Botulinum Toxin Type A: Efficacy  in the management of Lower Limb Spasticity in Children with Genetic Disorders

Botulinum Toxin Type A: Efficacy in the management of Lower Limb Spasticity in Children with Genetic Disorders | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Botulinum Toxin Type A: Efficacy in the management of Lower Limb Spasticity in Children with Genetic Disorders Dina Amin Saleh, Mohamed Ashraf, George Halim, Mohamed Ali, Marwa A Nassef, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4548232/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Botulinum toxin type A (BoNT) is a well-established therapeutic modality for the treatment of lower limb spasticity in children with cerebral palsy. Objective: To assess the functional outcomes and tolerability of BoNT injection for the treatment of lower limb spasticity in children with neurometabolic/genetic disorders. Methods: We conducted a retrospective chart review for history, demographic data, comorbidities, neurological examination, and neuroimaging findings for all patients diagnosed with neurometabolic/genetic disorders from December 2020 to December 2022. The outcomes were assessed by recording the Gross Motor Function Classification system (GMFCS) for Cerebral Palsy "Initially and after 6 months' post-treatment", the Modified Ashworth scale (MAS) "initially and at 1,3,6 month post-treatment" and the achieved preset functional goals using the Goal Attainment Scaling (GAS) at 4-6 months post-treatment. Results: A total of 90% of the patients showed improvement in their GAS scores, with 20% achieving the preset goal, 55% achieving a better outcome than anticipated and 15% achieving the best possible outcome. Furthermore, the GMFCS and MAS scores showed a significant statistical improvement after six months post-injection (p=0.02, p=0.03), respectively. None of the patients developed serious adverse effects except one who had mitochondrial cytopathy. Conclusion: BoNT injections were effective and showed a high safety profile in children with neurometabolic/genetic disorders. To our knowledge, this is the first study that specifically targets this patient population, filling a gap in the literature and providing valuable insights into the potential benefits of BoNT injections for this group. However, further large-scale studies are recommended to confirm these findings. Biological sciences/Biochemistry Biological sciences/Cell biology Biological sciences/Genetics Biological sciences/Molecular biology Biological sciences/Neuroscience Biological sciences/Structural biology Health sciences/Medical research Health sciences/Neurology Botulinum toxin type A cerebral palsy children neurometabolic/genetic modified ashworth scale spasticity Figures Figure 1 Figure 2 Figure 3 Introduction Botulinum toxin type A (BoNT) has changed the roadmap in medicine by offering a non-traditional therapeutic approach for the treatment of many neurological disorders since its approval in 1989. It has shown to be an effective and safe therapeutic option for the treatment of different central and peripheral neurological disorders such as blepharospasm, cervical dystonia, chronic migraine, hemifacial spasm, hyperhidrosis, neurogenic bladder, post-stroke spasticity, and multiple sclerosis (Jankovic, 2004; Simpson et al., 2016). A few years later in 1993, BoNT was successfully used for the treatment of spasticity in children with cerebral palsy (CP)(Koman et al., 1993), which is considered the most common cause of spasticity and physical disability in children (E. Blair, 2000), (Ronan & Gold, 2007). It is well known that BoNT injection relieves the spasticity of target muscles peripherally by hindering the cholinergic transmission at the neuromuscular junction (Aoki, 2001), resulting in a state of neuro-paralysis or chemical denervation (Cocco & Albanese, 2018). The literature has focused on improving the quality of life in children with CP by using BoNT as a therapeutic tool either for improving gait and function in ambulatory children (Koman et al., 1993; Russo et al., 2007) or to comfort and ease the care in non-ambulatory ones (Copeland et al., 2014). According to evidence-based practice, BoNT has become a standard of care for children and adolescents with CP that should be offered as an effective and generally safe treatment of spasticity (level A) (Delgado et al., 2010). A growing body of evidence supports BoNT's central effect on neuronal plasticity (Caleo & Restani, 2018) with potential applications in the treatment of neurodegenerative disorders (Anandan & Jankovic, 2021). Although there are many studies addressing the effect and safety of BoNT in the management of muscle spasticity, few publications and insufficient data about the use of BoNT in the management of spasticity in physically disabled children due to underlying neurometabolic/genetic disorders. Genetic etiologies represent a separate entity from other causes of spasticity as the effect and safety BoNT are potentially unpredictable in such diseases. Previously, 1–2% of CP cases were thought to be of primary genetic origin rather than of an acquired perinatal cause. Recently, a higher percentage (14%) of CP cases were diagnosed when more intensive genetic sequencing was done for sporadic CP cases. An even higher percentage (31%) had mutation carriers with copies of genetic variation without clinically relevant symptoms. This means that acquired causes may simply act as triggers for those cases with genetic susceptibility. (McMicheal G., 2014) It is crucial to be aware of potential hazards or unpredictable responses that may accompany specific genetic etiologies when treated with BoNT. We aim to provide preliminary insights on the efficacy and safety of BoNT in genetic mimics of cerebral palsy. Methods Study design: This retrospective study included database of 849 children with spastic diplegia who underwent BoNT injection for management of lower limb spasticity. They were recruited from the multidisciplinary cerebral palsy clinic of the pediatric neurology, neurosurgery department and physical medicine and rehabilitation department in Ain Shams University Hospitals during the period between December 2020 and December 2022. Further classification of children according to the confirmed diagnosis of the cause of cerebral palsy was done. Children with confirmed genetic mutations were subjected to a more focused analysis regarding the efficacy and safety of BoNT injection in both lower limbs. Intended study population: Of the 849 children included from the database, children between 2-18 years of age diagnosed with genetic mutations and having lower limb spasticity were selected in our study. Recruited children received pharmacological treatment of spasticity and regular physical therapy sessions but with limited improvement of their condition. The patient’s diagnosis, clinical presentation, spasticity patterns, deformities, and brain magnetic resonance imaging (MRI) findings were reviewed. The list below is the inclusion and exclusion criteria of the study:- Inclusion criteria: Genetic diagnosis for the developmental delay Age 2-18 years Mild to moderate spasticity (MAS I+/II) Medications failed to control spasticity. Regular physiotherapy sessions Informed consent for procedure Exclusion criteria: Movement disorders (Involuntary movements) Absolute contraindications to BoNT Contraindications to intramuscular injections Previous spasticity surgical interventions Non-compliance to physical therapy of follow-up visits Bleeding disorders Demographic data including gender, parental consanguinity (referring to first cousins and double first cousins' marriages), perinatal history, age at presentation, diagnosis and BoNT injection were registered. Family history for similar cases was recorded. The details of patient demographics are listed in table 1 below . Sample size: A variety of spasticity etiologies are indicated for treatment with BoNT. The effect of BoNT is well-established in the literature, however very limited studies in the literature address the effect of BoNT on genetic diseases only, with very few sample sizes. For example this study on HSP with 18 cases. (Paparella, G., 2020) In our registry of cases injected with BoNT for spasticity, only 20 genetic cases were selected given the rarity and variability of genetic disorders. Assessments, procedure & outcome measures: According to our spasticity clinic protocol, all the patients who will receive BoNT injection underwent a thorough neurological examination, videotaping, and functional status assessment before the procedure. The pre-injection assessment included the following measures: Gross Motor Function Classification system for CP (GMFCS) is used for functional grading (Palisano et al., 2008). The modified Ashworth scale (MAS) is considered a clinically relevant tool for grading the resistance of a relaxed limb to rapid passive stretch with a grading score ranging from 0 (which indicates normal or lowered muscle tone), up to 4 (which indicates a state in which passive movement of the affected limb is unfeasible)(Bohannon & Smith, 1987) (I just removed the quotations). It was used for tone assessment for each muscle group (hip flexors, hip adductors, knee flexors, extensors, calf planters, and dorsiflexion), and the mean of the scores for the whole limb is calculated. For the statistical analysis purpose of the study, the grade of 1+ was considered as 2, and 1 was added to the remaining grades, so the grades ranged from 2 to 5. To check the response and outcome after Bo