Ataxia-telangiectasia: case series review from Centro Hospitalar Universitário do Santo António

doi:10.21203/rs.3.rs-3124562/v1

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Systematic Review

Ataxia-telangiectasia: case series review from Centro Hospitalar Universitário do Santo António

https://doi.org/10.21203/rs.3.rs-3124562/v1

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Purpose: Characterize epidemiologically and clinically the individuals diagnosed with ataxia-telangiectasia (A-T), know the therapies performed and evaluate factors of worse prognosis.

Methods: Retrospective study, from clinical records of patients diagnosed with A-T in CHUdSA from 1992 to 2022, inclusive.

Results: The sample consists of 7 patients, 85.7% male. The mean age at diagnosis was 4.01 ± 1.76 years. The consanguinity rate was 42.9% and the mean BMI at diagnosis was 15.74kg/m². At diagnosis, cerebellar ataxia was present in 100% of patients, dysarthria in 57.1%, oculomotor apraxia in 42.9%, dystonia in 28.6%, and dysphagia in 14.3%. Telangiectasias were seen in 57.1% of cases and skin changes in 28.6%. Recurrent respiratory infections covered 57.1% of patients. The mean AFP at diagnosis was 95.28 ± 23.48 ng/ml, lymphopenia was observed in 57.1%, IgA absence in 100%, IgG deficit in 42.9%, and CD4+ T lymphocyte deficit in 100% of patients. At the time of the last evaluation, 100% had dysarthria, 85.7% had oculomotor apraxia and/or dysphagia, and 57.1% had dystonia. Also, 85.7% had telangiectasias and 71.4% had skin changes. Diabetes mellitus developed in 14.2% of patients. The mean age of gait loss was 15.75 ± 3.30 years and 57.1% of the cases were wheelchair dependent at the time of the last evaluation.

Conclusions: The results observed are mostly according to those described in the literature. In A-T, the prognosis varies according to the severity and presence of secondary complications, and it is crucial to act early to prevent them.

Ataxia-Telangiectasia

Ataxia telangiectasia mutated gene

Cerebellar Ataxia

Telangiectasia

Ataxia telangiectasia (A-T) is a rare and disabling disorder with a huge impact on the quality of life of children. It presents with severe neurological involvement, which is the disease's main hallmark. It progresses quite rapidly, with patients being wheelchair-dependent at a very young age. It has an average life expectancy of about 25 years.

What is New: We compared the clinical data at the date of diagnosis with the same data at the date of the last evaluation, which allowed us to understand its evolution. Cerebellar ataxia was described as being present in all cases at the time of diagnosis. It was found to be the most frequent reason for parents to seek medical help, noting that gait alteration is one of the factors of greatest concern in the child's development. Telangiectasias weren’t present in all patients at the last medical evaluation, which proves that this diagnosis must be considered even without the presence of telangiectasias, a disease hallmark. In this study, 3 patients presented with mild cerebellar atrophy, proving the disease's early neurological involvement. As this is one of the few clinical case series carried out in Portugal, we believe that it has contributed to a better understanding of the disease, allowing for future earlier diagnoses as well as preventing complications.

Ataxia-telangiectasia (A-T), or Louis-Bar Syndrome, is an autosomal recessive disease caused by mutations in the ataxia telangiectasia mutated (ATM) gene that causes genome instability. [1, 2] A-T is a rare genetic condition with an estimated incidence of 1:40,000 to 1:100,000 live births and affects both sexes equally. It is considered the second most common cause of autosomal recessive ataxia in pediatric age.[11] The ATM gene is in the chromosomal region 11q22-23 and encodes a protein kinase (ATM), playing an important role in DNA double-strand repair and, consequently, in the control of the cell cycle. [2, 4]

Cerebellar ataxia is described as the first manifestation of the disease, beginning in the first years of life. It is noticeable when children are in the sitting and when they start walking. [7, 11] They present a narrow-based gait, unlike most ataxias, with a tendency to accelerate the gait or even to run. [12] By the age of 10 to 15 years, most children are wheelchair-dependent.[5] Involuntary movements can be present as well as eye movement alterations, namely oculomotor apraxia.[3, 11, 12] Dysarthria is very common, interfering with interaction and communication abilities.[7] Telangiectasias are frequently at the bulbar conjunctiva but can also occur on the face, nose and ear.[5, 12]

