Bridging the gap: neurodevelopmental disorder risks in inborn errors of immunity

Abstract

Purpose of review

The aim of this review is to examine published reports of neurodevelopmental phenotypes in patients with inborn errors of immunity (IEI). We briefly discuss potential interactions between the immune and the central nervous system and the implications of this crosstalk for current clinical management guidelines.

Recent findings

An increasing number of reports have described neurodevelopmental disorders (NDDs) comorbid with immune-mediated signs. However, the prevalence of this association in IEIs remains unknown.

Summary

IEIs comprise a group of clinically heterogeneous disorders associated with a number of nonimmune comorbidities. Although certain neurological conditions such as microcephaly are recognized as associated features of some IEIs, NDDs are less well described. We reviewed published clinical descriptions of IEIs and found a number of comorbid NDDs in these patients, including autism spectrum disorder (ASD), behavioral deficits, and intellectual disability. Given the lack of uniform assessments for NDDs, we suspect they may be underdiagnosed in IEIs. As NDDs manifest early and can result in life-long cognitive and emotional deficits, which diminish quality of life and increase healthcare utilization, we hope to elucidate relevant pathomechanisms and raise clinician awareness of these comorbidities so appropriate and timely interventions are sought.

INTRODUCTION

Inborn errors of immunity (IEI) are characterized by increased susceptibility to infections, autoimmunity, atopy, and malignancies. Although each disease is individually rare, IEIs as a group affect between 1 : 1000 and 1 : 5000 people [1^▪]. IEI research has predominantly focused on the immunological and oncological manifestations, genetic causes, and treatment options, which range from immunoglobulin replacement to hematopoietic stem cell transplant [2,3,8]. In recent years, however, there has been growing interest in multiorgan presentations, with reports describing comorbidities of the central nervous, gastrointestinal, and hepatic systems [1^▪,2].

Neurological signs such as microcephaly and epilepsy are well documented in a few IEIs [3]. However, more subtle, but no less critical, neurological and neurodevelopmental complications are increasingly being found in IEIs, ranging from depression and anxiety to autism, speech delay, and cognitive deficits [4^▪▪,5]. Although mental health has an important and varying impact in IEIs, including on clinical outcomes, the focus of this review will be on neurodevelopmental disorders (NDDs) [6,7].

NDDs are defined as conditions with an onset during the developmental period (typically before school age), characterized by deficits that produce impairments of personal, social, academic, or occupational functioning [8]. In the setting of an IEI, these may be difficult to disambiguate from immune-driven signs, and clinicians may expect resolution once immunological dysfunction is normalized. This, coupled with the heterogeneity of NDD presentations and a paucity of multidisciplinary care, may delay accurate diagnosis and access to support services [9].

Evidence is revealing that many of the genetic variants that cause IEIs also directly modulate brain processes that contribute to the development of comorbid NDDs [10]. The aim of this review is to shed light on the presence of neurodevelopmental presentations in patients with IEIs, discuss the mechanisms that are likely to underlie these comorbidities, and highlight the need for a multidisciplinary team during IEI assessment. 

Box 1.

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METHODOLOGY

Literature search

To identify previously reported NDD signs in IEI patients, literature was selected from PubMed, Google Scholar, BASE, and Semantic Scholar using the keywords ‘Neurodevelopmental’, ‘Neurodevelopment’, ‘Neurological’, ‘Autism’, ‘ASD’, ‘Intellectual Disability’ and ‘ID’, and combined with ‘Primary Immune Deficiency’, ‘Primary Immunodeficiency’, ‘PID’, ‘Inborn Errors of Immunity’, and ‘IEI’. After identifying and excluding duplicates, we included a total of 41 publications in the final analysis.

Presentation categorization

To categorize the neurodevelopmental signs reported in the selected publications, we collected the terms used to describe each disorder. Afterwards, we grouped the identified terms based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) [11]. Descriptions of the presence of neurological, neurodevelopmental, and behavioral deficits were then compiled (Table 1) [12]. Patient count was evaluated by reviewing individual data or by calculating it from reported percentages in large cohort studies. When individual cases overlapped with cohort studies, information from the larger study was preferred, unless this did not provide patient counts for signs, in which case individual reports were included instead (Table 2).

Table 1.

