A diagnosis of progressive myoclonic ataxia guided by blood biomarkers: Expert commentary

Dubot and colleagues [[1]Dubot P. Rafiq M. Curot J. Simonetta-Moreau M. Sabourdy F. Pettazzoni M. Froissart R. Levade T. Ory-Magne F. A diagnosis of progressive myoclonic ataxia guided by blood biomarkers.Park. Relat. Disord. 2021; S1353–8020 (Advance online publication): 247-249https://doi.org/10.1016/j.parkreldis.2021.06.027Google Scholar] report a patient with a progressive myoclonus ataxia (PMA) syndrome associated with a SCARB2 defect. SCARB2 encodes the lysosomal integral membrane protein 2 (LIMP2), a receptor involved in lysosomal transport of beta-glucocerebrosidase [[2]Reczek D. Schwake M. Schröder J. Hughes H. Blanz J. Jin X. Brondyk W. Van Patten S. Edmunds T. Saftig P. LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase.Cell. 2007; 131: 770-783https://doi.org/10.1016/j.cell.2007.10.018Google Scholar]. Bi-allelic variants in SCARB2 are associated with the so-called action myoclonus and renal failure syndrome (AMFR) [[3]Dibbens L. Schwake M. Saftig P. Rubboli G. SCARB2/LIMP2 deficiency in action myoclonus-renal failure syndrome.Epileptic Disord. 2016; 18: 63-72https://doi.org/10.1684/epd.2016.0843Google Scholar]. The patient presented with myoclonic movements in the hands and gait ataxia. Myoclonus subtypes, classified by their anatomical origin (cortical, subcortical, spinal, or peripheral), have different etiology and treatment responsiveness [[4]Zutt R. van Egmond M.E. Elting J.W. van Laar P.J. Brouwer O.F. Sival D.A. Kremer H.P. de Koning T.J. Tijssen M.A. A novel diagnostic approach to patients with myoclonus.Nat. Rev. Neurol. 2015; 11: 687-697https://doi.org/10.1038/nrneurol.2015.198Google Scholar]. In the described patient the clinical phenotype best fits a cortical myoclonus (CM) as it is irregular and stimulus-sensitive and located mainly in the distal arms. One can discuss whether this is polyminimyoclonus, a specific form of CM. The jerks in the patient are larger and more prominent than usually seen in typical cases with a polyminimyoclonus phenotype. A further support for CM is the occurrence of both positive and negative myoclonus, with loss of tone in the legs. The negative myoclonus is extremely disabling while standing and walking (‘bouncing gait’ [[5]Eberhardt O. Topka H. Myoclonic disorders.Brain Sci. 2017; 7: 103https://doi.org/10.3390/brainsci7080103Google Scholar]) and probably the main reason the patient became wheelchair bounded. Neurophysiological testing adds valuable information to diagnosis and subtyping myoclonus. CM bursts are expected to be shorter than 100 ms [[4]Zutt R. van Egmond M.E. Elting J.W. van Laar P.J. Brouwer O.F. Sival D.A. Kremer H.P. de Koning T.J. Tijssen M.A. A novel diagnostic approach to patients with myoclonus.Nat. Rev. Neurol. 2015; 11: 687-697https://doi.org/10.1038/nrneurol.2015.198Google Scholar]. EEG/EMG co-registration could show cortical activity coupled to jerks. If not present, as in this case, more advanced electrophysiological techniques such as jerk-locked back-averaging and cortico-muscular coherence analysis may demonstrate the cortical origin, as described previously in individuals with SCARB2 deficiency [[6]Rubboli G. Franceschetti S. Berkovic S.F. Canafoglia L. Gambardella A. Dibbens L.M. Riguzzi P. Campieri C. Magaudda A. Tassinari C.A. Michelucci R. Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations.Epilepsia. 2011; 52: 2356-2363https://doi.org/10.1111/j.1528-1167.2011.03307.xGoogle Scholar]. Furthermore, CM might be associated with giant sensory-evoked potentials and abnormal long-latency reflexes, suggesting interaction abnormalities between primary somatosensory and motor cortex [[4]Zutt R. van Egmond M.E. Elting J.W. van Laar P.J. Brouwer O.F. Sival D.A. Kremer H.P. de Koning T.J. Tijssen M.A. A novel diagnostic approach to patients with myoclonus.Nat. Rev. Neurol. 2015; 11: 687-697https://doi.org/10.1038/nrneurol.2015.198Google Scholar,[7]Latorre A. Rocchi L. Magrinelli F. Mulroy E. Berardelli A. Rothwell J.C. Bhatia K.P. Unravelling the enigma of cortical tremor and other forms of cortical myoclonus.Brain J. Neurol. 