Movement Disorders and Renal Diseases Authors and affiliations: Suvorit S. Bhowmick, MD,1 Anthony E. Lang, MD, FRCPC1 1

Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program

in Parkinson’s Disease, Toronto Western Hospital, Division of Neurology, Department of Medicine, University Health Network, Toronto, Ontario, Canada Correspondence information: Dr. Anthony E. Lang Movement Disorders Clinic, Toronto Western Hospital 399 Bathurst Street, MC 7-412, Toronto, Ontario M5T 2S8, Canada. E-mail: [email protected] Tel: (416) 603-5112. Fax: (416) 603-5004

Running title: Movement Disorders and Renal Diseases Key words: movement disorders, nephropathy, neurogenetics

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/mdc3.13005

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Abstract Movement disorders often emerge from the interplay of complex pathophysiological processes involving the kidneys and the nervous system. Tremor, myoclonus, ataxia, chorea, and parkinsonism can occur in the context of renal dysfunction (azotemia and electrolyte abnormalities) or they can be part of complications of its management (dialysis and renal transplantation). On the other hand, myoglobinuria from rhabdomyolysis in status dystonicus and certain drugs used in the management of movement disorders can cause nephrotoxicity. Distinct from these well recognized associations, it is important to appreciate that there are several inherited and acquired disorders in which movement abnormalities do not occur as a consequence of renal dysfunction or vice versa but are manifestations of common pathophysiological processes affecting the nervous system and the kidneys. These disorders are the emphasis of this review. Increasing awareness of these conditions amongst neurologists may help them to identify renal involvement earlier, take timely intervention by anticipating complications, and focus on therapies targeting common mechanisms in addition to symptomatic management of movement disorders. Recognition of renal impairment in a patient with complex neurological presentation may narrow down the differentials and aid in reaching a definite diagnosis.

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The relationship between movement disorders and renal diseases is complex and multifaceted. Movement disorders can occur as manifestations of azotemia (uremic encephalopathy, uremic striatopallidal syndrome, and restless leg syndrome), manifestations of electrolyte abnormalities arising out of renal dysfunction, consequences of complications arising from dialysis (dialysis disequilibrium syndrome, osmotic demyelination syndrome, thiamine deficiency, and aluminum toxicity), consequences of complications arising from renal transplantation (immunosuppression related infections and neoplasia of the central nervous system), and manifestations of drug toxicity in the setting of renal dysfunction. Alternatively, renal dysfunction can be caused by some movement disorders (myoglobinuria in status dystonicus and neuroleptic malignant syndrome) and their management (retroperitoneal fibrosis induced by bromocriptine and other ergot derivatives). Finally, both the kidneys and the nervous system can be affected by common pathophysiological processes, which may be inherited or acquired. In this educational review, our focus is on important inherited and acquired disorders manifesting with movement disorders and renal dysfunction. We lay out phenomenology of movement abnormalities and salient renal features of each of these. The classification of inherited disorders adopted here is based on predominant pathophysiology; it should be noted that mechanisms of neurological and renal involvement can be diverse and overlapping. For additional details on the inherited disorders, please refer to Tables 1, 2, and 3. The manifestations of renal dysfunction are depicted in Figures 1 and 2. The emphasis of this review is on inherited disorders manifesting renal glomerular or tubular dysfunction rather than disorders with structural changes such as cysts or neoplasia as seen, for example, in von Hippel-

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Lindau disease. Tables 4 and 5 briefly summarize the movement disorders caused by azotemia, electrolyte abnormalities, and complications of dialysis and renal transplantation; readers are directed to excellent reviews on this topic for more information (1-5). Finally, renal complications due to movement disorders and their treatment are summarized in Supplementary Table 1.

Search strategy We reviewed English-written articles and abstracts published in PubMed from January, 1964 to February, 2020 using the combination of Medical Subject Headings (MeSH) “kidney disease” and “movement disorders”, “parkinsonian disorders”, “chorea”, “athetosis”, “dystonia”, “dyskinesias”, “tremor”, “myoclonus”, “tics” or “stereotypic movement disorder”. We selected the articles relevant to our review and included additional articles from the references.

Inherited disorders Lysosomal disorders Action myoclonus renal failure (AMRF) syndrome AMRF syndrome is caused by biallelic pathogenic variants in the SCARB2 gene (6). When it was first described in 1986 in four French-Canadian individuals from three families, the authors recognized that the clinical features resulted from a pathophysiological process

