Botulinum toxin in the treatment of tics

Pandey S, Srivanitchapoom P, Kirubakaran R, Berman BD. Botulinum toxin for motor and phonic tics in Tourette's syndrome. Cochrane Database Syst Rev. 2018 Jan 5;1(1):CD012285. doi: 10.1002/14651858.CD012285.pub2. PMID: 29304272; PMCID: PMC6491277.

Abstract

Background: Gilles de la Tourette syndrome, or Tourette's syndrome, is defined as the presence of both motor and vocal (phonic) tics for more than 12 months, that manifest before the age of 18 years, in the absence of secondary causes. Treatment of motor and phonic tics is difficult and challenging.

Objectives: To determine the safety and effectiveness of botulinum toxin in treating motor and phonic tics in people with Tourette's syndrome, and to analyse the effect of botulinum toxin on premonitory urge and sensory tics.

Search methods: We searched the Cochrane Movement Disorders Group Trials Register, CENTRAL, MEDLINE, and two trials registers to 25 October 2017. We reviewed reference lists of relevant articles for additional trials.

Selection criteria: We considered all randomised, controlled, double-blind studies comparing botulinum toxin to placebo or other medications for the treatment of motor and phonic tics in Tourette's syndrome for this review. We sought both parallel group and cross-over studies of children or adults, at any dose, and for any duration.

Data collection and analysis: We followed standard Cochrane methods to select studies, assess risk of bias, extract and analyse data. All authors independently abstracted data onto standardized forms; disagreements were resolved by mutual discussion.

Main results: Only one randomised placebo-controlled, double-blind cross-over study met our selection criteria. In this study, 20 participants with motor tics were enrolled over a three-year recruitment period; 18 (14 of whom had a diagnosis of Tourette's syndrome) completed the study; in total, 21 focal motor tics were treated. Although we considered most bias domains to be at low risk of bias, the study recruited a small number of participants with relatively mild tics and provided limited data for our key outcomes. The effects of botulinum toxin injections on tic frequency, measured by videotape or rated subjectively, and on premonitory urge, are uncertain (very low-quality evidence). The quality of evidence for adverse events following botulinum toxin was very low. Nine people had muscle weakness following the injection, which could have led to unblinding of treatment group assignment. No data were available to evaluate whether botulinum injections led to immunoresistance to botulinum.

Authors' conclusions: We are uncertain about botulinum toxin effects in the treatment of focal motor and phonic tics in select cases, as we assessed the quality of the evidence as very low. Additional randomised controlled studies are needed to demonstrate the benefits and harms of botulinum toxin therapy for the treatment of motor and phonic tics in patients with Tourette's syndrome.

Moretti A. Is botulinum toxin effective and safe for motor and phonic tics in patients affected by Tourette syndrome? A Cochrane Review summary with commentary. Dev Med Child Neurol. 2020 Mar;62(3):274-276. doi: 10.1111/dmcn.14472. Epub 2020 Jan 20. PMID: 31957864.

Commentary on the above Cochrane review.

Kwak CH, Hanna PA, Jankovic J. Botulinum toxin in the treatment of tics. Arch Neurol. 2000 Aug;57(8):1190-3. doi: 10.1001/archneur.57.8.1190. PMID: 10927800.

Abstract

Objective: To evaluate the safety and efficacy of botulinum toxin A (BTX) injections in the treatment of tics in patients with Tourette syndrome (TS).

Background: BTX is an effective treatment for an increasing number of conditions characterized by abnormal muscle contractions. BTX may improve not only the motor component of tics, but also premonitory sensations that precede tics.

Methods: Thirty-five patients (30 male, 5 female) were treated with BTX in the sites of their most problematic tics. Response to BTX was based on a 0 to 4 clinical rating scale (0, no improvement, to 4, marked improvement in both severity and function). Questionnaires were administered to evaluate patients' impressions of overall efficacy and degree of benefit with premonitory sensations.