Presentation categorization

	Category	Reported terms and descriptions
Neurodevelopmental disorders
AD	Attention deficits	Attention problems, ADHD, hyperactivity
ASD	Autism spectrum disorder	Autism, ASD, autism spectrum disorder, inflexibility, rigidity
CgD	Cognitive deficits	Cognitive issues, cognitive problems, cognitive disability
CmD	Communication deficits	Speech, language, communication, social issues, social interaction deficits
ID	Intellectual deficits	Defined as IQ <70 points, mental retardation (DSM-IV diagnosis)
LD	Learning deficits	Learning difficulties (not IQ-related), inability to maintain day-to-day tasks, daily behavior
MD	Movement or motor deficits	Any movement-based disability (could be related to sitting, crawling, head lag, walking, coordination), dysarthria
Neurological and other behavioral deficits
BD	Behavioral deficits	Behavioral issues not classified as ASD or otherwise unspecified
DD	Developmental delay	Unspecified developmental issues, usually related to growth retardation
DM	Dysmorphism	Microcephaly, facial features, shapes of the head
HI	Hearing impairment	Hearing issues, deafness
SZ	Seizures	Seizures, epilepsy, tremors

Clinical signs were grouped based on the DSM-5 categorization of neurodevelopmental disorder subgroups.

Table 2.

Reported neurological and neurodevelopmental presentations in inborn errors of immunity patients

Condition	Gene described in report(s)	Total patient count	Neurodevelopmental disorders							Neurological and cognitive deficits
			AD	ASD	CmD	CgD	ID	LD	MD	BD	DD	DM	HI	SZ
Activated phosphoinositide 3-kinase delta syndrome (APDS)	PIK3CD, PIK3R1	132 [16–20],a	–	3	10	9	2	9	2	4	20	5	13	6
Ataxia-telangiectasia (AT)	ATM	26 [21,22]	22	–	24	22	23	–	16	–	–	–	–	10
Cohen syndrome	VPSI3B	50 [23]	–	9	–	–	21	–	–	–	–	21	–	1
Common variable immunodeficiency disorder (CVID)	NFKB1	1 [24]	–	–	1	–	–	1	1	–	1	1	–	–
Hermansky–Pudlak syndrome (HPS)	AP3D1	10 [25]	–	–	–	–	–	–	–	–	4	4	7	3
Hyper-lgE syndrome with recurrent infections (HIES)	Undescribed in this report	1 [26]	–	1	1	–	1	–	1	–	1	–	–	–
Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome	DNMT3B, ZBTB24	38 [27–30]	–	–	26	–	22	1	17	–	1	–	–	4
Immune skeletal dysplasia with neurodevelopmental abnormalities	EXTL3	9 [31]	–	–	–	–	n	–	n	–	n	–	–	n
Lowry–Wood syndrome (LWS)	RNU4ATAC	3 [32]	–	–	1	–	3	–	–	–	–	2	–	–
Nijmegen breakage syndrome (NBS)	NBS1	11 [33]	–	–	n	–	11	–	–	–	11	11	1	–
Polymerase delta deficiency	POLD1, POLD2	2 [34]	1	–	1	–	2	–	1	–	2	1	1	–
Roifman syndrome	RNU4ATAC	9 [35–39]	1	–	4	1	5	2	7	1	7	1	–	–
Schimke immuno-osseous dysplasia (SIOD)	SMARCAL1	1 [40]	–	–	–	–	–	–	–	–	1	1	–	–
Severe combined immunodeficiency (SCID)	ADA, PNP, NHEJ1, CORO1A, LIG4	46 [41–48]	7	–	5	–	21	3	10	–	21	7	2	–
Severe congenital neutropenia (SCN)	HAX1, RBSN c	4 [49,50]	–	–	2	–	2	–	1	–	2	–	–	1
Shwachman–Diamond Syndrome (SDS)	SBDS	32 [51]	n	–	n	–	n	n	–	n	n	–	–	–
Vici syndrome	EPG5	51 [52,53]	–	–	n	–	–	–	–	–	51	46	n	30
Wiedemann–Steiner syndrome	KMT2A	104 [54]	46	22	–	–	n	–	–	–	101	n	–	21
X-linked agammaglobulinemia (XLA)	BTK	3 [55],b	–	1	–	–	–	–	–	–	–	–	3	–
X-linked immunodeficiency with magnesium defect (XMEN)	MAGT1	3 [56]	–	–	–	–	2	–	–	1	–	–	–	–

Summary of patient count with reported neurological and neurodevelopmental presentations across various IEIs, defined using the International Union of Immunological Societies (IUIS) Expert Committee classification [3]. –, no data reported; AD, attention deficits; ASD, autism spectrum disorder; BD, behavioral deficits; CmD, communication deficits; CgD, cognitive deficits; DD, developmental delay; DM, dysmorphism; HI, hearing impairment; ID, intellectual deficits; LD, learning deficits; MD, movement or motor deficits; n, reported but with unspecified patient numbers; SZ, seizures.

