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July 2016

Choreoathetosis, Dystonia, and Myoclonus in 3 Siblings With Autosomal Recessive Spinocerebellar Ataxia Type 16

Author Affiliations
  • 1Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
  • 2Department of Neurology, Tokushima Prefectural Central Hospital, Tokushima, Japan
  • 3Laboratorio di Neurogenetica, CERC-IRCCS Santa Lucia, Rome, Italy
  • 4Dipartimento di Scienze Chirurgiche e Biomediche, Università di Perugia, Perugia, Italy
JAMA Neurol. 2016;73(7):888-890. doi:10.1001/jamaneurol.2016.0647

Extracerebellar symptoms may be seen in most cases of both autosomal dominant and recessive cerebellar ataxias, being characterized by multisystem involvement.1 Autosomal recessive spinocerebellar ataxia type 16 (SCAR16) is an adolescent-onset ataxia with cerebellar atrophy, occasionally accompanied by cognitive decline, spasticity, hypogonadism, and movement disorders.2 In 2013, the STIP1 homologous and U Box–containing protein 1 gene (STUB1; 16p13.3; OMIM: *607207), was identified as a novel causative gene for SCAR16, which encodes the C-terminus of the heat shock protein 70–interacting protein,3 which has a biological role in regulating protein quality control.4 We report 3 sibling cases with SCAR16 with choreoathetosis, dystonia, and myoclonus.

Report of Cases

The proband is a 46-year-old man (Figure, A: IV-3), who was born to consanguineous parents (fourth-degree relatives) and grew up without any developmental delay. He graduated from high school and worked at a factory. He developed balance impairment and speech difficulty at age 19 years. Over the years, he showed some disease progression, although he was able to walk without support. He began to experience an irreversible decline in intellectual function at age 30 years. His speech became unintelligible and the neurologic examination at age 37 years showed unsteady gait, appendicular ataxia, mild truncal ataxia, mild horizontal gaze-evoked nystagmus with no restriction of extraocular movements, and ataxic dysarthria with explosive speech. At age 45 years, he began to show dystonic posture and choreoathetotic movements (Figure, B, and Video).

Figure.  Pedigree, Photographs, Magnetic Resonance Images, and Whole-Exome Sequencing
Pedigree, Photographs, Magnetic Resonance Images, and Whole-Exome Sequencing

A, Pedigree chart showing a marriage with the fourth-degree consanguinity and 3 affected members. B and C, Posture of the 2 affected members. B, The proband (IV-3) shows left lateral shift of the neck and trunk in the supine position. C, The proband's brother (IV-5) shows athetotic posture of the hand. D, Brain magnetic resonance imaging studies of the proband (IV-3; upper panels) at 37 years of age and his younger brother (IV-4; lower panels) at 36 years of age revealing severe atrophy of the cerebellum. Enlargement of the fourth ventricle and widened cerebellar folia can be observed in T2-weighted sagittal images (left panels) and axial fluid-attenuated inversion recovery images (middle panels). The brainstem remains intact. No abnormal intensity is observed in the globus pallidus, putamen, caudate nucleus, and thalamus in axial fluid-attenuated inversion recovery magnetic resonance images (right panels). A mild enlargement of the lateral ventricles can be observed in IV-4 (right lower panel). E, Sequence of the normal STUB1 exon 6 sequence as well as the mutation detected in the proband are presented. The top sequence is of the control; middle, unaffected sister (IV-1); bottom, proband. The arrowheads indicate the missense mutation, c.724G>A (p.E242K). Arg indicates arginine, Cys, cysteine; Glu, glutamate; Lys, lysine; Met, methionine; and Phe, phenylalanine.

Video. Involuntary Movements Observed in Patients With -SCAR16
Segment 1, proband (IV-3) choreoathetosis and dystonic posture. Segment 2, proband’s brother (IV-5) athetotic posture of the right hand and dystonic posture of the left foot and myoclonus and tremulous movements. Segment 3, proband’s brother (IV-5) vertical ocular flutter.

