Movement Disorders in PURA Syndrome: A Video Case Series

ABSTRACT

Background

PURA syndrome is a rare genetic disorder characterized by neonatal hypotonia, neurodevelopmental delay, facial dysmorphism, epileptic seizures, complex movement disorders, among other features. Although many pathogenic variants have been reported, there is currently no clear genotype–phenotype association identified.

Cases

Four patients diagnosed with PURA syndrome, despite carrying different pathogenic variants, presented a similar mixed hyperkinetic movement disorder. The phenomenology presented a complex set of symptoms, including chorea, interspersed with dystonic and uncoordinated movements. All patients presented also hypotonia, nystagmus, feeding difficulties, craniofacial dysmorphisms. Hypersomnolence and breathing problems were common and observed in three patients, while seizures were found in three patients.

Conclusions

PURA syndrome may be considered in the differential diagnosis of infants with severe hypotonia, feeding difficulties and severe developmental delay with epileptic seizures, that start to develop a mixed hyperkinetic movement disorder. These complex movements may be an important clue for the diagnosis of this rare disorder.

Purine‐rich element‐binding protein A (PURA)‐related neurodevelopmental disorders or PURA syndrome (PS) encompasses the clinical syndrome caused by a heterozygous pathogenic variant in PURA, and the formerly called 5q31.3 microdeletion syndrome, caused by a genomic 5q31.3 deletion in PURA gene. ¹ , ² PS has recently been identified ³ and still may be underestimated. ⁴ , ⁵ , ⁶ Since the initial description, 97 different pathogenic variants have been reported, but no clear genotype–phenotype correlations have emerged so far. ¹ , ³ , ⁴ , ⁵ , ⁶

PS is a heterogeneous condition, characterized by neonatal hypotonia, epileptic seizures, complex nonepileptic movement disorders, neurodevelopmental delay with the absence of speech and lack of independent ambulation in most patients. Patients may also present in variable frequency: feeding difficulties, ophthalmological disorders, hypersomnolence, hypothermia, central apnea, urogenital malformations, skeletal abnormalities, and craniofacial dysmorphisms. ¹ , ³ , ⁴ , ⁵ , ⁶ Movement disorders in PS are very rich phenomenologically. The patient may present complex hyperkinetic movements, in which chorea‐like dyskinesia may be the core movement, but often, associated with dystonic movements, myoclonus, hand stereotypies, and ataxia. ¹ , ⁴ , ⁵ , ⁷ , ⁸ The presence of those movements is variable, but when present, can be very useful to the diagnosis. ⁷ , ⁸

In this study, we aimed to describe and discuss the complex phenomenology of the movements exhibited by four patients diagnosed with PS. All patients’ parents provided written consent for publication, video, and image. The patients presented different, but previously described gene mutations. Despite this, all patients demonstrated a complex movement disorder with similarities, characterized by a combination of hyperkinetic movements.

Case Report

Case 1

A male infant, the first child of healthy non‐consanguineous parents, was born full‐term following an uneventful pregnancy. At birth, he was hypotonic, did not cry, and exhibited poor sucking. At 21 days of age, he experienced his first focal seizure. The child's condition progressed to myoclonic epilepsy, and later, generalized tonic–clonic seizures. During the first years of life, the patient began to develop dyskinetic movements, with intermittent dystonic postures of the extremities, eyelid myoclonus, strabismus, and an exaggerated startle response. During follow‐up, bilateral hip luxation, chronic constipation, intellectual disability, hearing loss, and distinctive facial features with thin eyebrows, a high anterior hairline, wide nasal tip, and epicanthus were detected. There was significant neurodevelopmental delay; he achieved cephalic support at 2 years of age and sat with support and babbled at 4 years of age. At 7 years old, he is unable to speak, walk, control his sphincter, and he exhibits global muscle hypotrophy and hypotonia. Initial investigations, including EEG, brain MRI, and laboratory tests such as metabolic screening, were all normal. Consequently, a genetic investigation was performed, revealing a pathogenic PURA gene variant Chr5:140,114,693 G > C (alternatively, c.512G > C–ENST00000331327). In the video, the patient displays severe muscle hypotrophy, hypotonic posture with poor trunk control, and a choreiform movement disorder mixed with intermittent dystonic movements, myoclonus, and mild limb ataxia. The patient is confined to a wheelchair and cannot walk independently, as shown (Video 1).

Video 1.

