Concomitant Calcium Channelopathies Involving CACNA1A and CACNA1F: A Case Report and Review of the Literature

Calcium channels are an integral component in maintaining cellular function. Alterations may lead to channelopathies, primarily manifested in the central nervous system. This study describes the clinical and genetic features of a unique 12-year-old boy harboring two congenital calcium channelopathies, involving the CACNA1A and CACNA1F genes, and provides an unadulterated view of the natural history of sporadic hemiplegic migraine type 1 (SHM1) due to the patient’s inability to tolerate any preventative medication. The patient presents with episodes of vomiting, hemiplegia, cerebral edema, seizure, fever, transient blindness, and encephalopathy. He is nonverbal, nonambulatory, and forced to have a very limited diet due to abnormal immune responses. The SHM1 manifestations apparent in the subject are consistent with the phenotype described in the 48 patients identified as part of a systematic literature review. The ocular symptoms of CACNA1F align with the family history of the subject. The presence of multiple pathogenic variants make it difficult to identify a clear phenotype–genotype correlation in the present case. Moreover, the detailed case description and natural history along with the comprehensive review of the literature contribute to the understanding of this complex disorder and point to the need for comprehensive clinical assessments of SHM1.


Voltage-Gated Calcium Channels
Excitable cells are defined as containing voltage-gated ion channels and responding to depolarization by triggering electrical impulses. Voltage-gated calcium channels (VGCCs) rely on calcium (Ca 2+ ) to induce the change in the action potential. They function as an integral part of cellular regulation, both in maintaining membrane potential as well as controlling intracellular Ca 2+ levels [1,2]. Due to the calcium channel's key role in cell activities, any alteration to their structure will modify gating, resulting in too much or too little Ca 2+ intracellularly [1,2]. Not only does the channel change alter the cell's ability to respond to depolarization, but also its ability to regulate essential processes such as gene transcription, neurotransmitter release, hormone secretion, and enzymatic activity, resulting in multisystem dysregulation and diseases, termed "calcium channelopathies" [1,2]. The VGCC superfamily includes ten genes (Table 1) with tissue-dependent expression patterns [2]. The L-type, P/Q-type, N-type, R-type, and T-type channels have all been shown to be expressed in the brain as well as in other tissues to varying degrees [1,2]. An example of the pervasive effects of calcium channelopathies is apparent in patients carrying mutations in

SHM1 a CACNA1A-Related Phenotype
Hemiplegic migraine is an atypical acute form of migraine currently known to be caused by genetic mutations in CACNA1A, ATP1A2, SCN1A, and PRRT2 [3]. As an allelic disease, CACNA1A pathogenic variants result in multiple phenotypes, including hemiplegic migraine, ataxia, and epilepsy [3][4][5]. The hemiplegic migraine produced by pathogenic CACNA1A variants can be as mild as transient episodes of unilateral paralysis with headache or as severe as long-term hemiparesis with coma, seizure, respiratory distress, cerebral edema, fever, acute encephalopathy, and ataxia [3,4,[6][7][8]. Although the hereditary form of hemiplegic migraine caused by CACNA1A variants-familial hemiplegic migraine 1, or FHM1 (OMIM #141500)-has been studied extensively, the far broader and more severe sporadic form of the disorder that is produced by de novo variants-sporadic hemiplegic migraine 1, or SHM1-has had limited clinical description in humans [5,8].
CACNA1A maps on chromosome 19p13.1 and is translated into the main protein, subunit α 1A of the P/Q type voltage-gated neuronal channel, Ca V 2.1. The CACNA1A gene product contains six membrane-spanning regions (S1-S6) that comprise four equivalent domains (DI-DIV). The S4 region acts as a voltage sensor, while S5-loop-S6 is the Ca 2+ -discerning pore. The channel facilitates Ca 2+ ion entry into the cell contributing to the maintenance of calcium homeostasis, which is integral in multiple cellular pathways, including gene expression and neurotransmitter discharge [9,10]. Alterations to the channel can cause either loss of function (LOF), in which channel production or activity is significantly reduced, or gain of function (GOF), in which the channels are produced but have abnormal properties. LOF variants have been linked to episodic ataxia and epilepsy [10]. GOF variants have similarly been associated with ataxia, developmental delay, and epilepsy, but also hemiplegic migraine. It has been postulated that the GOF variants associated with hemiplegic migraine results in increased susceptibility to neuronal hyperexcitability with an abnormal glutamate release and decreased ceiling for cortical spreading depression, which is the initiation of hemiplegic migraine [11,12].
Investigators hypothesize that the type of alteration, GOF or LOF, as well as variant location within the gene result in the spectrums of phenotypic presentations [4,5,11]. Due to small cohorts and short-term follow-up, these correlations have eluded current investigations [5].

