The classical form of A-T presents early during the first decade. Usually, ataxia is the first noticeable sign. In particular, it can be noticed as instability of the trunk when toddlers are sitting or as an unstable gait. Because of the ataxia, patients often need a wheelchair accessible vehicle by the age of 10. As the disease progresses, dysarthria and oculomotor apraxia manifest, sometimes affecting vision and reading skills that can impact children during their first years of school. Nystagmus, saccadic intrusions, and hypometric saccades can be present as well. 

Telangiectasias, which is the other distinctive feature of the disease, are present in almost all cases. They usually become evident after the age of 6. Telangiectasias occur most frequently in the eyes, in particular in the conjunctiva, and/or in sun-exposed areas (such as face and ears).[6]. They can also be found in the brain and the bladder.[7] Telangiectasias do not evolve and do not tend to bleed. Other skin manifestations previously reported in these patients are premature aging and cutaneous graying.

Not infrequently, other neurological manifestations can be present. In particular, basal ganglia involvement is common, manifesting with tremor, parkinsonism, chorea, dystonia, and myoclonus. Axonal neuropathy is part of the clinical picture of A-T as well.[8] This latter may be responsible for the orthopedic abnormalities frequently observed in these patients. Mild to moderate cognitive impairment have been reported and can affect different domains, such as language, memory, and executive functions. However, these symptoms can be variably present and show a wide spectrum of the degree in severity.[9].

Immunological impairment is common, affecting about two-thirds of cases. Usually, patients present with low IgA and IgG levels, with variable IgM, which can be either low or high, together with low total CD4 cells count.[10] The immunodeficiency predisposes to recurrent infections, in particular, sinopulmonary infections, as well as to autoimmune and chronic inflammatory diseases. However, autoimmune deficiency is not progressive over time. The combination of recurrent pulmonary infections and restrictive pulmonary disease which are common in these patients can end up in bronchiectasis and interstitial lung diseases.[11]

About 25% to 30% of patients with A-T will develop a tumor. Most frequently leukemia and lymphoma arise early in life. Later on, solid tumors such as breast and ovarian cancer, melanomas, gastric, or liver tumors can present.[12] Tumors can also be associated with the severe radiosensitivity. In particular, x-ray and gamma-ray but not ultraviolet (UV) have been reported to be detrimental in A-T patients, and therefore, should be avoided.

Insulin resistance or diabetes, as well as hypercholesterolemia and steatosis, can be present, especially later in the course of the disease. The endocrine system can also be involved in growth hormone deficiency, resulting in short stature and failure to grow, and gonadal failure, causing infertility.[13] Both of these symptoms are more frequent in females. Microcephaly has been reported as well.

Variant Forms

Some authors reported adult-onset form of A-T which are characterized by a much milder phenotype that manifests later in life and progresses slowly. An intermediate phenotype which still presents during the first or second decade but is milder in course has also been reported. [14]

Ataxia-Telangiectasia-Like Phenotypes

Different genetic mutations have been found in patients with a phenotypic presentation similar to A-T.[15]

In particular, mutations of the genes NBS1 (nibrin) or MRE11, which encode for 2 proteins whose functions are strictly related to ATM, have been associated with diseases that resemble A-T. Nijmegen breakage syndrome, which is caused by the mutation of the NBS1 gene, is characterized by an increased risk of cancer, microcephaly and syndromic features, recurrent respiratory infections, and intellectual disability. Ataxia and telangiectasia are not present.

Ataxia-telangiectasia-like disorder 1 (ATLD1), instead, is caused by the genetic mutations of the MRE11 gene. This disorder can present with progressive ataxia, oculomotor apraxia, and dysarthria, but without telangiectasias. Moreover, the age of onset can be delayed compared to A-T, and the level of immunoglobulin in the peripheral blood is usually normal.

The diagnosis of A-T can be challenging due to the rarity of the disorder. The diagnosis is usually based on the following features:

Clinical Picture

Early onset of ataxia within the first decade in the classical form and oculomotor apraxia are usually crucial to narrow the diagnostic algorithm. The concomitant presence of tumors may raise the suspicion of A-T. The cohort of other symptoms, such as other neurological manifestations, the involvement of the immunological, pulmonary and endocrinological systems, can help in the diagnosis as well. 

Telangiectasias

Telangiectasias are present in almost all the patients, and therefore, are an important and almost unequivocal sign to make the correct diagnosis. However, telangiectasias are not always easy to recognize. Moreover, they can present in unusual locations, and therefore, can go undetected if not searched for attentively.

Neuroimaging

Cerebellar atrophy mostly involving the vermis is the cardinal radiological feature of this disease. Brain MRI is the best current imaging for these findings. Cerebellar atrophy becomes more prominent with age and may be absent early on. In older patients, white matter abnormalities have been reported as well.

Laboratory Tests

Elevation of the alpha-fetoprotein is a characteristic feature of A-T, even if it is not exclusive of this condition. Blood tests can also show a decrease in the total amount of IgG and IgA and variable levels of IgM.

