predominant extra-neurologic features. However, neurologic manifestations should be taken into consideration in the diagnostic work-up of subjects carrying symptoms commonly related to CTLA4 haploinsufficiency, such as CVID and multi-organ autoimmunity. Referring patients with familial opportunistic infections and organ autoimmunity to tertiary centers where appropriate diagnostic procedures are available, together with their management by a multidisciplinary team (including immunologists, clinical geneticists, hematologists, neurologists, and gastroenterologists, as appropriate) is strongly recommended to achieve optimal management and improve their clinical outcome. In these cases, immunophenotyping and a genetic assessment may be very helpful in reaching a definitive diagnosis. This is because a potentially effective targeted immunotherapy, such as abatacept (a fusion protein consisting of the extracellular domain of human CTLA-4 bound to the modified Fc portion of human IgG1, which selectively modulates a key costimulatory signal required for the full activation of CD28-expressing T cells), or allogeneic bone marrow transplantation [50], may be offered to affected subjects.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/genes16030306/s1, Figure S1: Hydropathy plots (Expasy ProtScale) comparing wild-type (left) and mutant (right) CTLA-4; Table S1: List of CTLA-4 interactors;

Author Contributions

Conceptualization, E.E.; formal analysis, E.G. and E.E.; investigation, E.G., M.L., R.C. and E.E; data curation, M.L. and E.E.; writing—original draft preparation, E.G., M.L., R.C. and E.E; writing—review and editing, E.G., M.L., R.C. and E.E.; supervision, E.E.; project administration, E.E.; funding acquisition, E.E. All authors have read and agreed to the published version of the manuscript.

Funding

This research was partly supported by the Jeffrey Modell Foundation (JMF).

Informed Consent Statement

Written informed consent for publication was obtained from all participants.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Acknowledgments

The authors sincerely thank the proband and family for participating in this study. This study was supported by the Jeffrey Modell Foundation (JMF).

Conflicts of Interest

The authors declare no conflicts of interest.