Alterations in cellular and humoral immunity are very common, such as lymphopenia with low CD4 + T lymphocytes and a deficit of one or more classes of immunoglobulins. The most frequent immunodeficiencies are IgA and IgG deficiencies; however, IgM alterations may also exist.[3, 11]. Immunodeficiencies play a decisive role in the predisposition of these patients to infections. [7, 12] Elevated apha-fetoprotein (AFP) is very common and can suggest the diagnosis.[5, 12] Patients with A-T have a greater risk to develop cancer in the first two decades of life, particularly of lymphoid origin. They also have an increased risk of developing solid tumors after the age of 20, such as breast, gastric, and liver cancer. [11, 12] Growth retardation can be noticed by the low percentiles and can occur even before any other symptom. Diabetes mellitus can also develop as a consequence of higher insulin resistance. [9, 12]

In A-T, brain MRI is the method of choice, however, it may be normal in the early stages of the disease. Over time, it may show signs of diffuse cerebellar atrophy as a consequence of progressive neurodegeneration and Purkinje cell loss.[12, 13]

The diagnosis of A-T is based on high clinical and analytic suspicion and confirmed with the genetic test, where is identified the ATM mutation.[11] There is still no curative treatment, however, a symptomatic and supportive approach is crucial.[14] Multidisciplinary rehabilitation therapy, including physiotherapy and speech therapy, is the basis of treatment, providing a better quality of life for these patients.[12, 14] Immunoglobulin replacement therapy, antibiotics and vaccines are important to prevent respiratory infections in these patients. Studies have shown promising results after treatment with oral corticosteroids in these patients, with improvements in the motor performance of these individuals.[10]

A-T evolves rapidly and markedly, leading to a very poor prognosis. The average life expectancy is around 25 years, and considering the high immunological compromise, the main causes of death are progressive respiratory failure and cancer. [12, 14]

This study consists of a retrospective observational study of CHUdSA patients diagnosed with A-T between January 1992 and December 2022. During this period, 7 cases were diagnosed, and these were the cases analyzed.

Several demographic parameters were analyzed, including gender, age, weight percentiles, BMI, as well as the reason for the first visit, and follow-up time. The presence of a family history of A-T was assessed, as well as consanguinity relationships. Clinical manifestations were collected at the time of definitive diagnosis, such as the presence of ataxic gait, dysarthria, dysphagia, the presence of dystonia and oculomotor apraxia, as well as other changes on neurological examination. The appearance of telangiectasias and dermatological changes, diabetes mellitus, recurrent respiratory infections, and cancer were also evaluated. The same clinical data were collected at the time of the last medical appointment and compared with previous ones. Data were collected from the blood count (presence of lymphopenia and neutropenia), serological studies (AFP, IgA, IgG, IgM, CD3+, CD4+, CD8+, CD19+), genetic test and imaging tests (MRI). In addition, information regarding the therapeutic approach adopted and clinical evolution (gait loss, mortality) was collected at the date of the last evaluation.

From 1992 to 2022, 7 patients diagnosed with A-T at CHUdSA were identified. Table 1 shows that in a total of 7 cases, with ages ranging from 5 to 30 years, there was a predominance of males, with about 6 cases (85.7%). The mean age at diagnosis was 4.01 ± 1.76 years. Although none of the cases had a family history of A-T in siblings, about three cases (42.9%) reported consanguinity. Weight percentiles at diagnosis were described in six patients, with two (28.6%) between P3 and P15, three (42.9%) between P15-P50, and only one (14.3%) between P50 and P85. The mean BMI of the patients at diagnosis was about 15.74 kg/m².

From the analysis of Table 1, we conclude that gait ataxia was the most frequent reason for consultation, being described as the main complaint in all patients (100%). Recurrent infections and telangiectasis are described as other reasons for consultation in two patients (28.6%), coming second in the most frequent complaints. Other reasons include delayed growth and evidence of bronchiectasis, described by two patients, respectively.

