Rare Disease Day: Updates on Rare Neurological Diseases

Since 2008, the medical field has honored those with rare diseases of all varieties on February 28, designated as Rare Disease Day. Established by the European Organisation for Rare Diseases in an effort to raise awareness, the day has been celebrated globally since 2009, when the National Organization for Rare Disorders offered its hand in spreading the day to others, helping to get advocacy groups in the United States—and eventually around the world—to observe the day.

NeurologyLive^® partners with a number of rare disease advocacy organizations—including the ALS Association, Cure SMA, the Dravet Syndrome Foundation, the Lennox-Gastaut Syndrome Foundation, the TSC Alliance—aiming to increase awareness and inform clinicians of the latest advances for these rare and challenging-to-treat disorders. As such, in observance of Rare Disease Day, the team has compiled this roundup of the current state of care and treatment for a number of rare diseases implicated in neurological care, including Pompe disease, Duchenne muscular dystrophy, and Charcot-Marie Tooth disease, among others.

Kleine-Levin Syndrome

Kleine-Levin syndrome, a rare disorder of sleep that is characterized by hypersomnolence, compulsive hyperphagia, and behavioral changes, affects an estimated 1-3 individuals per million,^1-3 though the exact prevalence is unknown due to its rarity and under-diagnosis. A 2005 literature search by Arnulf et al between 1962 and 2004 identified 186 cases.⁴ The disorder primarily occurs in adolescent men, often at a rate 3-fold higher than occurs in women, though women have had longer disease course, on average.²

Treatment for Kleine-Levin syndrome has been a clinical challenge for some time, with no definitive or targeted therapies available to address the condition, and response to standard approaches—often with anticonvulsant medications and stimulants—has been historically refractory.^1,2 Lithium, phenytoin, carbamazepine, valproate, and phenobarbital have been administered during interepisodic periods, though only lithium has a reported a response rate significantly higher than medical abstention.^2,4 Some success has been demonstrated with amphetamines in treating sleepiness, but no benefits for other associated symptoms have been shown.² The recently updated American Academy of Sleep Medicine guidelines offered a conditional suggestion that clinicians use lithium for the treatment of Kleine-Levin syndrome in adult patients, though the task force noted that the overall quality of evidence for its use was very low, having been downgraded due to imprecision.⁵

For more related to Kleine-Levin syndrome, head here:

• New AASM Guideline for Treatment of Central Disorders of Hypersomnolence: Lynn Marie Trotti, MD
• AASM Guideline Updates Recommendations for Central Disorders of Hypersomnolence

Lennox-Gastaut Syndrome

Lennox-Gastaut syndrome (LGS) is a developmental brain disorder that frequently evolves from early-life-onset epilepsy. In LGS, seizures typically begin in the pre-school years, and LGS usually emerges between 3-5 years of age. The disorder is estimated to occur in 0.1-0.28 people per 100,000 and is believed to account for 1%-4% of all cases of childhood epilepsy.⁶ The annual incidence in children is estimated to be 2 per 100,000 children. LGS is a developmental and epileptic encephalopathy, which means that they will have developmental and behavioral problems as well as epilepsy, with these problems worsened by seizures and seizure activity. Children without a history of epilepsy may develop LGS, although this is rare. Most cases of LGS are evolved from another type of epilepsy.⁷

There are several different FDA-approved medications that treat seizures associated with LGS, although no specific therapy has proven to be effective in all cases. Therapies such as topiramate (Topamax; Ortho-McNeil Neurologics), lamotrigine (Lamictal), rufinamide (Banzel; Eisai), are used as add-ons, while medications like felbamate (Felbatol; Meda Pharmacueticals), clobazam (Onfi; Lundbeck), and most recently, cannabidiol (Epidiolex; GW Pharmaceuticals), can be used as main therapeutic options.⁸ Due to the severity of the disease, individuals often use between 3-5 concomitant antiseizure medications at once. There are also surgical options like palliative surgery and neuromodulation, which includes vagus nerve stimulation, responsive neurostimulation, and deep brain stimulation. All of these require some type of surgery to implant the device.