CACNA1F-Related Phenotype
CACNA1F is located on chromosome Xp11.23, comprising 48 exons, and produces a subunit of the L-type calcium channel Ca v 1.4. Ca v 1.4 is structurally similar to Cav2.1, with six transmembrane regions (S1-S6), repeated in four equivalent domains (I-IV) [13]. However, as an L-type channel, it is responsible for the transfer of large amounts of current [14]. Initially, Ca v 1.4 was believed to be expressed only in the retina. However, it was more recently discovered in the adrenal glands, bone marrow, brain, muscle, spine, spleen, and thymus, with implications regarding potential immune regulation [13,14].
In retinal neurons, Ca v 1.4 channels are situated at photoreceptor terminals and are responsible for the tonic Ca 2+ entry needed to facilitate a sustained neurotransmitter release [13]. Without the channel's unique properties, including activation at a negative potential and delayed voltage-dependent deactivation, the retina would not function properly [14,15]. Alterations in the Ca v 1.4 structure have been shown to result in a host of retinal disorders, including incomplete congenital stationary night blindness type 2 (CSNB2, OMIM #3000071), Aland island eye disease (AIED, OMIM #300600), and X-linked rod and cone dystrophy type 3 (CORDX3, OMIM #300476) [14,16,17].
With the identification of Ca v 1.4 in immune system tissue, including bone, spleen, lymph nodes, and thymus, researchers investigated how a voltage-gated channel may impact a non-excitable cell, a point lacking current consensus [14,18]. Over the next few years, multiple scientists uncovered that L-type calcium channels, specifically Ca v 1.4, were expressed in lymphocytes and postulated the integral role in T lymphocyte development, regulation, activation, and death through optimal Ca 2+ signaling [18][19][20][21]. Additionally uncovered were novel splice variants, Ca v 1.4a and Ca v 1.4b, that alter the voltage-gating properties of the channel [22]. In Ca v 1.4a, exons 31-34 and 37 are removed, which eliminates the voltage sensor for domain IV [17,22]. Alternative splicing in Ca v 1.4b removes exons affecting the potential voltage gating properties and causes a frameshift resulting in 40% homology with Ca v 1.1 at the C-terminus [22]. This channel variant is no longer responsive to membrane depolarization and potentially responsive to antigen binding instead [18]. Studies have demonstrated that Ca v 1.4 deficient mice express a phenotype of T lymphocyte dysfunction and potentially immunodeficiency [21]. The impact of the CACNA1F gene on the immune system is highly controversial and still under debate.

Case Report
This case report describes the first patient ever documented with two concomitant pathogenic variants in genes coding for Ca 2+ channel proteins, CACNA1A and CACNA1F. Additionally, this patient provides a "pure" natural history of CACNA1A-related SHM1 due to his incapacity to tolerate any oral therapeutics, a valuable contribution to generalizable knowledge about the disorder. The resulting clinical presentation is complex, possibly due to multiple phenotypes and the systemic effects of Ca 2+ channelopathies. SHM1 has been coupled with a diverse group of signs, and the complete phenotype may include other established disorders. Therefore, the purpose of this case report is to document the longitudinal history of SHM1 and compare this case to the phenotypes from pathogenic variants noted in the literature to elucidate where the SHM1 phenotype ends, and the CACNA1F phenotype begins. With most published data focused on the milder familial form (FHM1), there is a misconception that headache with hemiparesis is the only manifestation in a patient with SHM1 when seen by clinicians (Supplementary Document S1). This fallacy can lead to unnecessary invasive testing, improper therapeutic interventions, and delays in obtaining an accurate diagnosis [23][24][25]. Regarding the second identified pathogenic variant, research on the CACNA1F gene encoding the L-type channel has primarily focused on its manifestations in the eyes, with recent studies highlighting its expression in other tissues [14,18]. Through the description of the longitudinal disease history presented by the reported case, this study strives to broaden the clinicians' knowledge on diagnosing and managing complex patients with simultaneous rare disorders.