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Genes 16 00306 g001
Figure 1. Family pedigree showing variable immune-mediated phenotypes associated with the pathogenic heterozygous missense variant c.436G>A (p.Gly146Arg) in CTLA4.
Figure 1. Family pedigree showing variable immune-mediated phenotypes associated with the pathogenic heterozygous missense variant c.436G>A (p.Gly146Arg) in CTLA4.
Genes 16 00306 g001
Table 1. Phenotypic manifestations associated with the CTLA4 c.436G>A variant.
Table 1. Phenotypic manifestations associated with the CTLA4 c.436G>A variant.
Study (PMID)ImmunologicalGastrointestinalRespiratoryNeurologicalHematologicalSkinEndocrineSkeletalOthers
29729943
(Individual
#53,
fam V.II.1)		LymphadenopathyLymphocytic organ infiltration (retroperitoneum) ITP; AIHA; autoimmune neutropenia;
Evans syndrome		 Renal involvement
29729943
(Individual #99,
fam SS.II.1)		Hypogammaglobulinemia
(low IgG, IgM, IgA);
fungal infections (Candida)		Splenomegaly; diarrhea/enteropathy,
atrophic gastritis		Respiratory involvement, (upper and lower respiratory tract); severe respiratory infections (pneumonia); GLILD; bronchiectasis;
lymphadenopathy and lymphocytic organ infiltration (lungs)		Lymphadenopathy and lymphocytic organ infiltration (brain); retinal tear due to lymphocytic infiltrations into the retina RA
28960754Autoimmune lymphoproliferative syndrome (ALPS)Hepatomegaly; splenomegaly Evans syndrome
31993940Positivity for anti-parietal cell antibody; hypogammaglobulinemia
(low IgG)		Recurrent diarrhea;
atrophic gastritis;
lymphoid hyperplasia at the ileal end		Recurrent respiratory infectionDysphagia since age 3 yearsIDA; ITP;
leukopenia;		Bilateral axillary lymphadenopathy Cervical lymphadenopathy; bilateral knee arthralgia;
steroid refractory RA
32996901Reduction of CD19+ B cells, low levels
of total IgG and IgA, and a normal IgE level; CMV infection; reduced PBMC count		Chronic diarrhea; enteropathy;
cholecystectomy (probably due to AIHA)		Chronic sinusitis ITP;
Evans syndrome		Alopecia areataHypothyroidism, diabetes mellitus type 1
35753512
(P0003698)		Chronic infections; feverAbdominal pain; splenomegaly; diarrheaAbnormal lung morphology; pulmonary obstructionAbnormality of vision; nausea; vomiting;
anxiety; seizures; abdominal pain; distal muscle weakness;
headache		AIHA; IDAUrticaria; blepharitis Weight loss
32623363Hypogammaglobulinemia; polyvalent allergyCrohn’s disease; sphincter dysfunction (bowel)Bilateral pulmonary interstitial infiltration; chronic pansinusitisProgressive headache and focal right-side-sensitive epileptic paroxysm;
presence of an isolated infiltrating mass (16 × 20 × 22 mm) and lesions in the white-matter (left parieto-occipital region); T2-hyperintense lesion in the right counterpart;
positive sensory symptoms in both hands; static tremor and hypesthesia of the left upper extremity (suspected MS);
idiopathic intracranial hypertension;
moderate central paraparesis of the lower extremities; hypesthesia;
disseminated intramedullary lesions; CSF oligoclonal bands 		Autoimmune thyroiditisJuvenile seronegative RARecurrent uveitis, with permanent moderate vision loss due to papilledema;
sphincter dysfunction (bladder)
31955317Immunodeficiency with low IgG and undetectable IgA and IgM levels;
CD19+ B cells
were absent; lower count of CD4+ T cells; elevated lactate
dehydrogenase level		Cholestasis; mediastinal adenopathy; hepato-splenomegaly, multiple lytic lesions of the liverInterstitial fibrosis of the left lung with focal honeycombing and lymphocytes infiltrates in the fibrotic areas; sinopulmonary infections;
progressive respiratory distress with hypoxemia; dyspnea		 ITP progressed to pancytopenia with lymphopenia by age 23 years; erythroid and megakaryocytic hyperplasiaAnasarca; axillary lymphadenopathy Multiple lytic lesions in the skull, ribs, and spine; cervical lymphadenopathy
36790564Unspecified primary B cell defects
30443250Immune dysregulation-IPEX
Current studyImmunodeficiency; hypogammaglobulinemia
(low IgG, IgA, IgM, IgE);
CVID		Chronic diarrhea; enteropathy; gallstones; celiac disease/IBD; poliposisInterstitial pneumopathyHypodensity in the pons region; vermis lesions; hydrocephalus; seizures; CNS demyelinationAutoimmune thrombocytopenia; hemolytic anemiaPsoriasiform dermatitis (father)Hashimoto thyroiditis (father and cousin) Osteoporosis;
RA (niece)		Growth delay
AIHA (Autoimmune Hemolytic Anemia), ALPS (Autoimmune Lymphoproliferative Syndrome), BCG (Bacillus Calmette–Guérin), CSF (Cerebro-Spinal Fluid), CT (Computer Tomography), CVID (Common Variable Immuno-Deficiency), GLILD (Granulomatous Lymphocytic Interstitial Lung Disease), IBD (Inflammatory Bowel Disease); IDA (Iron Deficiency Anemia); IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked), ITP (Immune Thrombocytopenic Purpura); MS (Multiple Sclerosis); PBMC (Peripheral Blood Mononuclear Cells); RA (Rheumatoid Arthritis).
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Genio, E.; Lecca, M.; Ciccocioppo, R.; Errichiello, E. CTLA4 Alteration and Neurologic Manifestations: A New Family with Large Phenotypic Variability and Literature Review. Genes 2025, 16, 306. https://doi.org/10.3390/genes16030306

AMA Style

Genio E, Lecca M, Ciccocioppo R, Errichiello E. CTLA4 Alteration and Neurologic Manifestations: A New Family with Large Phenotypic Variability and Literature Review. Genes. 2025; 16(3):306. https://doi.org/10.3390/genes16030306

Chicago/Turabian Style

Genio, Edoardo, Mauro Lecca, Rachele Ciccocioppo, and Edoardo Errichiello. 2025. "CTLA4 Alteration and Neurologic Manifestations: A New Family with Large Phenotypic Variability and Literature Review" Genes 16, no. 3: 306. https://doi.org/10.3390/genes16030306

APA Style

Genio, E., Lecca, M., Ciccocioppo, R., & Errichiello, E. (2025). CTLA4 Alteration and Neurologic Manifestations: A New Family with Large Phenotypic Variability and Literature Review. Genes, 16(3), 306. https://doi.org/10.3390/genes16030306

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