Ataxia Telangiectasia Arising as Immunodeficiency: The Intriguing Differential Diagnosis

Abstract

Ataxia telangiectasia (AT) is a rare disease characterized by the early onset and slow progression of neurodegenerative defects, mainly affecting the cerebellum, associated with immunodeficiency and teleangiectasias. Ataxia is the hallmark of the disease and usually its first manifestation. Overt cerebellar ataxia usually becomes evident between 16 and 18 months of age, after the onset of walking, and is characterized by frequent falls and an ataxic gait with an enlarged base. We report the case of a child who first presented with serious recurrent infectious, without exhibiting neurological symptoms. The patient was initially diagnosed with combined immunodeficiency (CID) of unknown etiology for nearly 3 years, before he was definitively diagnosed with ataxia telangiectasia.

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Citation: Cavone, F.; Cappelli, S.;
Bonuccelli, A.; D’Elios, S.;
Costagliola, G.; Peroni, D.; Orsini, A.;
Consolini, R. Ataxia Telangiectasia
Arising as Immunodeficiency: The
Intriguing Differential Diagnosis. J.
Clin. Med. 2023,12, 6041. https://
doi.org/10.3390/jcm12186041
Academic Editors: Federica
Pulvirenti, Antonio Marzollo and
Riccardo Castagnoli
Received: 18 July 2023
Revised: 29 August 2023
Accepted: 8 September 2023
Published: 19 September 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Journal of
Clinical Medicine
Case Report
Ataxia Telangiectasia Arising as Immunodeficiency:
The Intriguing Differential Diagnosis
Federica Cavone 1, Susanna Cappelli 2, Alice Bonuccelli 3, Sofia D’Elios 2, Giorgio Costagliola 1, Diego Peroni 1,
Alessandro Orsini 3and Rita Consolini 2, *
1Pediatrics Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy;
f.cavone@studenti.unipi.it (F.C.); giorgio.costagliola@hotmail.com (G.C.); diego.peroni@unipi.it (D.P.)
2Section of Clinical and Laboratory Immunology, Division of Pediatrics, Department of Clinical and
Experimental Medicine, University of Pisa, 56126 Pisa, Italy; su.cappelli@ao-pisa.toscana.it (S.C.);
s.delios@ao-pisa.toscana.it (S.D.)
3Section of Pediatric Neurology, Division of Pediatrics, Department of Clinical and Experimental Medicine,
University of Pisa, 56126 Pisa, Italy; al.bonuccelli@ao-pisa.toscana.it (A.B.); aorsini.md@gmail.com (A.O.)
*Correspondence: rita.consolini@unipi.it; Tel.: +39-050-992-100
Abstract:
Ataxia telangiectasia (AT) is a rare disease characterized by the early onset and slow
progression of neurodegenerative defects, mainly affecting the cerebellum, associated with immunod-
eficiency and teleangiectasias. Ataxia is the hallmark of the disease and usually its first manifestation.
Overt cerebellar ataxia usually becomes evident between 16 and 18 months of age, after the onset of
walking, and is characterized by frequent falls and an ataxic gait with an enlarged base. We report the
case of a child who first presented with serious recurrent infectious, without exhibiting neurological
symptoms. The patient was initially diagnosed with combined immunodeficiency (CID) of unknown
etiology for nearly 3 years, before he was definitively diagnosed with ataxia telangiectasia.
Keywords: ataxia; immunodeficiency; inborn errors of immunity; movement disorders
1. Introduction
Ataxia telangiectasia (AT) is a multisystemic autosomal recessive inherited disease
associated with defective DNA repair mechanisms and clinically characterized by cerebellar
ataxia, oculo-cutaneous telangiectasias, immunodeficiency, radiosensitivity, and high can-
cer susceptibility. In adulthood, the key signs of the disease are usually overall expressed,
but the onset time of the different manifestations and the rapidity of progression of the
disease lead to phenotypic variability in its presentation in childhood. Mild trunk ataxia
with anteroposterior and lateral oscillations and mild to moderate trunk hypotonia with
hypotonic posture may represent early clinical signs, appearing after the sixth month of age.
However, the majority of children appear normal at birth and their psychomotor develop-
ment is not different from that of healthy peers until the time of acquisition of autonomous
walking. The dyssynergy between the trunk and limbs makes their walking uncertain
with continuous adaptation of the support base. Moreover, cerebellar ataxia is usually the
first manifestation of the disease. We report the case of a child who firstly presented with
serious recurrent infections and had been diagnosed with combined immunodeficiency
(CID) of unknown etiology for nearly 3 years before he was definitively diagnosed with
AT. As AT diagnosis is particularly challenging in cases arising only with the features of
immunodeficiency, we focus on the differential diagnostic approach of patients presenting
with immunodeficiency and neurological defects.
2. Case Report
The patient was a male who came to our observation at the age of 3 years and 8 months.
He had previously received a diagnosis of CID in an another immunological center. His
J. Clin. Med. 2023,12, 6041. https://doi.org/10.3390/jcm12186041 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2023,12, 6041 2 of 11
medical history reported recurrent upper and lower airway infections since one year of
age, requiring intravenous (IV) antibiotic treatment. Immunologic examinations revealed
low expression of T lymphocyte receptor excision circles/DNA and kappa-deleting re-
combination excision circles (TREC and KREC) on neonatal spot, low IgA (<
−
2 DS) and
IgG (<
−
2 DS), elevated IgM (1450 mg/dL), lymphopenia (2198/mmc), low T cell sub-
populations (CD4+: 16%, 391/mmc; CD8+: 13%, 312/mmc), reduced CD4 naive T cells
(4.8%), and reduced lymphocyte proliferation evaluated with carboxyfluorescein succin-
imidyl ester (CFSE) flow cytometry. He underwent molecular analysis of IL2R
γ
and the
intron/exon junctions, CD40, and CD40L, which were found to be negative. The CGH
array was negative. Replacement therapy with immunoglobulins (first intravenous and
then subcutaneous) and prophylactic therapy with sulfamethoxazole-trimethoprim against
Pneumocystis jiroveci were introduced. At the age of three years and six months, chest
computed tomography (CT) was performed, showing bilateral bronchiectasis of cylindrical
type, bronchiolectasis, and bilateral interstitial nodular thickenings associated with acinar
opacities. After refusing to undergo hematopoietic stem cell transplantation (HSCT), the
family turned to our center.