Objectives
This investigation aimed to present a unique case study of a child harboring two calcium channel pathogenic variants, CACNA1A and CACNA1F, and to describe a clear natural history of the SHM1 disorder, never illustrated in the literature before due to the complication of concomitant therapeutics. An additional aim of this study was to conduct an original systematic literature review to describe the complete phenotype of SHM1 related to CACNA1A variants both during hemiplegic migraine episodes and outside of attacks, since all previous reviews have focused on the milder familial form (FHM1). Finally, the case was compared to the complete SHM1 phenotype described in the review to determine where the CACNA1F variant may be influencing the expressed phenotype in the patient.

Ethical Protocols
The case study protocol complies with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board at Children's Hospital of Philadelphia. Written informed consent was obtained from the subject's parents in the case report prior to the initiation of the study.

Systematic Review Procedure
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [26] guidelines were utilized to perform a systematic literature review. The search strategy is included in Section 2.3, and the inclusion/exclusion criteria are contained in Section 2.4. A two-step process was employed to screen the original article pool, beginning with the titles/abstracts, and followed by the entire text. Zotero Citation Manager (Version 5.0.96.3; Roy Rosenzweig Center for History and New Media, 2021) and the PRISMA flow diagram map captured the articles and the sifting process, respectively (Supplementary Document S1). Pertinent data were abstracted from reviewed publications and compiled.

Search Strategy
MEDLINE, through EBSCO, PubMed via NIH, and Web of Science by way of Clarivate, were the databases searched. The terminology was developed in consultation with a research librarian employing keywords and MeSH terms (Supplementary Document S1). To ensure all patients were captured, the term "Sporadic" was not included, since de novo patients are often incorrectly diagnosed with familial hemiplegic migraine type 1 (FHM1), not sporadic hemiplegic migraine type 1 (SHM1). Additional articles were identified through bibliography searches with matching inclusion criteria.

Criteria for Inclusion
Inclusion criteria included published manuscripts in peer-reviewed journals. Dissertations, meetings, congresses, or any other gray literature were omitted. Only articles published in English were integrated. Since CACNA1A was first identified in 1996, the included publication dates spanned from 1996 to 11 May 2022, when the search was terminated. Literature titles and abstracts were reviewed for phenotypic information on human patients diagnosed with hemiplegic migraine from a de novo CACNA1A variant. Articles describing pathophysiology, functional studies, or therapeutics lacking phenotypic information were excluded. Studies centered on animals, or cell culture but not on human patients were excluded. After the title and abstract review, all included articles were subject to full-text analysis.

Data Collection
The primary researcher abstracted the information from the studies during the complete article analysis. An excel spreadsheet was crafted for data collection with column titles including study design, authors, publication year, location, number of patients, patient sex, age at diagnosis, variant, phenotype reported information, additional clinical manifestations, unique findings, limitations, and article citation in APA format (Supplementary Document S2). To better summarize the symptoms experienced during a hemiplegic attack, another table was created in excel describing each participant included in the first review (Supplementary Document S3). All the phenotypic presentations outside of hemiplegic episodes were extracted from the original table and transferred to a new chart that links the participant to the features (Supplementary Document S4).

Case Report
A 12-year-old Caucasian male without any dysmorphic features was diagnosed at seven years of age with SHM1. At the evaluation, his height was 145 cm (30th centile), his weight was 39 kg (46th centile), and his head circumference was 55.5 cm (75th centile). The subject suffers periodic attacks that include migraine with hemiparesis in conjunction with noninfectious fever, vomiting, encephalopathy, seizure, cerebral edema, and transient blindness. Outside of attacks, the patient exhibits hypotonia, and paroxysmal events, including dyskinesia, and has documented cerebellar atrophy since 2014 at age 4. The patient experiences abnormal responses of the immune system to the exposure to all food outside of pork, sweet potatoes, and apple juice. If this extremely limited diet is altered, the result is a severe hemiplegic attack with cerebral edema and status epilepticus. He is nonverbal and nonambulatory and has been diagnosed with autism spectrum disorder and intellectual disability. Currently, the patient is not on any preventative therapeutic interventions.