injection MAS mean differences were documented initially in the charts for each patient and at 1, 3, and 6 months post BoNT injection. Goal attainment scaling (GAS) is used as an outcome measure to evaluate the progress toward targeted functional goals. These goals will be set with the caregivers before BoNT injection to ease the patient care “pain, positioning, mobility” and help in tone reduction guided by the MAS and GMFCS. This allows the caregivers to decide their own personalized preset goals (Krasny-Pacini et al., 2013). Our BoNT injection protocol follows the standard injection guidelines for a multilevel approach, where the BoNT dose is decided according to the muscle volume, the degree of spasticity, and muscle involvement in the pathological pattern (Heinen et al., 2010; R. & Graham, 1997). The selection of the group of muscles injected depends on the pathological spasticity pattern, deformity, and the functional goals set for each patient. We use anatomic landmarks; electromyogram and ultrasound guidance for accurate localization of the injection site under sedation using isoflurane. This will be followed by intensive rehabilitation and the use of orthotics whenever it’s indicated. Follow-up post-injection: Post-injection assessment was recorded at specified intervals to detect functional improvement by measurement of the difference between the initial and follow-up means as follows: GMFCS initial and at 6 months. MAS initial, at 1, 3, and 6 months. GAS goals achievement was determined at 4-6 months post-injection with scores ranging from a “no change’’ to a ‘‘much better than the expected outcome". For the statistical analysis to decide the level of achievement, a five-point scale was used: ‘‘-2’’ is the initial pre-injection (initial) level, ‘‘-1’’ constitutes advancement towards the goal without goal attainment, ‘‘0’’ is the anticipated goal post-injection, ‘‘+1’’ constitutes a better outcome than anticipated, and ‘‘+2’’ is the best possible outcome that could have been anticipated for this goal. The patient was defined as a responder if a GAS score of at least 0 was achieved at 4-6 months. Since there are several post-injection goals, we chose the GMFCS level as a guide for goal achievement to detect improvement in mobility. Statistical analysis: The IBM SPSS version 19 has been used as the statistical methodology. Descriptive analysis was applied for continuous variables. The statistical hypothesis was the presence or absence of significant differences between the variables before and after treatment. Because of a small-sized sample, the ANOVA test was used to evaluate the treatment effect on all objective variables with an alpha value of 0.05 with Bonferroni correction. Ethics: Ethical committee approval for the study design and statistical methodology was obtained by the Ethical Committee of the Faculty of Medicine, Ain Shams University. All research was performed in accordance with relevant guidelines and in accordance with the Declaration of Helsinski. Informed consent was obtained from all participants’ legal guardians. Results Patient’s clinical characteristics: Twenty pediatric patients with neurogenetic/metabolic disorders received BoNT injections for lower limb spasticity. They were 13 (65%) males and 7 (35%) females. The mean age on "presentation, diagnosis, and BoNT injection" was (7.6 ± 4.18), (15 ± 5.52) and (40.25 ± 11.75) months, respectively. One patient did not complete the study due to severe adverse effects, and the study was continued with 19 patients. Fourteen (70%) of parents were 1st -degree cousins, eight (40%) had a similar family history and eleven (55%) had other comorbidities as highlighted in Table (1). The spectrum of neurometabolic/genetic profile: Most of the patients 90% had a topographic pathological pattern of spastic diplegia while the rest had spastic quadriplegic with the following neurometabolic/genetic diagnosis; three patients had Canavan disease, two patients had Aicardi- Goutieres syndrome, two patients had Glutaric aciduria type 1, two patients had Maple syrup urine disease (MSUD), two patients had Metachromatic leukodystrophy, two patients had Mitochondrial cytopathy, two patients had Sjogren- Larsson syndrome (SLS), one patient had Cockayne syndrome, one patient had corpus callosum agenesis, one patient had Edward syndrome, one patient had Loeys - Dietz syndrome and one patient had Hallervorden- Spatz/pantothenate kinase-associated neurodegenerative disorder(HSS)(PKAN). Detailed demographic, clinical profile and neuroimaging findings were described in Table (1). Response to BoNT injection and outcome: GAS was achieved, showed a better outcome than anticipated, and showed the best possible outcome in 4(20%), 11(55%), and 3(15%), respectively in terms of muscle tone reduction and easing patient care. None of the patients had serious post-BoNT injection adverse effects except one patient with mitochondrial cytopathy who survived respiratory distress and renal shutdown in 2nd-week post-injection. The detailed descriptive data of the group of muscles injected and the functional assessment tools at specific time intervals were displayed in Table (2). The GMFCS showed significant improvement after 6 months post-injection (p = 0.02) as shown in Fig. (1). The mean scores of MAS showed statistically significant reduction at 1, 3, and 6 months as compared to initial MAS (p = 0.0008, 0.0009, 0.03), respectively indicating muscle tone reduction as shown in Fig. (2). Table 1 Demographic, neurometabolic/genetic diagnosis, clinical profile, and neuroimaging findings of all patients: Age (months) Mean ± SD At presentation (months) At diagnosis (months) At BoNT injection (months) 7.6 ± 4.18 15 ± 5.52 40.25 ± 11.75 Variables N (%) Gender Male Female 13(65%) 7(35%) Consanguinity Yes No 14(70%) 6 (30%) Perinatal history Unremarkable Complications 2 (10%) 18 (90%) Similar family history Yes No 8 (40%) 12 (60%) Neuroregression Global developmental delay Yes No Yes No 6(30%) 14(70%) 10(50%) 10(50%) Diagnosis Comorbidities Spasticity distribution (Topography) Canavan Disease Aicardi - Goutieres Syndrome Glutaric aciduria MSUD MLD Mitochondrial cytopathy SLS Cockayne syndrome Corpus Callosum agenesis Edwards Syndrome Loeys - Dietz Syndrome Hallervorden- Spatz No Feeding difficulties Seizures Visual impairment Hearing impairment Movement disorders Diplegia Quadriplegia 3(15%) 2(10%) 2(10%) 2(10%) 2(10%) 2(10%) 2(10%) 1(5%) 1(5%) 1(5%) 1(5%) 1(5%) 9(45%) 4(20%) 2(10%) 2(10%) 2(10%) 1(5%) 18 (90%) 2 (10%) Initial GMFCS Deformities Brain MRI findings II III IV V Talipus equinovarus & scissoring Scissoring Talipus equinovarus Brain atrophy & demyelination Megaloencephaly & demyelination Diffuse demyelination Bilateral basal ganglia signal Periventricular leukomalacia Brain atrophy & Chiari I malformation Brain atrophy, hypo myelination & intracranial calcifications Corpus callosum agenesis & mild brain atrophy Eye-of-the-tiger sign 3(15%) 10(50%) 6(30%) 1(5%) 18(90%) 1(5%) 1(5%) 4(20%) 3(15%) 3(15%) 3(15%) 2(10%) 1(5%) 1(5%) 1(5%) 1(5%) BoNT injection: botulinum toxin type A; HSS/PKAN: Hallervorden- Spatz/pantothenate kinase-associated neurodegenerative disorder; MRI: magnetic resonance imaging; MSUD: Maple syrup disease; MLD: Metachromatic leukodystrophy; SLS: Sjogren- Larsson syndrome Table 2 Descriptive data of the group of muscles injected, mean scores of GMFCS “initial and final”, MAS “initial, 1, 3 and 6 months”, GAS at 4–6 months and post-BoNT injection adverse effects of all patients: Patient Diagnosis Muscles injected Initial GMFCS Final GMFCS Initial MAS 1st month MAS 3rd month MAS 6th month MAS GAS Adverse effects 1 Canavan disease Hamstrings/hip adductors/ calf IV IV 3 1 2 2 + 1 Local pain 2 Canavan disease Hip adductors/ calf II II 3 1 1 2 + 2 None 3 Canavan disease Hip adductors/ calf III III 4 2 3 3 + 1 None 4 Aicardi - Goutieres Syndrome Hamstrings/hip adductors/ calf III II 3 1 1 1 + 1 Local pain 5 Aicardi - Goutieres Syndrome Hamstrings/hip adductors/ calf II II 3 2 2 3 0 Local pain 6 Glutaric aciduria Hamstrings/hip adductors/ calf IV IV 4 1 2 3 + 1 Local pain 7 Glutaric aciduria Hamstrings/hip adductors/ calf III II 3 1 1 2 + 2 Local pain 8 MSUD Hip adductors/ calf III II 4 2 3 4 0 None 9 MSUD Hamstrings/hip adductors/ calf IV III 3 2 3 3 + 1 Local pain 10 MLD Hamstrings/hip adductors/ calf III III 3 1 3 3 + 1 Local pain 11 MLD Hip adductors/ calf III II 4 3 3 4 0 None 12 Mitochondrial cytopathy Calf IV IV 3 2 4 5 -1 None 13 Mitochondrial cytopathy Hip adductors/ calf III IV 4 NA NA 5 -2 Respiratory distress & renal shutdown 14 SLS Hamstrings/hip adductors/ calf IV III 4 1 2 3 + 1 Local pain 15 SLS Hamstrings/hip adductors/ calf III II 4 2 3 3 + 1 None 16 Cockayne syndrome Hamstrings/ calf III III 3 1 3 3 + 2 None 17 Corpus Callosum agenesis Hip adductors/ calf III II 4 1 3 3 + 1 None 18 Edwards Syndrome Hamstrings/hip adductors/ calf IV IV 3 1 2 2 + 1 None 19 Loeys - Dietz Syndrome Hamstrings/hip adductors/ calf V V 4 2 2 3 + 1 None 20 HSS/PKAN Hamstrings/hip adductors/ calf II II 4 2 3 3 0 Local pain GAS : goal attainment scaling; GMFCS : gross motor function classification system for cerebral palsy; Calf: gastrocnemii and soleus; MAS: modified Ashworth scale; MSUD: Maple syrup disease; MLD: Metachromatic leukodystrophy; HSS/PKAN: Hallervorden- Spatz/pantothenate kinase-associated neurodegenerative disorder; SLS: Sjogren- Larsson syndrome Discussion Highlights on genetic cerebral palsy In addition to suggesting a demonstrating the safety and efficacy BoNT injections in hypertonia associated with