At our physical examination, the child was in fair general condition; pulmonary
auscultation demonstrated crackles on both lower lung bases. The neurological examination
was overall negative. Notably, mild postural uncertainty of the trunk with slight oscillations
was observed. The previous therapy was confirmed and antibiotic prophylaxis with
azithromycin was added, due to the recent history of numerous bacterial infections. After
one year, at the age of 4 years, the child had developed proximal hypotonia and progressive
postural instability of both the trunk and head, with worsening swaying. He showed
sudden uncoordinated and late postural trunk adjustments. Romberg’s test was positive.
Bradykinesia was evident in some movements, particularly of the upper limbs. Walking
appeared uncertain due to a level of dyssynergy between the trunk and limbs, already
visible in upright posture. Brain and cervical spine magnetic resonance imaging (MRI)
showed expansion of the IV ventricle and the liquor spaces surrounding the cerebellum, as
a consequence of cortical–subcortical cerebellar atrophy (Figure 1).
J. Clin. Med. 2023, 12, x FOR PEER REVIEW 2 of 11
2. Case Report
The patient was a male who came to our observation at the age of 3 years and 8
months. He had previously received a diagnosis of CID in an another immunological
center. His medical history reported recurrent upper and lower airway infections since
one year of age, requiring intravenous (IV) antibiotic treatment. Immunologic
examinations revealed low expression of T lymphocyte receptor excision circles/DNA and
kappa-deleting recombination excision circles (TREC and KREC) on neonatal spot, low
IgA (<−2 DS) and IgG (<−2 DS), elevated IgM (1450 mg/dL), lymphopenia (2198/mmc), low
T cell subpopulations (CD4+: 16%, 391/mmc; CD8+: 13%, 312/mmc), reduced CD4 naive T
cells (4.8%), and reduced lymphocyte proliferation evaluated with carboxyfluorescein
succinimidyl ester (CFSE) flow cytometry. He underwent molecular analysis of IL2Rγ and
the intron/exon junctions, CD40, and CD40L, which were found to be negative. The CGH
array was negative. Replacement therapy with immunoglobulins (first intravenous and
then subcutaneous) and prophylactic therapy with sulfamethoxazole-trimethoprim
against Pneumocystis jiroveci were introduced. At the age of three years and six months,
chest computed tomography (CT) was performed, showing bilateral bronchiectasis of
cylindrical type, bronchiolectasis, and bilateral interstitial nodular thickenings associated
with acinar opacities. After refusing to undergo hematopoietic stem cell transplantation
(HSCT), the family turned to our center.
At our physical examination, the child was in fair general condition; pulmonary
auscultation demonstrated crackles on both lower lung bases. The neurological
examination was overall negative. Notably, mild postural uncertainty of the trunk with
slight oscillations was observed. The previous therapy was confirmed and antibiotic
prophylaxis with azithromycin was added, due to the recent history of numerous bacterial
infections. After one year, at the age of 4 years, the child had developed proximal
hypotonia and progressive postural instability of both the trunk and head, with
worsening swaying. He showed sudden uncoordinated and late postural trunk
adjustments. Romberg’s test was positive. Bradykinesia was evident in some movements,
particularly of the upper limbs. Walking appeared uncertain due to a level of dyssynergy
between the trunk and limbs, already visible in upright posture. Brain and cervical spine
magnetic resonance imaging (MRI) showed expansion of the IV ventricle and the liquor
spaces surrounding the cerebellum, as a consequence of cortical–subcortical cerebellar
atrophy (Figure 1).
Figure 1.
Brain MRI features. Brain MRI features: (
A
,
F
) gray matter reduction; (
B
,
E
) enlargement of
the lateral ventricles; (C,D) cerebellar atrophy.

J. Clin. Med. 2023,12, 6041 3 of 11
In light of the MRI, blood tests were performed, revealing high levels of
α
-fetoprotein
(AFP: 230 mcg/L). CGH array did not reveal any microduplication or microdeletion, and
DNA tests for the expansion of repeated triplets in the genes associated with Friedreich’s
ataxia (FXN) and with other forms of ataxia (ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7,
ATXN8OS, PPP2R2B, TBP, ATN1) were also negative. Genetic analysis of the ATM gene
showed a variant of uncertain significance of both alleles (p.V1268 *- p.A1299fs * 3). There-
fore, genetic counselling was performed and segregation analysis revealed a heterozygous
mutation of the ATM gene in both parents. Based on the clinical phenotype (cerebellar
ataxia, recurrent lower airway infections), immunological profile (humoral and cellular
deficiency), elevation of AFP, and biallelic mutations of the ATM gene, the diagnosis of
ataxia telangiectasia was established (Figure 2).
J. Clin. Med. 2023, 12, x FOR PEER REVIEW 3 of 11
Figure 1. Brain MRI features. Brain MRI features: (A,F) gray matter reduction; (B,E) enlargement of
the lateral ventricles; (C,D) cerebellar atrophy.
In light of the MRI, blood tests were performed, revealing high levels of α-fetoprotein
(AFP: 230 mcg/L). CGH array did not reveal any microduplication or microdeletion, and
DNA tests for the expansion of repeated triplets in the genes associated with Friedreich’s
ataxia (FXN) and with other forms of ataxia (ATXN1, ATXN2, ATXN3, CACNA1A,
ATXN7, ATXN8OS, PPP2R2B, TBP, ATN1) were also negative. Genetic analysis of the
ATM gene showed a variant of uncertain significance of both alleles (p.V1268 *- p.A1299fs
* 3). Therefore, genetic counselling was performed and segregation analysis revealed a
heterozygous mutation of the ATM gene in both parents. Based on the clinical phenotype
(cerebellar ataxia, recurrent lower airway infections), immunological profile (humoral and
cellular deficiency), elevation of AFP, and biallelic mutations of the ATM gene, the
diagnosis of ataxia telangiectasia was established (Figure 2).
