Ataxia‐Telangiectasia Presenting as Tremor‐Predominant Syndrome in an Adult Patient without Ataxia and Telangiectasias

Ataxia‐telangiectasia (A‐T) is an autosomal recessive disorder caused by mutations in the ataxia‐telangiectasia mutated (ATM) gene, leading to impaired DNA repair mechanisms. The classic presentation typically includes early‐onset cerebellar ataxia and telangiectasias, especially of conjunctivae and skin, associated with immunodeficiency and increased risk of malignancies. ¹ However, A‐T can manifest with atypical features, such as a late onset, absence of telangiectasias, and mild or even absent ataxia at presentation, making the diagnosis challenging. ² This report describes an atypical presentation of A‐T in a young woman.

Case Report

A 36‐year‐old Caucasian woman was referred for evaluation of long‐standing tremors. Her symptoms began around the age of 20, with a slowly worsening tremor in both hands, later spreading to the head and legs. The tremor was moderate at rest and persisted while holding postures, although it improved significantly with purposeful movement. By age 30, her tremors were noticeable and bothersome for her. Recently, she noticed some slowness of movements without a functional impact on her daily activities. She had already tried low‐dose levodopa and trihexyphenidyl, which was poorly tolerated, but also propranolol, primidone, clonazepam, and gabapentin without significant benefit.

Family history was unremarkable, although she lost contact with the paternal side of the family. She does not have siblings.

On examination, the patient demonstrated a 3‐ to 4‐Hz medium‐amplitude tremor involving the four limbs, which was most prominent at rest, with a slightly faster postural component and absent kinetic one. She also showed a moderate yes‐yes head tremor (Video 1). Neurological examination revealed mild slowness of movement, without decrement in dexterity maneuvers, with a reduction in spontaneous arm swing during walking. Her upper limb coordination was slightly impaired, with mild overshooting on the finger‐chase test. She also showed dystonic features, including facial grimaces and abnormal postures of the hands. There was no rigidity. She had a narrow‐based gait, with mild difficulty in heel‐to‐toe walking. Sensation and reflexes were normal. No telangiectasias were observed on the skin, sclera, or mucous membranes.

VIDEO 1.

The video shows a moderate yes–yes postural tremor of the head, moderate rest and postural tremors of the extremities without kinetic component. Other features: facial hypomimia and dystonic grimaces; dystonic postures of the hands, slowness and slight incoordination on performance of alternate repetitive movements of the extremities; mild dysmetria during finger‐chase test; narrow‐based gait with reduced arm swing a mild difficulty in heel‐to‐toe walking.

Her brain magnetic resonance imaging (MRI) at the age of 34 showed an isolated mild cerebellar atrophy of the vermis (Fig. 1). Cerebral dopamine transporter‐single‐photon emission computed tomography scanner showed normal tracer uptake. Blood tests, including a comprehensive metabolic panel, were all normal, but for an elevated α‐fetoprotein level, 39.6 IU/mL (normal range, 0–8.1 IU/mL).

FIG. 1.

Sagittal T2‐weighted sequence of brain magnetic resonance imaging showing cerebellar vermis atrophy (B), compared to right (A) and left cerebellar hemispheres (C).

Next‐generation sequencing revealed a compound heterozygous mutation in the ATM gene (NM_000051.4): a missense variant (c.8147 T>C; p.(Val2716Ala)) and a frameshift variant (c.1564_1565del; p.(Glu522IlefsTer43)), consistent with a diagnosis of A‐T, despite the absence of classic telangiectasias and minimal cerebellar ataxia. Both variants are classified as pathogenic, according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria. The c.8147 T>C variant was also identified in her mother. Father could not be tested yet.

Immunoglobulin levels were within the normal range, with no evidence of immune dysfunction. Brain MRI and abdominal ultrasound excluded cerebral or visceral telangiectasias.

The patient was enrolled in a cancer screening program and genetic counseling was provided to the family.