For more related to Lennox-Gastaut syndrome, head here:

• Ganaxolone Associated With Decreased Seizure Frequency in Patients With CDD, LGS
• FDA Accepts sNDA, Grants Priority Review to Fenfluramine for Lennox-Gastaut syndrome
• Investigational Encephalopathy Agent LP352 Safe and Effective in Phase 1 Trial
• NIH Awards Funding to Study RNS System in Lennox-Gastaut Syndrome

Dravet Syndrome

Dravet syndrome (DS), also known as Severe Myoclonic Epilepsy of Infancy (SMEI), is a rare form of intractable epilepsy that begins in infancy and proceeds with accumulating morbidity that significantly impacts individuals throughout their lifetime.⁹ A 2016 study by E Wu. et al determined that the syndrome affects 1 in every 15,700 infants born in the US, with approximately 80% of those diagnosed as having an SCN1A mutation.¹⁰ The presence of this mutation alone is not sufficient for diagnosis, nor does the absence of a mutation exclusion the diagnosis. These patients will suffer from other comorbidities aside from seizures, including developmental delay and abnormal EEGs, which are often not evident until the second or third year of life.

Based on a 2017 North American Consensus Panel, there are several first, second, and third line antiseizure medications recommended. They include clobazam, valproic acid, stiripentol, topiramate, ketogenic diet, clonazepam, levetiracetam, zonisamide, ethosuximde, and vagus nerve stimulation.¹¹ Other common antiseizure medications such as carbamazepine, oxcarbazepine, lamotrigine, phenytoin, and vigabatrin were considered contraindicated medications because of their known profile to exacerbate seizures. The first FDA-approved drug was GW Pharmaceuticals’ cannabidiol in 2018, which was also approved for LGS at the same time.¹² Shortly after, the FDA approved stiripentol (Diacomit; Biocodex) in a capsule and powder formulation, for the treatment of seizures associated with DS.¹³ In 2020, the FDA added its third medication to the market, approving Zogenix’s fenfluramine oral solution.¹⁴ The medication does include a boxed warning for risk of valvular heart disease and pulmonary arterial hypertension.

For more related to Dravet syndrome, head here:

• Serotonin Receptor Agonisim in Dravet Syndrome
• Vaccination and Seizure Risk in Dravet Syndrome: Veronica Hood, PhD, MS
• The Comprehensive Management of Dravet Syndrome
• Insights: Dravet Syndrome: Fenfluramine and the Impact on Consensus Guidelines

Cerebral Palsy

Approximately 1 in 345 children are identified with cerebral palsy (CP), giving it the distinction as the most common motor disability of childhood. Made up of a group of disorders, CP is more common in boys than girls, and more common in Black children than White. Spastic CP, which results in stiffness, is found in about 75-85% of children with CP.¹⁵ Congenital CP, the damage occurring in the brain before or during birth, is mainly the cause for CP. Factors such as being born too small, too early, born a twin or other multiple birth, or having an infection during pregnancy, can all increase the risk for congenital CP. Diagnosis for CP occurs usually during the first or second year after birth.

Although there is no current method of preventing CP, individuals can lower their risk in several ways. Continuing prepregnant health habits throughout pregnancy, regular screening for potential complications, and continual check-ups with an obstetrician have all been recommended.¹⁶ CP is not expected to get worse over time, and patients may use various medications to help control spastic movements, seizures, relieve pain, and manage symptoms. These include stool softeners, anticholinergics, anticonvulsants, baclofen (Fleqsuvy; Azurity Pharmaceuticals) and other muscle relaxants, sleep aids, antacids, and diazepam. Children may also option for more commonly used therapies like physical, occupational, feeding, and speech, among others, to help improve physical, mental, social, and learning deficits.