Figure 2. Timeline from disease onset to definitive diagnosis.
At the age of seven, the patient did not report serious infections. His immunologic
profile was stable; replacement therapy and prophylaxis against opportunistic infections
were continued. At the neurological examination, the postural instability had worsened,
with difficulty in maintaining both standing and sitting positions. Walking was
discontinuous with a mowing appearance. The child displayed dysarthria, with slow and
slurred speech, initial signs of oculomotor apraxia, and initial conjunctival telangiectasias.
3. Discussion
Ataxia telangiectasia is an autosomal recessive disorder characterized by progressive
cerebellar degeneration, immunodeficiency, radiosensitivity, and cancer susceptibility.
The prevalence of the disease is estimated to be less than 1–9:100,000 individuals, and the
incidence ranges from 1:40,000 to 1:300,000 [1]. AT is caused by a recessive biallelic
mutation in the ataxia-telangiectasia-mutated (ATM) gene [2].
This gene, located on chromosome 11q22-23, encodes a protein kinase involved in the
repair of errors during DNA duplication and in the control of the cell cycle [1]. The
absence of ATM protein prevents DNA double-strand breaks (DSBs) from being repaired
by mediating early cellular responses to DSBs, generated during metabolic processes or
by DNA-damaging agents [2]. It also activates cell cycle checkpoints and induces
Figure 2. Timeline from disease onset to definitive diagnosis.
At the age of seven, the patient did not report serious infections. His immunologic
profile was stable; replacement therapy and prophylaxis against opportunistic infections
were continued. At the neurological examination, the postural instability had worsened,
with difficulty in maintaining both standing and sitting positions. Walking was discontin-
uous with a mowing appearance. The child displayed dysarthria, with slow and slurred
speech, initial signs of oculomotor apraxia, and initial conjunctival telangiectasias.
3. Discussion
Ataxia telangiectasia is an autosomal recessive disorder characterized by progressive
cerebellar degeneration, immunodeficiency, radiosensitivity, and cancer susceptibility.
The prevalence of the disease is estimated to be less than 1–9:100,000 individuals, and
the incidence ranges from 1:40,000 to 1:300,000 [
1
]. AT is caused by a recessive biallelic
mutation in the ataxia-telangiectasia-mutated (ATM) gene [2].
This gene, located on chromosome 11q22-23, encodes a protein kinase involved in
the repair of errors during DNA duplication and in the control of the cell cycle [
1
]. The
absence of ATM protein prevents DNA double-strand breaks (DSBs) from being repaired
by mediating early cellular responses to DSBs, generated during metabolic processes or by
DNA-damaging agents [
2
]. It also activates cell cycle checkpoints and induces apoptosis in
response to DSBs [
2
,
3
]. The role of ATM-mediated checkpoints in blocking the long-term
persistence and transmission of un-repaired DSBs in developing lymphocytes has been
highlighted [
3
]. Moreover, its mutation causes genomic instability, which implies radiosen-
sitivity, neurodegeneration, immunodeficiency, and cancer susceptibility [
4
]. Ataxia is the

J. Clin. Med. 2023,12, 6041 4 of 11
main neurological sign of the disease and is usually the first clinical manifestation that
occurs in childhood. The first symptoms in the form of truncal ataxia are seen usually in the
first year of life as excessive instability of the truncus and of the head in sitting and standing
posture, mild to moderate proximal hypotonia, and executive slowness in the upper limbs
and the manipulation of objects. The onset of walking can be characterized by an ataxic
gait with an enlarged base. Ataxia is progressive; at the beginning of the second decade
of age, most children must rely on a wheelchair. During the disease course, involuntary
movements such as chorea, athetosis, dystonia, and myoclonia [
1
] and progressive speaking
difficulties may appear. At school, patients have difficulties in reading, due to a lack of
coordination of eye movements, and in the finer motor functions such as writing or the
use of utensils for eating [
1
,
4
]. With advancing age, patients manifest weakness, muscular
atrophy, sensory deficit, absent deep reflexes, and peripheral neuropathy [5].
The other AT cardinal neurologic sign is oculomotor apraxia, with variable onset but
present in almost all patients. MRI demonstrates the diffuse and progressive degeneration
or atrophy of the cerebellar vermis and hemispheres [
6
]. Positron emission tomography
(PET) imaging shows a reduction in glucose metabolism in the cerebellum and its increase
in the globus pallidus, underlying the reduction in motor performance [
1
]. Telangiectasias
on the bulbar conjunctiva is the second pathognomonic sign of the disease, which generally
appears after the onset of ataxia, at 5–8 years of age [
7
], without impairing vision [
1
]. It can
also occur in the sun-exposed areas of the skin, such as the face and ears. Cardiovascular
defects, growth retardation, multiple endocrine dysfunction, premature aging, and insulin
resistance are often included in the complex clinical picture of AT patients [1,4].
Immunodeficiency is present in approximately 60% of patients, involving both cellular
and humoral immunity with variable degrees of severity. The most common abnormalities
are low levels of one or more isotypes of immunoglobulins, failure to generate a specific
antibody response to vaccines, and lymphopenia, especially affecting T lymphocytes. A
small percentage of AT patients may have elevated levels of IgM in combination with IgG
and/or IgA deficiency. IgE levels are also reduced. The anomalies of cellular immunity
are heterogeneous, including a reduction in the cell subsets CD3+, CD4+, and CD45+ cells,
whereas CD8+ cells are usually normal or slightly increased [
8
]. The T cell repertoire is
limited, and the mitogen response and cytokine production are poor. For most patients,
the pattern of immunodeficiency observed in early life persists throughout the lifetime;
therefore, immunological analyses must be monitored unless the individual develops
severe infections [
9
], as these remain the primary cause of death in AT patients despite early
and aggressive treatment. Interestingly, a recent paper indicates the feasibility of using
the TREC/KREC assay for early AT detection [10]. Immunodeficiency underlies a clinical
picture characterized by recurrent, mainly sino-pulmonary, infections that become chronic
in one third of patients, leading to bronchiectasis, pulmonary fibrosis, and interstitial lung
disease (ILD). Interestingly, an association between elevated serum IL-6 and IL-8 levels and
a reduction in lung function has been found in AT, suggesting that the evaluation of these
parameters allows one to identify patients who are more susceptible to developing chronic
lung disease [11].