Movement disorders presented in four cases related to PURA syndrome. Case 1 A wheelchair dependent patient showing a complex choreiform movement disorder, associated with myoclonic jerks, and dystonia. Case 2 Patient presents axial and limb hypotonia, and significant drooling. The main movement disorder is chorea, but there is some dystonic posture in the hands and feet, and also intermittent myoclonic jerks. Case 3 Patient restricted to a wheelchair, presenting a complex hyperkinetic movement disorder, with mild chorea, incoordination, and myoclonus. Case 4 Patient shows oculogyric crisis, dyskinesias compatible with chorea, interspersed with generalized myoclonus. Also, it is evident, feeding and breathing problems requiring nasoenteral and orotracheal tubes.

Case 2

A full‐term male infant, the third child of healthy non‐consanguineous parents, was born by cesarean section after a normal pregnancy. He was hypotonic and hypothermic at birth. Hypothermia persisted throughout the first year. Since the first days of life, he showed sucking and swallowing difficulties, which led to severe/moderate dysphagia, persisting over the next months of life. At 1 month, his mother noticed cyanosis and continued drowsiness, associated with recurrent vomiting. He evolved with seizures, involuntary movements in the limbs and the trunk, moderate incoordination of limbs, and poor trunk control. Also, he presented eyelid myoclonus, strabismus, and nystagmus. The patient also presented inguinal hernia, ectopic testis, and hip subluxation. Neurodevelopmental stages were severely delayed: he acquired cephalic support at 8 months, sat with support at 1 year, and crawled at 3 years. At 4 years old he is still not able to speak, to walk, and has no sphincter control (Table 1). Ophthalmologic and hearing acuity evaluations were normal. Magnetic resonance imaging (MRI) and electroencephalography (EEG) were also unremarkable. The karyotype investigation and a wide metabolic screening, which included quantitative plasma amino acids, acylcarnitines, ceruloplasmin, urinary organic acids, and mucopolysaccharides, were normal. Thus, a genetic investigation with array‐CGH was performed, detecting a de novo pathogenic variant on the 5q31.2, chr5:139,164,683‐140,755,975, confirming the diagnosis of PS. In the video, the patient presents a mild axial hypotonia but a marked limb hypotonia, and significant drooling. The main movement disorder is chorea, but there is some dystonic posture in the hands and feet, and also intermittent myoclonic jerks (Video 1).

TABLE 1.

Clinical features found in the patients described

Clinical Feature	CASE 1	CASE 2	CASE 3	CASE 4
Medical issues at birth
Low weight	−	−	−	−
Hypotonia	+	+	+	+
Feeding disorders	+	+	+	+
Hypersomnolence	+	+	+	−
Hypothermia	−	+	−	−
Breathing problems	−	+	+	+
Excessive fetal hiccups	+	−	−	−
Craniofacial Dysmorphisms	+	+	+	+
Neurological features
Neurodevelopmental delay	++++	++++	+++	*
Movement disorders	+	+	+	+
Age of mov. disorders onset	<1 year	<1 year	<3 years	<1 year
Epilepsy	+	+	+	−
Age of epilepsy onset	<1 month	1 month	< 1 month	−
Exaggerated startle response	+	−	−	+
Nystagmus	+	+	+	+
Strabismus	+	+	+	−
Skeletal abnormality
Scoliosis	+	+	−	−
Hip dysplasia	+	+	−	−
Constipation	+	−	−	−
Drooling	+	+	+	−
Urogenital abnormality	−	+	−	−
Hearing Loss	+	−	−	−

^*Due to his age, it cannot be properly determined.

Case 3

A female, full‐term infant of healthy parents, presented axial hypotonia and respiratory distress syndrome after birth. She was referred to the neonatal intensive care unit (NICU) and developed generalized tonic–clonic convulsive seizures within the first days of life, successfully controlled with phenobarbital. The patient had facial features, including a well‐defined philtrum, flat nasal bridge with a wide and triangular nasal tip, epicanthus, and thin upper lip. Also, she exhibited horizontal nystagmus, strabismus, and intellectual disability. The patient achieved cephalic support and social laughter at 1 year and sat without support at 1 year and 8 months. At 3 years‐old, she subtly began to present hyperkinetic movements, and currently, at 5‐years‐old, she is unable to speak and walk, and has no sphincter control. An EEG performed in the first days of life showed diffuse slowing. Brain MRI revealed mild frontal cortical atrophy, and laboratory investigation and metabolic screening were normal. In the genetic investigation, the karyotype was normal, and a CGH‐array was then performed, finding a pathogenic variant arr[GRCh37]5q31.2q31.3(139033279_140058893) × 1, compatible with neurodevelopmental disorder associated with the PURA gene. The video shows the patient at 5‐years‐old, restricted to a wheelchair, presenting a complex movement disorder, with mild chorea, incoordination, and myoclonus (Video 1).