genetic diseases, this study highlights the limitation of genetic diagnosis in our region (2%, 20 out of 849 cases). In our cohort, 70% of patients were of 1st -degree cousins’ marriage and 40% had a similar family history, highlighting the consequences of consanguineous marriage on the increased rate of neurogenetic disorders in our region (Tadmouri et al., 2009). It is worth mentioning that 55% of our patients had other comorbidities and 63.5% were dependent on their caregivers either totally (35% with GMFCS IV and V) or partially (28.5% with GMFCS III). This reflects the financial, physical, and mental burden on these families which in turn will affect their quality of life. It is well known that neurometabolic disorders present with multisystem involvement whether neurological or non-neurological with movement disorders being the most significant disabling morbidity (Ortigoza-Escobar, 2020). Spastic diplegia was the most prevalent topographic pattern identified (90%) while the rest of the patients had spastic quadriplegia with talipus equinovarus and scissoring being the most common deformity (90%) encountered. This explains why our entire patients except one patient required injection of multiple muscle groups to relieve spasticity. Although this is not the common practice in non-ambulatory patients for concerns about developing adverse effects. By injecting multiple muscles, our results show that the children can achieve functional improvement despite the progressive course of the disease with high safety profile. Mitochondrial cytopathy and BoNT All our patients had acceptable mild transient local pain except one patient who initially presented with an unidentified multisystem neurological disorder but was later diagnosed with mitochondrial cytopathy after receiving the BoNT and experiencing complications. The patient developed severe respiratory distress and renal shutdown which resolved without long-term consequences. This observation supports the existing literature on the general safety of BoNT injections in pediatric patients with CP (Delgado et al., 2010)and the risk of severe respiratory distress and mortality in multilevel injections (Howell et al., 2007), especially in patients with mitochondrial cytopathy (Gioltzoglou, 2005). Interpretation of GAS The results of this study revealed that BoNT injections were effective in achieving the preset functional goals of “muscle tone reduction, easing the patient care and rehabilitation” in pediatric patients with neurometabolic/genetic disorders. We found that the overall responder rate was 90% based on GAS scores, where 20% achieved the preset goals, 55% of patients achieved a better outcome than anticipated and 15% achieved the best possible outcome. We believe that this would have not been accomplished without receiving intensive rehabilitation and using appropriate orthotics. Similar promising findings were reported with functional and symptomatic improvement according to GAS in adult patients with poststroke lower limb spasticity (Munain et al., 2019). GMFCS versus MAS Furthermore, this functional improvement was supported by the significant improvement in the GMFCS and the MAS scores after BoNT injection. These findings are consistent with previous research on BoNT injections for the treatment of spasticity in children with CP due to perinatal complications (Delgado et al., 2010). The MAS scores showed the best response at the first follow-up visit (1st month) as compared to the 3rd and 6th months post-BoNT injection. However, although the improvement tends to decline by the 6th month, still there was a statistically significant improvement as compared to the initial MAS scores. This corresponds with the known process of recovery of neuromuscular transmission from 6 to 8 weeks, as new nerve terminals sprout (Rogozhin et al., 2008). In our results ( Fig. 3 ) at 1-month post-injection, we noticed a discrepancy between MAS and GMFCS results in the form of significant improvement in tone (mean 1.5) without corresponding improvement in GMFCS. The explanation could be that the decrease in muscle tone is not necessarily translated to improvement in function in short duration because the development of neuroplasticity is described in time factor. There are limited publications ``mainly case reports” on the efficacy and safety of using BoNT injections in patients with neurometabolic/genetic disorders. It was effectively and safely used for the treatment of lower limb spasticity and dystonia in patients with Glutaric aciduria type I (Burlina et al., 2004), HSS/PKAN (Lin et al., 2018; Neves et al., 2008), MLD (Borges et al., 2020; Singh et al., 2009), Pelizaeus-Merzbacher disease (PMD)(Brender et al., 2015), SLS (Anil G, 2019; Cho et al., 2018; Hidalgo et al., 2017), Alexander disease (Machol et al., 2018), Aicardi-Goutières syndrome (AGS) (Videira et al., 2020), Cockayne syndrome (Hsu et al., 2021)and in combination with epidural analgesia in one child with MSUD (Kaki & Arab, 2012). The idea that BoNT can be used as an alternative to maximum anticholinergics A study done by Burlina highlights that BoNT injection can be used as an alternative to anticholinergics, especially in high doses. It further highlights its efficacy in treating extrapyradmial symptoms in glutaryl CoA dehydrogenase type I deficiency. In our series two such cases were injected reporting GAS of + 1 and + 2 respectively. Our results in treating upper limb dystonia were encouraging. In conclusion, anticholinergic drugs, such as trihexyphenidyl, and botulinum can be used not only as a second line after anticholinergics but also as an alternative. (Burlina et al., 2004) Cut-off duration of improvement to consider injection. Is there a rationale to set a limit on the indication according to the natural history of the genetic disease? For example, in MLD is considered a terminal genetic disease with a life expectancy of 4 years. In our results with MLD cases (mean age at presentation is 7 in this study) initial improvement of spasticity was observed followed by rapid recurrence in less than 6 months. In retrospect, it may seem that BoNT injection in a short life expectancy is of minimal benefit even though GAS for one of the cases was + 1 (the other was 0). This study calls for a large-scale study analyzing the best cut off values for injecting in such diseases with short life expectancy. (Borges et al., 2020) The potential effects of BoNT on muscular structures should be explored. The concept of sarcomeric mechanotransduction in which genes that encode for sarcomere signaling proteins were upregulated in response to alterations of mechanical activity of the muscle following BoNT injection and exercise (Velders et al., 2008). This has implications on the effect of BoNT paralyzed muscles on muscle adaptation which in turn can influence motor activity of the spastic muscle and as a result modify gait and ambulation however such findings are yet to be explored. In this study, BoNT was used successfully in controlling spasticity and dystonia for at least 6 months without major adverse effects. Given limited options, it can be considered as a standard line of treatment. This was in agreement with Lin et al, who reports 25% improvement in Barry Alright dystonia scale in their cases, along with subtle improvement in functional independence measure. (Lin et al., 2018) Limitations Limitations of this study include its retrospective design and the relatively small number of patients, however; this is difficult to avoid since it involves a relatively rare target population with neurometabolic/genetic disorder from a single center. This might limit the generalizability of the results. Therefore, we believe that although the study’s sample, albeit small, it can be considered as a nidus for future research in this population. When considering possible clinical trials, it must be remembered that genetic disorders are a highly heterogeneous group and as such, research should be disease-specific rather than focusing upon generalized trends of spasticity. As the understanding of the nature of spasticity in genetic disorders develops, it will become possible to better define suitable outcome measures for assessing change in severity with an emphasis on developing measurement tools specific to the disorders in question. Conclusion This study provides preliminary evidence supporting the use of BoNT injections as a safe and effective therapeutic option for the treatment of lower limb spasticity in children with neurometabolic/genetic disorders. This will in turn improve the functional outcomes and quality of life for this patient population and their caregivers. However, further research involving larger sample sizes and multicenter designs is needed to confirm these findings and to identify specific patient subgroups that may benefit most from this treatment approach, especially in resource-limited countries where more invasive approaches such as baclofen pump implantation are not feasible. To the best of our knowledge, this is the first pilot study of its kind to evaluate the efficacy and the safety of BoNT injection for the treatment of lower limb spasticity in pediatric patients with neurometabolic/genetic etiology in our region. Declarations Author Contribution D.A.S , M.A. , W.A.G wrote the manuscriptG.H., M.N., M.I.A., revised it and prepared the figures A.A. and N.F. did the statistics and prepared the tables W.A.G. conceptualized and provided the data for the patients All authors reviewed the manuscript Data Availability All data generated or analyzed during this study are included in this published article, any further enquiries regarding the data are available from the corresponding author upon reasonable request. References Anandan, C., & Jankovic, J. (2021). Botulinum Toxin in Movement Disorders: An Update. Toxins , 13 (1), 42. https://doi.org/10.3390/toxins13010042 McMichael, G., Girirajan, S., Moreno-De-Luca, A. et al. 