Gabapentin contains a cyclohexyl group and is a form of gamma-aminobutyric acid (GABA). Despite its name, gabapentin does not affect the inhibitory neurotransmitter GABA or its receptors. Instead, it acts as a ligand, binding strongly to the α2δ (Ca) channel subunit and interfering with its regulatory function and the release of excitatory neurotransmitters. Gabapentin is approved by the FDA for treating seizure disorders and neuropathic pain, except for trigeminal neuralgia. However, it is frequently used off-label to treat other pain conditions and psychological disorders, such as anxiety. Unlike other drugs, gabapentin is not metabolized in the liver and is solely excreted by the kidneys. Therefore, it is crucial to adjust the dosage in patients with renal insufficiency to avoid severe adverse effects. In this case report, we present a patient with chronic renal impairment who experienced devastating myoclonic jerky movements shortly after increasing his gabapentin dose.

Action myoclonus-renal failure (AMRF) syndrome is a rare autosomal recessive disorder characterized by myoclonic epilepsy with occasional renal failure comorbidity. This study examines a consanguineous family with multiple members presenting myoclonic epilepsy. The disease's continued transmission within the family is attributable to a lack of genetic testing and the inability to establish a definitive diagnosis. Our objective is to guide physicians toward accurate diagnoses and reduce the disease's recurrence through appropriate genetic counseling. Various diagnostic approaches can contribute to identifying AMRF. While magnetic resonance imaging (MRI) results and blood panels may not yield definitive diagnoses, electromyography (EMG) studies can serve as a robust diagnostic tool, leading to genetic confirmation. In line with standardized protocols, EMG findings consistent with AMRF present a polyneuropathy characterized by axonal degeneration and demyelinating features. These features manifest as decreased amplitude for axonal degeneration and decreased nerve conduction velocity (NCV) for demyelination. The presence of such EMG findings in a patient exhibiting both renal and central nervous system involvement may reinforce a preliminary diagnosis and warrant further genetic analysis.

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. 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. 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. 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.

Biallelic pathogenic variants in the SCARB2 gene have been associated with action myoclonus-renal failure (AMRF) syndrome. Even though SCARB2 associated phenotype has been reported to include typical neurological characteristics, depending on the localization and the feature of the pathogenic variants, clinical course and the presentations have been shown to differ. Whole exome sequencing (WES) analysis revealed a homozygous truncating variant (p.N45MfsX88) in SCARB2 gene in the index case, and subsequent sanger sequencing analysis validated the variant in all affected family members from a Turkish family with the clinical characteristics associated with AMRF and related disorders. Intrafamilial clinical heterogeneity with common features including dysarthria, tremor and proteinuria, and distinct features such as peripheral neuropathy (PNP), myoclonus and seizures between the affected cases, was observed in the family. In-depth literature review enabled the detailed investigation of the reported variants associated with AMRF and suggested that while the type of the variant did not have a major impact on the course of the clinical characteristics, only the C terminal localization of the pathogenic variant significantly affected the clinical presentation, particularly the age at onset (AO) of the disease. In this study we showed that biallelic SCARB2 pathogenic variants might cause a spectrum of common and distinct features associated with AMRF. Of those features while the common features include myoclonus (100%), ataxia (96%), tonic clonic seizures (82%), dysarthria (68%), tremor (65%), and renal impairment (62%), the uncommon features involve PNP (17%), hearing loss (6.8%), and cognitive impairment (13.7%). AO has been found to be significantly higher in the carriers of the p.G462DfsX34 pathogenic variant. SCARB2 pathogenic variants have not been only implicated in AMRF but also in the pathogenesis of Parkinson's disease (PD) and Gaucher disease (GD), suggesting the importance of genetic and functional studies in the clinical and the diagnostic settings. Given the proven role of SCARB2 gene in the pathogenesis of AMRF, PD and GD with a wide spectrum of clinical symptoms, investigation of the possible modifiers, such as progranulin and HSP7, has a great importance.