Case 4

A full‐term male neonate was admitted to the neonatal intensive care unit due to respiratory insufficiency. Upon admission, a physical assessment revealed global hypotonia, global hyperreflexia, feeding difficulties, and facial features including a cleft palate and micrognathia. On his sixth day of life, the infant presented tonic spasms in upper and lower limbs, followed by central cyanosis during a 5‐minute apnea. He later developed an exaggerated startle response, oculogyric crises, and hyperkinetic movements. During hospitalization, he experienced several complications (infections, chyloperitoneum, panhypopituitarism) and required a tracheostomy tube, gastrostomy tube, and continuous oxygen. EEG recording detected no abnormalities. Brain MRI showed diffuse cerebral atrophy. The metabolic screening and lumbar puncture were normal. Anti‐NMDA Receptor Encephalitis was considered, but after a deeper investigation, including a genetic panel, was identified a heterozygous pathogenic 152Kb deletion in the PURA gene, encompassing the region Chr5:140,042,370 to Chr5:140,194,652. In the video, the patient is presenting an oculogyric crisis, dyskinesias compatible with chorea, interspersed with generalized myoclonus (Video 1). Oculogyric crisis is not a common feature of PS, and due to the patient's young age, the degree of diagnostic difficulty increased. Since the patient was still a newborn, the expected developmental delay aspects of the disease are not yet observed, but the complex combination of hyperkinetic movement disorders was key to the early diagnosis in this case. Detailed clinical features of all patients are summarized in Table 1.

Discussion

All four patients described in this series presented typical manifestations of PURA syndrome (PS), despite having different genetic mutations. The phenomenology of movement disorders presented in PS is rich and complex, and challenging to distinguish. The patients exhibit choreiform dyskinetic movements, accompanied by dystonic movements and postures. These movements are interspersed with myoclonic jerks. This combination of hyperkinetic movements appears to be a hallmark of PS, as it confers a very distinctive particularity to the disease. ⁷ , ⁸ In other series, abnormal movements were detected in 23.9% ¹ to 36% ⁵ of the patients. All reported patients exhibited hypotonia, feeding disorders, nystagmus, and a complex movement disorder. Possibly, all patients might present neurodevelopmental delay; however, the patient in case 4, was still a newborn. This data is in accordance with the highly variable neurodevelopmental delay reported in the scientific literature. ¹ , ⁴ , ⁵ , ⁹

The cases presented and the detailing of the clinical characteristics enhance the understanding of PS, which appears to be a very underestimated cause of neurodevelopmental delay still. Complex movement disorder in infants can be easily misdiagnosis as dyskinetic cerebral palsy. Still, chorea in in early childhood, could be misdiagnosis as Anti‐NMDA Receptor Encephalitis, which would, undoubtedly, lead to a path of iatrogenics, highlighting the importance of well‐performed clinical reasoning and accurate genetic investigation.

Johannesen et al. found that 60% of the patients developed generalized tonic–clonic and focal seizures, and/or epileptic spasms, with drug‐resistant epilepsy in 2/3 of them. In this case series, three patients presented epileptic seizures, but the fourth one, had no epileptic discharges at the time of the last examination. Finally, the combined presence of neurodevelopmental delay, nystagmus, feeding disorder, hypotonia, epilepsy, and mixed hyperkinetic movements, may be important clues to the diagnosis of PS.

Therefore, PURA syndrome should be considered as a differential in the challenging diagnosis of infants with severe hypotonia, developmental delay, seizures, and complex movement disorders. In this series, four cases were gathered, discussing their phenomenology documented in videos, and showing some important common features, that may be useful to recognize this rare condition.

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.

A.C.S.C.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B

E.P.B.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B

D.B.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B

L.P.F.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B

A.T.M.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B

G.L.F.: 1A, 1B, 1C, 2A, 2B, 2C, 3B

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. All patients’ parents gave written consent for publication, video and image. They also confirm that the Journal's position on issues involved in ethical publication was read and they affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: No specific funding was received for this research. The authors declare that there is no conflict of interest.

Financial Disclosures for the Previous 12 Months: There are no disclosures to report.