Results: Mean duration of tics prior to initial injection was 15.3 years (range, 1-62 years) and mean duration of follow-up was 21.2 months (range, 1. 5-84 months). The mean peak effect response in 35 patients treated in 115 sessions was 2.8 (range, 0-4); the mean duration of benefit was 14.4 weeks (maximum, 45 weeks); and the mean latency to onset of benefit was 3.8 days (maximum, 10 days). Twenty-one (84%) of 25 patients with premonitory sensations derived marked relief of these symptoms (mean benefit, 70.6%). Total mean dose was 502.1 U (range, 15-3550 U); mean number of visits, 3.3 (range, 1-16); and mean dose per visit, 119.9 U (range, 15-273 U). Sites of injections were as follows: cervical or upper thoracic area (17), upper face (14), lower face (7), vocal cords (4), upper back and/or shoulder (3), scalp (1), forearm (1), leg (1) and rectus abdominis (1). Complications included neck weakness (4), dysphagia (2), ptosis (2), nausea (1), hypophonia (1), fatigue (1), and generalized weakness (1), which were all mild and transient.

Conclusions: Botulinum toxin A injections are an effective and well-tolerated treatment of tics. In addition to improving the motor component of tics, BTX also provides relief of premonitory sensations.

Abnormal brain MRI in anti-NMDA receptor encephalitis

Khatib L, Pique J, Ciano-Petersen NL, Criton G, Birzu C, Aubart M, Benaiteau M, Picard G, Marignier R, Carra-Dalliere C, Ayrignac X, Psimaras D, Labauge PM, Honnorat J, Cotton F, Joubert B. Abnormal Brain MRI in Anti-NMDA Receptor Encephalitis: Clinical and Prognostic Implications. Neurol Neuroimmunol Neuroinflamm. 2025 May;12(3):e200378. doi: 10.1212/NXI.0000000000200378. Epub 2025 Feb 25. PMID: 39999393; PMCID: PMC11867192.

Abstract

Background and objectives: Abnormal brain MRI is associated with poor outcomes in anti-N-methyl-d-aspartate receptor encephalitis (NMDARE). We aimed to characterize the lesions on brain MRI in NMDARE and to assess the clinical and prognostic associations.

Methods: This retrospective cohort study included patients with NMDARE identified at the French Reference Center for Autoimmune Encephalitis, with at least a one-year follow-up, and with available brain MRI results. In case of brain extralimbic lesion, the image files were reviewed when available. Clinical data were collected from medical records. Multivariable logistic regression analysis was used to study the outcomes at 2-year follow-up; recovery was defined as modified Rankin Scale score ≤1.

Results: Among the 255 patients included, 37 (14.5%) had limbic hyperintensities and 41 (16.1%) had extralimbic lesions that included multiple sclerosis (MS)-like lesions (14/41, 34.1%); extensive lesions (5/41, 12.2%); and poorly demarcated fluffy lesions, either multifocal (10/41, 24.4%) or involving the cerebral cortex or cerebellum (6/41 each, 14.6%). Extralimbic lesions coexisting with limbic lesions (19/41 patients, 46.3%) were mostly fluffy lesions (11/19, 57.9%). Ten patients had overlapping demyelinating syndromes: 4 with MS, 4 with myelin oligodendrocyte glycoprotein-associated disorder, and 2 with neuromyelitis optica spectrum disorder; all had MS-like (7/10 patients) or extensive (3/10 patients) lesions, and none had fluffy lesions. Extralimbic lesions were associated with symptoms nontypical for NMDARE (23/41, 56.1%, p < 0.001), especially cerebellar ataxia (17/41, 41.5%) and motor impairment (12/41, 29.3%). At 2 years, patients with MS-like or extensive lesions had a lower recovery rate (5/12, 41.7%, and 1/4, 25%, respectively) compared with the patients without extralimbic lesions (124/162, 76.5%; p = 0.014 and p = 0.047, respectively). In multivariable analysis, MS-like lesions, but not hippocampal nor fluffy lesions, were associated with absence of recovery at 2 years (adjusted OR 0.1, 95% CI 0.03-0.42, p = 0.002; extensive lesions [n = 4] not included in the analysis).

Discussion: Brain MRI lesions in NMDARE include limbic hyperintensities and 3 patterns of extralimbic lesions, which are associated with nontypical NMDARE symptoms. Moreover, MS-like and extensive lesions, but not fluffy nor hippocampal lesions, are associated with overlapping demyelinating syndromes and poor clinical outcomes at 2 years. These findings can have practical implications on the monitoring of patients with NMDARE.