Developmental History
The patient is the youngest child in a family with two older healthy siblings, a maternal half-sister, and a full sister. The parents suffered three miscarriages-including one case with trisomy 22-before the patient's birth. His maternal uncle died at age 17 from complications from coarctation of the aorta. He was exposed, in utero, to pityriasis rosea during the 16th week of gestation. Born at 39 weeks of gestation via vaginal birth after induction due to complications from preeclampsia and immune thrombocytopenic purpura (ITP), the patient had a posterior occipital presentation. At birth, his weight was 3.912 kg (75th centile), and he was 50.8 cm long (75th centile), with a 34 cm head circumference (50th centile), and his Apgar score was 9 both at 1 min and at 5 min. The patient experienced developmental delay. He rolled at one year old but could not sit without support at 15 months. Due to the severity of the developmental delay, the patient received physical therapy as well as occupational and speech therapy with slow improvement. By the age of five years, he could sit independently and crawl on his abdomen to move around the room.
Since the age of seven, with assistance and the use of a walker, the patient can ambulate for short durations.

Neurological History
By three months of age, the child was seen by pediatric neurology and diagnosed with moderate hypotonia, mild nonfixed torticollis, mild inconsistent "sun-setting" or downward-gaze, and megacephaly (>97 • centile). At 21 months, the patient suffered his first attack. Figure 1 provides a graphic of the natural history of the disorder over time. Table 2 offers a synopsis of attacks (see Supplementary Document S5 for a more detailed description of each attack). He suffered from episodes of transient hemiplegia and vomiting, which became more frequent at 11 years of age and included paroxysmal dyskinesia. At that time, a propensity for focal seizures due to spikes seen on EEGs during hemiplegic attacks was identified. It was later determined that the patient was inadvertently exposed to mold in the home for over a year during an increased frequency of hemiplegic events. It is unclear why the presentation of the more recent episodes, post-puberty, lacked coma, lethargy, and vomiting and included involuntary movements with impaired consciousness. It may be due to the evolution of the disorder or tied to medications used to treat each attack.

Medical History
Within his first year, the patient developed periodic noninfectious fevers (102-103 • F) for 24-48 h with and without hives that continued throughout his first decade. After the first "attack", an allergist/immunologist evaluated the patient, who suspected Food proteininduced enterocolitis syndrome (FPIES). Radioallergosorbent test (RAST) testing uncovered a severe airborne allergic reaction to peanuts and multiple other IgE-mediated allergens. The allergist recommended removing all foods from the patient's diet and reintroducing them one at a time to determine intolerances, which resulted in identification of toleration of only the two foods the patient tolerated and is currently eating. All subsequent food trials resulted in moderate to severe episodes. Due to his immune issues, the patient is homeschooled to reduce the chances of exposure to airborne allergens that have been linked to past episodes. The patient was diagnosed with scoliosis and hip dysplasia, which were addressed through physical therapy and monitored for progression by an orthopedist. At six years of age, the patient was diagnosed with myopia, hyperopia, astigmatism, and "abnormal" gaze development.
with moderate hypotonia, mild nonfixed torticollis, mild inconsisten downward-gaze, and megacephaly (>97° centile). At 21 months, the p first attack. Figure 1 provides a graphic of the natural history of the d Table 2 offers a synopsis of attacks (see Supplementary Document S5 f description of each attack). He suffered from episodes of transient hem ing, which became more frequent at 11 years of age and included parox At that time, a propensity for focal seizures due to spikes seen on EEGs attacks was identified. It was later determined that the patient was inad to mold in the home for over a year during an increased frequency of h It is unclear why the presentation of the more recent episodes, post-pub lethargy, and vomiting and included involuntary movements with im ness. It may be due to the evolution of the disorder or tied to medica each attack.

Medical History
Within his first year, the patient developed periodic noninfectiou F) for 24-48 h with and without hives that continued throughout his the first "attack", an allergist/immunologist evaluated the patient, wh protein-induced enterocolitis syndrome (FPIES). Radioallergosorbent t uncovered a severe airborne allergic reaction to peanuts and multiple o allergens. The allergist recommended removing all foods from the pati troducing them one at a time to determine intolerances, which resulte of toleration of only the two foods the patient tolerated and is currently quent food trials resulted in moderate to severe episodes. Due to his i patient is homeschooled to reduce the chances of exposure to airborne a been linked to past episodes. The patient was diagnosed with scoliosis which were addressed through physical therapy and monitored for orthopedist. At six years of age, the patient was diagnosed with myopia matism, and "abnormal" gaze development.