2020; 143: 2653-2663https://doi.org/10.1093/brain/awaa129Google Scholar]. PMA syndromes are rare neurological disorders with a genetic cause in most cases, with different inheritance modalities, age of onset, and neurological and/or non-neurological associated manifestations, that may lead to the diagnosis [[8]Rossi M. van der Veen S. Merello M. Tijssen M. van de Warrenburg B. Myoclonus-ataxia syndromes: a diagnostic approach.Mov. Disord. Clin. Pract. 2020; 8: 9-24https://doi.org/10.1002/mdc3.13106Google Scholar]. According to recent clinical criteria, PMA are defined by the presence of myoclonus, ataxia, preserved cognition or mild cognitive decline, and infrequent epilepsy (including treatment-responsive epilepsy), whereas prominent cognitive decline and frequent seizures are more consistent with progressive myoclonus epilepsy (PME) [[9]van der Veen S. Zutt R. Elting J. Becker C.E. de Koning T.J. Tijssen M. Progressive myoclonus ataxia: time for a new definition?.Mov. Disord. 2018; 33: 1281-1286https://doi.org/10.1002/mds.27412Google Scholar]. To define the clinical syndrome in the patient described, additional features include the parental consanguinity, a young age of onset, and a deceased elder sister with a similar clinical phenotype, all positive features pointing to a genetic disorder. More specifically, the patient showed abolished reflexes due to severe demyelinating neuropathy and a slight proteinuria. Sparing of cognitive function and positive signs of peripheral neuropathy should raise the suspect of SCARB2 defect, although other disorders such as celiac disease, GOSR2, AFG3L2, and STUB1 deficiency may present with similar phenotypes [[8]Rossi M. van der Veen S. Merello M. Tijssen M. van de Warrenburg B. Myoclonus-ataxia syndromes: a diagnostic approach.Mov. Disord. Clin. Pract. 2020; 8: 9-24https://doi.org/10.1002/mdc3.13106Google Scholar]. Conversely, renal involvement, present in roughly 50% of patients [[10]Tian W.T. Liu X.L. Xu Y.Q. Huang X.J. Zhou H.Y. Wang Y. Tang H.D. Chen S.D. Luan X.H. Cao L. Progressive myoclonus epilepsy without renal failure in a Chinese family with a novel mutation in SCARB2 gene and literature review.Seizure. 2018; 57: 80-86https://doi.org/10.1016/j.seizure.2018.03.015Google Scholar], is a specific manifestation of SCARB2 deficiency. Based on the clinical syndrome, the authors suspected an inborn error of metabolism (IEM). It is important to detect an IEM as some are treatable [[11]Jinnah H.A. Albanese A. Bhatia K.P. Cardoso F. Da Prat G. de Koning T.J. Espay A.J. Fung V. Garcia-Ruiz P.J. Gershanik O. Jankovic J. Kaji R. Kotschet K. Marras C. Miyasaki J.M. Morgante F. Munchau A. Pal P.K. Rodriguez Oroz M.C. Rodríguez-Violante M. International Parkinson's Disease Movement Disorders Society Task Force on Rare Movement DisordersTreatable inherited rare movement disorders.Mov. Disord. 2018; 33: 21-35https://doi.org/10.1002/mds.27140Google Scholar]. It is good to realize that all IEM are genetic disorders [[11]Jinnah H.A. Albanese A. Bhatia K.P. Cardoso F. Da Prat G. de Koning T.J. Espay A.J. Fung V. Garcia-Ruiz P.J. Gershanik O. Jankovic J. Kaji R. Kotschet K. Marras C. Miyasaki J.M. Morgante F. Munchau A. Pal P.K. Rodriguez Oroz M.C. Rodríguez-Violante M. International Parkinson's Disease Movement Disorders Society Task Force on Rare Movement DisordersTreatable inherited rare movement disorders.Mov. Disord. 2018; 33: 21-35https://doi.org/10.1002/mds.27140Google Scholar]. Guided by biochemical abnormalities, the authors subsequently sequenced different genes: GBA, PSAP and finally SCARB2. In these days, with the rapid development of Next Generation Sequencing (NGS) techniques, a novel approach to genetic (and thus IEMs related) movement disorders could be considered [[12]Gannamani R. van der Veen S. van Egmond M. de Koning T.J. Tijssen M. Challenges in clinicogenetic correlations: one phenotype - many genes.Mov. Disord. Clin. Pract. 2021; 8: 311-321https://doi.org/10.1002/mdc3.13163Google Scholar]. As different IEM are included in genetic causes of PMA [[8]Rossi M. van der Veen S. Merello M. Tijssen M. van de Warrenburg B. Myoclonus-ataxia syndromes: a diagnostic approach.Mov. Disord. Clin. Pract. 2020; 8: 9-24https://doi.org/10.1002/mdc3.13106Google Scholar,[9]van der Veen S. Zutt R. Elting J. Becker C.E. de Koning T.J. Tijssen M. Progressive myoclonus ataxia: time for a new definition?.Mov. Disord. 