Abstract
Multiple Sulfatase Deficiency (MSD) is a rare autosomal recessive disease with specific clinical findings such as psychomotor retardation and neurological deterioration. No therapy is available for this genetic disorder. Previous studies have shown that N-acetyl-L-leucine (NALL) can improve the neurological inflammation in the cerebellum.
In the current study, the effects of NALL on ataxia symptoms and quality of life were explored in a patient with MSD.
This study was a crossover case study. The subject, a girl aged 12 years old, received NALL at a dose of 3 g/day (1 g in the morning, 1 g in the afternoon, and 1 g in the evening). A fasting blood sample was taken from the subject to evaluate side effects before the intervention and 4 weeks after taking supplement/placebo in every study stage. The ataxia moving symptoms were evaluated using the Scale for the Assessment and Rating of Ataxia (SARA) score in every study stage. Dietary intake was measured using 24-h dietary recall before and after the intervention. The diet compositions were assessed by Nutritionist IV software. Serum IL-6 level was measured using an ELISA kit.
There was no significant change in complete blood count (CBC) and serum biochemical factors in the patient with MSD after receiving NALL (3 g/day) over 4 weeks. The SARA score was reduced by 25%. The gait whose maximum score accounts for approximately one-fifth of the maximum total SARA score (8/40) was decreased. The heel-to-shin slide, the only SARA item performed without visual control, was also improved after therapy. Furthermore, there was a downward trend in the 8MWT (8.71 to 7.93 s). Regarding quality of life assessments, the parent and child reported improved quality of life index, physical health, and emotional function after taking NALL. Moreover, total energy intake was increased with NALL treatment through the study period.
Supplementation with NALL at a dose of 3 g/day over 4 weeks was well tolerated and improved ataxia symptoms, quality of life measure, and serum IL-6 levels in the patient with MSD. Further proof-of-concept trials are warranted to confirm the present findings.
Keywords: Multiple Sulfatase Deficiency, N-acetyl-leucine, Lysosomal Storage Disease, Clinical Study
Introduction
Multiple sulfatase deficiency (MSD) is a lysosomal storage disease (LSD), which is a rare genetic disorder with autosomal recessive inheritance [1, 2]. Sulfatases can catalyze the hydrolysis of sulfate ester bonds in numerous substrates including glycosaminoglycans (GAGs), sulfolipids, and steroid sulfates [3]. Seventeen sulfatase genes have been found in the human genome [4]. In MSD, a severe reduction or complete absence of all sulfatase functions occurs due to a mutation in the gene encoding the formylglycine (FGly)-generating enzyme (FGE) that generates FGly [5, 6]. The mutations in the SUMF1 gene, encoding FGE, affect the posttranslational modification of sulfatases, thereby causing the replacement of a cysteine situated in the catalytic site of sulfatase by α-FGly [5, 6].
Specific clinical manifestations of MSD are psychomotor retardation and neurological deterioration, as well as vision and hearing loss, organomegaly, corneal clouding, cardiac valve disease, dystosis multiplex, stiff joints and ichthyosis, and ultimately premature death [5–7]. A total of 18 missense mutations over 17 different residues of mature FGE have been found to date [5, 6, 8].
No therapy is yet available for this genetic disorder. Previous studies have shown that N-acetyl-L-leucine (NALL) can improve the neurological inflammation in the cerebellum. An in vivo study in a rat model with traumatic brain injury (TBI) has shown that treatment with NALL improves lysosome-associated autophagy and can restore neuroprotective function in the ipsilateral cortex after TBI [9]. To date, no clinical study has been performed with NALL in patients with MSD. Moreover, due to the fact that this progressive genetic disorder can affect patients’ quality of life, administration of NALL as a low-cost supplement might be effective in improving patients’ symptoms and quality of life. Therefore, in the current study, we evaluated the effects of NALL intervention on ataxia symptoms and quality of life in a patient with MSD.