Genetic Testing

The definitive diagnosis of A-T is reached through the detection of homozygous or compound heterozygous mutation of the ATM gene that can be reached through targeted sequencing of the gene, or though sequencing done as part of ataxia panels or whole exome sequencing. In case of a new gene variant, immunoblotting of the ATM protein can be performed to confirm whether the detected mutation causes a significant reduction of the levels of ATM.

The management of patients with A-T requires a multidisciplinary team since the disease presents with a great variety of manifestations.[16] A specific treatment to cure this disease is not available yet. Therefore, addressing the specific symptoms associated with the disease and surveillance to prevent complications is crucial

Neurological  Symptoms

Ataxia and other neurological manifestation can severely affect patients’ everyday life. Physical therapy and regular assessment for possible aids that may be needed are extremely important. One of the main goals of these assessments should be to prevent complications such as falls. Children usually require support at school because of the motor and cognitive impairment.

Cancer and Radiosensitivity 

Proper surveillance for breast and ovary cancer can be lifesaving. Hematological tumors cannot be prevented, but regular monitoring can allow early diagnosis. The treatment of these tumors is not different from the best standard of care approach; specific care must be considered due to the radiosensitivity of these patients.

Immunological Disease

Treatment of recurrent infections and prophylactic antibiotic administration, when required, have been able to prolong life expectancy in patients with A-T. Intravenous immunoglobulin has been considered a good option for these patients as well. While inactivated vaccinations have not been associated with complications in patients with A-T, live vaccines may be contraindicated, especially in the presence of a low T-cell count.

Complications secondary to restrictive lung disease must always be considered in case of anesthesia or surgery.[17] Pulmonary complications can be prevented with adequate surveillance of pulmonary function and prevention of recurrent respiratory infections.

Future Treatments 

Antioxidant, antisense morpholino oligonucleotides (AMO), aminoglycoside antibiotics that can affect ATM protein function, as well as different small molecules targeting the ATM gene to address tumorigenesis, have been tested. Most of these new therapeutic approaches are still under investigations.[18] Therapeutic trials are ongoing to test the efficacy of treatment with dexamethasone through innovative ways of delivery such patients’ autologous red blood cells loaded with dexamethasone (ATTeST study).

The main categories of diseases that must be considered in the differential diagnosis of A-T are as follows:

Recessive Forms of Ataxia

These disorders usually present an early age of onset, and no other family members are affected. Autosomal recessive disorders are more common in cases of consanguinity in the family. The list of autosomal recessive ataxia is very long, and the incidence of these disorders can vary in different populations. Among autosomal recessive ataxia, Friedreich’s ataxia can be easy misdiagnosed as A-T since both can present with early-onset cerebellar ataxia, polyneuropathy, and systemic involvement. The other autosomal recessive cerebellar ataxias can be grouped into metabolic disorder (such as abetalipoproteinemia, cerebrotendinous xanthomatosis, Refsum disease), congenital ataxias like Joubert syndrome, degenerative disease such as Charlevoix-Saguenay spastic ataxia, mitochondrial disorders like the myoclonic epilepsy with ragged-red fibers (MERRF), NARP syndrome (neuropathy, ataxia, retinitis pigmentosa), sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO), infantile-onset spinocerebellar ataxia (IOSCA), and Marinesco-Sjogren syndrome.[19]

Ataxia with Oculomotor Apraxia

Oculomotor apraxia is a distinctive sign of A-T. However, there are other disorders where this can be found. Ataxia with oculomotor apraxia types 1 and 2 (AOA1 and AOA2) are autosomal recessive ataxias characterized by an early age of onset. The systemic symptoms which are commonly found in patients with A-T are not characteristically seen in these other forms.[20]

Ataxia-Telangiectasia-Like Disorders (ATLD)

The disorders due to the mutations of the MRE11 gene and the NBS1 genes, associated with the ATDL1 and the Nijmegen breakage syndrome (NBS), should always be considered when assessing the diagnosis of an early onset progressive ataxia and/or the concomitant presence of immunological deficit, tumorigenesis and growth failure. However, both of these disorders lack the typical telangiectasias.[15]

In these patients, the overall survival is greatly affected by the attentive care and careful screening, which allow recurrent prevention infections and identifying tumors early. Usually, patients affected by the classical form of A-T can reach early adulthood. Milder forms and adult-onset variants have a significantly longer life expectancy. Median survival was noted to be 19-25 years with wide variability in two large cohorts.[21]The atypical forms of the disease usually present with a milder phenotype and a much longer life expectancy.[21].

Carriers of the ATM gene mutation have an increased risk of cancer and, as a result, reduced life expectancy. The incidence of radiosensitivity in carriers is still debated.

Since the disease presents with a great variety of manifestations, the management of patients with A-T requires an interprofessional team that includes a geneticist, pediatrician, neurologist, oncologist, dermatologist, nurse practitioner and an infectious disease expert.[16] A specific treatment to cure this disease is not available yet. Therefore, addressing the specific symptoms associated with the disease and surveillance to prevent complications is crucial.

In these patients, the overall survival is greatly affected by the attentive care and careful screening, which allow recurrent prevention infections and identifying tumors early. Usually, patients affected by the classical form of A-T can reach early adulthood. Milder forms and adult-onset variants have a significantly longer life expectancy. The atypical forms of the disease usually present with a milder phenotype and a much longer life expectancy.[21].