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T., Orillac, C., Hersh, A., Harter, D. H., Rizzo, W. B., & Weiner, H. L. (2017). Intrathecal Baclofen Therapy for the Treatment of Spasticity in Sjögren-Larsson Syndrome. Journal of Child Neurology , 32 (1), 100–103. https://doi.org/10.1177/0883073816671440 Howell, K., Selber, P., Graham, H. K., & Reddihough, D. (2007). Botulinum neurotoxin A: An unusual systemic effect. Journal of Paediatrics and Child Health , 43 (6), 499–501. https://doi.org/10.1111/j.1440-1754.2007.01122.x Hsu, L.-C., Chiang, P.-Y., Lin, W.-P., Guo, Y.-H., Hsieh, P.-C., Kuan, T.-S., Lien, W.-C., & Lin, Y.-C. (2021). Botulinum toxin injection for Cockayne syndrome with muscle spasticity over bilateral lower limbs: A case report. World Journal of Clinical Cases , 9 (18), 4728–4733. https://doi.org/10.12998/wjcc.v9.i18.4728 Hull, M., Parnes, M., & Jankovic, J. (2021). Botulinum Neurotoxin Injections in Childhood Opisthotonus. Toxins , 13 (2), 137. https://doi.org/10.3390/toxins13020137 Jankovic, J. (2004). Botulinum toxin in clinical practice. Journal of Neurology, Neurosurgery & Psychiatry , 75 (7), 951–957. https://doi.org/10.1136/jnnp.2003.034702 Kaki, A., & Arab, A. (2012). The use of botulinum toxin and epidural analgesia for the treatment of spasticity and pain in a patient with maple syrup urine disease. Saudi Journal of Anaesthesia , 6 (2), 175. https://doi.org/10.4103/1658-354X.97035 Koman, L. A., Mooney, J. F., Smith, B., Goodman, A., & Mulvaney, T. (1993). Management of Cerebral Palsy with Botulinum-A Toxin. Journal of Pediatric Orthopaedics , 13 (4), 489–495. https://doi.org/10.1097/01241398-199307000-00013 Krasny-Pacini, A., Hiebel, J., Pauly, F., Godon, S., & Chevignard, M. (2013). Goal Attainment Scaling in rehabilitation: A literature-based update. Annals of Physical and Rehabilitation Medicine , 56 (3), 212–230. https://doi.org/10.1016/j.rehab.2013.02.002 Lin, C.-I., Chen, K.-L., Kuan, T.-S., Lin, S.-H., Lin, W.-P., & Lin, Y.-C. (2018). Botulinum toxin injection to improve functional independence and to alleviate parenting stress in a child with advanced pantothenate kinase-associated neurodegeneration. Medicine , 97 (20), e10709. https://doi.org/10.1097/MD.0000000000010709 Machol, K., Jankovic, J., Vijayakumar, D., Burrage, L. C., Jain, M., Lewis, R. A., Fuller, G. N., Xu, M., Penas-Prado, M., Gule-Monroe, M. K., Rosenfeld, J. A., Chen, R., Eng, C. M., Yang, Y., Lee, B. H., Moretti, P. M., & Dhar, S. U. (2018). Atypical Alexander disease with dystonia, retinopathy, and a brain mass mimicking astrocytoma. Neurology Genetics , 4 (4), e248. https://doi.org/10.1212/NXG.0000000000000248 Munain, L. L. de, Valls-Solé, J., Pascual, I. G., & Maisonobe, P. (2019). Botulinum Toxin Type A Improves Function According to Goal Attainment in Adults with Poststroke Lower Limb Spasticity in Real Life Practice. European Neurology , 82 (1–3), 1–8. https://doi.org/10.1159/000503172 Neves, C. M., Joana, D., & Marina, M. (2008). Botulinum toxin in Hallervorden–spatz syndrome. Toxicon , 51 , 24. https://doi.org/10.1016/j.toxicon.2008.04.074 Ortigoza-Escobar, J. D. (2020). A Proposed Diagnostic Algorithm for Inborn Errors of Metabolism Presenting With Movements Disorders. Frontiers in Neurology , 11 . https://doi.org/10.3389/fneur.2020.582160 Paparella, G., Vavla, M., Bernardi, L., Girardi, G., Stefan, C., & Martinuzzi, A. (2020). Efficacy of a Combined Treatment of Botulinum Toxin and Intensive Physiotherapy in Hereditary Spastic Paraplegia. Frontiers in Neuroscience, 14. https://doi.org/10.3389/fnins.2020.00111 Palisano, R., Rosenbaum, P., Walter, S., Russell, D., Wood, E., & Galuppi, B. (2008). Development and reliability of a system to classify gross motor function in children with cerebral palsy. Developmental Medicine & Child Neurology , 39 (4), 214–223. https://doi.org/10.1111/j.1469-8749.1997.tb07414.x R., & Graham, H. K. B. (1997). Botulinum toxin A in the management of children with cerebral palsy: Indications and outcome. European Journal of Neurology , 4 (1351–5101), S15–S22. Rogozhin, A. A., Pang, K. K., Bukharaeva, E., Young, C., & Slater, C. R. (2008). Recovery of mouse neuromuscular junctions from single and repeated injections of botulinum neurotoxin A. The Journal of Physiology , 586 (13), 3163–3182. https://doi.org/10.1113/jphysiol.2008.153569 Ronan, S., & Gold, J. T. (2007). Nonoperative management of spasticity in children. Child’s Nervous System , 23 (9), 943–956. https://doi.org/10.1007/s00381-007-0396-4 Russo, R. N., Crotty, M., Miller, M. D., Murchland, S., Flett, P., & Haan, E. (2007). Upper-Limb Botulinum Toxin A Injection and Occupational Therapy in Children With Hemiplegic Cerebral Palsy Identified From a Population Register: A Single-Blind, Randomized, Controlled Trial. Pediatrics , 119 (5), e1149–e1158. https://doi.org/10.1542/peds.2006-2425 Simpson, D. M., Hallett, M., Ashman, E. J., Comella, C. L., Green, M. W., Gronseth, G. S., Armstrong, M. J., Gloss, D., Potrebic, S., Jankovic, J., Karp, B. P., Naumann, M., So, Y. T., & Yablon, S. A. (2016). Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache. Neurology , 86 (19), 1818–1826. https://doi.org/10.1212/WNL.0000000000002560 Singh, R. K., Leshner, R. T., Kadom, N., & Vanderver, A. L. (2009). Isolated Cranial Nerve Enhancement in Metachromatic Leukodystrophy. Pediatric Neurology , 40 (5), 380–382. https://doi.org/10.1016/j.pediatrneurol.2008.11.015 Tadmouri, G. O., Nair, P., Obeid, T., Ali, M. T. A., Khaja, N. A., & Hamamy, H. A. (2009). Consanguinity and reproductive health among Arabs. Reproductive Health , 6 (1), 17. https://doi.org/10.1186/1742-4755-6-17 Videira, G., Malaquias, M. J., Laranjinha, I., Martins, R., Taipa, R., & Magalhães, M. (2020). Diagnosis of Aicardi‐Goutières Syndrome in Adults: A Case Series. Movement Disorders Clinical Practice , 7 (3), 303–307. https://doi.org/10.1002/mdc3.12903 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4548232","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":328629502,"identity":"a4ae797d-304e-4625-9e63-dd1bbf423840","order_by":0,"name":"Dina Amin Saleh","email":"","orcid":"","institution":"Ain Shams University","correspondingAuthor":false,"prefix":"","firstName":"Dina","middleName":"Amin","lastName":"Saleh","suffix":""},{"id":328629503,"identity":"f36404d2-3f86-4744-95b7-f4b139808ae9","order_by":1,"name":"Mohamed 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22:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4548232/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4548232/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60944788,"identity":"ca124b29-93e8-4156-9643-27fefd51d200","added_by":"auto","created_at":"2024-07-23 22:15:01","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":14261,"visible":true,"origin":"","legend":"\u003cp\u003eGross motor function classification system level (GMFCS) pre-and post-botulinum toxin type A (BoNT) injection\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4548232/v1/0300f68f489ffbc34484345c.jpg"},{"id":60944789,"identity":"156b3265-4c1a-4ae1-9d42-16504b7ab68c","added_by":"auto","created_at":"2024-07-23 22:15:02","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":16962,"visible":true,"origin":"","legend":"\u003cp\u003eModified Ashworth scale (MAS) initial and at specified time intervals\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4548232/v1/ec3a076176fe4b3b28b2a68a.jpg"},{"id":60944787,"identity":"d9a1cfb2-602e-4d9a-8aae-6d565c2824ec","added_by":"auto","created_at":"2024-07-23 22:15:01","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":24724,"visible":true,"origin":"","legend":"\u003cp\u003eMedian values of Gross motor function classification system level (GMFCS) and Modified Ashworth scale (MAS) initial and at specified time intervals.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4548232/v1/c2b5d2c6fff23a3da2837a4e.jpg"},{"id":71256367,"identity":"93487a84-9e01-46d3-a858-b2dfd8bf0d1d","added_by":"auto","created_at":"2024-12-12 15:32:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":884291,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4548232/v1/01a1427a-60e7-46cd-90c8-e18f16fc3e9b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Botulinum Toxin Type A: Efficacy in the management of Lower Limb Spasticity in Children with Genetic Disorders","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBotulinum toxin type A (BoNT) has changed the roadmap in medicine by offering a non-traditional therapeutic approach for the treatment of many neurological disorders since its approval in 1989. It has shown to be an effective and safe therapeutic option for the treatment of different central and peripheral neurological disorders such as blepharospasm, cervical dystonia, chronic migraine, hemifacial spasm, hyperhidrosis, neurogenic bladder, post-stroke spasticity, and multiple sclerosis (Jankovic, 2004; Simpson et al., 2016). A few years later in 1993, BoNT was successfully used for the treatment of spasticity in children with cerebral palsy (CP)(Koman et al., 1993), which is considered the most common cause of spasticity and physical disability in children (E. Blair, 2000), (Ronan \u0026amp; Gold, 2007).