Effect of Acetazolamide in a Child with CACNA1A Channelopathy, Refractory Seizures, and ADHD

Article information

Ann Child Neurol. 2025;33(3):126-129

Publication date (electronic) : 2025 June 25

doi : https://doi.org/10.26815/acn.2025.00822

Thanisha Santhosh, MBBS, Prakriti Ramamurthy, MBBS, Divya Nagabushana, MD

Department of Neurology, Ramaiah Medical College, Bengaluru, India

Corresponding author: Divya Nagabushana, MD Department of Neurology, Ramaiah Medical College, MSRIT Post, Mathikere, Bengaluru 560054, India Tel: +91-80-62153125 E-mail: divya.nagabushana@gmail.com

Received 2025 February 11; Revised 2025 April 6; Accepted 2025 May 8.

Variants in the calcium voltage-gated channel subunit alpha1 A (CACNA1A) gene, located on chromosome 19p13, are implicated in diverse neurological syndromes, including epileptic encephalopathy, episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6), and familial hemiplegic migraine type 1 (FHM1) [1]. Often, calcium channelopathies are comorbid with behavioral disorders such as autism spectrum disorder and attention deficit hyperactivity disorder (ADHD), although this association is poorly documented. Herein, we report a case of a female child carrying the novel heterozygous missense variant c.5996c>T (p.Pro1999Leu) at exon 42 (NM_000068.4) of CACNA1A, who presented with intractable seizures complicated with ADHD and was treated with acetazolamide. This article describes the patient’s favorable response to acetazolamide, which alleviated the symptoms of her CACNA1A channelopathy.

A 10-year-old girl born of a non-consanguineous marriage presented with a history of right-sided focal motor clonic seizures involving her right-sided extremities since the age of 6. She was the second-born child, with an unremarkable birth and family history. Her developmental milestones were achieved normally. There was no family history of epilepsy. The first seizure episode occurred while the child was asleep and lasted approximately 30 seconds, manifesting as rhythmic jerking of her right extremities. Her subsequent episodes were nocturnal for 2 years and later occurred during wakefulness. All episodes were stereotypically characterized by clonic jerks of the right upper and lower extremities with preserved awareness. Initially, she was started on valproate and, later, clobazam; however, she continued to have seizures over the next 2 years, increasing in frequency to 4–5 times per week. Electroencephalography (EEG) during this period showed left centrotemporal interictal epileptiform sharp-wave discharges with a normal posterior dominant rhythm. Over the subsequent 3 years, she was administered various antiseizure medications (ASMs), including phenytoin, brivaracetam, and lacosamide. She developed side effects and intolerance to phenytoin and, subsequently, valproate, both of which were discontinued. Nevertheless, seizures remained frequent, occurring 1–3 times per day. A repeat awake EEG during this period showed continuous generalized 2–4 Hz slowing with no discernible posterior dominant rhythm. Serological investigations performed to evaluate for autoimmune encephalitis were negative. A course of oral prednisolone given during this time led to a transient improvement. She presented to our neurology clinic at this juncture with an increased frequency of focal motor seizures after the steroids had been tapered.

Additionally, a history of deterioration in scholastic performance, irritability, and hyperactivity was reported by the parents. Her physical and neurological examinations were within normal limits. She was referred for psychological evaluation to assess for ADHD and undergo developmental assessment. The Vanderbilt ADHD Diagnostic Parent Rating Scale was administered, yielding a significant score of 13, consistent with ADHD. Developmental assessment using the Vineland Social Maturity Scale revealed a social quotient of 60, indicating a delay in acquiring social and adaptive skills. Magnetic resonance imaging (MRI) of the brain performed externally demonstrated normal cerebral parenchyma, mild ventriculomegaly, and hypoplasia of the inferior vermis. Investigations evaluating metabolic etiologies—such as plasma and urine gas chromatography-mass spectrometry for metabolic disorders, biotinidase levels, folic acid, ammonia, lactate, and uric acid—were negative. Whole-exome sequencing was advised due to early-onset drug-refractory non-lesional focal motor seizures accompanied by behavioral changes. A heterozygous missense mutation c.5996c>T (p.Pro1999Leu) at exon 42 (NM_000068.4) of CACNA1A was identified. This variant was observed in the GnomAD Exomes at a minor allele frequency of 0.00001 (frequency <0.05 in the healthy population database). The variant is documented in the database of single nucleotide polymorphism (dbSNP) database (rs866667085) but is not reported in the ClinVar database, and is categorized as a variant of unknown significance with medium impact. Sanger sequencing of peripheral blood samples from the parents did not detect the CACNA1A variant mutation found in the patient, confirming that the mutation was de novo.