Methods
Ethics
The study protocol has been approved by the Ethics Committee at the Mashhad University of Medical Sciences (MUMS), (ID: IR.MUMS.MEDICAL.REC.1401.127) and registered in the Iranian Registry of Clinical Trials (registration number: IRCT20210413050958N5). A written consent form has been signed by her parents.
Subject
The subject was a girl with MSD aged 12 years old (weight 33.60 kg and height 136.00 cm). The MSD diagnosis had been confirmed by genetic testing at the age of 9 years {Variant: Homozygous NM: 182,760:exon4:c.G529C:p.A177P; SUMF1 class 2-Likely pathogenic}.
Drug Preparation
NALL powder was purchased from Shenzhen Ipure Biological Import and Export Co., Ltd (China). The caplets of NALL and placebo (500 mg) were prepared in the Industrial Laboratory of the Faculty of Pharmacy (MUMS, Mashhad, Iran).
Study Design
This study was a case crossover study. The subject received the NALL at a dose of 3 g/day (1 g in the morning, 1 g in the afternoon, and 1 g in the evening). A fasting blood sample was taken from the subject to evaluate side effects before the intervention and 4 weeks after taking supplement/placebo in every study stage. Serum IL-6 level was measured by the Karmania Pars gene ELISA kit (Kerman, Iran). The ataxia moving symptoms were evaluated using the Scale for the Assessment and Rating of Ataxia (SARA) score in every study stage. The quality of life has been assessed using the PedsQL questionnaire, in which the answers are in the form of Likert and five options {always (0), often: 1, sometimes: 2, very little: 3, never: 4}. The score obtained for each subscale will be from 0 to 100. Each phrase is scored as below: always: 0, often: 25, sometimes: 50, very low: 75, Never: 100. So that, a score < 25 shows a low quality of life. A score from 25 to 75 displays an average quality of life and a score > 75 indicates a high quality of life. It should be mentioned that the current study was conducted during the Coronavirus (COVID-19) pandemic, which significantly affected the schedule of events.
Dietary Intake Assessment
Dietary intake was measured using 24-h dietary recall before and after the intervention. The amount of dietary energy and nutritional intake of patients were then calculated using Nutritionist IV software (version 7.0; N‐Squared Computing, Salem, OR, USA) based on US Department of Agriculture (USDA) food composition table revised for Iranian foods [10]. The software computed the amount of calories consumed, macronutrients, micronutrients, fibers, and the percentage of macronutrients in the daily energy intake based on the meals ingested.
Results
Biochemical Markers
The main biochemical markers of the patient are summarized in Table 1. There was not any significant change in biochemical factors in our patient during study. The serum IL-6 level showed a downward trend.
Table 1.
The effect of N-acetyl-L-Leucine on clinical characteristics and serum biochemical factors in a girl with multiple sulfatase deficiency
| Variables | Phase I (Placebo) | Phase II (treatment) | ||
|---|---|---|---|---|
| Pre treatment | Post treatment | Pre treatment | Post treatment | |
| Weight (kg) | 33.60 | 34.35 | 34.55 | 35.10 |
| Constipation (per week) | 5 | 5 | 5 | 0 |
| Serum biochemical factors | ||||
| Urea (mg/dl) | 36.00 | 31.0 | 34.00 | 30.00 |
| Creatinine (mg/dl) | 1.00 | 0.80 | 0.80 | 0.80 |
| GOT(AST); (U/L) | 26.00 | 31.00 | 22.00 | 22.00 |
