SCARB2-Related Action Myoclonus – Renal Failure Syndrome

Clinical characteristics: SCARB2-related action myoclonus – renal failure syndrome (SCARB2-AMRF) comprises a continuum of two major (and ultimately fatal) manifestations: progressive myoclonic epilepsy (PME) and renal involvement that is apparently due to steroid-resistant nephrotic syndrome (SRNS). The neurologic and renal manifestations progress independently. In some instances, renal involvement is not observed; thus, PME without renal manifestations caused by biallelic SCARB2 pathogenic variants is considered to be one end of the spectrum of SCARB2-AMRF. All individuals reported to date developed neurologic findings; in some instances renal manifestations predated neurologic involvement by decades. The disease progresses relentlessly, with neurologic deterioration (especially increasing severity of myoclonus) and/or end-stage kidney disease (ESKD) leading to death within seven to 15 years after onset.

Diagnosis/testing: The diagnosis of SCARB2-AMRF is established in a proband with suggestive findings and biallelic loss-of-function pathogenic variants in SCARB2 identified by molecular genetic testing.

Management: Treatment of manifestations: There is no cure for SCARB2-AMRF.

The supportive care for neurologic manifestations that is recommended to improve quality of life, maximize function, and reduce complications includes pharmacotherapy to reduce myoclonus; anti-seizure medication (ASM) and vagus nerve stimulation to reduce seizures; physical and occupational therapy to help maintain mobility and optimize activities of daily living; adaptive devices to help maintain/improve independence in mobility; educational support for those with cognitive decline; speech-language therapy to explore use of alternative communication methods; feeding therapy programs for those with dysphagia to improve nutrition and reduce aspiration risk.

Treatment for renal involvement, under the care of a nephrologist, is typically focused on remission of proteinuria and often includes a combination of renin-angiotensin-aldosterone inhibition and immunosuppressive medications. Treatment of ESKD is supportive; while renal replacement therapy can prolong survival, it does not improve neurologic features.

Surveillance: Regular follow up with multidisciplinary care providers to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Agents/circumstances to avoid: Phenytoin may aggravate neurologic manifestations or even accelerate cerebellar degeneration; sodium channel blockers (carbamazepine, oxcarbazepine), GABAergic drugs (tiagabine, vigabatrin), and gabapentin and pregabalin may aggravate myoclonus and myoclonic seizures.

Pregnancy management: Some ASMs can increase the risk of malformations, growth restriction, and/or neurodevelopmental disabilities in exposed fetuses. However, when pregnant women experience prolonged seizures during pregnancy, the risk of adverse fetal outcomes is increased. Therefore, it is recommended that pregnant women with a known seizure disorder continue to take ASMs and that the prescribing physician follow standard measures to prevent fetopathy, including possible changes of medication prior to pregnancy; spacing of ASMs during pregnancy into four doses a day or taking extended-release medications, so that ASM levels do not have significant peaks or troughs; monitoring ASM dosages and levels during pregnancy.

In addition, all women of childbearing age should be advised to take 1 mg/day of folic acid and to increase it to 4 mg/day when planning a pregnancy (ideally three months prior to conception) and during the pregnancy, in order to reduce the risk of congenital malformations that can be associated with fetal exposure to ASMs.

Genetic counseling: SCARB2-AMRF is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a SCARB2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SCARB2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.