For more related to cerebral palsy, head here:

• Spasticity, Dystonia Commonly Under-Identified in Children With High Cerebral Palsy Risk
• Actigraphy Identified as a Valid Tool for Sleep Assessment in Children With Cerebral Palsy
• BotulinumtoxinA Improves Spasticity in Adults With Cerebral Palsy
• Podcast: Mind Moments: Episode 33: Problem Recognition: Cerebral Palsy Diagnosis

Duchenne Muscular Dystrophy

A genetic disorder characterized by progressing muscular atrophy and degeneration and weakness, Duchenne muscular dystrophy (DMD) is a result of alterations to dystrophin protein expression and production. DMD is inherited in an X-linked recessive pattern and can occur in those who do not have a family history of it.¹⁷ DMD is among a group of 4 conditions known as dystrophinopathies, the other 3 diseases being Becker Muscular dystrophy (BMD, a mild form of DMD); an intermediate clinical presentation between DMD and BMD; and DMD-associated dilated cardiomyopathy with little or no clinical skeletal, or voluntary, muscle disease.^17,18 Symptom onset most often occurs in early childhood between ages 2 and 3 years. The disease primarily affects boys, but in rare cases it can affect girls. In Europe and North America, the prevalence of DMD is approximately 6 per 100,000 individuals.^19-21

Patients with DMD and their clinicians do have a number of therapies available to them, though none yet are curative. Corticosteroids, such as prednisone and deflazacort (Emflaza; PTC Therapeutics), are often used to aid muscle strength and delay the progression of certain types of muscular dystrophy. The conditional approval of eteplirsen (Exondys 51; Sarepta), an antisense oligonucleotide targeting skipping of exon 51, by the FDA in 2016 marked the first DMD-targeted therapy to receive a conditional approval in the US; subsequent approvals have included exon 53 skipping treatment with golodirsen (Vyondys 53; Sarepta) and viltolarsen (Viltepso; NS Pharma) and exon 45 skipping treatment with casimersen (Amondys 45; Sarepta). Heart medications, such as angiotensin-converting enzyme inhibitors or beta blockers, if muscular dystrophy damages the heart, can be employed as well.^18,22,23

For more related to Duchenne muscular dystrophy, head here:

• Genetic Neurodegenerative Disorders: Close to a Symptom-Free Life?
• Capricor Announces Partnership for DMD Therapy CAP-1002 Ahead of Phase 3 Study
• Insights: Future of Treating DMD

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease, is a progressive neurodegenerative disease affecting nerve cells in the brain and spinal cord, leading to loss of muscle control.²⁴ Experts have yet to identify the underlying cause of ALS, but the condition is inherited in roughly 10% of cases and begins with muscle twitching and weakness, and/or slurred speech. According to the Rare Disease Database, ALS affects 1.5 to 3 per 100,000 people per year in North America and Europe, with an estimated 5000 new diagnoses each year and approximately 30,000 patients currently affected in the US.²⁵

As ALS can mimic other neurological diseases, it can be challenging to diagnose, and there is no available treatment that can reverse damage, solely slowing symptom progression. Currently, there are 2 FDA-approved treatments, riluzole (Rilutek; Sanofi), which is taken orally and has the potential to increase life expectancy by 3-6 months, and edaravone (Radicava; MTPA), which is given by IV infusion and has demonstrated effectiveness in reducing the decline in daily functioning. While edaravone’s effect on life expectancy remains a question, a new drug application for Mitsubishi Tanabe Pharma America’s oral formulation of the treatment (MT-1186) was recently accepted by the FDA and given priority review for the treatment of ALS, with a Prescription Drug User Fee Action date set for May 12, 2022.²⁶

Several clinical trials are ongoing in ALS, including a Compassionate Use Clinical Trial recently initiated by Zhittya Genesis Medicine to evaluate its proprietary FGF-1 biological drug with an intranasal delivery device.26 ZZ Biotech has a phase 2 trial (NCT05039258) underway to evaluate 3K3A-APC, a genetically engineered variant of human active protein C that previously saw success in acute ischemic stroke, and Amylyx Pharmaceuticals has begun patient dosing in the phase 3 PHOENIX study (NCT05021536) evaluating AMX0035, an investigational combination agent for patients with ALS.^27,28

For more related to ALS, head here:

• Compassionate Use Clinical Trial of FGF-1 Initiated for Amyotrophic Lateral Sclerosis
• Cognitive and Behavioral Involvement in ALS May Be Distinct Phenotype
• Long-Term IV Edaravone Not Associated With Disease-Modifying Benefit in ALS