| GPT(ALT); (U/L) | 20.00 | 31.00 | 14.00 | 15.00 |
| Alkaline phosphatase; (U/L) | 635.00 | 498.00 | 609.00 | 666.000 |
| Bilirubin Total (mg/dl) | 0.30 | 0.80 | 0.60 | 0.70 |
| Bilirubin Direct (mg/dl) | 0.10 | 0.10 | 0.30 | 0.10 |
| LDH (U/L) | 450.00 | 438.00 | 363.00 | 368.00 |
| Na(mEq/L) | 139.00 | 140.00 | 139.00 | 138.00 |
| K(mEq/L) | 4.10 | 4.10 | 4.30 | 4.30 |
| IL-6(ng/ml) | 14.32 | 15.02 | 14.22 | 13.12 |
| Complete blood count (CBC) | ||||
| WBC (109/L) | 8.40 | 4.50 | 7.70 | 7.90 |
| RBC (1012/L) | 4.47 | 4.26 | 4.30 | 4.55 |
| Hemoglobin (mmol/L) | 12.90 | 12.20 | 12.70 | 13.60 |
| Hematocrit (%) | 37.80 | 37.30 | 38.60 | 40.20 |
| Platelets (109/L) | 333.00 | 300.00 | 386.00 | 341.00 |
| RDW (%) | 12.30 | 12.30 | 12.30 | 12.50 |
| Neutrophils (%) | 55.70 | 30.40 | 46.00 | 48.70 |
| Lymphocytes (%) | 36.50 | 62.90 | 48.70 | 43.60 |
SARA and SCAFI Score
The SARA score reduced dramatically (by 25% overall) following NALL intervention. The gait whose maximum score accounts for approximately one-fifth of the maximum total SARA score (8/40) was decreased significantly. The heel-to-shin slide, the only SARA item performed without visual control, was also marginally improved after therapy. Furthermore, there was a downward tendency on the 8MWT (8.71 to 7.93 s). Moreover, 9HPT revealed no improvement in fine motor dexterity (Table 2).
Table 2.
The effect of N-acetyl-L-leucine on ataxia moving symptoms in a girl with multiple sulfatase deficiency
| Variable/Score | Phase I (Placebo) | Phase II (treatment) | ||
|---|---|---|---|---|
| Pre treatment | Post treatment | Pre treatment | Post treatment | |
| Scale for the assessment and rating of ataxia (SARA) | ||||
| Gait | 2 | 3 | 3 | 1 |
| Stance | 3 | 3 | 3 | 3 |
| Sitting | 2 | 1 | 2 | 2 |
| Speech disturbance | 2 | 2 | 3 | 2 |
| Finger chase | 2 | 1 | 1 | 1 |
| Nose-finger test | 3 | 2 | 2 | 2 |
| Fast alternating hand movements | 3 | 2 | 3 | 2 |
| Heel-shin slide | 3 | 3 | 3 | 2 |
| Total SARA score | 20 | 17 | 20 | 15 |
| SCAFI | ||||
| 8MWT (Second) | 8.50 | 9.11 | 8.71 | 7.93 |
| 9HPT | Unable to do due to tremor | Unable to do due to tremor | Unable to do due to tremor | Unable to do due to tremor |
Child Self-report and Parent Proxy Report of Quality of Life
Our patient’s Physical Health score in Child self-report was significantly higher than before treatment. The administration of NALL boosted both emotional and social functioning modestly. During the trial, there were no discernible changes in school functioning or psychosocial health. Besides, after therapy, the quality of life index improved (Table 3).
Table 3.
The effects of N-acetyl-L-Leucine on quality of life according to Child self-report in a girl with multiple sulfatase deficiency
| Phase I (Placebo) | Phase II (treatment) | |||
|---|---|---|---|---|
| Child self-report | Pre treatment | Post treatment | Pre treatment | Post treatment |
| Physical Health | 71.87 | 87.50 | 71.87 | 90.62 |
| Emotional Functioning | 85.00 | 90.00 | 80.00 | 90.00 |
| Social Functioning | 45.00 | 45.00 | 45.00 | 50.00 |
| School Functioning | 100.00 | 100.00 | 100.00 | 100.00 |
| Total Psychosocial Health | 68.33 | 78.33 | 75.00 | 80.00 |
| Quality of life index | 75.47 | 80.62 | 74.21 | 82.65 |
In Parent proxy report, the Physical Health score and emotional functioning of our patient were significantly higher than before treatment. Moreover, the quality of life index was improved after therapy (Table 4).
