Acetazolamide Improves Episodic Ataxia in a Patient with Non‐Verbal Autism and Paroxysmal Dyskinesia Due To PRRT2 Biallelic Variants

Variants in PRRT2 (proline‐rich transmembrane protein 2, OMIM*614386) can manifest as a variety of clinical phenotypes, including convulsions with paroxysmal choreoathetosis, paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile seizure, ¹ , ² , ³ and hemiplegic migraine. ⁴ At the same time, a subset of patients with biallelic PRRT2 variants demonstrate phenotypically distinct and more severe symptoms, including PKD, prolonged ataxia attacks, seizures, and other associated neurological manifestations such as learning difficulties, intellectual disability, and autism (ASD). ⁵ Acetazolamide (ACZ), as with other types of episodic ataxia, can help alleviate this symptom. ⁶

Case Report

Pregnancy, delivery, and the neonatal period were uneventful. When the patient was 2 months old, she began having epileptic seizures characterized by loud screaming, blinking, and mouth clonic movements, as well as generalized tonic–clonic seizures (GTCS). The patient began receiving valproic acid (VPA). She started holding her head up at 5 months, sat up at 7 months, and started walking independently at 18 months. She did, however, have a very severe language delay.

The patient was admitted at 2 years old for episodic ataxia. Drowsiness was confirmed by problems holding up the head, axial hypotonia, truncal ataxia, motor incoordination, and dysmetria, which made moving and sitting difficult. She was unable to stand. All ancillary tests were normal, except for hyponatremia of 128 mmol/L and video electroencephalogram (EEG), which revealed decreased basal activity and monomorphic delta activity in the right temporo‐occipital area, as well as diffuse voltage depression in the left hemisphere. Brain magnetic resonance imaging (MRI) revealed modest fluid‐attenuated inversion recovery (FLAIR) hyperintensity of uncertain relevance in both cerebellar lobes. Because of these findings, VPA was switched to clonazepam (CZP). However, she experienced a GTCS, and CZP was substituted for levetiracetam (LEV). She did not receive ACZ during this episode. During this admission, she also presented generalized dyskinetic movements, which were later restricted to the right side of the body, as well as dystonic right arm and leg position and orolingual dystonia (see Video 1). ASD features were also noted.

VIDEO 1.

(A) The patient had extensive dyskinetic movements, especially in the right hemibody. She required the support of the chair to remain upright. (B) The patient was lying in bed and exhibited predominantly right‐sided dyskinetic movements. The face muscles exhibited similar dyskinetic movements. At the conclusion of this segment of the video, it appeared that these movements had ceased. (C) Generalized dyskinesias were visible again in this segment of the video, notably in the right hemibody.

At 3 years of life, brain MRI revealed modest accentuation of the superior cerebellar foliae, whereas brain MRI at 6 years of age was normal. Considering the occurrences of paroxysmal PKD, CBZ started at the age of 3.5 years.

At the age of 11, she experienced another episode of episodic ataxia caused by a viral infection, characterized by gait disturbance with imbalance and an increased base of support. Although she was conscious, she did not do as many spontaneous things as she usually did. When she attempted to sit with assistance, she displayed dyskinetic/ballistic involuntary axial and upper and lower extremity movements and dystonic distal, which made sitting or standing difficult. Neither this episode nor the prior one exhibited myokymia, nystagmus, tonic upgaze deviation, torticollis, or associated hemiplegia. Therefore, carbamazepine (CBZ) was increased to 25 mg/kg/day on the first day of admission, and ACZ was started at a dose of 20 mg/kg/day. The following day, 24 hours after the initiation of ACZ, a positive evolution occurred, with progressive improvement in gait instability, adequate axial control, and the cessation of involuntary dystonic trunk and extremity movements. The mother reported an increase in drowsiness because the CBZ dose was increased. However, when the dose was reduced, the drowsiness resolved and the ataxia did not recur. Because of the presence of mild acidosis during admission, the dose of ACZ was reduced to 15 mg/kg/day. She received ACZ for 10 weeks.

At 11 years of age, the polymerase chain reaction (PCR) and Sanger sequencing of the exons and intronic flanking regions of the PRRT2 gene revealed the following variants: c.649dupC and c.649delC. The variant c.649dupC was inherited from her mother, and the variant c.649delC was inherited from her father (see Figure S1). The mother and maternal uncle both suffered from afebrile epileptic seizures during their first year of life and were treated with antiepileptic medication until they reached the age of 10. They do not suffer from paroxysmal dyskinesias. The father was asymptomatic.

At the age of 18 years, she has been free of dyskinesia, seizures, and episodic ataxia episodes for several years under CBZ treatment. She speaks around five words, but she can repeat two‐word phrases like “sit here.” She understands prohibitions as well as her own name and basic commands. She had difficulty falling asleep, which improved with the addition of melatonin. She exhibits frequent head stereotypies. She goes to a special education school and is completely dependent on others to do her daily activities (ASD level 3).

Discussion

Ten patients have been described in the literature with biallelic PRRT2 variants (Fig. 1), with only two of these patients not presenting with episodic ataxia attacks. ⁶ , ⁷ These episodes of ataxia can be present as early as 1 year of age and can be prolonged, lasting up to 6 weeks (see Table 1). Despite the fact that Labate et al ⁶ reported that ACZ improved episodic ataxia, only one biallelic PRRT2 patient has been treated with ACZ since the initial report. ⁸

TABLE 1.