Lei C, Chang X, Li H, Zhong L. Abnormal Brain MRI Findings in Anti-N-Methyl-D-Aspartate Receptor Encephalitis and Correlation With Outcomes. Front Neurol. 2022 Mar 14;13:834929. doi: 10.3389/fneur.2022.834929. PMID: 35359628; PMCID: PMC8963947.

Abstract

Purpose: The reported prevalence of abnormal findings by brain MRI varies from 11 to 83% among patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Here, we investigated the prevalence of abnormal MRI findings in Chinese patients and explored whether such findings are correlated with clinical outcomes.

Methods: This retrospective study analyzed a consecutive series of 52 patients with anti-NMDAR encephalitis admitted to our hospital. The patients were assigned to the "MRI-normal" or the "MRI-abnormal" group based on brain MRI after admission. The groups were compared in terms of clinicodemographic characteristics and scores on the Mini-Mental State Examination (MMSE) and modified Rankin Scale (mRS) 3 and 12 months after admission.

Results: Thirty-seven (71.15%) of the patients showed abnormalities on brain MRI; these patients were more likely to be men and showed abnormalities on electroencephalography. Patients who showed normal or abnormal MRI findings did not differ significantly in terms of clinical symptoms, rates of mortality or relapse, or mRS scores after 3 and 12 months. However, patients with abnormal MRI showed significantly lower MMSE scores than those with normal MRI after 3 and 12 months.

Conclusions: We found high prevalence of abnormal MRI findings in our sample of Chinese patients with anti-NMDAR encephalitis. We also found that the abnormal findings were associated with cognitive decline but not necessarily with mortality or functional outcomes in the short or long term.

Association between sun exposure and risk of relapse in pediatric-onset multiple sclerosis

Chang G, Sebastian P, Virupakshaiah A, Schoeps VA, Cherbuin N, Casper TC, Gorman MP, Benson LA, Chitnis T, Rensel M, Abrams AW, Lotze T, Mar SS, Schreiner TL, Wheeler YS, Rose JW, Graves J, Krupp LB, Waldman AT, Lucas R, Waubant E; as the US Network of Pediatric Multiple Sclerosis Centers. Association Between Sun Exposure and Risk of Relapse in Pediatric-Onset Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2025 Mar;12(2):e200375. doi: 10.1212/NXI.0000000000200375. Epub 2025 Feb 12. PMID: 39938013; PMCID: PMC11820808.

Abstract

Background and Objectives

Low sun and ultraviolet radiation (UVR) exposures have been associated with increased risk of developing pediatric-onset multiple sclerosis (MS); however, their effect on disease course has not been well characterized. We primarily investigated whether there was an association between time spent in the sun in early childhood and risk of relapse in pediatric MS. We secondarily investigated the effect of sun exposure during more recent periods on risk of relapse.

Methods

We conducted a multicenter cohort study of participants with pediatric-onset MS recruited from 18 pediatric MS clinics across the United States between November 1, 2011, and July 1, 2017. Relapses were identified prospectively after study enrollment; relapses preceding study enrollment were entered retrospectively. Time spent in the sun at various periods of life was measured using a detailed environmental questionnaire, and ambient UVR exposure was determined using zip codes. Multivariable Cox regression models were used to assess the association between time spent in the sun and UVR dose at specific periods of life and the risk of relapse. Models were adjusted for demographic, clinical, and sun exposure–related characteristics.

Results

In our cohort of 334 children with MS, 206 (62%) experienced at least one relapse from disease onset to the end of the follow-up period. After adjustment, ≥30 minutes of daily sun exposure during the first summer of life was associated with a lower risk of relapse compared with <30 minutes (adjusted hazard ratio [aHR] 0.67, CI 0.48–0.92, p = 0.01). Greater time spent in the sun during the second trimester of pregnancy was also associated with reduced risk of relapse (aHR 0.68, CI 0.48–0.97, p = 0.04). UVR dose and time spent in the sun later in life were not significantly associated with relapse risk.

Discussion

In this large cohort study of children with MS, greater early childhood and prenatal sun exposure time was associated with lower risk of relapse. Further investigation of sun exposure at other periods is needed to better characterize its impact on disease course and guide potential future interventions.

CHD8 mutations in autism and brain development

Hoffmann A, Spengler D. Chromatin Remodeler CHD8 in Autism and Brain Development. J Clin Med. 2021 Jan 19;10(2):366. doi: 10.3390/jcm10020366. PMID: 33477995; PMCID: PMC7835889.