Table 4.
The effects of N-acetyl-L-Leucine on quality of life according to Parent proxy-report in a girl with multiple sulfatase deficiency
| Phase I (Placebo) | Phase II (treatment) | |||
|---|---|---|---|---|
| Parent proxy-report | Pre treatment | Post treatment | Pre treatment | Post treatment |
| Physical Health | 75.00 | 87.50 | 71.87 | 93.75 |
| Emotional Functioning | 80.00 | 85.00 | 80.00 | 95.00 |
| Social Functioning | 90.000 | 90.00 | 90.00 | 90.00 |
| School Functioning | 100.00 | 100.00 | 100.00 | 100.00 |
| Total Psychosocial Health | 83.33 | 85.00 | 90.00 | 95.00 |
| Quality of life index | 86.25 | 90.62 | 85.47 | 94.68 |
Dietary Intake Status
The results for energy and macronutrient intake are displayed in Table 5. Total energy intake with NALL treatment was increased through the period. In the beginning phase, the total energy intake was 784.7 kcal/d, at the end of phase 2, the total energy intake increased by 1471 kcal/d.
Table 5.
The energy and macronutrient intake in a patient with multiple sulfatase deficiency
| Variables | Phase I (Placebo) | Phase II (treatment) | ||
|---|---|---|---|---|
| Pre treatment | Post treatment | Pre treatment | Post treatment | |
| Macronutrients | ||||
| Carbohydrate (g) | 49.22 | 378.2 | 209 | 230.8 |
| Dietary Fiber (g) | 6.79 | 22.53 | 37.36 | 12.55 |
| Total sugar (g) | 11.06 | 44.93 | 79.87 | 84.37 |
| Protein (g) | 33.79 | 46.76 | 82.26 | 57.71 |
| Fat (g) | 54.11 | 15.38 | 101.6 | 38.35 |
| SFA (g) | 5.98 | 3.48 | 16.29 | 7.73 |
| MUFA (g) | 11.65 | 6.50 | 50.97 | 20.77 |
| PUFA (g) | 33.68 | 1.92 | 28.53 | 3.86 |
| Trans (g) | 0.00 | 0.00 | 0.00 | 0.00 |
| Cholesterol (mg) | 37.10 | 253 | 52.82 | 94.68 |
| Energy (kcal) | 784.7 | 1811 | 1984 | 1471 |
| Micronutrients | ||||
| Ca (mg) | 102.2 | 283.9 | 351.4 | 282.3 |
| Mg (mg) | 150.4 | 307.6 | 763.8 | 133.7 |
| P (mg) | 1343 | 760.7 | 1899 | 459.6 |
| Fe (mg) | 5.53 | 8.91 | 23.38 | 8.54 |
| Copper (mg) | 1.97 | 2.49 | 3.02 | 0.70 |
| Zinc (mg) | 5.93 | 5.45 | 10.31 | 3.13 |
| Manganese (mg) | 4.59 | 4.28 | 7.57 | 5.75 |
| Se (mg) | 0.07 | 0.026 | 0.023 | 0.03 |
| Iodine (µg) | - | - | - | 0.00 |
| Carotene (µg) | 0 | 9.11 | 62.09 | 0.00 |
| Vit D (µg) | 0 | 0 | 0 | 0.00 |
| Vit E (mg) | 0 | 0.90 | 1.72 | 2.47 |
| Vit C (mg) | 1.64 | 217.9 | 321.2 | 190.5 |
| B1 (mg) | 0.40 | 1.86 | 1.64 | 1.46 |
| B2 (mg) | 0.46 | 0.84 | 0.96 | 0.66 |
| B3 (mg) | 7.95 | 23.9 | 15.11 | 22.06 |
| B5 (mg) | 8.36 | 8.16 | 3.68 | 3.36 |
| B6 (mg) | 0.82 | 4.02 | 0.90 | 1.19 |
| B9 (µg) | 247.2 | 183.4 | 381.3 | 48.22 |
| B12 (µg) | 3.742 | 0.854 | 0.146 | 0.92 |
Discussion
To the best of our knowledge, the present study is the first to investigate the effects of NALL on MSD. Our results showed that taking NALL over 4 weeks did not have any side effect in a subject with MSD. In response to treatment with NALL, the cerebellar function, as assessed by SARA and SCAFI improved, especially in gait domain that was correlated with the reduction of the inflammatory parameter IL-6. However, at baseline there were no significant differences between the two groups (placebo/ treatment) with respect to IL-6. Besides, the quality of life was improved by taking NALL and total energy intake through the study period.