Table 1 - Demographic characteristics and clinical data at the time of definitive diagnosis

Variables

Sex

Female

Male

(n=7)

14,3%

85,7%

Siblings with A-T

Yes

(n=7)

100%

Consanguinity

Yes

(n=7)

57,1%

42,9%

Pregnancy complications

Yes

(n=7)

100%

Weight Percentile

P3-15

P15-50

P50-85

(n=6)

33,3%

50,0%

16,7%

Reasons for consultation

Gait ataxia

Growth retardation

Bronchiectasis

Recurrent infections

Telangiectasias

100%

14,3%

28,6%

Mean

Definitive diagnosis age

4,01 ± 1,76 years

BMI

15,74 ± 2,07 kg/m²

Table 2 shows the clinical manifestations described at the time of the definitive diagnosis, where we can conclude that cerebellar ataxia was present in all patients (100%). Dysarthria was described in four patients (57.1%), oculomotor apraxia in three patients (42.9%), dystonia in two (28.6%), and dysphagia in only one case (14.3%). In addition to the neurological changes mentioned, three patients (42.9%) had toe walking, two had hypotonia (28.6%), and one patient (14.3%) had hyperreflexia.

Table 2 – Clinical manifestations at the time of definitive diagnosis

Variables	n	%
Cerebellar ataxia	7	100%
Dystonia	2	28,6%
Dysarthria	4	57,1%
Oculomotor apraxia	3	42,9%
Dysphagia	1	14,3%
Other neurologic changes: Toe walking Hypotonia Hyperreflexia MRI cerebellar atrophy	3 2 1 3	42,9% 28,6% 14,3% 42,9%
Telangiectasias	4	57,1%
Dermatological changes	2	28,6%
Recurrent respiratory infections	4	57,1%
Hematological malignancies	0	0%
Solid tumors	0	0%
Diabetes mellitus	0	0%

Telangiectasias (cutaneous or ocular) were observed in four cases (57.1%) and cutaneous alterations (café-au-lait spots; irregular melanic nevi) in two individuals (28.6%). Recurrent respiratory infections were described at the time of definitive diagnosis in four patients (57.1%).

The laboratory changes at diagnosis are shown in Table 3, where we can observe that AFP was high in all patients, with a mean value of 95.28 ± 23.48 ng/ml. The presence of lymphopenia was evaluated and was observed in four patients (57.1%). No patient presented neutropenia. Low levels of immunoglobulins were observed in all patients, where five of the cases (71.4%) had an absence of IgA and the rest had values within the reference of normality. In terms of IgG, only three individuals (42.9%) had decreased values. However, one of these patients had combined IgA and IgG deficiency. One patient (14.3%) with increased IgM was also reported. All patients (100%) had a CD4+ T-lymphocyte deficit at diagnosis. In six patients (85.7%) a CD3+ T-lymphocyte deficit was observed, in five patients (71.4%) a CD8+ T-lymphocyte deficit was observed, and in six cases (85.7%) a CD19+ B-lymphocyte deficit was observed. All individuals were genetically tested to obtain a definitive diagnosis, with a specific description of six of the mutations, described in Table 4. Brain MRI was also performed in all patients, and the presence of cerebellar atrophy was described in three cases (figure 1).

Table 3 – Analytical parameters at the date of definitive diagnosis

Variables

Lymphopenia

Yes

(n=7)

42,9%

57,1%

Neutropenia

Yes

(n=7)

100%

IgA

Absent

Normal

(n=7)

71,4%

28,6%

IgG

Low

Normal

(n=7)

42,9%

57,1%

IgM

Normal

Increased

(n=6)

83,3%

16,7%

CD3+ T lymphocytes

Low

Normal

(n=7)

85,7%

14,3%

CD4+ T lymphocytes

Low

Normal

(n=7)

100%

CD8+ T lymphocytes

Low

Normal

(n=7)

71,4%

28,6%

CD19+ B lymphocytes

Low

Increased

(n=7)

85,7%

14,3%

AFP

Increased

Normal

(n=7)

100%

ATM gene mutation

Present

Absent

(n=7)

100%

Mean

AFP

95,28 ± 23,48 ng/ml

Table 4 –ATM mutations

Case 1

Case 2

Case 3

Case 4

Case 5

Case 6

Case 7

c6677T>C (p.leu2226Pro)

exon 46

C.8292_8293Del (p.ser2764argfs*4)

exon 57

c.67C>T

(p.Arg23*)

homozygosity

c.3802delG (p.Val1268X)

exon 28

homozygosity

c.3802delG (p.val1268X)

exon 28

homozygosity

c.3049_3050ins26 (p.Gln1017LeufsX2)

exon 22

homozygosity

x+c56644C>T

exon 39

c6312G>A

exon 45

The evolution of symptoms was observed at the time of the last visit, as shown in Table 5. It was concluded that all patients (100%) had dysarthria, six cases (85.7%) had oculomotor apraxia and/or dysphagia, and four (57.1%) reported dystonia. Six patients (85.7%) had telangiectasias (ocular or cutaneous) and three patients eventually developed cutaneous manifestations (café-au-lait spots, hypopigmented macules and granulomas), making a total of five individuals (71.4%) with these alterations. The average follow-up period for these patients was 14.86 ± 8.71 years.