2018; 33: 1281-1286https://doi.org/10.1002/mds.27412Google Scholar] and phenotype-genotype relationships are not always that clear, as illustrated in the current patient, NGS should be considered. It depends on the local availability and time interval to NGS results whether NGS can be the first diagnostic choice in a patient. If NGS results are rapidly available, starting with genetic rather than biochemical investigations was shown to be cost-effective [[13]Chung C. Leung G. Mak C. Fung J. Lee M. Pei S. Yu M. Hui V. Chan J. Chau J. Chan M. Tsang M. Wong W. Tung J. Lun K.S. Ng Y.K. Fung C.W. Wong M. Wong R. Lau Y.L. Chung B. Rapid whole-exome sequencing facilitates precision medicine in paediatric rare disease patients and reduces healthcare costs.Lancet Reg. Health. 2020; 1 (Western Pacific)100001https://doi.org/10.1016/j.lanwpc.2020.100001Google Scholar]. After detection of the gene, post-NGS phenotyping can include biochemical testing to support the genetic findings [[12]Gannamani R. van der Veen S. van Egmond M. de Koning T.J. Tijssen M. Challenges in clinicogenetic correlations: one phenotype - many genes.Mov. Disord. Clin. Pract. 2021; 8: 311-321https://doi.org/10.1002/mdc3.13163Google Scholar,[14]Hennekam R.C. Biesecker L.G. Next-generation sequencing demands next-generation phenotyping.Hum. Mutat. 2012; 33: 884-886https://doi.org/10.1002/humu.22048Google Scholar]. As demonstrated by this patient, symptomatic treatment of CM may be challenging and usually requires polytherapy. Levetiracetam may be used as first choice, while clonazepam and valproate are the main other options [[15]Dijk J.M. Tijssen M.A. Management of patients with myoclonus: available therapies and the need for an evidence-based approach.Lancet Neurol. 2010; 9: 1028-1036https://doi.org/10.1016/S1474-4422(10)70193-9Google Scholar]. Usually, one ends up with a combination consisting of all three drugs in a lower dose to prevent side-effects [[15]Dijk J.M. Tijssen M.A. Management of patients with myoclonus: available therapies and the need for an evidence-based approach.Lancet Neurol. 2010; 9: 1028-1036https://doi.org/10.1016/S1474-4422(10)70193-9Google Scholar]. Other potential newer drugs include zonisamide and perampanel [[16]Caviness J.N. Treatment of myoclonus.Neurotherapeutics. 2014; 11: 188-200https://doi.org/10.1007/s13311-013-0216-3Google Scholar,[17]Assenza G. Nocerino C. Tombini M. Di Gennaro G. D'Aniello A. Verrotti A. Marrelli A. Ricci L. Lanzone J. Di Lazzaro V. Bilo L. Coppola A. Perampanel improves cortical myoclonus and disability in progressive myoclonic epilepsies: a case series and a systematic review of the literature.Front. Neurol. 2021; 12630366https://doi.org/10.3389/fneur.2021.630366Google Scholar]. Interestingly, miglustat, a drug used in Gaucher disease, was reported to reduce myoclonus and improve dysphagia in 2 SCARB2 patients [[18]Quraishi I.H. Szekely A.M. Shirali A.C. Mistry P.K. Hirsch L.J. Miglustat therapy for SCARB2-associated action myoclonus-renal failure syndrome.Neurology. 2021; 7: e614https://doi.org/10.1212/NXG.0000000000000614Google Scholar,[19]Chaves J. Beirão I. Balreira A. Gaspar P. Caiola D. Sá-Miranda M.C. Lima J.L. Progressive myoclonus epilepsy with nephropathy C1q due to SCARB2/LIMP-2 deficiency: clinical report of two siblings.Seizure. 2011; 20: 738-740https://doi.org/10.1016/j.seizure.2011.06.018Google Scholar]. Although these data need to be confirmed in larger cohorts, this finding once again illustrates the close pathophysiological and biochemical relationship between SCARB2 deficiency and Gaucher disease [[18]Quraishi I.H. Szekely A.M. Shirali A.C. Mistry P.K. Hirsch L.J. Miglustat therapy for SCARB2-associated action myoclonus-renal failure syndrome.Neurology. 2021; 7: e614https://doi.org/10.1212/NXG.0000000000000614Google Scholar]. This report illustrates the importance of a careful and multi-disciplinary approach in the differential diagnosis of rare movement disorders. NGS techniques, when available, may lead to a faster and more cost-effective diagnosis. All sources of financial support for the work have been declared in the Acknowledgements section of the manuscript. Marina A.J. Tijssen reports grants from the Netherlands Organisation for Health Research and Development ZonMW Topsubsidie ( 91218013 ), the European Fund for Regional Development from the European Union ( 01492947 ) and the province of Friesland, Dystonia Medical Research Foundation , from the Dystonie Wetenschapsfonds, and unrestricted grants from Actelion and Merz.