\u003c/p\u003e \u003cp\u003eIt is well known that BoNT injection relieves the spasticity of target muscles peripherally by hindering the cholinergic transmission at the neuromuscular junction (Aoki, 2001), resulting in a state of neuro-paralysis or chemical denervation (Cocco \u0026amp; Albanese, 2018).\u003c/p\u003e \u003cp\u003eThe literature has focused on improving the quality of life in children with CP by using BoNT as a therapeutic tool either for improving gait and function in ambulatory children (Koman et al., 1993; Russo et al., 2007) or to comfort and ease the care in non-ambulatory ones (Copeland et al., 2014). According to evidence-based practice, BoNT has become a standard of care for children and adolescents with CP that should be offered as an effective and generally safe treatment of spasticity (level A) (Delgado et al., 2010).\u003c/p\u003e \u003cp\u003eA growing body of evidence supports BoNT's central effect on neuronal plasticity (Caleo \u0026amp; Restani, 2018) with potential applications in the treatment of neurodegenerative disorders (Anandan \u0026amp; Jankovic, 2021).\u003c/p\u003e \u003cp\u003eAlthough there are many studies addressing the effect and safety of BoNT in the management of muscle spasticity, few publications and insufficient data about the use of BoNT in the management of spasticity in physically disabled children due to underlying neurometabolic/genetic disorders.\u003c/p\u003e \u003cp\u003eGenetic etiologies represent a separate entity from other causes of spasticity as the effect and safety \u003cb\u003eBoNT\u003c/b\u003e are potentially unpredictable in such diseases.\u003c/p\u003e \u003cp\u003ePreviously, 1\u0026ndash;2% of CP cases were thought to be of primary genetic origin rather than of an acquired perinatal cause. Recently, a higher percentage (14%) of CP cases were diagnosed when more intensive genetic sequencing was done for sporadic CP cases. An even higher percentage (31%) had mutation carriers with copies of genetic variation without clinically relevant symptoms. This means that acquired causes may simply act as triggers for those cases with genetic susceptibility. (McMicheal G., 2014)\u003c/p\u003e \u003cp\u003eIt is crucial to be aware of potential hazards or unpredictable responses that may accompany specific genetic etiologies when treated with BoNT. We aim to provide preliminary insights on the efficacy and safety of BoNT in genetic mimics of cerebral palsy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study included database of 849 children with spastic diplegia who underwent BoNT injection for management of lower limb spasticity. They were recruited from the multidisciplinary cerebral palsy clinic of the pediatric neurology, neurosurgery department and physical medicine and rehabilitation department in Ain Shams University Hospitals during the period between December 2020 and December 2022. Further classification of children according to the confirmed diagnosis of the cause of cerebral palsy was done. Children with confirmed genetic mutations were subjected to a more focused analysis regarding the efficacy and safety of BoNT injection in both lower limbs. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntended study population:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 849 children included from the database, children between 2-18 years of age diagnosed with genetic mutations and having lower limb spasticity were selected in our study. Recruited children received pharmacological treatment of spasticity and regular physical therapy sessions but with limited improvement of their condition.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe patient\u0026rsquo;s diagnosis, clinical presentation, spasticity patterns, deformities, and brain magnetic resonance imaging (MRI) findings were reviewed. The list below is the inclusion and exclusion criteria of the study:-\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eGenetic diagnosis for the developmental delay\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAge 2-18 years\u003c/li\u003e\n \u003cli\u003eMild to moderate spasticity (MAS I+/II)\u003c/li\u003e\n \u003cli\u003eMedications failed to control spasticity.\u003c/li\u003e\n \u003cli\u003eRegular physiotherapy sessions\u003c/li\u003e\n \u003cli\u003eInformed consent for procedure\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eMovement disorders (Involuntary movements)\u003c/li\u003e\n \u003cli\u003eAbsolute contraindications to BoNT\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eContraindications to intramuscular injections\u003c/li\u003e\n \u003cli\u003ePrevious spasticity surgical interventions\u003c/li\u003e\n \u003cli\u003eNon-compliance to physical therapy of follow-up visits\u003c/li\u003e\n \u003cli\u003eBleeding disorders\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDemographic data including gender, parental consanguinity (referring to first cousins and double first cousins\u0026apos; marriages), perinatal history, age at presentation, diagnosis and BoNT injection were registered. Family history for similar cases was recorded. The details of patient demographics are listed in \u003cstrong\u003etable 1\u003c/strong\u003e below .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA variety of spasticity etiologies are indicated for treatment with BoNT. The effect of BoNT is well-established in the literature, however very limited studies in the literature address the effect of BoNT on genetic diseases only, with very few sample sizes. For example this study on HSP with 18 cases. (Paparella, G., 2020)\u003c/p\u003e\n\u003cp\u003eIn our registry of cases injected with BoNT for spasticity, only 20 genetic cases were selected given the rarity and variability of genetic disorders.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssessments, procedure \u0026amp; outcome measures:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to our spasticity clinic protocol, all the patients who will receive BoNT injection underwent a thorough neurological examination, videotaping, and functional status assessment before the procedure. The pre-injection assessment included the following measures:\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eGross Motor Function Classification system for CP (GMFCS) is used for functional grading\u0026nbsp;(Palisano et al., 2008).\u003c/li\u003e\n \u003cli\u003eThe modified Ashworth scale (MAS) is considered a clinically relevant tool for grading the resistance of a relaxed limb to rapid passive stretch with a grading score ranging from 0 (which indicates normal or lowered muscle tone), up to 4 (which indicates a state in which passive movement of the affected limb is unfeasible)(Bohannon \u0026amp; Smith, 1987) (I just removed the quotations). It was used for tone assessment for each muscle group (hip flexors, hip adductors, knee flexors, extensors, calf planters, and dorsiflexion), and the mean of the scores for the whole limb is calculated. For the statistical analysis purpose of the study, the grade of 1+ was considered as 2, and 1 was added to the remaining grades, so the grades ranged from 2 to 5. To check the response and outcome after Bo injection MAS mean differences were documented initially in the charts for each patient and at 1, 3, and 6 months post BoNT injection.\u003c/li\u003e\n \u003cli\u003eGoal attainment scaling (GAS) is used as an outcome measure to evaluate the progress toward targeted functional goals. These goals will be set with the caregivers before BoNT injection to ease the patient care \u0026ldquo;pain, positioning, mobility\u0026rdquo; and help in tone reduction guided by the MAS and GMFCS. This allows the caregivers to decide their own personalized preset goals\u0026nbsp;(Krasny-Pacini et al., 2013).\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur BoNT injection protocol follows the standard injection guidelines for a multilevel approach, where the BoNT dose is decided according to the muscle volume, the degree of spasticity, and muscle involvement in the pathological pattern\u0026nbsp;(Heinen et al., 2010; R. \u0026amp; Graham, 1997). The selection of the group of muscles injected depends on the pathological spasticity pattern, deformity, and the functional goals set for each patient. We use anatomic landmarks; electromyogram and ultrasound guidance for accurate localization of the injection site under sedation using isoflurane. This will be followed by intensive rehabilitation and the use of orthotics whenever it\u0026rsquo;s indicated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up post-injection:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePost-injection assessment was recorded at specified intervals to detect functional improvement by measurement of the difference between the initial and follow-up means as follows:\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eGMFCS initial and at 6 months.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMAS initial, at 1, 3, and 6 months.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eGAS goals achievement was determined at 4-6 months post-injection with scores ranging from a \u0026ldquo;no change\u0026rsquo;\u0026rsquo; to a \u0026lsquo;\u0026lsquo;much better than the expected outcome\u0026quot;. For the statistical analysis to decide the level of achievement, a five-point scale was used: \u0026lsquo;\u0026lsquo;-2\u0026rsquo;\u0026rsquo; is the initial pre-injection (initial) level, \u0026lsquo;\u0026lsquo;-1\u0026rsquo;\u0026rsquo; constitutes advancement towards the goal without goal attainment, \u0026lsquo;\u0026lsquo;0\u0026rsquo;\u0026rsquo; is the anticipated goal post-injection, \u0026lsquo;\u0026lsquo;+1\u0026rsquo;\u0026rsquo; constitutes a better outcome than anticipated, and \u0026lsquo;\u0026lsquo;+2\u0026rsquo;\u0026rsquo; is the best possible outcome that could have been anticipated for this goal. The patient was defined as a responder if a GAS score of at least 0 was achieved at 4-6 months. Since there are several post-injection goals, we chose the GMFCS level as a guide for goal achievement to detect improvement in mobility.