Diagnostic Assessment
Multiple diagnostic testing modalities were employed, including basic metabolic and genetic assays, general laboratory panels, neurologic examination through magnetic resonance imaging (MRI), electroencephalogram (EEG), autism evaluation, cardiac studies, ocular evaluations, and multiple immune panels.

Genetic and Metabolic Testing
Initial genetic and metabolic testing were all negative and included a newborn screening panel, urine organic acids, blood amino acids, chromosomal microarray, and mitochondrial testing. After the diagnosis of SHM1, the family traveled to see a specialist who recommended whole-exome sequencing, suspecting multiple pathogenic variants. The exome was performed as a trio (patient and both parents) by GeneDx and revealed two likely pathogenic variants in the proband: a de novo missense c.2102G>A, p.Gly701Glu variant in CACNA1A, and a maternally inherited c.2322-2G>A variant in CACNA1F, disrupting the canonical splice acceptor site in intron 17. The mother of the patient is affected with congenital stationary night blindness, a CACNA1F-associated disorder. The full sister also has the familial CACNA1F variant but is unaffected. It is unknown whether the truncated CACNA1F protein results in an abnormal protein or nonsense-mediated mRNA decay. A third pathogenic variant in the BRCA2 gene was identified (c.4808dupA, p.N1603KfsX6) but has no impact on the patient's neurological health. Since this variant is associated with an increased risk of multiple cancers in adulthood, future screenings have been recommended.

MRI
An initial MRI was performed during the first severe attack at age 21 months, and it was suspicious for encephalitis. Subsequent MRIs were performed at every severe HM event, one outside of the HM event, and rapid sequences or abbreviated MRIs at minor HM events (Figure 2).

EEGs
EEGs were captured on all severe attacks and were initially normal until the onset of hemiplegia during the third attack. The one-sided paralysis was apparent in slowing on the corresponding side, with a slow background pattern observed throughout all subsequent EEGs. The slowing was seen when hemiplegia occurred. Diffuse encephalopathy with the right hemisphere demonstrating more cortical dysfunction as well as focal spikes were noted during his last EEG at 11 years and 9 months.

Labs
The patient's labs during an episode always suggested sepsis, including high WBC and CRP, yet the cultures verified the noninfectious nature of the symptoms. CSF findings documented lymphocytic pleocytosis on numerous occasions. Labs consistently revealed acidosis, high glucose, and low calcium.

Cardiac Evaluation
Due to a family history of congenital cardiac abnormalities, the patient was evaluated by a pediatric cardiologist. An echocardiogram and EKG were performed at three years of age and again at age seven years eight months during a severe attack when a murmur was noted with unremarkable findings.

Ocular Assessment
The patient was initially evaluated by a pediatric ophthalmologist at two years of age and again after losing his vision during his fifth severe attack. Ophthalmological findings were unremarkable, with a normal optic nerve. Within three months, the patient's vision returned. Subsequently, it was determined by an ophthalmologist that cortical blindness was the cause of his temporary loss of vision post-attacks.

Immune Analysis
Initial testing at age 2 looked at immune markers revealing consistently high IFNg. An autoimmune panel was negative. At age 4, an investigation into the patient's T and B Cells revealed low CD3 1382 (T Cells) (normal range 1484-5327 cells/µL), and an immunoglobulin assay uncovered a low IgG score 642 (normal range 700-1600 mg/dL). Once diagnosed with CACNA1F, an immunologist ran an extensive immune panel, including the proinflammatory cytokine panel, extended lymphocyte panel, B Cell panel, functional natural killer assay, sedimentation rate, and C-reactive protein combo, with unremarkable findings. This was performed during a time of no attacks and showed high IFN-g 8.

