Dopa‐Responsive Dystonia and Chorea as a Presenting Feature in Ataxia‐Telangiectasia

Clinical Details

A 2‐year‐old girl was evaluated for an unsteady gait that led to frequent falls. She was the first child to nonconsanguinous parents and had an unremarkable perinatal history. Her early motor developmental milestones were normal and she walked independently at 12 months. Her parents were concerned that at 18 months she continued to have an unsteady toddler‐like gait with frequent daily falls. They did not report any jerks or involuntary movements of limbs, abnormal eye movements or squint, or any unsteadiness when sitting. She was progressing well with regard to her other developmental milestones, and her fine motor skills and cognition were age appropriate.

There was a family history of intermittent torticollis (not requiring treatment) and malignant melanoma in the maternal grandmother, as well as squamous cell carcimona and two primary breast cancers in the maternal great‐grandmother.

On examination, she had no dysmorphic features, neurocutaneous markers, ocular or skin telangiectasias, or organomegaly. Her gait was unusual, not typically broad based, and she had intermittent dystonic posturing manifesting as tip‐toeing with a jerky quality (see Video 1). She also displayed dystonic posturing of her upper limbs along with choreiform movements, which were more noticeable while walking. She was able to balance herself on one foot and was able to pick up objects from the ground. These involuntary upper‐limb movements disappeared when seated and she was able to feed herself and display age‐appropriate fine motor skills when seated. There were no features of oculomotor apraxia or opsoclonus. Her head circumference was growing along the second centile.

Because she presented with dystonia, she was given a trial of l‐dopa and titrated to a dose of 5 mg/kg per day while awaiting the results of the investigations. There was a noticeable improvement in her movement disorder: the walking‐associated upper‐limb dystonia and choreiform movements improved as well as her intermittient tip‐toeing (see Video 2). On follow‐up, her movement disorder continued to remain well controlled and her gait was noticeably more broad based and ataxic.

Investigations

Neuroimaging of her brain and spine were normal. She had a raised alpha‐fetaprotein of 36.5 IU/mL (0–7). She had a raised immunoglobulin M level with CD4 T‐cell lymphopenia.

Exposure of blood lymphocytes to ionizing radiation confirmed a 10‐fold increased chromosomal radiosensitivity, compared to normal. There was no detectable ataxia‐telangiectasia mutated (ATM) protein and consequently no ATM kinase activity (Fig. 1). DNA sequencing of the complete ATM coding sequence revealed biallelic mutation of ATM, c.5156delA, p.(Asn1719Ilefs*5), and c.7308‐14T>G;p.Arg2436Serfs*18). The latter mutation is a single‐base change in intron 51, 14 bases 5 prime of exon 52. In order to confirm the pathogenicity of this sequence change, we made complementary DNA from the patient's cell line; this showed aberrant splicing that incorporated the last 13 bases of intron 51 into the messenger RNA. The effect of this will be a frameshift and premature termination of translation. The mutations were shown to be in trans by their separate identification in each parent. The biallelic presence of pathogenic truncating ATM mutations, absence of ATM protein, and a large increase in cellular radiosensitivity confirmed the clinical diagnosis of ataxia telangiectasia.

Discussion

A‐T is a multisystem condition characterized by progressive neurodegeneration and oculocutaneous telangiectasias. Other manifestations include cellular and humoral immunodeficiency predisposing to recurrent sinopulmonary infections, radiosensitivity, neuropathy, and a high risk of lymphoreticular malignancies.1, 2 A‐T arises as a result of a mutation of ATM gene on chromosome 11q22.3 encoding the ATM protein, which plays an important role in cellular response to DNA damage. Mutations in the genes closely related to ATM that play a role in DNA repair produce a variable phenotype/MRE11 gene cause A‐T‐like disease with mild ataxia and NBS1 produce Nijmegen breakage syndrome with predominantly microcephaly and immune deficiency.3