Abstract

Chromodomain Helicase DNA-binding 8 (CHD8) is a high confidence risk factor for autism spectrum disorders (ASDs) and the genetic cause of a distinct neurodevelopmental syndrome with the core symptoms of autism, macrocephaly, and facial dysmorphism. The role of CHD8 is well-characterized at the structural, biochemical, and transcriptional level. By contrast, much less is understood regarding how mutations in CHD8 underpin altered brain function and mental disease. Studies on various model organisms have been proven critical to tackle this challenge. Here, we scrutinize recent advances in this field with a focus on phenotypes in transgenic animal models and highlight key findings on neurodevelopment, neuronal connectivity, neurotransmission, synaptic and homeostatic plasticity, and habituation. Against this backdrop, we further discuss how to improve future animal studies, both in terms of technical issues and with respect to the sex-specific effects of Chd8 mutations for neuronal and higher-systems level function. We also consider outstanding questions in the field including 'humanized' mice models, therapeutic interventions, and how the use of pluripotent stem cell-derived cerebral organoids might help to address differences in neurodevelopment trajectories between model organisms and humans.

Weissberg O, Elliott E. The Mechanisms of CHD8 in Neurodevelopment and Autism Spectrum Disorders. Genes (Basel). 2021 Jul 26;12(8):1133. doi: 10.3390/genes12081133. PMID: 34440307; PMCID: PMC8393912.

Abstract

Chromodomain-helicase-DNA-binding protein 8 (CHD8) has been identified as one of the genes with the strongest association with autism. The CHD8 protein is a transcriptional regulator that is expressed in nearly all cell types and has been implicated in multiple cellular processes, including cell cycle, cell adhesion, neuronal development, myelination, and synaptogenesis. Considering the central role of CHD8 in the genetics of autism, a deeper understanding of the physiological functions of CHD8 is important to understand the development of the autism phenotype and potential therapeutic targets. Different CHD8 mutant mouse models were developed to determine autism-like phenotypes and to fully understand their mechanisms. Here, we review the current knowledge on CHD8, with an emphasis on mechanistic lessons gained from animal models that have been studied.

Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, Witherspoon K, Gerdts J, Baker C, Vulto-van Silfhout AT, Schuurs-Hoeijmakers JH, Fichera M, Bosco P, Buono S, Alberti A, Failla P, Peeters H, Steyaert J, Vissers LELM, Francescatto L, Mefford HC, Rosenfeld JA, Bakken T, O'Roak BJ, Pawlus M, Moon R, Shendure J, Amaral DG, Lein E, Rankin J, Romano C, de Vries BBA, Katsanis N, Eichler EE. Disruptive CHD8 mutations define a subtype of autism early in development. Cell. 2014 Jul 17;158(2):263-276. doi: 10.1016/j.cell.2014.06.017. Epub 2014 Jul 3. PMID: 24998929; PMCID: PMC4136921.

Abstract

Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.

Multiple sulfatase deficiency 2

Finglas A. View from inside: When multiple sulfatase deficiency changes everything about how you live and becomes your life. J Inherit Metab Dis. 2020 Nov;43(6):1143-1153. doi: 10.1002/jimd.12305. Epub 2020 Sep 24. PMID: 32845037.

Full article available through PubMed and Wiley. 

https://onlinelibrary.wiley.com/doi/10.1002/jimd.12305

10 CONCLUSION

I started this wave of support for MSD research hoping that Dylan could benefit in his lifetime from our efforts, and this hope remains. I also knew that many MSD patients and their families across the world could benefit if we can ensure science delivers a treatment. I will endeavor to do my best to assist the other MSD foundations that might wish to lean on my experience. Especially with regard to identifying research gaps and funding research in the future. I expect that together we can make life-changing differences for patients. I anticipate that funding from the various MSD charities can complement research initiatives that are underway and that show the most potential.

I wish that one day there will be treatment options available to MSD patients and that their families can appreciate it and enjoy a better life with their children. Without knowing the struggle and huge sacrifices by many, that it took to get treatments is something I wish my family could have had! There are many difficulties with trying to develop potential therapies for ultra-rare diseases that I realized in time due to my journey with MSD. There could be an element of bliss in not knowing these difficulties. If I ever get a call, one day, from a parent of a child affected by MSD to thank me for my efforts when there is a treatment… I would simply say that it was the many people who believed and supported our cause are the ones that really made it happen.