The proband’s brother (Figure, A; IV-5) and sister (Figure, A; IV-2) were also affected and showed similar clinical characteristics. The proband’s brother began to show myoclonic, dystonic, and tremulous movements, as well as vertical ocular flutter at age 37 years (Figure, C and Video). Brain magnetic resonance imaging revealed moderate atrophy of the cerebellar vermis and hemispheres, with sparing of the brainstem. No atrophy or abnormal intensity was observed in the basal ganglia (Figure, D). Single-photon emission computed tomographic (SPECT) images with technetium Tc 99m ethyl cysteinate dimer showed marked cerebellar hypoperfusion via volume effects, but almost normal perfusion at the basal ganglia, thalamus, and cortices. The sister showed myoclonic and tremulous movements, as well as spastic equinovarus deformity. Occasional painful muscle contractions appeared at age 38 years. She died suddenly of unknown causes soon after developing involuntary movements. Clinical features of all affected individuals are summarized in the Table. Genetic studies, including whole-exome sequencing (Figure, E), demonstrated that the homozygous missense variant c.724G>A (p.E242K) in STUB1 is common in the 2 affected members. The Ethics Committee of the Graduate School of Medicine, the University of Tokushima (Tokushima, Japan), approved this study.

Table.  Clinical Summary of the Family With STUB1 Mutations
Clinical Summary of the Family With STUB1 Mutations


To our knowledge, a total of 20 STUB1 mutations have been reported to date, including missense, truncation, and splice site donor mutations. The literature review of 11 SCAR16 families showed mutation-specific clinical heterogeneity. Pure progressive ataxia was reported in only 2 cases, and combination ataxia and cognitive impairment were observed in most cases. Movement disorders were reported in 3 of 11 families, and the interval from cerebellar symptoms to movement disorders varies from several months to more than 10 years. Movement disorders occasionally emerge as a presenting sign or a late-onset concomitant feature in many SCA subtypes.1 However, to our knowledge, there is no systematic study on the period of clinical latency.

Animal experiments have demonstrated the existence of a disynaptic pathway from the cerebellum to the striatum, through which the activity of the striatum is rapidly modulated. Aberrant or distorted modulation due to cerebellar dysfunction would result in developing movement disorders, including dystonia.6 An initial cerebellar dysfunction was followed by a subsequent dysfunction in other neuronal tissues, including the thalamus, basal ganglia, and cerebral cortex, leading to aberrant neuroplasticity of neural connections, which might have been developed in these cases. Vertical ocular flutter followed by involuntary movements indicates that neurodegeneration involved the gaze stabilization systems, including the paramedian pontine reticular formation.7

Spinocerebellar ataxia type 16 is a rare condition, but it is important to understand its pathogenesis, which has to be taken into account in the differential diagnosis of movement disorders.

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Article Information

Corresponding Author: Toshitaka Kawarai, MD, Department of Clinical Neuroscience, Institute of Biomedical Sciences, University of Tokushima Graduate School, Tokushima 770-0042, Japan (tkawarai@tokushima-u.ac.jp).

Published Online: May 16, 2016. doi:10.1001/jamaneurol.2016.0647.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by grant 26461294 from the Japan Society for the Promotion of Science (JSPS KAKENHI; Dr Kawarai); Grants-in-Aid from the Research Committee of CNS Degenerative Diseases and Grants-in-Aid from the Research Committee of Dystonia from the Japanese Ministry of Health, Labour, and Welfare (Drs Kawarai and Kaji); grant GR09.109 from the Italian Ministero della Salute (Dr Orlacchio); and grant E82I15000190005 from the Università di Roma “Tor Vergata,” Rome, Italy (Dr Orlacchio).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the patients and family for granting permission to publish this information. We also thank Michela Renna, MA (an independent translator/interpreter), for her language assistance and Antonella Casella, PhD, and Lucia Pedace, PhD (Laboratorio di Neurogenetica, CERC-IRCCS Santa Lucia, Rome, Italy), for their support with genetic analysis. They did not receive compensation for their contributions. We are grateful to our colleagues in the Department of Neurology, Tokushima National Hospital, National Hospital Organization (Kazuyuki Kawamura, MD, and Katsuhiko Adachi, MD), Itsuki Hospital (Yoshihiko Nishida, MD), and Tokushima University Hospital (Yuishin Izumi, MD), Tokushima, Japan, who sensitively cared for the patients. We are extremely grateful to the Institute for Genome Research Tokushima University Graduate School for the use of the next-generation sequencing facility and the Support Centre for Advanced Medical Sciences, Tokushima University Graduate School, for the use of their facilities to prepare the manuscript, as well as the Genetic Bank of the Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello-Istituto di Ricovero e Cura a Carattere Scientifico (CERC-IRCCS) Santa Lucia, Rome, Italy (http://www.hsantalucia.it/laboratorio-neurogenetica) for the service provided.

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