Classic A‐T is the result of frameshift or null mutations that lead to complete absence of ATM kinase activity and generally result in a severe phenotypic presentation. The most frequent symptom is ataxia, which often is the presenting symptom in 87% of children.3 The mean age of appearance is 1.4 years (range, 6 months–8 years). Interestingly, young children have a peculiar gait ataxia, which is a mixture of ataxia and gait apraxia with impairment of postural responses. Dysarthria is the second‐most common symptom, but can be difficult to ascertain in young children and, along with dysmetria, becomes more obvious with age. Hyperkinetic movemement disorders (chorea and myoclonus) are frequently observed in younger children, and dystonia is more common in adolescents and adults. These extrapyramidal symptoms may precede the occurrence or recognition of ataxia.3 Such movement disorders are reported to be induced and exacerbated by specific motor or cognitive tasks. Oculocutaneous telangiectasias, oculomotor apraxia, axonal sensorimotor neuropathy, bradykinesia, and other extrapyramidal movements manifest with increasing age along with progressive deterioration in ataxia. Most patients lose ambulation by 10 years of age. Death usually occurs in the second or third decade of life as a result of respiratory failure or malignancies.

In comparison, patients with variant A‐T are associated with missense mutations that leave some residual ATM kinase acitivty, leading to a milder phenotype. In a study of a cohort of 13 patients with variant A‐T, slowly progressive choreoathetosis and resting tremor were the presenting features in early childhood.4 The ataxia was mild to moderate and slowly progressive with a median age at onset of 27 years (range, 6–39). Ocular telangiectasias, immunodeficiency, and malignancies occurred late and infrequently.

Dystonia is infrequently reported in children diagnosed with A‐T. Most patients with A‐T develop dystonia later in the course of illness. In a cohort of A‐T in the British Isles, it was present in 78% of individuals.1 These were predominantly limb, trucal, oromandibular, and lingual. In a study of adults manifesting as primary dystonia who were subsequently diagnosed with variant A‐T, the mean age of onset was 12 years (range, 1–20).5 These individuals developed limb or cranial dystonia and lacked frank ataxia and ocular telangiectasia on presentation. The pathophysiology behind basal ganglia involvement in A‐T is not well understood. There are no abnormalities usually on imaging. Cerebellar functions are more complex than thought in the past, and intricate interconnections with the deeper subcortical structures are currently known. We hypothesize that the lack of inhibition from deeper cerebellar nuclei could lead to manifestation of these extrapyramidal symptoms. Although the phenotypic severity and course in A‐T depend on the level of ATM protein and ATM kinase activity, the different neurological symptoms do not correlate with specific mutations.6

l‐dopa has emerged as an important treatment modality in primary (hereditary) and secondary dystonias in childhood. The dramatic response as a treatment in GTP cyclohydrolase 1 deficiency (Segawa syndrome) has led to its use as a therapeutic trial in any child presenting with dystonia. The use of l‐dopa in treating dystonia in A‐T is rare. It has been reported only once before in 3 siblings from a consanguineous family who presented with cervical and brachial dystonia during adolescence and whose cervical dystonia improved dramatically with l‐dopa.7 They were later found to develop telangiectasias and had a positive mutation confirming A‐T. Nevertheless, the mechanisms leading to dopa‐responsive dystonia or dopa‐responsive movement disorder in A‐T remain unexplored. Dysregulation of dopamine in nigrostriatal circuits has been reported in spinocerebellar ataxias and ataxia oculomotor apraxia type 1, and there recent reports of the success of amantadine (dopaminergic, N‐methyl‐D‐aspartate receptor antagonist) in treating movement disorder in A‐T. It is possible that l‐dopa acts in a similar way by enhancing dopaminergic transmission in the basal ganglia, thereby improving dystonia and other extrapyramidal movements.

This report confirms dopa‐responsive dystonia and chorea as a phenotype of A‐T, which is important for several reasons. Clinicians should recognize movement disorder to be a presenting feature of A‐T in children even in the absence of frank ataxia or telangiectasias. A therapeutic trial with l‐dopa should be considered in this patient group. Long‐term placebo‐controlled or comparative studies of different agents (amantadine and l‐dopa) on treating the movement disorder early in the course of A‐T should be considered.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

S.T.: 1A, 1B, 3A

A.I.: 1A, 1B, 1C, 3A

P.B.: 1C, 3B

M.T.: 1C, 3B

S.S.: 1C, 3B

Disclosures

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months: The authors do not have any specific declarations regarding funding for any specific article.

Supporting information