Family July 2019


I have invested so much of myself in MSD research I cannot ever see myself being able to walk away. I want to witness the first child being treated, with the efforts that have gone in this would be a very emotional experience! Many research initiatives have moved on and real progress has been made and for this I am so grateful. However, when you have a child that is affected by something as relentless as MSD, research is never fast enough. You have no option but to witness a decline in your child, which is soul destroying, while you try to do your best for them due to love. Having a child affected by MSD, and no treatment, is like starting with a piece of rock, every day a little bit gets chipped away, you cannot necessarily see it, but one day it will be gone.

SORD neuropathy 2

Pons N, Fernández-Eulate G, Pegat A, Théaudin M, Guieu R, Ripellino P, Devedjian M, Mace P, Masingue M, Léonard-Louis S, Petiot P, Roche P, Bernard E, Bouhour F, Good JM, Verschueren A, Grapperon AM, Salort E, Grosset A, Chanson JB, Nadaj-Pakleza A, Bédat-Millet AL, Choumert A, Barnier A, Hamdi G, Lesca G, Prieur F, Bruneel A, Latour P, Stojkovic T, Attarian S, Bonello-Palot N. SORD-related peripheral neuropathy in a French and Swiss cohort: Clinical features, genetic analyses, and sorbitol dosages. Eur J Neurol. 2023 Jul;30(7):2001-2011. doi: 10.1111/ene.15793. Epub 2023 Apr 4. PMID: 36943151.

Abstract

Background and purpose: Biallelic variants in SORD have been reported as one of the main recessive causes for hereditary peripheral neuropathies such as Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary motor neuropathy (dHMN) resulting in lower limb (LL) weakness and muscular atrophy. In this study, phenotype and genotype landscapes of SORD-related peripheral neuropathies were described in a French and Swiss cohort. Serum sorbitol dosages were used to classify SORD variants.

Methods: Patients followed at neuromuscular reference centres in France and Switzerland were ascertained. Sanger sequencing and next generation sequencing were performed to sequence SORD, and mass spectrometry was used to measure patients' serum sorbitol.

Results: Thirty patients had SORD peripheral neuropathy associating LL weakness with muscular atrophy, foot deformities (87%), and sometimes proximal LL weakness (20%) or distal upper limb weakness (50%). Eighteen had dHMN, nine had CMT2, and three had intermediate CMT. Most of them had a mild or moderate disease severity. Sixteen carried a homozygous c.757delG (p.Ala253Glnfs*27) variant, and 11 carried compound heterozygous variants, among which four variants were not yet reported: c.403C > G, c.379G > A, c.68_100 + 1dup, and c.850dup. Two unrelated patients with different origins carried a homozygous c.458C > A variant, and one patient carried a new homozygous c.786 + 5G > A variant. Mean serum sorbitol levels were 17.01 mg/L ± 8.9 SD for patients carrying SORD variants.

Conclusions: This SORD-inherited peripheral neuropathy cohort of 30 patients showed homogeneous clinical presentation and systematically elevated sorbitol levels (22-fold) compared to controls, with both diagnostic and potential therapeutic implications.

Laššuthová P, Mazanec R, Staněk D, Sedláčková L, Plevová B, Haberlová J, Seeman P. Biallelic variants in the SORD gene are one of the most common causes of hereditary neuropathy among Czech patients. Sci Rep. 2021 Apr 19;11(1):8443. doi: 10.1038/s41598-021-86857-0. PMID: 33875678; PMCID: PMC8055917.

Abstract

Recently, biallelic variants in the SORD gene were identified as causal for axonal hereditary neuropathy (HN). We ascertained the spectrum and frequency of SORD variants among a large cohort of Czech patients with unknown cause of HN. Exome sequencing data were analysed for SORD (58 patients). The prevalent c.757del variant was tested with fragment analysis (931 patients). Sanger sequencing in additional 70 patients was done. PCR primers were designed to amplify the SORD gene with the exclusion of the pseudogene SORD2P. Sequence differences between gene and pseudogene were identified and frequencies of SNPs were calculated. Eighteen patients from 16 unrelated families with biallelic variants in the SORD gene were found and the c.757del was present in all patients on at least one allele. Three novel, probably pathogenic, variants were detected, always in a heterozygous state in combination with the c.757del on the second allele. Patients presented with a slowly progressive axonal HN. Almost all patients had moderate pes cavus deformity. SORD neuropathy is frequent in Czech patients and the third most common cause of autosomal recessive HN. The c.757del is highly prevalent. Specific amplification of the SORD gene with the exclusion of the pseudogene is essential for a precise molecular diagnostics.

