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eP022: Action myoclonus-renal failure syndrome: An atypical storage disorder with a treatment dilemma

      Background

      Action myoclonus-renal failure syndrome (AMRF) is a rare, autosomal recessive form of progressive myoclonic epilepsy associated with renal dysfunction, ranging from proteinuria to nephrotic syndrome and end stage renal disease, peripheral demyelinating polyneuropathy, and sensorineural hearing loss. SCARB2, the causative gene, encodes lysosomal-membrane type 2 protein (LIMP-2), a transmembrane protein responsible for trafficking of beta-glucocerebrosidase (GCase) to the lysosomes. LIMP-2 is particularly essential to GCase trafficking in neuronal cells, and in brains of LIMP-2 deficient mice, the significant reduction in GCase activity led to lipid storage, disturbed lysosomal function, and alpha-synuclein accumulation leading to neurotoxicity. although its necessity is somewhat tissue-dependent. Thus, SCARB2 pathogenic variants result in a shortage of GCase in lysosomes, similar to the pathology underlying Gaucher disease (GD), and yet affected patients have a vastly different phenotype to GD.
      AMRF typically starts presenting in the late teens to early twenties, and is rapidly progressive, with most patients surviving only 7 to 15 years after symptoms first develop and succumbing to complications of aspiration pneumonia and renal failure. Typically, patients with AMRF are managed symptomatically with antiepileptics for myoclonus and seizure prevention, physical therapy, and dialysis or kidney transplantation for renal insufficiency, however these do not improve neurologic disease.
      We report a case of AMRF in a young adult male and discuss the theoretical basis for treatment with substrate reduction therapy classically used in GD.

      Case presentation

      Our patient, a male of Gambian descent, initially presented at 24 years old with imbalance, falls, and jerking movements in his arms, legs, and jaw. Over time, the intensity and frequency of these symptoms increased. He was admitted to an outside hospital for a seizure-like episode which started during sleep, and video EEG was suggestive of myoclonic epilepsy. Head CT and MRI were normal. EMG showed evidence of conduction blocks, with some motor and sensory axon loss, and he was diagnosed with demyelinating polyneuropathy. An epilepsy gene panel was obtained by his neurologist, which revealed SCARB2 homozygous pathogenic variants (NM_005506.4(SCARB2):c.956del (p.Leu319fs). The patient denied any family history of AMRF or other hereditary disorders. He was started on valproic acid and levetiracetam and had no further seizures.
      The patient was referred to our clinic for evaluation and discussion of possible treatment for a lysosomal storage disorder. On our exam, he had tongue fasciculations, jerking movements of the face and jaw while speaking, and dysarthria. He had a resting tremor of the upper extremities and feet, and he had cerebellar signs with dysmetria and poor coordination with rapid alternating movements. His gait was stable, but he was unable to do heel-to-toe walk without losing balance. He reported difficulty chewing and progressive proximal muscle weakness. He was hypertensive and endorsed foamy-appearing urine.
      He was found to have an elevated serum creatinine, microscopic hematuria, and moderate albuminuria, and we referred him to nephrology for further evaluation. A subsequent kidney biopsy showed diffuse podocytopathy without deposits in the glomeruli. A renal ultrasound showed mildly echogenic kidneys, consistent with nonspecific parenchymal disease. An audiology exam was normal. On follow-up several months later, the patient’s dysarthria had worsened, and he reported decreased appetite. In anticipation of possibly starting him on substrate reduction therapy with eliglustat, we obtained CYP2D6 genotyping and baseline GD biomarkers. He had reduced leukocyte GCase activity (within the “inconclusive range”) in leukocytes, elevated plasma lyso-GL1 levels, and normal chitotriosidase activity, consistent with reports of other cases of AMRF.
      Given the similar biochemical pathway underlying AMRF and GD, we explored utilizing established GD therapy for treatment of AMRF. Substrate reduction therapy (SRT), aims to reduce the rate of glycosphingolipid biosynthesis and theoretically does not require functional LIMP-2 to be effective. There has been one case report in which a patient was treated with miglustat, an SRT for Gaucher disease, which resulted in significant reduction in myoclonic jerks, regaining of the ability to sit and eat orally, and improvement in speech. Venglustat, an SRT with blood-brain-barrier penetration, may be able to more effectively treat or stabilize the patient’s progressive neurological decline, however this medication is still in clinical trials.

      Conclusion

      AMRF is a very rare disorder with only about 40 individuals with the condition described in medical literature. The prognosis is poor, and, at this time, there is no treatment beyond symptom management. Our patient presented in his mid-20’s with classic AMRF symptoms, including seizures, resting tremor, dysarthria, action myoclonus worsened by stress or fatigue, muscle weakness, and chronic kidney disease. His symptoms are progressing, and despite management with antiepileptics, he is becoming more limited in his activities of daily living. Clinical trials are needed to further explore if SRT is beneficial in ameliorating the neurological and/or renal manifestations of AMRF.