As the child continued to have seizures despite treatment with three ASMs, a trial of acetazolamide was initiated. A trial of acetazolamide was started at a dosage of 8 mg/kg/day, while the previous regimen of clobazam, brivaracetam, and lacosamide was continued. During follow-up over the subsequent months, there was a significant reduction in seizure frequency to approximately one seizure every 2 months (a pictorial representation of response to ASMs is shown in Fig. 1) and a marked alleviation of behavioral issues and hyperactivity. The patient tolerated acetazolamide therapy well and reported no adverse symptoms, such as paresthesias, gastrointestinal disturbances, polyuria, tinnitus, or fatigue. Although serial arterial blood gas (ABG) measurements could not be performed due to patient-specific factors, clinical features suggestive of metabolic acidosis, such as Kussmaul breathing, nausea, vomiting, altered sensorium, and headaches, were not documented. The dosage of acetazolamide was gradually titrated to 20 mg/kg/day. Currently, the child experiences seizures approximately once every 2 to 3 months. The patient’s caregivers declined a repeat Vanderbilt assessment; however, during follow-up, the parents reported significant subjective improvement in the child’s behavioral symptoms, including inattention, irritability, and hyperactivity. They also reported that the child’s teachers had observed similar improvements. Her scholastic performance also improved following initiation of acetazolamide therapy. A repeat EEG conducted during this period showed improved background rhythm with infrequent left central epileptiform discharges and intermittent left frontocentral slowing (Fig. 1).

Fig. 1.

(A) A pictorial representation of the reduction in seizure frequency and response to antiseizure medications over time. (B) An electroencephalogram recorded after acetazolamide initiation, showing a normal posterior dominant rhythm, intermittent left frontocentral slowing (broad arrow), and left central sharps (narrow arrow).

The CACNA1A gene, located on chromosome 19p13, encodes the principal subunit of the P/Q-type calcium channel, a high-voltage gated channel responsible for neurotransmission at nerve terminals [2]. Mutations in this gene have been implicated in diverse neurological syndromes, including epileptic encephalopathy and intractable seizures [1].

One study demonstrated correlations between de novo CACNA1A variants and various epileptic entities, including epilepsy of infancy with migrating focal seizures and early-onset epileptic encephalopathy [3]. The management of CACNA1A-associated epilepsies is frequently complicated by poor responses to antiepileptic pharmacotherapy. A study identified a significant association between the TAGAA haplotype of CACNA1A and drug-resistant epilepsy in a cohort of 480 Chinese patients [4]. One of the largest cohorts examining the epilepsy spectrum among patients with pathogenic CACNA1A variants revealed that the phenotypes associated with CACNA1A epilepsy are broad and usually severe. More than half of the patients in this cohort exhibited refractory epilepsy. Most patients demonstrated early cerebellar dysfunction and global developmental delay (DD). MRI findings were frequently abnormal, showing cerebral and cerebellar atrophy [2].

Our patient displayed tendencies of inattention and hyperactivity, which were subsequently corroborated by a diagnosis of ADHD. Currently, there is a scarcity of literature exploring the possible correlation between behavioral and learning disabilities and calcium channelopathies. One study consisting of 16 individuals with loss-of-function mutations of the CACNA1A gene revealed that a substantial proportion of patients experienced DD (38%), intellectual disability (ID, 38%), learning difficulties (25%), and notably, ADHD and impulsivity (69%). These deficits were apparent from early childhood and ultimately significantly impaired educational and social integration [5]. This finding suggests the importance of investigating CACNA1A aberrations in children presenting with global DD, ID, or ADHD, particularly if accompanied by cerebellar symptoms and epilepsy. This evidence is further supported by a study that documented delayed psychomotor development in 50% of a cohort of 18 patients with the same mutation, and academic difficulties in 83% of patients. Notably, patients exhibiting vermian atrophy were found to have a higher risk of cognitive impairment, a finding consistent with the MRI results observed in our patient [6].