Therapeutic Interventions and Follow-Up
Due to an inability to tolerate most foods and a hyperimmune response, all daily preventative therapeutic interventions have failed. Within a few hours of starting verapamil 40 mg at age seven, the patient developed transient premature ventricular contractions and accelerated ventricular rhythm, although the reaction cleared as was seen on a 24 h Holter monitor. Within a few days, the patient vomited shortly after taking the medication, and it was discontinued. During the most recent attack, the protocol by Camia et al. [27], which consisted of dexamethasone IV 0.5 mg/kg/day, three pulses for up to three days, was employed and resulted in a significant reduction in the duration and severity of the attack. Twenty variants were identified among the 48 patients: 18 of them were missense, one was a deletion, and one disrupted a splice site. Almost all the variants were located either in the voltage sensor (S4) or in the pore-forming channel (S5-loop-S6) of any of the four domains (DI-DIV). The two exceptions were one alteration of a splice site (c.3825+1G>A) and the p.Phe363Ser substitution (p.F363S in Figure 3), which is situated on the I-II linker near the α-interaction domain (AID). The highest concentration of mutations, 9 of the 20, were positioned in domain III (45.0%), and 4 of them spanned the S4 voltage sensor (Figure 3). The amino acid substitutions varied from staying within polarity and hydrophilic/hydrophobic grouping to significant alterations such as going from nonpolar to polar or vice versa. Moreover, some shifts included exchanging a positively charged amino acid for a neutral one.

A Review of the
Twenty variants were identified among the 48 patients: 18 of them were missense, one was a deletion, and one disrupted a splice site. Almost all the variants were located either in the voltage sensor (S4) or in the pore-forming channel (S5-loop-S6) of any of the four domains (DI-DIV). The two exceptions were one alteration of a splice site (c.3825+1G>A) and the p.Phe363Ser substitution (p.F363S in Figure 3), which is situated on the I-II linker near the α-interaction domain (AID). The highest concentration of mutations, 9 of the 20, were positioned in domain III (45.0%), and 4 of them spanned the S4 voltage sensor (Figure 3). The amino acid substitutions varied from staying within polarity and hydrophilic/hydrophobic grouping to significant alterations such as going from nonpolar to polar or vice versa. Moreover, some shifts included exchanging a positively charged amino acid for a neutral one.

Symptoms During Hemiplegic Attacks N (%)
Migraine with aura 33/33 (100%)   Table 4). Six patients had no other symptoms other than hemiplegic migraine episodes [25,28,35,41], and two patients' phenotypes, other than hemiplegic incidents, were not defined (Supplementary Document S4) [3,7]. The most common comorbid feature in patients with SHM1 is movement disorders (80.4%). The symptoms range from jitteriness in infancy to progressive ataxia. Ataxia in multiple forms was documented, including early-onset ataxia, which presents within the first twenty-four months of life [10]. One patient (#29) lost the ability to ambulate by age 13 due to progressive cerebellar ataxia [8]. LeRoux et al. expanded on the ataxic phenotype to include other movement disorders, such as dystonia and choreoathetosis [33]. Falling under the dystonia umbrella is hypotonia, which was reported in 52.2% of patients, often occurring in infancy. Pyramidal signs, which include spasticity, weakness, hyperreflexia, and positive Babinski sign, were also noted in this patient population [33]. The tremor was exhibited in 23.9% of patients, leading to a Parkinson-like clinical presentation. Lastly, dyskinesia, an all-inclusive term to represent uncoordinated movements, can be seen periodically in this group (Table 4).

Global Developmental Delay and Intellectual Disability
Global developmental delay (GDD) and intellectual disability (ID) are also highly prevalent in the SHM1 population (Table 4). Delays in head control, sitting, crawling, and walking are widespread. Sometimes, the motor delay resolves, while improvement is not apparent in other cases [5]. Decline in function was observed in one case, where the patient lost the ability to ambulate at an undisclosed age prior to the age of six, after a prolonged hemiplegic event [33]. Included are multiple cases of nonambulatory patients [10,32]. Dysarthria is frequently noted, regarding verbalization and verbal acuity (28.3%). Like lack of ambulation, multiple nonverbal patients are reported throughout this review [30,32,33]. ID is more ubiquitous than GDD and can range from mild to profound. With mild classification correlating to IQ scores from 50 to 69, moderate from 36 to 49, severe from 20 to 35, and profound below 20 [42]. Of the 30 patients identified with ID, 10/30 (33.3%) were not defined, 9/30 (30%) were listed as mild, 4/30 (13.3%) were classified as moderate, and 7/30 (23.4%) were severe with no patients grouped in the profound class [5,6,28,29,31]. For nonverbal patients, the specific degree of impairment can be difficult to assess but estimates using IQ testing and other means were included in many of the studies [5,6,9,10,23,24,28,29,31,33,34,36,39]. Autism spectrum disorder (ASD) was documented in only 3 of the 48 patients (6.25%) [6,33].