Pompe Disease

Pompe disease is a rare, inherited lysosomal disease, manifesting in 3 variations: classic infantile-onset, appearing within a few months of birth; non-classic infantile-onset, appearing at about 1 year; and late-onset, which appears later in childhood, during adolescence, or during adulthood.²⁹ According to Cleveland Clinic, the Pompe disease affects 1 person in every 40,000, and approximately 1 out of every 28,000 babies born in the US are born with the condition. A variation in the GAA gene causes the disease, with the glycogen building damaging muscles and affecting mobility. Early detection and treatment can assist in prolonging life expectancy, particularly for those with late-onset variations, when the disease progresses at a slower rate, but patients with classic infantile-onset rarely live past 1 year of age.³⁰

The only approved treatment for Pompe disease is enzyme replacement therapy, requiring biweekly IV administration of recombinant human acid alphaglucosidase (GAA) (Nexviazyme) for the treatment of late-onset variations in patients 1 year and older.³¹ More recently, positive interim safety data were reported from the phase 1/2 FORTIS study (NCT04174105) of AT845, an investigational adeno-associated gene replacement therapy that delivers a functional GAA gene to express GAA directly into muscle cells, in adults with late-onset Pompe disease. According to interim findings collected from 4 enrolled patients, the treatment was well-tolerated, with no serious adverse events reported at the time of the data cut.³² Tahseen Mozaffar, MD, FAAN, director, UC Irvine-MDA ALS and Neuromuscular Center, director, Division of Neuromuscular Diseases, Neurology School of Medicine, and professor of neurology, pathology, and orthopaedic surgery, University of California, Irvine, recently shared what he had to say about the data thus far in a conversation with NeurologyLive^®.

For more related to Pompe disease, head here:

• Positive Interim Phase 1/2 Safety Data Reported for AT845 in Adults With Late-Onset Pompe Disease
• Avalglucosidase Alfa Approved for Late-Onset Pompe Disease

Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease caused by a mutation in the SMN1 gene, affecting approximately 1 in 11,000 births in the US. Those with SMA don’t produce survival motor neuron protein at levels that are high enough, impacting muscles used for breathing, eating, crawling, and walking, which can sometimes be fatal. The disease is the number 1 genetic cause of death in infants, and babies are diagnosed with 1 of 4 types of SMA, depending on the age when symptoms begin and the highest physical milestone they have achieved.³³

Most existing treatments, such as risdiplam (Evrysdi; PTC Therapeutics/Roche), nusinersen (Spinraza; Biogen), and onasemnogene abeparvovec (Zolgensma; Novartis) are SMN-enhancing treatments that target the SMN2 gene, which naturally produces a small amount of SMN protein to be used in the body, but not enough. Other treatments such as apitegromab (SRK-015; Scholar Rock) and intrathecal AVXS-10 (Zolgensma; Novartis), are non-SMN-enhancing, dubbed muscle drugs.33 Most recently, encouraging interim data from the RAINBOWFISH study (NCT03779334) evaluating risdiplam—a treatment being explored in several concurrent trials—supported a supplemental new drug application for the therapy, which was granted priority review by the FDA for presymptomatic babies younger than 2 years of age, having already been approved for children older than 2 years.³⁴ Cure SMA, an organization aimed at funding and directing research to hopefully eradicate SMA, further advocates for standardized newborn screening as a way to positively impact outcomes in the disease.

For more related to SMA, head here:

• Risdiplam Gets Priority Review for Presymptomatic SMA in Babies Under 2 Months
• Phase 3 SAPPHIRE Trial of Apitegromab in SMA Types 2, 3 Announced

Charcot-Marie Tooth disease

Charcot-Marie Tooth (CMT) disease, also known as hereditary motor sensory neuropathy, is among the most commonly occurring inherited neurological disorders. Named after Jean-Martin Charcot, Pierre Marie, and Howard Henry Tooth, current estimates set its prevalence at approximately 19 per 100,000 individuals, with about 126,000 patients in the United States and 2.6 million on a global scale.^35,36 CMT is characterized by muscle weakness and atrophy, as well as the loss of sensation in the lower legs and feet, with the hands, wrists, and forearms sometimes affected as well. CMT also often causes contractures, and occasionally scoliosis or kyphosis.^35,37