^aOne patient carried an APDS variant, and a Smith–Magenis syndrome (SMS) variant in the RAI1 gene.

^bTwo-thirds of patients had genetic variants in addition to BTK, namely in TIMM8A, TAF7L, and DRP2.

^cGene currently not recognized as IEI causing.

RESULTS AND DISCUSSION

Prevalence of neurological complications in Inborn errors of immunity

Neurological manifestations in IEI patients have been recognized for decades, with early reports focusing on complications like meningitis due to opportunistic infections [13]. Subtle neurological and developmental abnormalities were occasionally noted, though not emphasized. Ataxia-telangiectasia, identified in 1941, was among the first IEIs linked to neurological signs namely ataxia, which presents as poor muscle control or clumsy movement [14]. Notably, medical reports may not fully capture the extent of neurological difficulties experienced by patients. A recent study by De Almeida et al.[15] aimed to elucidate this by documenting daily neurological complications as reported by patients (n = 78) with CVID. Participants reported issues such as changes in speech, vision, memory problems, sleep disturbances, numbness, depression, vertigo, and headaches, illustrating a burden of neurological symptoms that could be addressed with coordinated care.

Neurodevelopmental disorder presentations in Inborn errors of immunity

Most of the reported patients with IEIs and NDDs presented with APDS, Wiedemann–Steiner syndrome (WSS), immunodeficiency with centromeric instability and facial anomalies (ICF), ataxia-telangiectasia, and Vici syndrome. Regarding WSS, a review by Sheppard et al. [54] found that nearly 97% of 104 individuals had developmental deficits or intellectual disability. Additionally, 44% exhibited hyperactivity, 33% displayed aggressive behavior, and 21% were diagnosed with ASD. In ataxia-telangiectasia, patients at early and late stages of disease presented with below average results when tested for verbal IQ, comprehension and vocabulary, visuospatial skills, and working memory [19]. Late-stage patients had additional impairments in attention, working memory, and abstract reasoning, with lower comprehension scores than early-stage patients. This progression underscores the broad spectrum of cognitive and developmental challenges associated with ataxia-telangiectasia, as well as the progressive nature of comorbid NDDs in this disease.

In ICF, one study observed intellectual disability in most patients with speech delays noted in virtually all, although descriptions of motor delays are also common [27–30]. A study on Vici syndrome, which is well known to be a multisystem disorder, reported gross developmental delays in all 50 study patients, particularly noting the presence of delayed social and communication skills [52,53]. Finally, NDD presentations have also been relatively common in APDS, with cohort studies reporting developmental delay associated with speech and learning deficits in 20–30% of patients [16,20]. Eickholt et al.[57] demonstrated that a protein product mutated in APDS, Pik3cd, was strongly expressed in the mouse's developing CNS, providing a putative link between brain and immunological deficits. Of note, Serra and colleagues described a patient with APDS who underperformed on a series of visuomotor tasks, despite normalized immune function and lack of apparent NDD symptomatology [15], further suggesting that altered brain function in IEIs can putatively arise from immune-independent mechanisms.

Underlying mechanisms of neuroimmunological interaction

For several IEIs, delays in early developmental milestones, including crawling, talking, or walking, have been reported [4^▪▪,19,21,28,33,58,59]. Physiologically, proteins considered to be strictly immune-related are expressed in the brain and participate in a number of processes essential for typical development including neurogenesis, cell migration, and synapse formation and remodeling [60]. For example, complement component 1q, whose deficiency leads to IEI, affects neuronal translation mechanisms in an age-dependent manner [61], whereas MHC class I molecules, that function as antigen-presenting receptors in the immune system, are expressed in the developing human cerebral cortex and regulate dendritic spine morphology and total number of synapses [62,63]. Dysregulation of some of these ‘typically immune’ genes has also been found in people with NDDs [64,65]. Transcriptomic studies in postmortem brains of people with ASD revealed broad dysregulation of multiple immune response genes [66], with large-scale GWAS studies, identifying associations of immune genes with specific autistic traits like ‘attention to detail’ and ‘social skills’ [67].