Brain Atrophy and Abnormal EEGs
Cerebellar Atrophy is a frequently reported manifestation of SHM1 (75.7%), as seen in MRI and computed tomography (CT). It is usually not an initial finding but typically occurs after multiple hemiplegic attacks later in childhood or early adolescence [4,6,30]. Nearly one-third (32.1%) of cases were reimaged after multiple years, and attacks exhibited progressive atrophy or degeneration (Table 4). Abnormal EEGs are common for patients with SHM1 during hemiplegic attacks ( Table 3). The results cited in the literature discuss EEGs measured during hemiplegic attacks and demonstrate slowing backgrounds corresponding to the side of the brain edema and the opposite side of paralysis. Occasionally, spike waves were observed. No baseline nor follow-up post-resolution of hemiplegia EEGs were disclosed (Supplementary Document S3) [5,8,12,23,25,31,32,35,39,41].

Paroxysmal Events and Abnormal Eye Movements
Paroxysmal movements consist of periodic unintentional actions and have been recently documented in SHM1 patients before they exhibit hemiplegic attacks. Episodic events may be linked to migraine because both are repeated short-lived assaults [30]. Paroxysmal disorders specific to this patient population include benign paroxysmal torticollis (BPT), paroxysmal tonic upgaze (PTU), benign paroxysmal vertigo (BPV), and paroxysmal ataxia (PA). Nine patients were acknowledged to have at least one of these conditions, and three were diagnosed in infancy (Table 4) [5,6,8,30,34]. Another early signal of SHM1 is abnormal eye movements, specifically nystagmus and strabismus. Nearly 50% of patients in this review presented with either or both features, and many manifested in early childhood (Table 4) [4][5][6]10,24,25,[31][32][33][34]40].

A Scoping
Within the 54 patients, thirty-one variants were detected. Twelve missense mutations made up most of the pathogenic variants, followed by eight nonsense mutations, six splice site variants, and five deletions. The variant type and location did not appear to correlate to the severity of the phenotypes captured in this review (Supplementary Document S7). Patients with early termination nonsense mutations or deletions did not present as any more severe than those who suffered from later missense variants. Unlike CACNA1A, where variants in the voltage sensor and pore-forming channel proved the most damaging, the variants appear equally deleterious throughout the channel. This heterogeneity may be related to the discovery of 19 alternative splice variants during an extensive investigation of the retina, which suggests that different splicing may relate to the mechanism of how calcium influx is maintained in L-type channels, specifically Ca v 1.4 [18].

Neurocognitive Signs
With CACNA1F expression in the presynaptic regions of the hippocampus and cerebellum and the Ca v 1.4 channel's role in neurotransmitter release, alterations in the protein are linked to multiple neurocognitive disorders [55]. Like other channelopathies, intellectual disability is evident in this patient population. It does not appear to be as common as retinal dystrophies but was documented in eight patients (14.8%). Epilepsy (5.3%) and autism spectrum disorder (ASD) (5.3%) were also noted in three patients, respectively [55].

Immune Symptoms
Although discussed in animal models in the literature, no studies in humans have been published to elucidate the possible immune manifestations apparent in subjects harboring CACNA1F pathogenic variants [18][19][20][21][22].

