In this study, we presented a clinical genetic study of Chinese A-T family presenting with atypically craniocervical dystonia through targeted exome-sequencing and further reviewed previously published dystonia-dominant A-T cases. No signs of ocular motor apraxia, cerebellar ataxia, as well as telangiectasia were observed in present case.
Dystonia occurring either in isolation or in combination with other clinical features, has been described in variant A-T patients. Dystonia affecting the neck, head, trunk and limbs, may be present as initial symptoms in about 18%(24/130) of A-T patients. The present case showed obviously isolated segmental dystonia without any signs of ataxia and telangiectasias. After reviewed previously published literatures of genetically confirmed A-T cases with predominant dystonia, we found that these dystonia-dominant A-T cases may have a significantly different clinical picture compared to the typical A-T. In total, 11 pedigrees including 29 patients (13 Female, 16 Male patients) with ATM mutations were reviewed[7–14] (Table 1). The median age of onset was 10.67 years, ranging from 1 to 20 years old. The group of dystonia-dominant A-T cases showed isolated dystonic features or accompanied by choreoathetosis, tremor and/or myoclonic jerks, but without involvement of ataxia and telangiectasias. Other phenotypes, including peripheral neuropathy, delayed motor development, speech and swallowing difficulties, could also be seen in the group. A few patients also experienced recurrent pneumonia and increase risk of malignancy. Overall, the patients with dystonia-dominant A-T tend to have a later-onset and slower progression of the disease. However, the relationship between dystonic phenotype and particular ATM genotype in variant A-T is not well understood. As previously reported, mutations in exon 42 of the ATM gene may predispose to dystonia-dominant A-T, which is needed to be confirmed in further analysis. Notably, the transient amnesia observed in present case was rare and first described in patients with A-T. Further investigation and analysis of amnesia presentation in patients with A-T are needed.
In line with previous study, significantly elevated AFP levels and decreased serum levels of immunoglobulin and complements (IgG, IgA, C3 and C4) were observed in this family. Previous studies revealed that elevated IgM levels are indicative of a distinct and more severe phenotype. IgM levels was normal in present case, which suggests the mild phenotype observed in our case. Unfortunately, the ATM kinase activity was not detection in our patients.
The neuropathological hallmark of A-T is cerebellar Purkinje cell loss, leading to cerebellar symptoms and degeneration. The exact pathogenesis of dystonia in A-T remains less clear. A review of pathological findings in 17 patients with A-T and movement disorders found that neurona loss occurs in basal ganglia and brain stem nuclei. Previous positron emission tomography (PET) study revealed reduced glucose metabolism in the cerebellum of A-T patients and increased metabolism in the globus pallidus which often resulted in decreased motor performance. Additional studies are required to assess the association of dystonia with cerebellum and basal ganglia degeneration in A-T patients.
In summary, our study expanded the clinical and molecular spectrum of dystonia-dominant A-T in China. Dystonia may appear as one of the predominant manifestations or initial symptom of A-T. Isolated dystonia without any signs of ataxia or telangiectasias may result in the delays in the diagnosis of A-T. ATM genetic testing should be early considered for those patients with predominant dystonia, despite without accompanying ataxia or telangiectasia.