Additionally, cutaneous granulomas are a recognized phenomenon in AT, with extra-
dermal manifestations rarely found in bone and synovial fluid [12].
AT patients are more susceptible to ionizing radiation and have a higher incidence of
cancer (approximately 25% lifetime risk). Lymphomas and leukemia often occur in people
aged under 20 years, while adults are susceptible to both lymphoid and solid tumors
including breast, liver, gastric, and esophageal cancers. It has been reported that residual
ATM kinase activity suggests a protective effect against the development of cancer in AT
childhood [13].
The current treatment modalities for AT involve symptomatic and supportive care and
require a multidisciplinary approach for both pharmacological and non-pharmacological
interventions [
14
]. Neurological manifestations progress and compel the patients to use a
wheelchair at the beginning of the first decade. In some cases, a modest improvement can be

J. Clin. Med. 2023,12, 6041 5 of 11
obtained with the use of L-Dopa, dopamine agonists, and, occasionally, anticholinergics [
15
].
A short-term improvement in ataxia can be obtained using steroids [
16
]. Short-term
beneficial effects on neurological symptoms (as evidenced by the assessment of neurological
impairment rating scales) with the use of betamethasone have been reported [
17
]. To
avoid the adverse long-term effects of steroid administration, an innovative method of
delivering the drug, by incorporating dexamethasone within autologous erythrocytes, was
developed [17].
The knowledge that chronic inflammation and immune activation mediate the neu-
rodegenerative process and the multisystemic damage of AT patients has suggested promis-
ing experimental and clinical therapeutic strategies. This is based on the hypothesis that
pharmacologically targeting proinflammatory markers can contribute to preventing the
progression of inflammation and cancer [
16
]. Furthermore, timely AT diagnosis will allow
the prevention of the development of severe infections and improve quality of life, as well
as commencing genetic counselling of the family and implementing cancer prevention
measures [18].
The Differential Diagnosis
Ataxia telangiectasia is a very rare disease; the differential diagnosis includes essen-
tially three disorders: cerebral palsy, congenital ocular motor apraxia, and Friedreich’s
ataxia. Cerebral palsy is caused by the malformation or early damage of cerebellar struc-
tures and describes a non-progressive disorder of motor function, resulting in ataxic palsy
in approximately 5–10% of all cases of cerebral palsy. These patients present with a decrease
in muscle tone and experience difficulties in movement coordination, being the intention
tremor the most common manifestation [
19
]. Congenital ocular motor apraxia (COMA)
is a rare delayed developmental disorder of the visual saccades. COMA arises early and
improves over time, whereas, in AT patients, similar saccadic difficulties worsen typically in
early school age [
20
]. Friedreich’s ataxia (FRDA) is the most prevalent autosomal recessive
cerebellar ataxia and the most common genetic cause of ataxia in children, starting typically
between 10 and 15 years of age. Unlike FRDA, AT patients have telangiectasias, oculomotor
apraxia, early absence of tendon reflexes, and an elevated level of AFP [
21
]. Since, in the
presenting case, AT arose with a clinical picture compatible with an inborn error, leading to
an initial diagnosis of combined immunodeficiency of unknown etiology, we focused on
primary immune defects whose clinical phenotype included neurologic manifestations, to
contribute to the improvement of the differential diagnosis process. The definition of several
inborn errors of immunity—ataxia-telangiectasia-like disorder (ATLD), adenosine deam-
inase (ADA) deficiency, purine nucleoside phosphorylase (PNP) deficiency, Nijemegen
breakage syndrome (NBS), DNA ligase IV deficiency (LIG4), Cernumnos/XLF deficiency,
common variable immunodeficiency disease (CVID), immunodeficiency centromeric region
instability and facial anomalies syndrome (ICF), Riddle syndrome, Hoyeraal–Hreidarsson
syndrome (HHS), phosphoglucomutase 3 (PGM3) deficiency), and chronic granulomatous
disease (CGD)—is based on the International Union of Immunological Societies: Update
2019 Primary Immunodeficiency Disease Committee Report on Inborn errors of Immu-
nity [22,23].
Ataxia-telangiectasia-like disorder is a very rare disease due to mutations in the MRE11
gene, which is involved in DNA repair. The encoded Mre11 protein is biochemically linked
to the ATM protein. It is a part, together with NBN and RAD50, of the trimeric protein
complex MRN. The MRN complex has a direct role in DNA repair by both homologous
recombination and non-homologous end-joining repair pathways, and it is also involved
in the activation of ATM, and thus in the triggering of cell cycle checkpoints [
24
]. Patients
present with a neurological picture, including involuntary movements and central and
peripheral neuropathy, whose symptoms arise later and progress slower than AT. Moreover,
they do not develop telangiectasias; the
α
-fetoprotein level is normal and immunological
abnormalities are milder than those observed in AT [24].

J. Clin. Med. 2023,12, 6041 6 of 11
Adenosine deaminase (ADA) deficiency is a severe CID due to an autosomal recessive
mutation in the ADA gene, which encodes adenosine deaminase, an enzyme essential for
the deamination of adenosine and deoxyadenosine in the purine salvage pathway [
25
].
Impaired enzyme function results in the accumulation of toxic metabolites, adenosine,
deoxyadenosine, and deoxyadenosine triphosphate (dATP). dATP inhibits ribonucleotide
reductase, a critical enzyme for DNA synthesis. The clinical phenotype of ADA patients is
characterized by recurrent severe infections, skeletal abnormalities, hepatic and renal dis-
eases, behavioral disorders, and autoimmune diseases [
25
,
26
]. Neurological manifestations
include ataxia, motor dysfunction, hypotonia, nystagmus, development delay, cognitive
impairment, reduced verbal expression, learning disability, hyperactivity, attention deficit,
seizure, and sensorineural deafness [
26
]. The immunological findings include lymphopenia
and the impairment of both cellular and humoral immunity due to abnormal T, B, and NK
cell development and function. Ataxia, as the predominant sign of AT, is decisive in the
differential diagnosis. The extra-neurological manifestations, especially skeletal abnormali-
ties; brain MRI images revealing leukoencephalopathy; and the dilation of either ventricles
or subarachnoidal spaces are of additional help in the differential diagnosis approach.