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe IBM SPSS version 19 has been used as the statistical methodology. Descriptive analysis was applied for continuous variables. The statistical hypothesis was the presence or absence of significant differences between the variables before and after treatment. Because of a small-sized sample, the ANOVA test was used to evaluate the treatment effect on all objective variables with an alpha value of 0.05 with Bonferroni correction.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical committee approval for the study design and statistical methodology was obtained by the Ethical Committee of the Faculty of Medicine, Ain Shams University. All research was performed in accordance with relevant guidelines and in accordance with the Declaration of Helsinski. Informed consent was obtained from all participants\u0026rsquo; legal guardians.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePatient\u0026rsquo;s clinical characteristics:\u003c/h2\u003e \u003cp\u003eTwenty pediatric patients with neurogenetic/metabolic disorders received BoNT injections for lower limb spasticity. They were 13 (65%) males and 7 (35%) females. The mean age on \"presentation, diagnosis, and BoNT injection\" was (7.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.18), (15\u0026thinsp;\u0026plusmn;\u0026thinsp;5.52) and (40.25\u0026thinsp;\u0026plusmn;\u0026thinsp;11.75) months, respectively. One patient did not complete the study due to severe adverse effects, and the study was continued with 19 patients.\u003c/p\u003e \u003cp\u003eFourteen (70%) of parents were 1st -degree cousins, eight (40%) had a similar family history and eleven (55%) had other comorbidities as highlighted in \u003cb\u003eTable\u0026nbsp;(1).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eThe spectrum of neurometabolic/genetic profile:\u003c/h2\u003e \u003cp\u003eMost of the patients 90% had a topographic pathological pattern of spastic diplegia while the rest had spastic quadriplegic with the following neurometabolic/genetic diagnosis; three patients had Canavan disease, two patients had Aicardi- Goutieres syndrome, two patients had Glutaric aciduria type 1, two patients had Maple syrup urine disease (MSUD), two patients had Metachromatic leukodystrophy, two patients had Mitochondrial cytopathy, two patients had Sjogren- Larsson syndrome (SLS), one patient had Cockayne syndrome, one patient had corpus callosum agenesis, one patient had Edward syndrome, one patient had Loeys - Dietz syndrome and one patient had Hallervorden- Spatz/pantothenate kinase-associated neurodegenerative disorder(HSS)(PKAN). Detailed demographic, clinical profile and neuroimaging findings were described in \u003cb\u003eTable\u0026nbsp;(1).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eResponse to BoNT injection and outcome:\u003c/h2\u003e \u003cp\u003eGAS was achieved, showed a better outcome than anticipated, and showed the best possible outcome in 4(20%), 11(55%), and 3(15%), respectively in terms of muscle tone reduction and easing patient care. None of the patients had serious post-BoNT injection adverse effects except one patient with mitochondrial cytopathy who survived respiratory distress and renal shutdown in 2nd-week post-injection. The detailed descriptive data of the group of muscles injected and the functional assessment tools at specific time intervals were displayed in \u003cb\u003eTable\u0026nbsp;(2).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe GMFCS showed significant improvement after 6 months post-injection (p\u0026thinsp;=\u0026thinsp;0.02) as shown in Fig.\u0026nbsp;(1). The mean scores of MAS showed statistically significant reduction at 1, 3, and 6 months as compared to initial MAS (p\u0026thinsp;=\u0026thinsp;0.0008, 0.0009, 0.03), respectively indicating muscle tone reduction as shown in Fig.\u0026nbsp;(2).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic, neurometabolic/genetic diagnosis, clinical profile, and neuroimaging findings of all patients:\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAge (months)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAt presentation (months)\u003c/p\u003e \u003cp\u003eAt diagnosis (months)\u003c/p\u003e \u003cp\u003eAt BoNT injection (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.18\u003c/p\u003e \u003cp\u003e15\u0026thinsp;\u0026plusmn;\u0026thinsp;5.52\u003c/p\u003e \u003cp\u003e40.25\u0026thinsp;\u0026plusmn;\u0026thinsp;11.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVariables\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eN (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13(65%)\u003c/p\u003e \u003cp\u003e7(35%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eConsanguinity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14(70%)\u003c/p\u003e \u003cp\u003e6 (30%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePerinatal history\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnremarkable\u003c/p\u003e \u003cp\u003eComplications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (10%)\u003c/p\u003e \u003cp\u003e18 (90%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSimilar family history\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (40%)\u003c/p\u003e \u003cp\u003e12 (60%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeuroregression\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eGlobal developmental delay\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(30%)\u003c/p\u003e \u003cp\u003e14(70%)\u003c/p\u003e \u003cp\u003e10(50%)\u003c/p\u003e \u003cp\u003e10(50%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiagnosis\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eComorbidities\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eSpasticity distribution (Topography)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCanavan Disease\u003c/p\u003e \u003cp\u003eAicardi - Goutieres Syndrome\u003c/p\u003e \u003cp\u003eGlutaric aciduria\u003c/p\u003e \u003cp\u003eMSUD\u003c/p\u003e \u003cp\u003eMLD\u003c/p\u003e \u003cp\u003eMitochondrial cytopathy\u003c/p\u003e \u003cp\u003eSLS\u003c/p\u003e \u003cp\u003eCockayne syndrome\u003c/p\u003e \u003cp\u003eCorpus Callosum agenesis\u003c/p\u003e \u003cp\u003eEdwards Syndrome\u003c/p\u003e \u003cp\u003eLoeys - Dietz Syndrome\u003c/p\u003e \u003cp\u003eHallervorden- Spatz\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003eFeeding difficulties\u003c/p\u003e \u003cp\u003eSeizures\u003c/p\u003e \u003cp\u003eVisual impairment\u003c/p\u003e \u003cp\u003eHearing impairment\u003c/p\u003e \u003cp\u003eMovement disorders\u003c/p\u003e \u003cp\u003eDiplegia\u003c/p\u003e \u003cp\u003eQuadriplegia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(15%)\u003c/p\u003e \u003cp\u003e2(10%)\u003c/p\u003e \u003cp\u003e2(10%)\u003c/p\u003e \u003cp\u003e2(10%)\u003c/p\u003e \u003cp\u003e2(10%)\u003c/p\u003e \u003cp\u003e2(10%)\u003c/p\u003e \u003cp\u003e2(10%)\u003c/p\u003e \u003cp\u003e1(5%)\u003c/p\u003e \u003cp\u003e1(5%)\u003c/p\u003e \u003cp\u003e1(5%)\u003c/p\u003e \u003cp\u003e1(5%)\u003c/p\u003e \u003cp\u003e1(5%)\u003c/p\u003e \u003cp\u003e9(45%)\u003c/p\u003e \u003cp\u003e4(20%)\u003c/p\u003e \u003cp\u003e2(10%)\u003c/p\u003e \u003cp\u003e2(10%)\u003c/p\u003e \u003cp\u003e2(10%)\u003c/p\u003e \u003cp\u003e1(5%)\u003c/p\u003e \u003cp\u003e18 (90%)\u003c/p\u003e \u003cp\u003e2 (10%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInitial GMFCS\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eDeformities\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eBrain MRI findings\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eII\u003c/p\u003e \u003cp\u003eIII\u003c/p\u003e \u003cp\u003eIV\u003c/p\u003e \u003cp\u003eV\u003c/p\u003e \u003cp\u003eTalipus equinovarus \u0026amp; scissoring\u003c/p\u003e \u003cp\u003eScissoring\u003c/p\u003e \u003cp\u003eTalipus equinovarus\u003c/p\u003e \u003cp\u003eBrain atrophy \u0026amp; demyelination\u003c/p\u003e \u003cp\u003eMegaloencephaly \u0026amp; demyelination\u003c/p\u003e \u003cp\u003eDiffuse demyelination\u003c/p\u003e \u003cp\u003eBilateral basal ganglia signal\u003c/p\u003e \u003cp\u003ePeriventricular leukomalacia\u003c/p\u003e \u003cp\u003eBrain atrophy \u0026amp; Chiari I malformation\u003c/p\u003e \u003cp\u003eBrain atrophy, hypo myelination \u0026amp; intracranial calcifications\u003c/p\u003e \u003cp\u003eCorpus callosum agenesis \u0026amp; mild brain atrophy\u003c/p\u003e \u003cp\u003eEye-of-the-tiger sign\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(15%)\u003c/p\u003e \u003cp\u003e10(50%)\u003c/p\u003e \u003cp\u003e6(30%)\u003c/p\u003e \u003cp\u003e1(5%)\u003c/p\u003e \u003cp\u003e18(90%)\u003c/p\u003e \u003cp\u003e1(5%)\u003c/p\u003e \u003cp\u003e1(5%)\u003c/p\u003e \u003cp\u003e4(20%)\u003c/p\u003e \u003cp\u003e3(15%)\u003c/p\u003e \u003cp\u003e3(15%)\u003c/p\u003e \u003cp\u003e3(15%)\u003c/p\u003e \u003cp\u003e2(10%)\u003c/p\u003e \u003cp\u003e1(5%)\u003c/p\u003e \u003cp\u003e1(5%)\u003c/p\u003e \u003cp\u003e1(5%)\u003c/p\u003e \u003cp\u003e1(5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eBoNT injection: botulinum toxin type A; HSS/PKAN: Hallervorden- Spatz/pantothenate kinase-associated neurodegenerative disorder; MRI: magnetic resonance imaging; MSUD: Maple syrup disease; MLD: Metachromatic leukodystrophy; SLS: Sjogren- Larsson syndrome\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDescriptive data of the group of muscles injected, mean scores of GMFCS \u0026ldquo;initial and final\u0026rdquo;, MAS \u0026ldquo;initial, 1, 3 and 6 months\u0026rdquo;, GAS at 4\u0026ndash;6 months and post-BoNT injection adverse effects of all patients:\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMuscles injected\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInitial GMFCS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFinal GMFCS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eInitial MAS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1st month MAS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3rd month MAS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6th month MAS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eGAS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eAdverse effects\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCanavan disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHamstrings/hip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eLocal pain\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCanavan disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCanavan disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAicardi - Goutieres Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHamstrings/hip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eLocal pain\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAicardi - Goutieres Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHamstrings/hip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eLocal pain\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGlutaric aciduria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHamstrings/hip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eLocal pain\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGlutaric aciduria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHamstrings/hip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eLocal pain\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMSUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMSUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHamstrings/hip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eLocal pain\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMLD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHamstrings/hip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eLocal pain\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMLD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMitochondrial cytopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCalf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMitochondrial cytopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eRespiratory distress \u0026amp; renal shutdown\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHamstrings/hip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eLocal pain\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHamstrings/hip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCockayne syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHamstrings/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCorpus Callosum agenesis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEdwards Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHamstrings/hip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLoeys - Dietz Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHamstrings/hip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHSS/PKAN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHamstrings/hip adductors/ calf\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eLocal pain\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003e\u003cb\u003eGAS\u003c/b\u003e: goal attainment scaling; \u003cb\u003eGMFCS\u003c/b\u003e: gross motor function classification system for cerebral palsy; Calf: gastrocnemii and soleus; MAS: modified Ashworth scale; MSUD: Maple syrup disease; MLD: Metachromatic leukodystrophy; HSS/PKAN: Hallervorden- Spatz/pantothenate kinase-associated neurodegenerative disorder; SLS: Sjogren- Larsson syndrome\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e \u003cb\u003eHighlights on genetic cerebral palsy\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIn addition to suggesting a demonstrating the safety and efficacy BoNT injections in hypertonia associated with genetic diseases, this study highlights the limitation of genetic diagnosis in our region (2%, 20 out of 849 cases).\u003c/p\u003e \u003cp\u003eIn our cohort, 70% of patients were of 1st -degree cousins\u0026rsquo; marriage and 40% had a similar family history, highlighting the consequences of consanguineous marriage on the increased rate of neurogenetic disorders in our region (Tadmouri et al., 2009). It is worth mentioning that 55% of our patients had other comorbidities and 63.5% were dependent on their caregivers either totally (35% with GMFCS IV and V) or partially (28.5% with GMFCS III). This reflects the financial, physical, and mental burden on these families which in turn will affect their quality of life. It is well known that neurometabolic disorders present with multisystem involvement whether neurological or non-neurological with movement disorders being the most significant disabling morbidity (Ortigoza-Escobar, 2020).\u003c/p\u003e \u003cp\u003eSpastic diplegia was the most prevalent topographic pattern identified (90%) while the rest of the patients had spastic quadriplegia with talipus equinovarus and scissoring being the most common deformity (90%) encountered. This explains why our entire patients except one patient required injection of multiple muscle groups to relieve spasticity. Although this is not the common practice in non-ambulatory patients for concerns about developing adverse effects. By injecting multiple muscles, our results show that the children can achieve functional improvement despite the progressive course of the disease with high safety profile.\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eMitochondrial cytopathy and BoNT\u003c/h2\u003e \u003cp\u003eAll our patients had acceptable mild transient local pain except one patient who initially presented with an unidentified multisystem neurological disorder but was later diagnosed with mitochondrial cytopathy after receiving the BoNT and experiencing complications. The patient developed severe respiratory distress and renal shutdown which resolved without long-term consequences. This observation supports the existing literature on the general safety of BoNT injections in pediatric patients with CP (Delgado et al., 2010)and the risk of severe respiratory distress and mortality in multilevel injections (Howell et al., 2007), especially in patients with mitochondrial cytopathy (Gioltzoglou, 2005).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eInterpretation of GAS\u003c/h2\u003e \u003cp\u003eThe results of this study revealed that BoNT injections were effective in achieving the preset functional goals of \u0026ldquo;muscle tone reduction, easing the patient care and rehabilitation\u0026rdquo; in pediatric patients with neurometabolic/genetic disorders. We found that the overall responder rate was 90% based on GAS scores, where 20% achieved the preset goals, 55% of patients achieved a better outcome than anticipated and 15% achieved the best possible outcome.\u003c/p\u003e \u003cp\u003eWe believe that this would have not been accomplished without receiving intensive rehabilitation and using appropriate orthotics. Similar promising findings were reported with functional and symptomatic improvement according to GAS in adult patients with poststroke lower limb spasticity (Munain et al., 2019).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eGMFCS versus MAS\u003c/h2\u003e \u003cp\u003eFurthermore, this functional improvement was supported by the significant improvement in the GMFCS and the MAS scores after BoNT injection. These findings are consistent with previous research on BoNT injections for the treatment of spasticity in children with CP due to perinatal complications (Delgado et al., 2010). The MAS scores showed the best response at the first follow-up visit (1st month) as compared to the 3rd and 6th months post-BoNT injection. However, although the improvement tends to decline by the 6th month, still there was a statistically significant improvement as compared to the initial MAS scores. This corresponds with the known process of recovery of neuromuscular transmission from 6 to 8 weeks, as new nerve terminals sprout (Rogozhin et al., 2008).\u003c/p\u003e \u003cp\u003eIn our results \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e at 1-month post-injection, we noticed a discrepancy between MAS and GMFCS results in the form of significant improvement in tone (mean 1.5) without corresponding improvement in GMFCS. The explanation could be that the decrease in muscle tone is not necessarily translated to improvement in function in short duration because the development of neuroplasticity is described in time factor.