PURA syndrome is a severe neurodevelopmental disorder named after its causative gene, the purine‐rich element‐binding protein A gene. It is characterized by neonatal hypotonia, feeding and respiratory problems during infancy, global developmental delay, with or without seizures. Although a variety of movement disorders have been observed in some of these patients,1 they were less systematically investigated. Herein, we report on a pediatric patient with PURA syndrome featuring multiple types of involuntary movements during school age.
A 10‐year‐old boy presented with hypotonia and central‐type apnea during neonatal period. The respiratory problem gradually resolved with age, but global developmental delay was noted since infancy. He did not have psychomotor regression throughout the course, albeit the developmental progress was very slow. Despite continued rehabilitation from infancy onward, he has neither independent ambulation nor speech by age 10. No major problems were identified in other organ systems, except that strabismus and hyperopia have been diagnosed. The boy began to exhibit hyperkinetic movements at around age 6. A mixture of choreoathetosis and dystonia was often observed, particularly in upper limbs (Video 1). Orolingual dyskinesia was also seen. Besides, he had prominent head and hand stereotypies. These different types of involuntary movements were either simultaneous or occurring in succession. The parents also reported that he was easily startled. On the other hand, he had decreased sensitivity to pain and often showed happy demeanor. Cerebrospinal fluid (CSF) study during neonatal period showed no pleocytosis, and normal glucose and protein levels. Serial brain MRI showed nonspecific hypomyelination which improved with age (Fig. 1). Targeted genetic investigations for spinal muscular atrophy, Prader‐Willi syndrome, and congenital central hypoventilation syndrome had been performed during infancy, and all failed to identify the root cause of his neurodevelopmental problems. Chromosomal microarray detected microduplication of 13q12.12, which was interpreted as a likely benign variant. Trio‐based whole genome sequencing revealed a de novo pathogenic variant in PURA (c.363C > G, p.Tyr121Ter), which was confirmed by Sanger sequencing.
Video 1.
Video of the patient at age 8. The boy demonstrated multiple types of hyperkinetic movements including repetitive figure‐8 or side‐to‐side head movement and hand stereotypy, orolingual dyskinesia, choreoathetosis, and dystonia in the limbs. These involuntary movements occurred either concurrently or in rapid succession. The facial expression of the patient was relatively hypomimic or hypotonic, even while he was smiling.
FIG. 1.
Brain MRI at the age of 2.5 (panels A‐C) and 8 (panels D‐F) years. Representative images, including axial views at the levels of basal ganglia/thalami (panels A & D) and cerebellum (panels B & E), and coronal views (panels C & F), were shown. Delayed myelination was evident on T2‐weighted imaging at 2.5 years of age, as reflected by the diffusely increased signal intensities in cerebral white matter (panels A & C). Myelination has improved significantly at 8 years of age, with only faintly increased signals in peripheral white matter (panels D & F).
Hyperkinetic movement disorders, though reported in only one patient in initial two case series of PURA syndrome,2, 3 were recognized to be more frequent in a recent cohort.1 The observed motor phenomena were diverse, including dystonia, choreoathetosis, and stereotypy. Other movement disorders, such as ataxia and exaggerated startle, also seem to be overrepresented in patients with PURA syndrome (Table 1).1, 2, 3, 4 Given the relatively non‐progressive nature of this syndrome, affected patients could have been assigned the diagnosis of dyskinetic cerebral palsy if genetic studies were not pursued.
TABLE 1.
Movement disorders in PURA syndrome
| Number of Patients | Choreoathetosis | Dystonia | Ataxia | Stereotypy | Exaggerated Startle | |
|---|---|---|---|---|---|---|
| N (%) | ||||||
| Lalani et al.3 | 11 | nm | nm | 1 (9%) | nm | 1 (9%) |
| Hunt et al.2 | 4 | 1 (25%) | 1 (25%) | 1 (25%) | nm | 2 (50%) |
| Lee et al.4 | 18 | nm | nm | 1 (6%) | nm | 5 (28%) |
| Reijnders et al.1 | 32 | {6*/30 (20%)} | 8/22 (36%) | 11/19 (58%) | ||
| Our patient | 1 | + | + | − | + | +? |
+, presence; −, absence; nm, not mentioned.
Among the 6 patients, 1 had chorea‐like movements, 1 had dystonia, 2 had ataxia, and 2 had unspecified movement disorders.
The mechanisms underlying these motor manifestations of PURA syndrome, as well as their variable expression among patients, remain to be elucidated. A single patient with PURA syndrome has been found to have persistent hypoglycorrhachia and low lactic acid in CSF.5 Decreased glucose transporter type 1 (GLUT1) expression in red and white blood cells was documented in that patient, raising the possibility that secondary GLUT1 deficiency may occur in PURA syndrome. Indeed, the promoter region of SLC2A1 (the gene encoding GLUT1) contains PURA‐binding sequences. It has been known that GLUT1 deficiency is associated with several movement disorder phenotypes. Whether GLUT1 dysregulation is causally related to involuntary movements in PURA syndrome awaits further research. Our patient had received CSF examination during neonatal period; however, no hypoglycorrhachia was noted at that time.
Several animal studies provided hints at the potential mechanisms or neural substrates of movement disorders in PURA syndrome. PURA −/− mice exhibited waddling gait by 2 weeks of age.6 Moreover, they also developed tremor which became severe and persistent for the rest of life. Cerebellar pathology, including reduced number of neurons and aberrant lamination, was found in these mice. PURA +/− mice had much milder phenotypes, while gait problem could still be detected at 11 months of age, and reduced number of neurons was noted in cerebellar vermis.7 More comprehensive investigations of these animal models may help elucidate the neurobiological basis of motor control problems in PURA syndrome.
To sum up, our case illustrates the diversity of involuntary motor phenomena in PURA syndrome. Hopefully further research on this molecularly‐defined clinical entity could yield physiological and molecular insights into relevant pediatric movement disorders.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.
S.J.L.: 1B, 1C, 3A
Y.F.L.: 1B, 1C, 3B
C.H.T.: 1C, 3B
C.H.H.: 1C, 3B
F.H.: 1C, 3B
S.F.T.: 1B, 3B
W.S.L.: 1A, 1B, 1C, 3A, 3B
Disclosures
Ethical Compliance Statement
The authors confirm that the approval of an institutional review board was not required for this work. Written informed consent for publication of the case and his video images was obtained from the patient's parents. 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
This study was in part supported by grants from Taiwan's Ministry of Science and Technology (MOST106‐3114‐Y‐043‐001) and National Health Research Institutes (MG‐109‐GP‐02). The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months
C.H. Tsai has received speaker honoraria from Abbott Laboratories and Sanofi. W.S. Lin has received a grant from Taiwan's Ministry of Science and Technology for research unrelated to the present study. Other authors declare nothing to report.
Shan‐Ju Lin and Yung‐Feng Lin contributed equally to this study.
References
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