Miglustat as Disease‐Modifying Therapy in a Patient with <scp><i>SCARB2</i></scp>‐Related Action Myoclonus Renal Failure

Homozygosis mutation of the scavenger receptor class B member 2 gene (SCARB2, OMIN*602257) causes action myoclonus renal failure (AMRF) syndrome, an ultrarare autosomal recessive disease that combines progressive myoclonus epilepsy and focal glomerulosclerosis.1 SCARB2 encodes lysosomal integral membrane protein type 2 (LIMP-2), which acts as a receptor for β-glucocerebrosidase (GCase) and facilitates its transport from the endoplasmic reticulum to the lysosomes.2 This glycosphingolipid pathway is also involved in Gaucher's disease (GD), a more common lysosomal storage disorder, whose therapies include miglustat, a glucosylceramide synthesis inhibitor.3 Here, we report the off-label use of miglustat in a patient with AMRF. A 40-year-old Caucasian female, during her only pregnancy (at 34 years), complained of bilateral finger jerky tremors at rest and during action. Concurrently, she exhibited mild proteinuria and hypertension without renal biopsy abnormalities. After delivery, jerks worsened, involving her proximal lower limbs as well. Neurological examination revealed dysarthria, generalized hypotonia, gait ataxia, upper- and lower-limb tremor (irregular, rapid, and variable in amplitude), and diffuse action myoclonus triggered by movements and exacerbated by anxiety and auditory stimuli (Video 1). The neurophysiological recordings revealed limbs' action myoclonus during motor tasks, rest myoclonus (Fig. 1A), and stimulus-sensitive myoclonus (noise: Fig. 1B, intermittent light: Fig. 1C), not associated with electroencephalogram spikes at back-averaging analysis. Cortical excitability (Fig. 1D,E) and brain magnetic resonance imaging (Fig. 1F) were normal. Over the following 3 years, renal failure occurred and myoclonus became worse, affecting sitting, walking (requiring assistive devices), eating, and speaking. At the age of 37, molecular analysis using next generation sequencing identified a homozygous pathogenic mutation c.1087C > A, p.(His363Asn) in SCARB2 gene.4 Segregation analysis of the family members confirmed the recessive inherited pattern. Consanguinity from her parents could not be ruled out, as the parents originated from the same Italian township. Valproate and levetiracetam were initiated, with slight benefits on myoclonus. In addition, miglustat was started off-label with 100 mg daily and gradually increased up to 200 mg thrice a day to allow brain delivery.1 The efficacy of miglustat was assessed on both laboratory and clinical levels monthly. After 18 months of treatment, GCase activity increased and blood Lyso-Gb1 decreased (23.32 to 9.6 ng/ml).5 During follow-up, creatinine, estimated Glomerular Filtration Rate (eGFR), and proteinuria levels remained stable (Fig. 2B), and action myoclonus gradually improved on the Unified Myoclonus Rating Scale (Fig. 2A,C; Videos 2-5), regaining independence in walking and feeding (Videos 2 and 5). However, the patient presented with weight loss (10 kg in the first year) due to the occurrence of known side effects such as nausea and diarrhea.6 Side effects gradually improved with a diet low in simple sugars and probiotic treatment with Saccharomyces Boulardii.7 Biallelic mutation of the SCARB2 gene, leading to AMRF syndrome, alters the glycosphingolipid pathway.1, 2 This pathway is also implicated in GD, for which miglustat, a glucosylceramide synthesis inhibitor, represents a therapeutic option for managing and addressing its various complications related to the glycosphingolipid metabolism pathway.3 A few but positive experiences on the use of miglustat in treating SCARB2-AMRF syndrome have been reported.8-10 Chaves et al. described the first AMRF patient (24 year-old) treated with miglustat 600 mg/day, 7 years after symptom onset, continuing for 2 years. Akin to our patient, this lady exhibited stable renal function and resumed oral feeding and the ability to sit and speak.8 Similarly, Quraishi et al. reported dysphagia/speech improvement and seizure control in a 33-year-old SCARB2-mutated lady who, after 10 years from symptom onset, received miglustat for 3 years (longer follow-up).9 Improvement in speech and myoclonus after 9 months of miglustat therapy has also been reported in a 34-year-old man with a 9-year history of AMRF10 (Table S1). These literature reports analyzed GCase activity in cultured skin fibroblasts8 or leukocytes only before miglustat treatment.8, 9 Conversely, we monitored the GCase activity and Lyso-Gb1 in blood before and after 18 months of treatment, detecting an increase in GCase activity and a decrease in Lyso-Gb1, and highlighting an endo-lysosomal glycosphingolipid pathway enhancement after miglustat use.5 Additionally, we included monthly evaluations of clinical changes through the Unified Myoclonus Clinical Scale, incorporating video recordings, which offered more definitive evidence of the motor outcomes. Finally, in the literature reports, no side effects were described, although 2 patients died from pneumonia and septic shock, 2 years8 and 9 months10 after miglustat use, respectively. Conversely, our patient exhibited weight loss, which requires careful monitoring to prevent malnutrition, as in GD patients.6 The outcome of this clinical case encourages the off-label use of miglustat as a disease-modifying therapy in AMRF. Similar to GD, lysosomal accumulation of the glycosphingolipid glucosylceramide occurs in neurons upon LIMP-2 loss. Therapies targeting the glucosylceramide pathway, already approved for GD and able to cross the blood–brain barrier (ie substrate reduction therapy, chemical chaperon therapy), should be considered as treatment in this rare, progressive, and devastating disease for which no therapies are currently available. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Study design, B. Study execution, C. Review and critique; (3) Manuscript preparation: A. Writing of the first draft, B. Review and critique. F.C.: 1A, 1B, 1C, 3A A.D.: 1A, 1B, 1C, 3B E.P.: 1A, 1C, 3B M.S.: 1A, 1C, 3B A.G.: 1B, 3B P.A.: 1B, 3B M.F.: 1A, 1C, 3B M.N.: 1A, 1C, 3B A.F.: 1A, 1C, 3B V.T.: 1A, 1B, 3B A.S.: 1A, 1B, 1C, 3B Mc.S.: 1A, 1B, 3B We thank the patient and her family. Open access publishing facilitated by Universita degli Studi di Ferrara, as part of the Wiley - CRUI-CARE agreement. Ethical Compliance Statement: We confirm that the approval of an institutional review board was not required for this work. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The manuscript was submitted for publication following the ethical standards of the 1964 Declaration of Helsinki and its later amendments. The Emilia Romagna Regional Centers for Pharmaceutical and Rare Diseases approved off-label use. Written informed consent was obtained from the patient for the publication of this case report and all iconographic and video materials. Funding Sources and Conflicts of Interest: The authors declare that there are no funding sources or conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: The authors report no disclosures relevant to the manuscript. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1. Clinical characteristics of patients affected by action myoclonus renal failure and treated with miglustat reported in the literature. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.