Discussion

This case demonstrated that A‐T can manifest in adulthood with a complex movement disorder and atypical features, including the absence of telangiectasia, with tremor as a prominent symptom rather than the expected ataxia and associated dystonic features. ³ Furthermore, the characteristics of the tremor, although non‐specific, appear to be highly peculiar in this case. It is most prominent at rest and while walking, with mild re‐emergent worsening and no kinetic component, and involves the limbs both proximally and distally. Its etiology is debatable, whereas a mixed cerebellar and dystonic origin would be more consistent with the features of A‐T, and co‐manifesting dystonic features, the predominance at rest and the absence of a kinetic component argue against this. Additionally, the predominance at rest and the mild global slowness could make it resemble a parkinsonian feature, although the quality of movement is not typical. The c.8147 T>C variant has already been described in both typical and atypical A‐T with severe resting tremors ⁴ , ⁵ and later‐onset ataxia, ⁵ showing minimal telangiectasias and increased α‐fetoprotein. ⁴ , ⁵ The c.1564_1565del variant has been previously described in association with classical A‐T and malignancies, but all the patients reported had compound heterozygosity with truncating variants. ⁶ , ⁷ Phenotypic variability, at least partially, has been explained by differences in the genotype. Patients carrying truncating ATM variants suffer a more severe phenotype, whereas missense or site variants leading to even small amounts of active residual ATM protein can rescue the patient from classic A‐T. ⁸ In fact, compound heterozygous mutations of the ATM gene may exhibit a milder clinical phenotype, resulting in a delayed onset, slower progression of neurological symptoms and longer life expectancy. ⁹ This case highlights the pleiotropy of A‐T, which corresponds to a clinical spectrum rather than a specific clinical entity, also including dystonia, tremors, myoclonus, and parkinsonian features that can be predominant. ² , ³ The nomenclature “ataxia‐telangiectasia” can be misleading, and the term “ATM‐related disorder” would be more appropriate for these cases. Unexplained movement disorders of early adulthood often lead to a broad differential diagnosis, involving genetic diseases. The choice of genetic tests is crucial for a timely and correct diagnosis. Although genetic panels are more time‐ and cost‐effective than whole exome or genome testing, they offer a limited number of genes explored, and the ATM gene is often included only in ataxia or dystonia panels. α‐Fetoprotein dosage may assist in narrowing the differential diagnosis to a few recessive ataxias, particularly A‐T and ataxia with oculomotor apraxia (AOA), and may enhance diagnostic accuracy in analogous cases. ¹⁰

A‐T is among the actionable genetic disorders, especially in terms of motor symptoms treatment and cancer prevention. ³ The pathophysiology of A‐T involves defects in the ATM gene, which is involved in DNA damage response and repair. This causes genomic instability, which explains the increased risk of malignancies, particularly lymphoma and leukemia, immunodeficiency, radiosensitivity, and premature aging. ¹¹ Early diagnosis can mitigate their effects on patients' lives, and an accurate identification of the predominant movement disorder can improve its management. Further, recent evidence supports the use of nicotinamide riboside to improve motor coordination and eye movements in A‐T patients. ¹²

This case emphasizes the clinical variability of A‐T, particularly in adult‐onset cases where atypical symptoms may dominate the clinical presentation and represent a diagnostic challenge. Genetic testing is an essential tool to confirm the diagnosis and awareness of useful diagnostic biomarkers, such as α‐fetoprotein, is critical for timely diagnosis and management.

Author Roles

Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript preparation: A. Writing of the First Draft, B. Review and critique.

D.G.: 1A, 1B, 1C, 2A, 2B

G.D.L.: 1A, 1B, 2B

M. G. P.: 1C

F.D.T.: 1C

I.C.: 1C

A.T.C.: 1A, 2A, 2B

M.P.: 2B

P.C.: 2B

A.R.B.: 1A, 2B

Disclosures

Ethical Compliance Statement: This work did not require ethics committee approval. The patient provided written consent. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the previous 12 months: The authors declare that there are no additional disclosures to report.

Data Availability Statement

The data supporting the findings of this case report are available on reasonable request from the corresponding author.