Table 5 – Clinical manifestations and clinical data at the date of the last consultation

Variables	n	%
Cerebellar ataxia	7	100%
Dystonia	4	57,1%
Dysarthria	7	100%
Oculomotor Apraxia	6	85,7%
Dysphagia	6	85,7%
Gait loss*	4	57,1%
Telangiectasias	6	85,7%
Dermatological changes	5	71,4%
Recurrent respiratory infections	2	28,6%
Hematological malignancies	0	0%
Solid tumors	0	0%
Diabetes mellitus	1	14,3%
Prophylactic antibiotic therapy	3	42,9%
Immunoglobulin replacement therapy	4	57,1%
Corticosteroids	3	42,9%
Speech therapy	3	42,9%
Physiotherapy	5	71,4%
Mortality**	1	14,3%
	Mean
Follow-up time	14,86 ± 8,71 years

* Mean age at gait loss: 15.75 ± 3.30 years

All patients were offered a multidisciplinary follow-up, and the development of type II diabetes mellitus was observed in one of the cases (14.3%), as seen in Table 5. At the time of the last medical evaluation, four patients (57.1%) had a complete loss of gait and were wheelchair dependent. One of the cases (14.3%) had partial loss of gait, using supportive instruments. The youngest patients (5 and 11 years old) still maintain the ability to move without support. The average age of gait loss is about 15.75 ± 3.30 years. One of the patients died at the age of 19 years after cardiorespiratory arrest associated with aspiration.

Considering that A-T still has no curative treatment, supportive treatment is essential. Table 5 shows the types of treatment carried out by patients at the time of the last assessment. Five patients (71.4%) were undergoing physiotherapy, and three of them were also using speech therapy. Of the seven, four patients (57.1%) were receiving immunoglobulin replacement therapy, and three of them were simultaneously receiving prophylactic antibiotic therapy. Three patients (42.9%) were on low-dose corticosteroid therapy.

This study allowed interesting conclusions to be drawn regarding clinical and laboratory findings. The affected sex ratio did not correspond to that described in the literature [11]; there was a significant male predominance, with a 6:1 ratio, when compared to females. This discrepancy was expected considering the small size of the study sample. The mean age at diagnosis was close to recent studies[6, 15], and the onset of symptoms was established months before diagnosis, as expected. However, it was not possible to accurately describe the period between the onset of symptoms and the definitive diagnosis. Low BMI and weight percentiles were observed at the time of definitive diagnosis, suggesting probable growth retardation, which is expected in these patients. [9]

The most relevant risk factor for the development of this disease was consanguinity, with a rate of 42.9%, lower than that described in previous studies[1, 2]. This finding allows us to conclude that in a population with increased rates of consanguineous relationships, the incidence of A-T may be higher compared to the general population. Although observed in other studies[1, 4, 11], no family history was found in siblings.

Our study confirms the variable clinical presentation of A-T and the early manifestation of neurological symptoms in the development of the disease.[2] Cerebellar ataxia was described as being present in all cases at the time of diagnosis, presenting with varying degrees of impairment of balance and coordination. This was found to be the most frequent reason for parents to seek medical help, noting that gait alteration is one of the factors of greatest concern in the child's development.

More than half of the patients reported the presence of telangiectasis, dysarthria, and recurrent infections at the time of diagnosis. The literature [7] describes the appearance of telangiectasias after the onset of ataxia, and it was effectively proven in this study, in at least two individuals, who developed telangiectasias in the follow-up of the disease. In patients who already had both symptoms at diagnosis, it was not possible to establish a chronological relationship between them. Dysarthria was present in all patients at the last follow-up visit, and it is considered one of the most common symptoms in this pathology, by the data presented in the literature and some studies.[1, 8, 11]

In this study, laboratory data at the time of diagnosis were evaluated and the existence of immunoglobulin deficit was described in all patients. As would be expected, given previous studies[1, 8, 11, 12], the most frequent change was the absence of IgA, followed by IgG deficit. In addition, deficits of CD3+, CD4+, CD8 + T lymphocytes, and CD19 + B lymphocytes were observed in most cases at diagnosis, demonstrating that immunodeficiency is an important factor in the predisposition of these patients to recurrent infections, given its implication at the level of humoral and cellular immunity. The infections described in this study are present in a large majority at diagnosis and are still among the reasons for visiting the clinic. In A-T, the prognosis varies according to the severity of the disease and the presence of secondary complications. Thus, the presence of recurrent infections may suggest a more severe immune dysfunction and consequently be associated with a worse outcome.