There are 6 main subtypes of CMT, including CMT1, which causes myelin sheath abnormalities; CMT2, which is less common and occurs as a result in peripheral nerve cell axon abnormalities; CMT3, also known as Dejerine-Sottas disease, is a severe form of the disease that presents as demyelinating neuropathy; CMT4, which is a composition of multiple subtypes of axonal and motor neuropathies; and CMTX1, which is the second most common form and an X-linked disease driven by connexin-32 protein gene mutations.³⁵

Currently, no curative treatment is available for CMT, and commonly used approaches include only supportive ones—physical and occupational therapies, and orthopedic devices and surgeries are often used to manage symptoms. A number of approaches, the bulk of which aimed at treating CMT1, have been assessed in clinical trials, though none have failed to show significant improvements in treated patients. Medical diagnosis of CMT is most often made by the neurological specialist, but optimal management is multidisciplinary in nature, and includes genetic counselors, physical and occupational therapists, physiatrists, orthotists, social workers, mental health providers, and community resources.^35,38

For more related to Charcot-Marie Tooth disease, head here:

• PXT3003 Meets Phase 3 Primary End Point in Charcot-Marie-Tooth Disease Type 1A
• Physical Activity a Useful End Point for Charcot-Marie-Tooth Disease Trials
• The State of Charcot-Marie-Tooth Disease: An In-Depth Interview With K. Florian P. Thomas, MD

Rett Syndrome

Rett syndrome, which affects girls more often than boys, is a rare genetic neurological disorder with a prevalence of 1 in 10,000 girls. Most boys with the condition die before birth or in early infancy. It often begins to present amid missed milestones or regression around 6-18 months of age, with a hallmark symptom of near constant repetitive hand movements while awake. The syndrome leads to severe impairments, affecting speech, walking, eating, and breathing ability, and it can cause seizures and intellectual disability.^39,40 An estimated 90%-95% of Rett syndrome cases are caused by identifiable mutations of the MECP2 gene, of which more than 200 different mutations have been identified.⁴¹

The syndrome is divided commonly into 4 stages.⁴⁰ The first, early onset, begins between the ages of 6 and 18 months, during which babies may show less eye contact and lose interest in toys, as well as develop delays in sitting or crawling. The second stage is characterized by rapid deterioration during ages 1-4 years, with loss of skills occurring quickly or gradually, and the symptoms of Rett syndrome beginning to present. The third stage, occurring most often between ages 2 and 10 years, is a plateau. There may be limited improvement in behavior and movement, though seizures may also begin in this stage. The fourth and final stage, late motor deterioration, usually begins after the age of 10 years and can persist for decades. Communication and hand skills may remain stable and seizure rates can decline, with the stage marked mainly by reduced mobility, muscle weakness, joint contractures, and scoliosis.

Although there is no cure for Rett syndrome, potential treatments are being studied, including blarcamesine (Anavex Life Sciences) and trofinetide (Acadia Pharmaceuticals), among others. Treatment of the disorder is complex, with current guidelines suggesting a focus on improving movement and communication, treating seizures, and providing care and support.^40,42 Treatment options are similarly complex and varied, with highly individualized approaches needed based on each individuals’ needs. Early developmental intervention is crucial to ensure that affected children reach their potential, and the majority of affected children benefit from occupational, physical, and speech therapy, and other methods of rehabilitative and behavioral therapy have shown benefit.