NALL is the L-enantiomer of N-acetyl-DL-leucine (NADLL), a modified amino acid available in France since 1957 as a racemate under the trade name of Tanganil®, indicated for the treatment of acute vertigo [11]. The mechanism of action of NADLL for dizziness has not been fully determined. It may directly affect the neurons in the vestibular nuclei [11]. Previous studies have reported that the L-enantiomer is the pharmacologically active enantiomer of NADLL [12, 13]. NALL has not yet been approved for any indication in any jurisdiction.
Another type of neurodegenerative LSD is GM2 gangliosidosis, which is a rare autosomal recessive genetic disorder that includes two disorders (Tay–Sachs and Sandhoff disease). These disorders result in the progressive deterioration of nerve cells as well as an inherited deficiency in the production of hexosaminidases A, B, and AB [14].
In 2020, Kaya et al. explored the efficacy of NADLL at a dose of 0.1 g/kg/day in a mouse model of Sandhoff disease. It was reported that NADLL significantly extended the lifespan, improved motor function, and decreased glycosphingolipid (GSL) storage in the forebrain and cerebellum. Furthermore, NADLL normalized glucose and glutamate metabolism, increased autophagy, reactive oxygen species (ROS) scavenging, and superoxide dismutase-1 (SOD1) expression (15).
In 2021, Martakis et al. evaluated the effects of NALL on 30 subjects aged > 6 years old with a confirmed genetic diagnosis of GM2 gangliosidosis. The patients were recruited from 4 countries including Germany, the UK, Spain and the USA. Their results showed that NALL intervention over 42 days was safe and well tolerated and could improve the symptoms, functioning, and quality of life in patients with GM2 gangliosidosis [16].
Bremova-Ertl et al. have investigated the safety and efficacy of NALL in 33 subjects with Niemann–Pick disease type C (NPC) aged 7–64 years in an open-label, rater-blinded Phase II study. NALL was safe and well tolerated without any serious adverse events. NALL improved neurological symptoms, functioning, and quality of life over 6 weeks [17]. Moreover, there is a Phase III crossover placebo-controlled clinical trial running right now in 53 patients (aged ≥ 4 years) with a confirmed genetic diagnosis of Niemann-Pick Disease Type C (NPC) in the USA (NCT number NCT05163288) (https://clinicaltrials.gov/ct2/show/NCT05163288?cond=Niemann-Pick+Disease%2C+Type+C&draw=2&rank=9).
In an in vitro study, Vibert et al. showed in guinea-pig whole brain that NADLL can specifically decrease vestibular-related neural asymmetries that cause acute vertigo crises. NADLL inhibits the abnormal depolarization of neurons on the hyperactive side without changing other normally functioning brain structures. However, its underlying molecular mechanism of action is still unknown and needs to be identified [11]. Previous studies have shown that aminopyridines can increase gait variability mostly during fast walking [18, 19]. On the other hand, NADLL is effective in decreasing the gait variability during slow walking. Schniepp et al. assessed the effects of NADLL (5 g/day) over at least 4 weeks on walking stability in patients with cerebellar ataxia. Treatment with NADLL significantly improved the SARA scores and coefficient of variation of stride time in the patients [19].