In this study, all patients had ATM gene mutations, which coincides with the well-established genetic etiology of the disease. Furthermore, the fact that there are several mutations may have important implications for genetic counseling and individualized treatment of these individuals. Genetic counseling is a key step in the approach to A-T and should be suggested to patients and individuals with a family history of the disease. It aims to provide information about the disease and its evolution, as well as the risk of recurrence in future generations.

The cerebellar atrophy found is consistent with the data in the current literature.[1, 5] Thus, it is possible to consider MRI as a useful tool not only in supporting the diagnosis but also in the follow-up of these patients.

Although the development of solid tumors and hematological cancer has not been observed, these patients must be regularly followed up to allow for early detection of any signs of malignancy.

Currently, there is no curative treatment for A-T, however, given the severity of this pathology, supportive treatment is considered essential. It was verified that the loss of mobility and the great dependence that it entails is the greatest constraint on the quality of life of these patients. The average age of gait loss in this study was around 15.8 years, suggesting a very rapid progression of the disease. In this sense, physiotherapy is one of the main pillars of treatment, aiming at delaying gait loss and total dependence on a wheelchair. In addition, it can act at the level of dysphagia, allowing better comfort for the patient, and reducing the risk of aspiration and consequent associated infections. This study also allowed us to understand that dysarthria is quite prevalent and disabling. Given the relevance of communication skills in establishing social and family relationships, speech therapy is crucial, especially if started early, enabling these patients to have a better quality of life. Immunoglobulin replacement treatment and prophylactic antibiotic therapy are very important in the approach to this pathology, essentially regarding the prevention of recurrent infections, one of the main causes of mortality in these patients. Therapy with corticosteroids has, according to studies [3], some impact on motor performance. In addition to therapy, all patients should receive multidisciplinary follow-up and be monitored for the development of neoplasms and other complications.

A-T has a very rapid evolution, leading to a poor prognosis, with a medical life expectancy of 25 years. The present study presents three patients between 24 and 30 years of age, in agreement with the published literature. However, the death of one of the patients at 19 years of age was described, demonstrating the disease's severity and the occurrence of fatal complications.

This study characterizes the main clinical manifestations of A-T, demonstrating its variability and long-term evolution. It emphasizes the importance of diagnosis and consequent early therapeutic intervention to provide patients with a better quality of life. A-T requires multidisciplinary care and constant monitoring, to prevent complications and reduce the speed of disease progression.

One of the major limitations of this study is the small sample size, which limits the ability to generalize the results. However, despite the observed limitations, we were able to better understand patients diagnosed with A-T at CHUdSA, its complications, and the implication of the disease on their quality of life, as well as the treatments adopted.

Considering that A-T is a neurodegenerative disease, it would be relevant to study its progression through a longitudinal prospective study with a regular medical evaluation to evaluate the treatments performed and their consequent impact on patient's lives. One of the most important goals for future studies would be to develop new treatments to improve patient's quality of life and, ideally, to reverse disease progression.

AFP	Alpha-fetoprotein
A-T	Ataxia-telangiectasia
ATM	Ataxia-telangiectasia mutated
BMI	Body mass index
CHUdSA	Centro Hospitalar Universitário do Santo António
DNA	Deoxyribonucleic Acid
ESID	European Society for Immunodeficiencies
IgA	Immunoglobulin A
IgG	Immunoglobulin G
IgM	Immunoglobulin M
MRI	Magnetic Resonance Imaging

Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Ethical approval: This is a retrospective and observational study. Approval was granted by the Ethics Committee of Centro Hospitalar Universitário do Santo António.

Consent to participate: Informed consent is not applicable.

Conflict of interest: The authors have no relevant financial or non-financial interests to disclose.

Authors contribution: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Carlota Gomes de Almeida. All authors read and approved the final manuscript.

Availability of data and materials: 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 ethical restrictions.

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No competing interests reported.

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Ataxia-telangiectasia: case series review from Centro Hospitalar Universitário do Santo António

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