Limited data exist, and there are currently no clear recommendations for clinicians managing patients with pathological phenotypic variants of CACNA1A. One study involving a cohort of 18 patients found that ASMs such as topiramate, levetiracetam, lamotrigine, valproate, acetazolamide, and calcium channel blockers like verapamil and flunarizine were effective in seizure control among epileptic phenotypes. This group found that 89% of the cohort responded favorably to topiramate with reduced seizure frequency, while between 50% and 60% responded positively to levetiracetam, lamotrigine, and valproate. Acetazolamide rendered one patient completely seizure-free (5.6%) and reduced seizures in two additional cases (11.1%). However, the authors theorized that the apparent effectiveness of topiramate in controlling epilepsy in CACNA1A channelopathies could potentially be explained by its inhibitory action on the enzyme carbonic anhydrase [2]. Our patient did not achieve seizure control and developed intolerance to valproate, an ASM known for significant calcium channel-blocking properties, as well as to several other ASMs, but experienced a notable reduction in seizure frequency upon initiation of adjunctive acetazolamide therapy (pictorial representation of response to ASMs in Fig. 1).

Acetazolamide has also been previously reported to interrupt and decrease the frequency of attacks of EA2 and FHM1, two pathologic phenotypes of CACNA1A channelopathy; in fact, it was considered the first-line therapy for EA2 [7,8]. Other drugs that have shown promise in the treatment of different phenotypic variants of CACNA1A include 4-aminopyridine and fampiridine in EA2 and SCA6, flunarizine as first line for migraine prophylaxis in FHM1 and topiramate in cases with overlapping phenotypes [8].

Specifically regarding acetazolamide, the precise mechanisms by which this carbonic anhydrase inhibitor improves calcium channel function remain poorly understood. It has been hypothesized that acetazolamide may enhance neurotransmission either by increasing levels of ionized calcium or through a direct effect on P/Q calcium channel function [9]. Additionally, the beneficial effects of acetazolamide have also been attributed to its impact on extracellular and intracellular pH, subsequently influencing potassium currents as well as the opening of sodium and calcium channels [8].

In our case, a variant of unknown significance was identified. Occasionally, variants of unknown significance can be reclassified as pathogenic as additional data accumulates over several years. Given the novel nature of this particular mutation, which, to the best of our knowledge, has not been previously reported, there remains a need for further functional validation, and our single-patient experience must be interpreted with caution. As additional cases with the same mutation emerge, the causal relationship between the observed symptoms and the specific mutation may become better established.

An extensive workup for potential structural, metabolic, and immune-mediated causes of drug-resistant epilepsy yielded negative results. Given that the clinical phenotype was characteristic of calcium channelopathies reported in the literature, a decision was made to attempt seizure treatment with acetazolamide. Remarkably, a significant improvement in behavior, scholastic performance, and seizure frequency was subsequently observed. However, in our case, although subjective alleviation of symptoms was recorded, objective assessments such as repeat Vanderbilt scoring could not be conducted. Therefore, conclusions drawn regarding this observed improvement must be approached carefully. Potential confounding factors, including concurrent medications, the natural progression of the disease, and placebo effects, should be carefully considered and excluded as alternative explanations for the improvements observed in patients who appear to respond favorably to acetazolamide. Ultimately, larger longitudinal studies and controlled trials would be beneficial in providing more convincing and objective evidence supporting a trial of acetazolamide in alleviating not only neurological but also psycho-behavioral symptoms in this population. Additionally, such research would facilitate a better understanding of the underlying mechanisms through which the medication exerts its effects.

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