\u003c/p\u003e \u003cp\u003eThere are limited publications ``mainly case reports\u0026rdquo; on the efficacy and safety of using BoNT injections in patients with neurometabolic/genetic disorders. It was effectively and safely used for the treatment of lower limb spasticity and dystonia in patients with Glutaric aciduria type I (Burlina et al., 2004), HSS/PKAN (Lin et al., 2018; Neves et al., 2008), MLD (Borges et al., 2020; Singh et al., 2009), Pelizaeus-Merzbacher disease (PMD)(Brender et al., 2015), SLS (Anil G, 2019; Cho et al., 2018; Hidalgo et al., 2017), Alexander disease (Machol et al., 2018), Aicardi-Gouti\u0026egrave;res syndrome (AGS) (Videira et al., 2020), Cockayne syndrome (Hsu et al., 2021)and in combination with epidural analgesia in one child with MSUD (Kaki \u0026amp; Arab, 2012).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eThe idea that BoNT can be used as an alternative to maximum anticholinergics\u003c/h2\u003e \u003cp\u003eA study done by Burlina highlights that BoNT injection can be used as an alternative to anticholinergics, especially in high doses. It further highlights its efficacy in treating extrapyradmial symptoms in glutaryl CoA dehydrogenase type I deficiency. In our series two such cases were injected reporting GAS of +\u0026thinsp;1 and +\u0026thinsp;2 respectively. Our results in treating upper limb dystonia were encouraging. In conclusion, anticholinergic drugs, such as trihexyphenidyl, and botulinum can be used not only as a second line after anticholinergics but also as an alternative. (Burlina et al., 2004)\u003c/p\u003e \u003cp\u003e \u003cb\u003eCut-off duration of improvement to consider injection.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIs there a rationale to set a limit on the indication according to the natural history of the genetic disease? For example, in MLD is considered a terminal genetic disease with a life expectancy of 4 years. In our results with MLD cases (mean age at presentation is 7 in this study) initial improvement of spasticity was observed followed by rapid recurrence in less than 6 months. In retrospect, it may seem that BoNT injection in a short life expectancy is of minimal benefit even though GAS for one of the cases was +\u0026thinsp;1 (the other was 0). This study calls for a large-scale study analyzing the best cut off values for injecting in such diseases with short life expectancy. (Borges et al., 2020)\u003c/p\u003e \u003cp\u003e \u003cb\u003eThe potential effects of BoNT on muscular structures should be explored.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe concept of sarcomeric mechanotransduction in which genes that encode for sarcomere signaling proteins were upregulated in response to alterations of mechanical activity of the muscle following BoNT injection and exercise (Velders et al., 2008). This has implications on the effect of BoNT paralyzed muscles on muscle adaptation which in turn can influence motor activity of the spastic muscle and as a result modify gait and ambulation however such findings are yet to be explored.\u003c/p\u003e \u003cp\u003eIn this study, BoNT was used successfully in controlling spasticity and dystonia for at least 6 months without major adverse effects. Given limited options, it can be considered as a standard line of treatment. This was in agreement with Lin et al, who reports 25% improvement in Barry Alright dystonia scale in their cases, along with subtle improvement in functional independence measure. (Lin et al., 2018)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eLimitations of this study include its retrospective design and the relatively small number of patients, however; this is difficult to avoid since it involves a relatively rare target population with neurometabolic/genetic disorder from a single center. This might limit the generalizability of the results. Therefore, we believe that although the study\u0026rsquo;s sample, albeit small, it can be considered as a nidus for future research in this population.\u003c/p\u003e \u003cp\u003eWhen considering possible clinical trials, it must be remembered that genetic disorders are a highly heterogeneous group and as such, research should be disease-specific rather than focusing upon generalized trends of spasticity. As the understanding of the nature of spasticity in genetic disorders develops, it will become possible to better define suitable outcome measures for assessing change in severity with an emphasis on developing measurement tools specific to the disorders in question.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study provides preliminary evidence supporting the use of BoNT injections as a safe and effective therapeutic option for the treatment of lower limb spasticity in children with neurometabolic/genetic disorders. This will in turn improve the functional outcomes and quality of life for this patient population and their caregivers. However, further research involving larger sample sizes and multicenter designs is needed to confirm these findings and to identify specific patient subgroups that may benefit most from this treatment approach, especially in resource-limited countries where more invasive approaches such as baclofen pump implantation are not feasible. To the best of our knowledge, this is the first pilot study of its kind to evaluate the efficacy and the safety of BoNT injection for the treatment of lower limb spasticity in pediatric patients with neurometabolic/genetic etiology in our region.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eD.A.S , M.A. , W.A.G wrote the manuscriptG.H., M.N., M.I.A., revised it and prepared the figures A.A. and N.F. did the statistics and prepared the tables W.A.G. conceptualized and provided the data for the patients All authors reviewed the manuscript\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article, any further enquiries regarding the data are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAnandan, C., \u0026amp; Jankovic, J. 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Diagnosis of Aicardi‐Gouti\u0026egrave;res Syndrome in Adults: A Case Series. \u003cem\u003eMovement Disorders Clinical Practice\u003c/em\u003e, \u003cem\u003e7\u003c/em\u003e(3), 303\u0026ndash;307. https://doi.org/10.1002/mdc3.12903\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Botulinum toxin type A, cerebral palsy, children, neurometabolic/genetic, modified ashworth scale, spasticity","lastPublishedDoi":"10.21203/rs.3.rs-4548232/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4548232/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Botulinum toxin type A (BoNT) is a well-established therapeutic modality for the treatment of lower limb spasticity in children with cerebral palsy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e To assess the functional outcomes and tolerability of BoNT injection for the treatment of lower limb spasticity in children with neurometabolic/genetic disorders.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We conducted a retrospective chart review for history, demographic data, comorbidities, neurological examination, and neuroimaging findings for all patients diagnosed with neurometabolic/genetic disorders from December 2020 to December 2022. The outcomes were assessed by recording the Gross Motor Function Classification system (GMFCS) for Cerebral Palsy \"Initially and after 6 months' post-treatment\", the Modified Ashworth scale (MAS) \"initially and at 1,3,6 month post-treatment\" and the achieved preset functional goals using the Goal Attainment Scaling (GAS) at 4-6 months post-treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 90% of the patients showed improvement in their GAS scores, with 20% achieving the preset goal, 55% achieving a better outcome than anticipated and 15% achieving the best possible outcome. Furthermore, the GMFCS and MAS scores showed a significant statistical improvement after six months post-injection (p=0.02, p=0.03), respectively. None of the patients developed serious adverse effects except one who had mitochondrial cytopathy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBoNT injections were effective and showed a high safety profile in children with neurometabolic/genetic disorders. To our knowledge, this is the first study that specifically targets this patient population, filling a gap in the literature and providing valuable insights into the potential benefits of BoNT injections for this group. However, further large-scale studies are recommended to confirm these findings.\u003c/p\u003e","manuscriptTitle":"Botulinum Toxin Type A: Efficacy in the management of Lower Limb Spasticity in Children with Genetic Disorders","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-23 22:14:57","doi":"10.21203/rs.3.rs-4548232/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"84e41fa9-f050-4db5-ab71-68685afa8253","owner":[],"postedDate":"July 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":34783127,"name":"Biological sciences/Biochemistry"},{"id":34783128,"name":"Biological sciences/Cell biology"},{"id":34783129,"name":"Biological sciences/Genetics"},{"id":34783130,"name":"Biological sciences/Molecular biology"},{"id":34783131,"name":"Biological sciences/Neuroscience"},{"id":34783132,"name":"Biological sciences/Structural biology"},{"id":34783133,"name":"Health sciences/Medical research"},{"id":34783134,"name":"Health sciences/Neurology"}],"tags":[],"updatedAt":"2024-12-12T15:24:03+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-23 22:14:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4548232","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4548232","identity":"rs-4548232","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}