For more related to Rett syndrome, head here:

• Blarcamesine Shows Promise as Potential Rett Syndrome Treatment, New Data Indicate
• Trofinetide Meets Primary, Secondary End Points in Phase 3 Rett Syndrome Study

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12. FDA Approves first drug comprised of an active ingredient derived from Marijuana to treat rare, severe forms of epilepsy. News release. FDA. June 25, 2018. Accessed February 15, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms
13. FDA approves Diacomit (Stiripentol) for the treatment of seizures associated with Dravet syndrome (DS) in patients 2 years of age and older taking clobozam. News release. Biocodex. August 23, 2018. Accessed February 15, 2022. https://www.prnewswire.com/news-releases/fda-approves-diacomit-stiripentol-for-the-treatment-of-seizures-associated-with-dravet-syndrome-ds-in-patients-2-years-of-age-and-older-taking-clobazam-300701663.html
14. FDA approves Fintepla (fenfluramine) for the Treatment of Seizures Associated with Dravet Syndrome. News release. Zogenix. June 25, 2020. Accessed February 15, 2022. https://www.globenewswire.com/news-release/2020/06/26/2053803/0/en/FDA-Approves-FINTEPLA-fenfluramine-for-the-Treatment-of-Seizures-Associated-with-Dravet-Syndrome.html
15. 11 things to know about cerebral palsy. Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/cp/features/cerebral-palsy-11-things.html. Updated February 9, 2022. Accessed February 15, 2022.
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26. Mitsubishi Tanabe Pharma America announces FDA acceptance of new drug application (NDA) for oral edaravone formulation for the treatment of ALS. News release. Mitsubishi Tanabe Pharma America, Inc. January 12, 2022. Accessed February 14, 2022. https://www.prnewswire.com/news-releases/mitsubishi-tanabe-pharma-america-announces-fda-acceptance-of-new-drug-application-nda-for-oral-edaravone-formulation-for-the-treatment-of-als-301459460.html
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28. Amylyx Pharmaceuticals announces participants dosed in the global phase 3 PHOENIX study of AMX0035 in ALS. News release. Amylyx Pharmaceuticals. November 4, 2021. Accessed February 14, 2022. hsttps://www.businesswire.com/news/home/20211104005663/en/Amylyx-Pharmaceuticals-Announces-Participants-Dosed-in-the-Global-Phase-3-PHOENIX-Study-of-AMX0035-in-ALS
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31. FDA approves Nexviazyme® (avalglucosidase alfa-ngpt), an important new treatment option for late-onset Pompe disease. News release. Sanofi Genzyme. August 6, 2021. Accessed February 14, 2022. https://www.sanofi.com/en/media-room/press-releases/2021/2021-08-06-17-42-21-2276588
32. Astellas announces positive safety data from the FORTIS study of AT845 in adults with late-onset Pompe disease. News release. February 7, 2022. Accessed February 14, 2022. https://www.biospace.com/article/releases/astellas-announces-positive-safety-data-from-the-fortis-study-of-at845-in-adults-with-late-onset-pompe-disease/
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34. Genentech’s Evrysdi (risdiplam) granted FDA priority review for treatment of presymptomatic babies under 2 months of age with spinal muscular atrophy (SMA). News release. Genentech. January 25, 2022. Accessed February 17, 2022. https://www.biospace.com/article/releases/genentech-s-evrysdi-risdiplam-granted-fda-priority-review-for-treatment-of-pre-symptomatic-babies-under-2-months-of-age-with-spinal-muscular-atrophy-sma-/
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37. Charcot-Marie-Tooth Disease. Mayo Clinic website. Accessed February 18, 2022. https://www.mayoclinic.org/diseases-conditions/charcot-marie-tooth-disease/symptoms-causes/syc-20350517
38. McCorquodale D, Pucillo EM, Johnson NE. Management of Charcot–Marie–Tooth disease: improving long-term care with a multidisciplinary approach. J Multidiscip Healthc. 2016;9:7-19. doi:10.2147/JMDH.S69979
39. About Rett Syndrome. Rett Syndrome Foundation website. Accessed February 18, 2022. https://www.rettsyndrome.org/about-rett-syndrome/
40. Rett Syndrome. Mayo Clinic website. Updated October 11, 2018. Accessed February 18, 2022. https://www.mayoclinic.org/diseases-conditions/rett-syndrome/symptoms-causes/syc-20377227
41. Rett Syndrome. National Organization for Rare Diseases website. Accessed February 18, 2022. https://rarediseases.org/rare-diseases/rett-syndrome/
42. Fu C, Armstrong D, Marsh E, et al. Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatrics Open. 2020;4:e000