Microglia, the resident immune cells of the brain, also mediate interactions between the immune system and CNS. Unlike neurons, which derive from neuronal progenitor cells, microglia originate from the hematopoietic lineage. From the fourth postconception week, microglia leave the periphery and colonize the developing brain, where they regulate the production of neural precursor cells and the formation of brain circuitries [68]. Maternal infections, which are thought to increase the risk of autism [69], were shown to disrupt these processes, triggering abnormal cytokine production and the activation of inflammatory pathways during development [70].

These overlaps suggest that NDD comorbidities in IEIs could arise from genetic variations causing direct effects both in the CNS and immune system, in addition to secondary effects resulting from immune dysregulation and chronic disease. Because neurodevelopmental symptoms carry a large disease burden, negatively impact the quality of life of the affected individuals [71], and can be progressive, there is a growing urgency to understand the actual pathomechanisms of these comorbidities in IEIs.

Future directions for neurodevelopmental disorder assessments in inborn errors of immunity

Despite the lack of systematic neurodevelopmental assessments in IEI, available evidence suggests that NDDs might be more common in these patients than in the general population. This, together with the already described neurological signs and other features, calls for a concerted effort towards the inclusion of more formal neuropsychiatric evaluations at least in some IEI subgroups.

Though diagnostic delays are reducing, IEI diagnoses remain variable between countries and significant delays in diagnoses persist worldwide [72^▪,73,74]. Nonetheless, it is estimated that around 2/3 of IEI patients are diagnosed during pediatric ages and that roughly 1/5 are diagnosed before the age of 4 [75]. This time period represents a crucial window of opportunity to identify NDDs, with the hope that early intervention may prevent progressive dysfunction and maximize therapeutic effectiveness [76]. Thus, early IEI diagnoses not only lessen the personal, disease and economic burden associated with immune dysfunction but may positively affect neurodevelopmental trajectories [73].

Providing added neuropsychiatric care to IEI patients should not come at the cost of unnecessary additional pressure in the medical system and, therefore, patient selection is paramount. We posit Table 2 could be used to identify patients who could benefit from a neuropsychological evaluation. Additionally, the International Union of Immunological Societies (IUIS) classification of IEIs already acknowledges the presence of a large group of conditions and mutations that are associated with increased reporting of NDD features (category 2: combined immunodeficiencies with associated or syndromic features). We argue that patients who meet clinical or genetic criteria for category 2 disorders should be preferentially referred for a formal neuropsychiatric evaluation, especially during pediatric ages and despite the possible absence of noticeable NDD symptomatology [76]. Finally, NDDs can also be a significant barrier to the pediatric to adult transition of care in IEI patients, highlighting once more the relevance of these phenotypes for overall patient management and outcome [77–79].

Limitations

The terminology used for the search, although accurate, may not be fully representative of how clinical immunologists tracked neurodevelopmental patient signs in literature. For example, a clinician may have noted a child presented with ‘trouble with school’. This presentation could actually encompass many neurodevelopmental issues while lacking the word ‘neurodevelopment’ or other DSM-V diagnoses. Furthermore, these signs may not be captured in immunological literature at all. For these reasons, we think the prevalence of NDDs in IEIs herein are appreciably low, especially as IEIs with known cognitive deficits such as DiGeorge syndrome, Jacobsen syndrome, and others were not returned in the results. A systematic review using additional terminology could attempt to improve these results; however, we posit that the need for coordinated care and collaborative, interdepartmental investigations, and a move toward unified terminology are the main recommendations of this work.

CONCLUSION

Although individually rare, collectively, IEIs affect a significant number of people. NDDs within these IEIs significantly affect the quality of life and independence of patients, and pose considerable burden to healthcare systems. Although the prevalence and distribution of NDDs in IEIs require further investigation, patients would benefit, firstly, from increased awareness of this comorbidity and, secondly, from access to multidisciplinary teams that can facilitate their early detection and care. Intervention timing matters because the brief window of childhood neurodevelopment sets the foundation for lifelong cognition and emotional regulation.

Acknowledgements

We thank Virgil Dalm for constructive discussions regarding the subject of this review.

Financial support and sponsorship

This work was supported by the Netherlands Organization for Scientific Research (NWO), the NWO NWA-ORC 2022 SCANNER grant, the Erasmus MC Convergence Health and Technology Integrative Neuromedicine Flagship Program 2022 (A.B. and I.S.) and the Horizon 2020 Research and Innovation programme, MSCA-ITN PIPgen #955534 (A.B and D.K.).

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

• ▪ of special interest

• ▪▪ of outstanding interest