Purine nucleoside phosphorylase (PNP) deficiency is caused by an autosomal recessive
mutation of the PNP gene, which encodes an enzyme playing an essential role in the purine
salvage pathway [
27
]. The PNP mutations result in the accumulation of purine metabo-
lites, which are toxic for lymphocytes [
27
]. PNP-deficient patients typically present with
recurrent and unusual infections involving the respiratory and gastrointestinal systems;
two thirds of patients suffer from neurologic abnormalities and one third from autoim-
mune disorders [
28
]. Neurological symptoms include ataxia, motor system dysfunction,
cerebral palsy, hyper/hypotonia, spastic paresis, disequilibrium, development delay, cogni-
tive impairment, and behavioral disorders [
27
,
29
]. Patients show lymphopenia with low
CD3+, CD4+, and CD8+ lymphocyte subsets; immunoglobulin levels and B cell function
may be affected to variable degrees [
28
]. Despite the clinical similarities, the elevation of
α-fetoprotein and the finding of cerebellar atrophy orient towards the diagnosis of AT.
Nijmegen breakage syndrome is a rare, autosomal recessive disease resulting from a
mutation in the nibrin (NBN) gene. The protein encoded (nibrin) is one of the three major
components, together with MRE11 and RAD50, of the MRN complex. Patients present
with microcephaly, cognitive development delay, behavioral or psychiatric disorders, and
other clinical abnormalities described in detail in Table 1, but do not share ataxia and
telangiectasias with AT. The immunodeficiency is more severe than in AT. Laboratory
examinations show panhypogammaglobulinemia, profound T cell cytopenia, and a reduced
T cell response to mitogens. Moreover, patients are at high risk of developing lymphoid
malignancies [30].
DNA ligase IV deficiency is an autosomal recessive disease caused by hypomorphic
mutations in the DNA ligase IV gene, encoding a key component of the non-homologous
end-joining (NHEJ) pathway, the principal pathway employed to repair double-stranded
DNA breakage. The affected patients present with microcephaly, ataxia, growth, and
cognitive delays; the presence of facial dysmorphisms and bone deformities may help in the
AT differential diagnosis [
31
]. Immune abnormalities may range from a clinical phenotype
compatible with CID to a milder presentation with various degrees of lymphopenia and
hypogammaglobulinemia, underlying the appearance of severe recurrent infections and an
increased risk for lymphoid malignancies [32].
Cernunnos/XLF deficiency is a very rare autosomal recessive syndrome due to a mutation
of the NHEJ1 gene (2q35), which interacts closely with LIG4 and has a similar clinical
phenotype [
33
]. Patients present with profound microcephaly, developmental delay, facies
dysmorphisms, and recurrent infections. Immune findings range from mild to severe B
and T lymphopenia (NK cells are normal) and hypogammaglobulinemia (low IgG and IgA
isotypes) with normal or increased IgM levels [33].

J. Clin. Med. 2023,12, 6041 7 of 11
Table 1. Inborn errors of immunity with neurologic features: the differential diagnosis with ATP.
Similarities in Clinical and Laboratory
Features with AT
Differentiating Features Not Commonly
Observed in AT
Ataxia-Telangiectasia-like
Disorders (ATDL)
-Ataxia
-Involuntary movements (tremor, chorea,
dystonia)
-Central/peripheral neuropathy
-Late onset
-Less severe phenotype, slow progression
-Telangiectasias, immunodeficiency, AFP
increase rarely present
Adenosine Deaminase (ADA)
Deficiency
-Ataxia
-Motor dysfunction
-Hypotonia
-Combined immunodeficiency, recurrent severe
infections
-Neurocognitive delay, epilepsy
-Sensorineural deafness
-Skeletal abnormalities
-Normal AFP level
-Brain MRI: leukoencephalopathy, dilatation of
ventricles and subarachnoid spaces
Purine Nucleoside
Phosphorylase (PNP)
Deficiency
-Ataxia
-Involuntary movements (tremor, chorea,
dystonia)
-Hyper/hypotonia
-T cell lymphopenia, recurrent, unusual
infections
-Autoimmune disorders (one third of patients)
-Delay in neurocognitive development
-Sensorineural deafness
-Normal level of AFP
-Brain MRI: absence of cerebellar atrophy
Nijmegen Breakage
Syndrome (NBS)
-Severe combined immunodeficiency, severe
infections
-Radiosensitivity
-Increased susceptibility to lymphoid
malignancies
-Intrauterine growth retardation
-Microcephaly
-Facial dysmorphism (mid-facial prominence
accentuated by the obliquity of the forehead
and the receding jaw)
-Neurocognitive delay, behavioral disorders
-Skeletal abnormalities (clinodactyly of the fifth
finger and partial syndactyly of the second and
third toes)
DNA Ligase IV
Deficiency (LIG4)
-Ataxia
-Growth delay
-Microcephaly, facial dysmorphisms, bone
deformations
-Cognitive delay, learning difficulties
-Skin abnormalities (psoriasis, eczema,
erythroderma)
Cerunnos/XLF Deficiency -Recurrent infections
-Lymphopenia, hypogammaglobulinemia
-Microcephaly
-Dysmorphic features, including “bird-like”
facial dysmorphism
Riddle Syndrome
-Mild motor control
-Ataxia
-Conjunctival teleangectasias
-Radiosensitivity and cancer susceptibility
-Combined immunodeficiency
-Recurrent infections
-Increase in AFP
-Psychomotor retardation
-Atopy, serum IgE elevation
-Sensorineural hearing loss
Hoyeraal–Hreidarsson
Syndrome (HHS)
-Ataxia
-Hypotonia
-Progressive combined immunodeficiency
-Prenatal growth retardation
-Microcephaly
-Neurocognitive delay
-Epilepsy
-Pancytopenia
-Hyperpigmentation, nail dystrophy
-Premalignant leukoplakia oral and
gastrointestinal
Immunodeficiency,
Centromeric Region Instability
and Facial Anomalies
Syndrome (ICF)
-Ataxia
-Hypotonia
-Hypo/agammaglobulinemia, decrease in T
cell count (half of cases)
-Psychomotor delay
-Facial abnormalities: hypertelorism and
epicant folds, micrognathia, low ear
implantation, and macroglossia
-Macrocephaly

J. Clin. Med. 2023,12, 6041 8 of 11
Table 1. Cont.