Summary of episodic ataxia attacks reported in patients with homozygous PRRT2 variants

Reference (patient)	Age	Sex	PRRT2 variants	Ataxia attacks characteristics	Treatment
Labate et al 6 (IV2)	16	M	c.649dupC/c.649dupC	Patient has presented with episodes since the age of 5 years old; he had 1 episode with blurred vision, sometimes leading to falls without loss of consciousness, lasting from 60 min up to 24–72 h; there were no identifiable precipitants	LMT, ACZ
Labate et al 6 (IV4)	7	M	c.649dupC/c.649dupC	Patient had no ataxia attacks; he had been treated earlier with ACZ	LMT, ACZ
Huang et al 1 (PA0234)	25	F	c.931C > T/c.931C > T (uniparental disomy)	Patient has presented episodes since the age of 12 years old; she had 2 episodes lasting a week each	NA
Delcourt et al7 (1)	15	M	c.649dupC/c.649delC (de novo)	Patient has presented episodes since he was 18 months old; he had 6 episodes of strabismus and vomiting, lasting 10 days to 6 weeks	CBZ
Delcourt et al7 (2)	20	M	c.649dupC/ c.649dupC	No	CBZ, PHT
Delcourt et al7 (3)	15	F	c.649dupC/ c.649dupC	Patient has presented episodes since she was 6 years old; she had 2 episodes following a febrile illness, with headache, vomiting, dysarthria, and dyskinesia, lasting 2 weeks	LMT
Delcourt et al7 (4)	25	F	c.649dupC/c.649dupC	Patient has presented episodes since she was 7 years old; she had 3 episodes, preceded by 1–2 days of vomiting; during the episodes, she had rigidity of the body, distal chorea, and swallowing difficulties requiring nasogastric tube feeding, lasting 5–6 days	LMT
Delcourt et al7 (5)	5,5	F	c.913G > A/c.913G > A	Patient has presented with episodes since she was 1 year old; she had 4 episodes of somnolence, vomiting, and pyramidal tract signs, lasting 2–4 weeks	No
Najmabadi et al 14 (M010)	NA	NA	c.639_640insC/c.639_640insC	NA	NA
El Achkar et al 8 (P1)	4	M	c.649dupC/c.913G > A	Patient has been presenting with episodes since he was 2 years old; he had 2 episodes, including ataxia and inability to walk, with or without nausea and vomiting, occurring spontaneously or following clusters of seizures or minor head trauma, lasting 1–3 weeks	OXC, LEV, PB, ACZ

Abbreviations: ACZ, acetazolamide; CBZ, carbamazepine; LEV, levetiracetam; LMT, lamotrigine; OXC, oxcarbamazepine; PB, phenobarbital; PHT, phenytoin; NA, not available.

Interestingly, acute ataxia attacks have also been described in heterozygous PRRT2 patients, ³ even with neuroimage alterations, including transient cerebellar diffusion‐weighted imaging (DWI) hyperintensity and decreased ADC. ⁹ Contrary to this, none of these alterations have been reported in biallelic PRRT2 patients.

Other disorders, such as KCNA1 (episodic ataxia, type 1, OMIM#160120) and CACNA1A (episodic ataxia, type 2, OMIM#108500), have been associated with ataxic episodes. The severity of KCNA1 episodic ataxia is very variable, with symptoms triggered by sudden movement, stress, fatigue, and illness. Attacks often last between seconds and minutes, and patients exhibit myokymia. Moreover, episodes of ataxia in CACNA1A are often longer, lasting anywhere from an hour to several days, and are frequently accompanied by torticollis, tonic upgaze deviation, and nystagmus. Similar to biallelic PRRT2, both disorders had a positive response to ACZ, although neither condition is related to ASD or paroxysmal kinesigenic dyskinesia, despite the fact that the semiology of these episodes may be difficult to characterize. ¹⁰

Mutations in SCN8A (OMIM*600702), ADCY5 (OMIM*600293), SLC16A2 (OMIM*300095), and RHOBTB2 (OMIM*607353) are also involved with complex PKD attacks with some particular characteristics. ¹¹ , ¹² The length of PKD episodes, the existence of epilepsy, hypotonia, or intellectual disability, and the exacerbation of the movement disorder during sleep, among other variables, distinguish these disorders. The description of PKD in these disorders has been established in recent years; therefore, we did not consider a differential diagnosis for our patient.

Some authors have studied the differences between patients with biallelic or heterozygous variants of PRRT2. Fruscione et al ⁵ found that homozygous PRRT2 induced pluripotent stem cells (iPSC)‐derived human neurons display increased Na⁺ current densities and intrinsic hyperexcitability. Aj et al ¹³ found slower traverse time in homozygous Prrt2 knockout mice, consistent with the ataxia seen in humans with biallelic PRRT2 variants.

In summary, we present a case of a patient with biallelic PRRT2 variants with severe autism, intellectual disability, paroxysmal kinesigenic dyskinesia, and prolonged ataxia attacks, and urge that these patients be treated with ACZ during the ataxia attacks.

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.

L.M.: 1C, 3B

A.M.: 1C, 3B

B.P.D.: 1C, 3B

J.D.O.E.: 1A, 1B, 1C, 3A, 3B

Disclosures

Ethical Compliance Statement: The legal guardians gave their written consent to the recording of the patient for publication, and the study received ethical approval by the Ethics Committee (ART‐02‐22). 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: No specific funding was received for this work. The authors declare that there are no other conflicts of interest relevant to this work. The authors declare that there are no additional disclosures to report.

Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.

Supporting information

Figure S1. Sanger sequencing confirming the c.649dupC/c.649delC variants in the proband, the c.649delC variant inherited from her father, the c.649dupC inherited from her mother and the normal PRRT2 sequencing in a control.