Discussion
The systematic literature review identified forty-eight patients diagnosed with CACNA1A-SHM1 and detailed the severe neurologic symptoms during and outside of attacks, capturing a comprehensive description of the phenotype and matching the case in all but two symptoms: phonophobia and seizures outside of hemiplegic attacks ( Table 5). The case patient is nonverbal, so assessment of phonophobia is not possible.  In 2000, the grave symptoms affiliated with SHM1 surprised investigators when they identified the first de novo case [31] after exclusively studying families with inherited CACNA1A variants associated with the familial form, FHM1. The phenotypes for SHM1 and FHM1 are strikingly different. The literature review has highlighted the clinical differences between patients with SHM1 versus the more recognized FHM1 by providing the most complete description of their phenotype during and outside attacks. In alignment with these findings, the case patient exhibited the hallmark severe symptoms seen by patients with SHM1 in the literature, including early dystonia, paroxysmal events, cerebellar atrophy, and GDD, while the attacks were significantly more critical with prolonged encephalopathy.
In conjunction with the CACNA1F phenotype described in the scoping literature review, the patient presented with intellectual disability and ASD, although being consistent with the CACNA1A phenotype as well. Present in the case family is CSNB2A, similar to most of the subjects included in the review. Currently, the patient has not been evaluated due to sensitivity to reagents used for diagnosis. Finally, the immune manifestations do not align with the SHM1 phenotype reported in the literature, bringing into question the impact of the CACNA1F variant on the case study's phenotype, but without data, conclusions remain uncertain.

Limitations
Different study designs were used for the systematic review including case reviews, cross-sectional studies, and observational cohorts. Some studies conducted systematic patient assessments while others focused on a few specific clinical features potentially under-reporting certain symptoms. It was assumed that if a symptom was not reported, it was not present, which may erroneously underestimate the prevalence of clinical features. Longitudinal data was rarely available, and until this case study, the natural history of SHM1 was not documented. For the case report, medical records came from four different children's hospitals, and seven years of testing introduced variations in equipment and staffing, which can lead to interpretational differences in diagnostic images.
A rigorous systematic literature review was conducted using PRISMA guidelines, including two reviewers and an arduous procedure employing three databases to capture all documented cases. However, articles may have been overlooked. The primary review created the largest sample to date of 48 patients with SHM1. All patients were systematically assessed for a comprehensive evaluation.

Clinical Implications
This case report with the included systematic literature review and scoping review has multiple clinical implications. It clearly highlights that hemiplegic attacks associated with SHM1 are serious, unpredictable, and require an immediate, accurate diagnosis. Patients with SHM1 display significant challenges beginning in early childhood with paroxysmal events and GDD. Over time, the continuous periodic assaults are associated with increasing brain atrophy. This complete picture may help clinicians establish an earlier diagnosis, avoiding unnecessary invasive tests to rule out other infectious agents and provide the best supportive care possible. However, SHM1 is still understudied and lacks a complete phenotypic presentation, demanding future investigations to uncover a more comprehensive natural history of the disorder and potentially expose triggers that initiate these periodic attacks. The demonstrated case of an individual treated without any preventative medications allows us to assess the distribution of hemiplegic migraine attacks over time and highlights no clear pattern. Both severity and time of recurrence are difficult to estimate.

Future Research Directions
This investigation identified multiple knowledge gaps in need of future research. Longitudinal natural history studies are required to assess CACNA1A-SHM1 and to develop an age-dependent phenotype. Most data populated in clinical ontologies for CACNA1A lack the comprehensive phenotype terminology associated with the more severe SHM1, which is not fully captured in OMIM. Likewise, the differences in hemiplegic migraine are not captured in Human Phenotype Ontology, and neither is there a disease classification. Larger studies are essential to explore the genotype-phenotype correlation between specific variants and phenotypes and should consider epigenetic factors during the investigation, specifically gene expression patterns for CACNA1A.

Conclusions
With an accompanying systematic literature review, this case report offers a unique perspective into a rare, understudied disorder. It is the first documented case of the natural history of SHM1 without preventative therapeutics and the first description of a single patient harboring two calcium channel pathogenic variants. The review focusing on CACNA1A-SHM1 has not been reported previously in the literature. This investigation identified the clinical features and increased severity of SHM1 compared to FHM1 and demonstrates the demand for improved therapeutics to treat this disorder. The information provided may help diagnose new patients earlier and identify clinical features of concern. In this case, the patient's symptoms correlate with nearly all the severe symptoms seen in patients with SHM1 in the literature. However, it is difficult to relate the immune phenotype in the case to its corresponding genotype due to the lack of comprehensive data for CACNA1F, highlighting the difficulties in rare disease research to attribute symptoms to specific modifying genes.  Informed Consent Statement: Informed consent was obtained from the patient's family involved in the case study.

Data Availability Statement:
The data presented in this study are available in the Supplementary Materials.