Similarities in Clinical and Laboratory
Features with AT
Differentiating Features Not Commonly
Observed in AT
Common Variable
Immunodeficiency
Disease (CVID)
-Humoral immunodeficiency, recurrent
infections
-Ataxia, dysarthria, tremor
-Paraesthesia
-Myoclonic dystonia
-Entheropathy
-Vitamin E deficiency
-Guillain BarréSyndrome
Phosphoglucomutase 3
(PGM3) Deficiency
-Ataxia, hypotonia, dysarthria
-Thymic dysfunction, recurrent infections
-Cancer susceptibility
-Retinitis pigmentosa
Chronic Granulomatous
Disease (CGD)
-CNS granulomatous disease
-Cutaneous granulomas, chronic inflammation
-Recurrent severe infections
-Defective bactericidal function
-Hypergammaglobulinemia
-Normal level of AFP
Riddle syndrome is a rare autosomal recessive syndrome due to mutations in the gene
RNF168, encoding an E3 ubiquitin ligase protein involved in DNA double-strand break
repair. Its clinical profile includes mild motor control and ataxia, conjunctival telangiectasis,
and recurrent infections [34].
Hoyeraal–Hreidarsson syndrome is an X-linked syndrome caused by mutations in
the DKC1 gene (Xq28), encoding the nucleolar protein dyskerin, that interacts with the
human telomerase RNA complex. The neurologic manifestations include microcephaly
ataxia, epilepsy, and delays in neurocognitive development. Hyperpigmentation, nail
dystrophy, oral mucocutaneous lesions, and the early onset of bone marrow failure resulting
in pancytopenia differentiate the syndrome from AT. The immunologic profile shows a
progressive combined immunodeficiency [35].
Immunodeficiency centromeric region instability and facial anomalies syndrome is a
rare autosomal recessive disease due to mutations in a DNA methyltransferase gene [
36
]
and characterized by specific chromosomal rearrangements targeted adjacent to the cen-
tromeric region of chromosome 1 and/or 16. Patients suffer from neurologic manifestations
including ataxia, hypotonia, and psychomotor delay [
36
]. The presence of dysmorphic
facial features (see Table 1), macrocephaly, and, in many cases, of growth failure differenti-
ates ICF from AT. Laboratory investigations show, in most cases, hypogammaglobulinemia
with a normal B cell count; T cells are decreased in approximately half of the patients [37].
Common variable immunodeficiency disease (CVID) is an immune disorder char-
acterized by low levels of protective antibodies and a wide spectrum of clinical manifes-
tations due to immunodeficiency and immune dysregulation. Neurologic dysfunction
is less frequently reported in CVID and its complex nature includes infectious, autoim-
mune/inflammatory, and vascular origins. CVID’s neurologic manifestations similar to
AT are related to free-radical-mediated neuronal damage due to vitamin E deficiency and
include ataxia, hyporeflexia, paresthesia, and rarely myoclonic dystonia [38].
Phosphoglucomutase 3 (PGM3) deficiency is an autosomal recessive form of hyper-IgE
syndrome (HIES), due to hypomorphic PGM3 gene mutations, encoding for PGM3, which
is involved in the protein glycosylation pathway, and it causes a multisystem phenotype.
Patients present with early onset of neurological impairment, including ataxia, hypotonia
(see Table 1), and the clinical triad of the HIES phenotype: recurrent pneumonia, recurrent
skin abscesses, and highly elevated serum IgE [39].
Chronic granulomatous disease (CGD) is the most common inherited phagocytic cell
defect, leading to impaired microbicidal function. It is caused by mutations of genes encod-
ing the subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
(PHOX) complex: gp91phox (X-linked form), p22phox, p47phox, and p67pxox (autosomal
and recessive forms), whose deficiency results in a defect in superoxide production. The
clinical picture is characterized by recurrent life-threatening bacterial and fungal infections

J. Clin. Med. 2023,12, 6041 9 of 11
and tissue granuloma formation, which rarely affects the central nervous system (CNS),
resulting in CNS granulomatous disease [40].
4. Conclusions
Ataxia telangiectasia (AT) is a multisystemic neurodegenerative disease with pro-
gressive evolution. The onset time of the different manifestations and the rapidity of
progression of the disease lead to phenotypic variability in its presentation in childhood.
When immunodeficiency is the first feature, in the absence of the cardinal clinical neurolog-
ical signs, the diagnosis is extremely challenging. An immunological profile that should
raise suspicion is preferably the T(
−
) B(
−
) NK(+) CID phenotype with preserved NK cell
count (NK cells do not undergo V(D)J recombination) and raised IgM. Neurological mani-
festations may appear later than recurrent infections, leading to misdiagnosis or delayed
diagnosis. Therefore, the physical examination of a child with clinical manifestations of
immunodeficiency, immune dysregulation, or malignancy needs to include an accurate
neurologic evaluation. Similarly, strong suspicion of an underlying immune defect is
relevant in any case of a clinical picture arising with a neurological pattern associated with
or followed by severe, recurrent, or unusual infections. In patients presenting with features
of immunodeficiency and neurological involvement, the laboratory routine must include,
together with the immunological profile, AFP analysis. The diagnosis of radiosensitivity
is difficult and available in only a few laboratories. Regarding this issue, we provide a
review of the primitive inborn defects associated with neurological signs, to contribute to
untangling the complex diagnostic procedure of the patient with AT, before the key signs
of the disease are overall expressed.