The effects of NADLL (dose of 3–5 g/day) in 6 patients with AT least over 4 weeks have been reported by Brueggemann et al. in 2022. They showed that NADLL can improve ataxia and ocular stability in these patients [20]. Likewise, a recent case study suggested the beneficial effects of NADLL supplementation (4 g/day for 16 weeks) in improving ataxia and quality of life in a 9.7-year-old girl with AT [21].
The findings from our study are consistent with those of previous investigations that reported the safety of NALL. The strength of the current study is its crossover design, although it was conducted only in one patient. Another strength is that this study is a placebo-controlled trial. Hence, it is necessary to conduct future proof-of-concept randomized controlled trials based on the results of this case study.
Conclusion
NALL intervention at a dose of 3 g/day over 4 weeks was safe and well tolerated in a young girl with MSD. The results showed that the ataxia symptoms and quality of life measures can be improved. Moreover, the serum IL-6 concentration showed a downward trend that may be improved by increasing the study period.
Author contribution
Conceptualization: MS, AS Investigation: MS, MH, TJ, PS, MN Methodology: MS, AS Analysis: SA, TJ Writing-original draft: MS Writing-review and editing: MH, TJ, PS, MN, SA, AS.
Data availability
Data are available upon request.
Declarations
Ethics approval
The study protocol has been approved by the Ethics Committee of Mashhad University of Medical Sciences (ID: IR.MUMS.MEDICAL.REC.1401.127), Mashhad, Iran.
Competing interests
None.
Footnotes
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Schlotawa L, Adang LA, Radhakrishnan K, et al. Multiple sulfatase deficiency: a disease comprising mucopolysaccharidosis, sphingolipidosis, and more caused by a defect in posttranslational modification. Int J Mol Sci. 2020;21(10):3448. doi: 10.3390/ijms21103448. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Thomas D, Lars S, Andre FM, et al. Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease-Lysosomal storage disorders caused by defects of non-lysosomal proteins. Biochim Biophys Acta Mol Cell Res. 2009;1793(4):710–25. [DOI] [PubMed]
- 3.Hopwood JJ, Ballabio A. in The metabolic and molecular basis of the inherited disease (McGraw–Hill, New York), 1997 pp 3725–3732.
- 4.Sardiello M, Annunziata I, Roma G, Ballabio A. Hum Mol Gen. 2005;14:3203–3217. doi: 10.1093/hmg/ddi351. [DOI] [PubMed] [Google Scholar]
- 5.Cosma MP, Pepe S, Annunziata I, Newbold RF, Grompe M, Parenti G, Ballabio A. The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. Cell. 2003;113:445–456. doi: 10.1016/S0092-8674(03)00348-9. [DOI] [PubMed] [Google Scholar]
- 6.Dierks T, Schmidt B, Borissenko LV, Peng J, Preusser A, Mariappan M, von Figura K. Multiple sulfatase deficiency is caused by mutations in the gene encoding the human Cα-formylglycine generating enzyme. Cell. 2003;113:435–444. doi: 10.1016/S0092-8674(03)00347-7. [DOI] [PubMed] [Google Scholar]
- 7.Parini R, Andria G. Lysosomal storage diseases. John Libbey Eurotext; 2010 Jun 1.
- 8.Cosma MP, Pepe S, Parenti G, Settembre C, Annunziata I, Wade-Martins R, Di Domenico C, Di Natale P, Mankad A, Cox B, et al. Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Hum Mutat. 2004;23:576–581. doi: 10.1002/humu.20040. [DOI] [PubMed] [Google Scholar]
- 9.Sarkar C, Hegdekar N, Lipinski MM. N-acetyl-L-leucine treatment attenuates neuronal cell death and suppresses neuroinflammation after traumatic brain injury in mice. bioRxiv. 2019. p. 759894. 10.1101/759894.