POLG mutation

Prince Frederik of Luxembourg, the son of Prince Robert of Luxembourg and Princess Julie of Nassau, has died at the age of 22.

Prince Robert shared the news in a statement on the website for the POLG Foundation, an organization started by Frederik to help with treatments and a cure for the illness.

Frederik was born with PolG mitochondrial disease, a rare genetic condition.

"It is with a very heavy heart that my wife and I would like to inform you of the passing of our son," Prince Robert wrote in the statement, sharing that Frederik had died on March 1.

The day before on "Rare Disease Day," Prince Robert shared that Frederik spoke with his family, including his brother Alexander and sister Charlotte, as well as cousins and other extended family, "one last time."

"After gifting each of us with our farewells – some kind, some wise, some instructive – in true Frederik fashion, he left us collectively with a final long-standing family joke. Even in his last moments, his humor, and his boundless compassion, compelled him to leave us with one last laugh… to cheer us all up."

He also wrote that Frederik asked, "Papa, are you proud of me?"

"He had barely been able to speak for several days, so the clarity of these words was as surprising as the weight of the moment was profound. The answer was very easy, and he had heard it oh so many times, but at this time, he needed reassurance that he had contributed all that he possibly could in his short and beautiful existence and that he could now finally move on," his father wrote.

The statement continued, "Frederik knows that he is my Superhero, as he is to all of our family, and to so very many good friends and now in great part thanks to his POLG Foundation, to so very many people the world over. Part of his superpower was his ability to inspire and to lead by example."

Prince Robert explained that Frederik was born with PolG mitochondrial disease.

Frederik wasn’t diagnosed until he was 14, "when his symptoms were showing more clearly and when the progression of his disease had become more acute."

The disease causes "such a wide range of symptoms and affects so many different organ systems, it is very difficult to diagnose and has no treatments much less a cure. POLG disease is a genetic mitochondrial disorder that robs the body’s cells of energy, in turn causing progressive multiple organ (brain, nerves, liver, intestines, muscles, swallowing and ocular function, etc.) dysfunction and failure. One might compare it to having a faulty battery that never fully recharges, is in a constant state of depletion and eventually loses power."

Prince Robert said Frederik "jumped" at the opportunity to create a foundation to find a cure.

"Though he always made it very clear that he did not want this dreadful disease to define him, he nonetheless immediately identified with and helped define the mission of The POLG Foundation."

According to his father’s statement, Frederik created the look for the charity in the United States, and launched a MITO clothing line, encouraged by Donna Karan.

He also "actively and literally gave of himself to develop multiple mouse models and cell lines in Switzerland, the United States, and Europe and to make these available to further facilitate research into POLG."

Prince Robert concluded, "On behalf of Frederik, Julie, Charlotte, Alexander, Mansour and the entire global POLG community, we thank you for helping this worthy cause that will honor our son. We will be resolutely focused on alleviating suffering for the POLG community and other diseases and conditions far beyond, associated with mitochondrial diseases."

https://www.foxnews.com/entertainment/prince-frederik-luxembourg-dead-22-from-rare-genetic-condition

Rahman S, Copeland WC. POLG-related disorders and their neurological manifestations. Nat Rev Neurol. 2019 Jan;15(1):40-52. doi: 10.1038/s41582-018-0101-0. PMID: 30451971; PMCID: PMC8796686.

Abstract

The POLG gene encodes the mitochondrial DNA polymerase that is responsible for replication of the mitochondrial genome. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later-onset syndromes arising from mtDNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations. POLG-related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood. The six leading disorders caused by POLG mutations are Alpers-Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life; myoclonic epilepsy myopathy sensory ataxia; ataxia neuropathy spectrum; autosomal recessive progressive external ophthalmoplegia; and autosomal dominant progressive external ophthalmoplegia. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG-related disorders, focusing particularly on the neurological manifestations of these conditions.