Author Contributions:
F.C., S.D., G.C. and S.C. drafted the original paper, which was critically
revised by A.B., A.O., D.P. and R.C. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement:
Written informed consent has been obtained from the patient to
publish this paper.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Rothblum-Oviatt, C.; Wright, J.; Lefton-Greif, M.A.; McGrath-Morrow, S.A.; Crawford, T.O.; Lederman, H.M. Ataxia telangiectasia:
A review. Orphanet J. Rare Dis. 2016,11, 159. [CrossRef] [PubMed]
2.
Savitsky, K.; Bar-Shira, A.; Gilad, S.; Rotman, G.; Ziv, Y.; Vanagaite, L.; Tagle, D.A.; Smith, S.; Uziel, T.; Sfez, S.; et al. A single
ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995,268, 1749–1753. [CrossRef] [PubMed]
3.
Bredemeyer, A.L.; Sharma, G.G.; Huang, C.-Y.; Helmink, B.A.; Walker, L.M.; Khor, K.C.; Nuskey, B.; Sullivan, K.E.; Pandita, T.K.;
Bassing, C.H.; et al. ATM stabilizes DNA double-strand-break complexes during V(D)J recombination. Nature
2006
,442, 466–470.
[CrossRef] [PubMed]
4.
Alyasin, S.; Esmaeilzadeh, H.; Ebrahimi, N.; Nabavizadeh, S.H.; Nemati, H. Clinical Presentation of Ataxia-Telangiectasia. Arch.
Iran. Med. 2019,22, 682–686. [PubMed]
5.
van Os, N.J.; Chessa, L.; Weemaes, C.M.; van Deuren, M.; Fiévet, A.; van Gaalen, J.; Mahlaoui, N.; Roeleveld, N.; Schrader, C.;
Schindler, D.; et al. Genotype-phenotype correlations in ataxia telangiectasia patients with ATM c.3576G>A and c.8147T>C
mutations. J. Med. Genet. 2019,56, 308–316. [CrossRef]
6.
Sahama, I.; Sinclair, K.; Pannek, K.; Lavin, M.; Rose, S. Radiological imaging in ataxia telangiectasia: A review. Cerebellum
2014
,
13, 521–530. [CrossRef]
7.
Cabana, M.D.; Crawford, T.O.; Winkelstein, J.A.; Christensen, J.R.; Lederman, H.M. Consequences of the delayed diagnosis of
ataxia-telangiectasia. Pediatrics 1998,102, 98–100. [CrossRef]
8.
Bredemeyer, A.L.; Helmink, B.A.; Innes, C.L.; Calderon, B.; McGinnis, L.M.; Mahowald, G.K.; Gapud, E.J.; Walker, L.M.; Collins,
J.B.; Weaver, B.K.; et al. DNA double-strand breaks activate a multi-functional genetic program in developing lymphocytes.
Nature 2008,456, 819–823. [CrossRef]
9.
Nowak-Wegrzyn, A.; Crawford, T.O.; Winkelstein, J.A.; Carson, K.A.; Lederman, H.M. Immunodeficiency and infections in
ataxia-telangiectasia. J. Pediatr. 2004,144, 505–511. [CrossRef]

J. Clin. Med. 2023,12, 6041 10 of 11
10.
Boyarchuk, O.; Makukh, H.; Kostyuchenko, L.; Yarema, N.; Haiboniuk, I.; Kravets, V.; Shulhai, O.; Tretyak, B. TREC/KREC levels
in children with ataxia-telangiectasia. Immunol. Res. 2021,69, 436–444. [CrossRef]
11.
McGrath-Morrow, S.A.; Collaco, J.M.; Detrick, B.; Lederman, H.M. Serum Interleukin-6 Levels and Pulmonary Function in
Ataxia-Telangiectasia. J. Pediatr. 2016,171, 256–261.e1. [CrossRef] [PubMed]
12.
Paller, A.S.; Massey, R.B.; Curtis, M.A.; Pelachyk, J.M.; Dombrowski, H.C.; Leickly, F.E.; Swift, M. Cutaneous granulomatous
lesions in patients with ataxia-telangiectasia. J. Pediatr. 1991,119, 917–922. [CrossRef] [PubMed]
13.
Reiman, A.; Srinivasan, V.; Barone, G.; Last, J.I.; Wootton, L.L.; Davies, E.G.; Verhagen, M.M.; Willemsen, M.A.; Weemaes, C.M.;
Byrd, P.J.; et al. Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase
activity against childhood tumours. Br. J. Cancer 2011,105, 586–591. [CrossRef] [PubMed]
14.
van Os, N.J.; Haaxma, C.A.; van der Flier, M.; Merkus, P.J.; van Deuren, M.; de Groot, I.J.; Loeffen, J.; van de Warrenburg, B.P.;
Willemsen, M.A.; A-T Study Group. Ataxia-telangiectasia: Recommendations for multidisciplinary treatment. Dev. Med. Child.
Neurol. 2017,59, 680–689. [CrossRef] [PubMed]
15.
Lavin, M.F.; Gueven, N.; Bottle, S.; Gatti, R.A. Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia.
Br. Med. Bull. 2007,81–82, 129–147. [CrossRef] [PubMed]
16.
Biagiotti, S.; Bianchi, M.; Rossi, L.; Chessa, L.; Magnani, M. Activation of NRF2 by dexamethasone in ataxia telangiectasia cells
involves KEAP1 inhibition but not the inhibition of p38. PLoS ONE 2019,14, e0216668. [CrossRef]
17.
Buoni, S.; Zannolli, R.; Sorrentino, L.; Fois, A. Betamethasone and improvement symptoms in ataxia-telangiectasia. Arch. Neurol.
2006,63, 1479–1482. [CrossRef]
18.
Martire, B.; Azzari, C.; Badolato, R.; Canessa, C.; Cirillo, E.; Gallo, V.; Graziani, S.; Lorenzini, T.; Milito, C.; Panza, R.; et al.
