Clinical neurogenetics: autosomal dominant spinocerebellar ataxia

Abstract

The autosomal dominant spinocerebellar ataxias are a diverse and clinically heterogeneous group of disorders characterized by degeneration and dysfunction of the cerebellum and its associated pathways. Clinical and diagnostic evaluation can be challenging because of phenotypic overlap among causes, and a stratified and systematic approach is essential. Recent advances include the identification of additional genes causing dominant genetic ataxia, a better understanding of cellular pathogenesis in several disorders, the generation of new disease models that may stimulate development of new therapies, and the use of new DNA sequencing technologies, including whole-exome sequencing, to improve diagnosis.

Keywords: Ataxia; Autosomal dominant; Cerebellum; SCA; Spinocerebellar.

Figure 1. Diagnostic evaluation of an acquired cerebellar ataxia

All patients with clinically identified cerebellar ataxia should have an MRI of the brain performed to assess for masses, vascular lesions/anomalies, traumatic injury, and/or structural problems in addition to evidence of neurodegeneration and/or white matter changes. Additional diagnostic studies (gray boxes) should be performed as warranted based upon the clinical examination (dashed line). If the MRI does not reveal the cause, then laboratory tests (white boxes) should be performed systematically as indicated. Studies are listed under the heading of the class of disorders they most often identify. Note that some tests could identify disorders in more than one class. In a complete evaluation, a patient should receive, at a minimum, all studies listed above the dotted line. Items listed below the dotted line are chosen for more in-depth evaluation of specific etiologies and not all patients may require all studies. The dotted line represents the threshold for performing a lumbar puncture in a patient undergoing initial workup. Suggested cerebral spinal fluid studies are indicated (arrow). Specific cerebellar (paraneoplastic), celiac, and thyroid autoantibodies are also shown (arrow). Note that there are additional rare acquired causes of cerebellar ataxia which are not listed in this figure. Abbreviations: ACE = angiotensin converting enzyme, ANA = antinuclear antibodies, BAER = brainstem auditory evoked response, CBC = complete blood count, C/T/L = cervical, thoracic, and/or lumbar, CSF = cerebral spinal fluid, CT = computed tomography, DTI = diffusion tensor imaging, EEG = electroencephalogram, EMG = electromyogram, ENG = electronystagmogram, ESR = erythrocyte sedimentation rate, GAD = glutamic acid decarboxylase, HC = homocysteine, HGB = hemoglobin, HIV = human immunodeficiency virus, HTLV = human T-lymphotropic virus, IFE = immunofixation electrophoresis, MMA = methylmalonic acid, MRI = magnetic resonance imaging, MRA = magnetic resonance angiography, MRS = magnetic resonance spectroscopy, NCS = nerve conduction study, PET = positron emission tomography, PSG = polysomnogram, RPR = rapid plasma reagin, SSA/SSB = Sjögren’s syndrome antigen, SPEP = serum protein electrophoresis, SSEP = somatosensory evoked potentials, TSH = thyroid stimulating hormone, UPEP = urine protein electrophoresis, VDRL = venereal disease research laboratory test, VEP = visual evoked potential, VIT = vitamin. Original figure previously published[4] © Cambridge University Press 2011. Reprinted with permission.

Figure 2. MRI Findings in Spinocerebellar Ataxia

Sagittal T1-weighted magnetic resonance imaging is shown for a patient with A) Spinocerebellar Ataxia Type 3 (SCA3) and B) Multiple System Atrophy (MSA). Cerebellar atrophy (arrow) and brainstem atrophy (bracket) are noted. Note the similarity in imaging characteristics between these patients as this is common among the different ataxia etiologies (i.e., acquired, hereditary, and idiopathic).

Figure 3. Diagnostic evaluation of a genetic cerebellar ataxia

Abbreviations: FRDA = Friedreich ataxia, FXTAS = Fragile X tremor/ataxia syndrome, SCA = spinocerebellar ataxia.