- 10.Azar M, Sarkisian E. Food composition table of Iran. Tehran: National Nutrition and Food Research Institute, Shaheed Beheshti University Press. 1980. p. 65.
- 11.Vibert N, Vidal PP. In vitro effects of acetyl-DL-leucine (tanganil) on central vestibular neurons and vestibulo-ocular networks of the guinea-pig. Eur J Neurosci. 2001;13:735–48. doi: 10.1046/j.0953-816x.2000.01447.x. [DOI] [PubMed] [Google Scholar]
- 12.Neuzil E, Ravaine S, Cousse H. La N-ace ´tyl-DL-leucine, me ´dicament symptomatique de vertigineux. Bull Soc Pharm Bordx. Bull Soc Pharm Bordx. 2002;141:15–38. [Google Scholar]
- 13.Churchill GC, Strupp M, Galione A, Platt FM. Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance. PLoS ONE. 2020;15(2):e0229585. doi: 10.1371/journal.pone.0229585. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Karimzadeh P, Jafari N, Nejad Biglari H, et al. GM2-Gangliosidosis (Sandhoff and Tay Sachs disease): diagnosis and neuroimaging findings (an Iranian pediatric case series) Iran J Child Neurol. 2014;3:55–60. [PMC free article] [PubMed] [Google Scholar]
- 15.Kaya E, Smith DA, Smith C, Boland B, Strupp M, Platt FM. Beneficial effects of acetyl-DL-leucine (ADLL) in a mouse model of Sandhoff disease. J Clin Med. 2020;9(4):1050. doi: 10.3390/jcm9041050. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Martakis K, Claassen J, Gascon-Bayarri J, Goldschagg N, Hahn A, Hassan A, Hennig A, Jones SA, Lau H, Perlman S, Sharma R. N-acetyl-L-leucine improves symptoms and functioning in GM2 Gangliosidosis (Tay-Sachs & Sandhoff). medRxiv. 2021. 10.1101/2021.09.24.21264020.
- 17.Bremova-Ertl T, Claassen J, Foltan T, Gascon-Bayarri J, Gissen P, Hahn A, Hassan A, Hennig A, Jones SA, Kolnikova M, Martakis K. Efficacy and safety of N-acetyl-l-leucine in Niemann-Pick disease type C. J Neurol. 2022;269(3):1651–1662. doi: 10.1007/s00415-021-10717-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Laumen A, Schneider S, Bremova-Ertl T, Kraus L, Feil K, Strupp M. Rates of responsiveness of acetyl-DL-leucine treatment for ataxia symptoms. Eur J Neurol. 2019. p. 26.
- 19.Schniepp R, Strupp M, Wuehr M, Jahn K, Dieterich M, Brandt T, Feil K. Acetyl-DL-leucine improves gait variability in patients with cerebellar ataxia-a case series. Cerebellum & ataxias. 2016;3(1):1–4. doi: 10.1186/s40673-016-0046-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Brueggemann A, Bicvic A, Goeldlin M, Kalla R, Kerkeni H, Mantokoudis G, Abegg M, Kolníková M, Mohaupt M, Bremova-Ertl T. Effects of acetyl-DL-leucine on ataxia and downbeat-nystagmus in six patients with ataxia telangiectasia. J Child Neurol. 2022;37(1):20–27. doi: 10.1177/08830738211028394. [DOI] [PubMed] [Google Scholar]
- 21.Saberi-Karimian M, Beyraghi-Tousi M, Mirzadeh M, Gumpricht E, Sahebkar A. The Effect of N-Acetyl-DL-Leucine on Neurological Symptoms in a Patient with Ataxia-Telangiectasia: a Case Study. Cerebellum. 2022. 10.1007/s12311-022-01371-x. [DOI] [PubMed]
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Data Availability Statement
Data are available upon request.