Vaccination in immunocompromised host: Recommendations of Italian Primary Immunodeficiency Network Centers (IPINET).
Vaccine 2018,36, 3541–3554. [CrossRef]
19.
Herskind, A.; Greisen, G.; Nielsen, J.B. Early identification and intervention in cerebral palsy. Dev. Med. Child. Neurol.
2014
,57,
29–36. [CrossRef]
20.
Salman, M.S.; Ikeda, K.M. The syndrome of infantile-onset saccade initiation delay. Can. J. Neurol. Sci./J. Can. des Sci. Neurol.
2013
,
40, 235–240. [CrossRef]
21.
Anheim, M.; Tranchant, C.; Koenig, M. The autosomal recessive cerebellar ataxias. N. Engl. J. Med.
2012
,366, 636–646. [CrossRef]
22.
ESID Registry—Working Definitions for Clinical Diagnosis of PID 2019. Available online: https://esid.org/Working-Parties/
Registry-Working-Party/Diagnosis-criteria (accessed on 22 January 2019).
23.
Dehkordy, S.F.; Aghamohammadi, A.; Ochs, H.D.; Rezaei, N. Primary immunodeficiency diseases associated with neurologic
manifestations. J. Clin. Immunol. 2011,32, 1–24. [CrossRef]
24.
Taylor, A.M.; Groom, A.; Byrd, P.J. Ataxia-telangiectasia-like disorder (ATLD)—Its clinical presentation and molecular basis. DNA
Repair. 2004,3, 1219–1225. [CrossRef]
25.
Sauer, A.V.; Aiuti, A. New insights into the pathogenesis of adenosine deaminase-severe combined immunodeficiency and
progress in gene therapy. Curr. Opin. Allergy Clin. Immunol. 2009,9, 496–502. [CrossRef]
26.
Nofech-Mozes, Y.; Blaser, S.I.; Kobayashi, J.; Grunebaum, E.; Roifman, C.M. Neurologic abnormalities in patients with adenosine
deaminase deficiency. Pediatr. Neurol. 2007,37, 218–221. [CrossRef] [PubMed]
27.
Cohen, A.; Grunebaum, E.; Arpaia, E.; Roifman, C.M. Immunodeficiency caused by purine nucleotide phosphorylase deficiency.
Immunol. Allergy Clin. N. Am. 2000,20, 143–159. [CrossRef]
28.
Dalal, I.; Grunebaum, E.; Cohen, A.; Roifman, C. Two novel mutations in a purine nucleoside phosphorylase (PNP)-deficient
patient. Clin. Genet. 2001,59, 430–437. [CrossRef]
29.
Tabarki, B.; Yacoub, M.; Tlili, K.; Trabelsi, A.; Dogui, M.; Essoussi, A.S. Familial spastic paraplegia as the presenting manifestation
in patients with purine nucleoside phosphorylase deficiency. J. Child. Neurol. 2003,18, 140–141. [CrossRef] [PubMed]
30.
Digweed, M.; Sperling, K. Nijmegen breakage syndrome: Clinical manifestation of defective response to DNA double-strand
breaks. DNA Repair. 2004,3, 1207–1217. [CrossRef] [PubMed]
31. Chistiakov, D.A.; Voronova, N.V.; Chistiakov, A.P. Ligase IV syndrome. Eur. J. Med. Genet. 2009,52, 373–378. [CrossRef]
32.
Enders, A.; Fisch, P.; Schwarz, K.; Duffner, U.; Pannicke, U.; Nikolopoulos, E.; Peters, A.; Orlowska-Volk, M.; Schindler, D.;
Friedrich, W.; et al. A severe form of human combined immunodeficiency due to mutations in DNA ligase IV. J. Immunol.
2006
,
176, 5060–5068. [CrossRef] [PubMed]
33.
Buck, D.; Malivert, L.; de Chasseval, R.; Barraud, A.; Fondanèche, M.-C.; Sanal, O.; Plebani, A.; Stéphan, J.-L.; Hufnagel, M.; le
Deist, F.; et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly.
Cell 2006,124, 287–299. [CrossRef] [PubMed]
34.
Stewart, G.S.; Panier, S.; Townsend, K.; Al-Hakim, A.K.; Kolas, N.K.; Miller, E.S.; Nakada, S.; Ylanko, J.; Olivarius, S.; Mendez, M.;
et al. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell
2009
,136,
420–434. [CrossRef] [PubMed]
35.
Yang, C.R.; Wei, Q.; Jiang, M.; Zhang, X.B.; Zhang, Z.X.; Nong, G.M. Hoyeraal-Hreidarsson syndrome with combined immunode-
ficiency and enterocolitis caused by a DCK1 gene variant. Chin. J. Pediatr. 2022,60, 248–249.
36.
Hagleitner, M.M.; Lankester, A.; Maraschio, P.; Hulten, M.; Fryns, J.P.; Schuetz, C.; Gimelli, G.; Davies, E.G.; Gennery, A.;
Belohradsky, B.H.; et al. Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome).
J. Med. Genet. 2007,45, 93–99. [CrossRef]

J. Clin. Med. 2023,12, 6041 11 of 11
37.
Ehrlich, M. The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease. Clin. Immunol.
2003
,109,
17–28. [CrossRef]
38.
Nguyen, J.T.U.; Green, A.; Wilson, M.R.; DeRisi, J.L.; Gundling, K. Neurologic Complications of Common Variable Immunodefi-
ciency. J. Clin. Immunol. 2016,36, 793–800. [CrossRef]
39.
Sassi, A.; Lazaroski, S.; Wu, G.; Haslam, S.M.; Fliegauf, M.; Mellouli, F.; Patiroglu, T.; Unal, E.; Ozdemir, M.A.; Jouhadi, Z.; et al.
Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels. J.
Allergy Clin. Immunol. 2014,133, 1410–1419. [CrossRef]
40.
Dasovic, B.; Borys, E.; Schneck, M.J. Granulomatous Diseases of the Central Nervous System. Curr. Neurol. Neurosci. Rep.
2022
,22,
33–45. [CrossRef]
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