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involving both the brain and the kidney and were not consequences of renal failure (7). Since then, at least 40 affected individuals from 29 families have been reported worldwide. The median age of onset of neurological manifestations or renal abnormalities is 19 years (range: 9–52 years). Neurological symptoms can manifest before, with, or after biochemical evidence of renal dysfunction. Typically, patients initially have tremor (likely rhythmic cortical myoclonus; see below) of fingers and hands, which may be present at rest but is markedly worsened with action such as writing. Later, tremor may involve head, trunk, legs, tongue, and voice. Within months or few years, patients develop action myoclonus of distal extremities. In some patients, gait instability and falls due to myoclonic jerks of the legs are the presenting features. Patients may have bulbar myoclonus particularly while speaking. Myoclonus may be variably sensitive to touch, light, or sound and may be worsened with anxiety, fatigue, concentration, fever, and menses. There may be myoclonic status with hyperhidrosis (8). Photosensitivity may be extreme in some patients causing them to prefer darkness. Patients also have asynchronous jerks involving arms, legs, trunk, and face at rest. Action myoclonus is the most disabling feature of the disorder and is refractory to treatment. In the final stages, it renders the patients bound to wheelchair or bedridden. With disease progression, most patients develop ataxia and dysarthria. Although it is difficult to distinguish ataxia from action myoclonus, other features such as hypotonia, pendular reflexes, nystagmus, abnormal rebound, abnormal neuroimaging in some patients, and pathological findings support cerebellar involvement. Many patients develop generalized tonic-clonic seizures during the course of the disease. Some of them have drug refractory seizures and convulsive status epilepticus followed

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by worsening of symptoms and death. Slowed horizontal saccades, sensorineural hearing loss, and demyelinating peripheral neuropathy (mostly subclinical) are other neurological features reported in some patients. Sparing of cognitive function differentiates AMRF syndrome from other progressive myoclonus epilepsies (PMEs) such as neuronal ceroid lipofuscinoses and Lafora body disease. Magnetic resonance imaging (MRI) of the brain is usually normal or may show cerebellar or cerebral atrophy in some patients. Electroencephalography (EEG) may show generalized epileptiform abnormalities with normal background activity initially, similar to idiopathic generalized epilepsies; there is slowing of background activity subsequently. Intermittent photic stimulation can trigger bursts of generalized spike-wave or polyspike-wave discharges; these manifest clinically as myoclonic jerks that can evolve to myoclonic seizures. Surface electromyography (EMG) recordings show quasi-rhythmic bursts lasting less than 50 ms at 12–20 Hz frequency in upper extremities while maintaining posture, clinically resembling postural tremor, in addition to erratic myoclonic jerks at rest. Coherence spectral analysis of EEG-EMG reveals that tremor in these patients is actually rhythmic myoclonus of cortical origin (9). Pathologically, there is extraneuronal accumulation of irregularly shaped, refractile, and autofluorescent pigment granules in the cerebral cortex, the globus pallidus, the putamen and the cerebellar cortex. Based on staining pattern, it is perhaps lipofuscin-like oxidized lipid or proteolipid (7, 10). Mild neuronal loss and gliosis were found in the pallidolusian and the cerebello-olivary regions in addition to extraneuronal pigment accumulation in the autopsy specimens of two atypical Japanese patients who developed prominent dementia (11).

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Renal dysfunction can vary from isolated proteinuria to nephrotic syndrome and endstage renal disease (ESRD). In two-thirds of patients with renal involvement there is relentless progression to ESRD requiring dialysis or renal transplantation by the third decade of life. Renal histopathology shows predominantly glomerular involvement in the form of focal segmental glomerulosclerosis (FSGS) and collapsing glomerulopathy (6, 10). Isometric vacuolization in distal and collecting tubules and granular material in cortical tubules may also be seen (12, 13). Neurological features continue to progress despite management of renal disease (transplantation or otherwise), frequently leading to death by the third or fourth decade. About one-third of patients with SCARB2 mutations have been followed for a median duration of 10 years without demonstrating clinical and biochemical evidence of renal involvement. Thus, before renal dysfunction manifests this disorder mimics other PMEs such as Unverricht-Lundborg disease, sialidosis, PRICKLE-1 mutation, and mitochondrial cytopathies, all of which can spare cognitive functions. The SCARB2 gene encodes lysosomal integral membrane protein type 2 (LIMP-2), a ubiquitously expressed transmembrane protein in the lysosomes and the late endosomes (6). A total of 19 mutations (frameshift, splice-site, nonsense, and missense) have been identified so far, including two founder mutations (Q228X in the French-Canadian population of Quebec and W146SfsX161 in the Scottish population). LIMP-2 binds β-glucocerebrosidase in the endoplasmic reticulum and escorts it to the late endosomes and the lysosomes where acidic pH dissociates the complex. Absence of LIMP-2 leads to a depletion of post-Golgi forms of βglucocerebrosidase. SCARB2-/- mice manifest peripheral neuropathy, deafness, ataxic gait, hydronephrosis secondary to uretero-pelvic obstruction, and glomerular abnormalities

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including mesangial hypercellularity and effacement of foot processes (6). Interestingly, one patient had sustained improvement in myoclonic jerks and speech for almost two years by substrate reduction therapy with miglustat 600 mg/day (12). Anderson-Fabry disease (AFD) AFD is an X-linked disorder caused by pathogenic variants in the GLA gene causing complete or partial deficiency of the enzyme α-galactosidase A and progressive accumulation of globotriaosylceramide within lysosomes (14). It may be an underdiagnosed disorder because the systemic complications are often mild, non-specific, and occur commonly in the general population. Not only males but also females can be affected with variable severity of symptoms (15). Cerebrovascular events and renal dysfunction are among the protean manifestations of AFD (see Table 1). Vascular parkinsonism is a rare manifestation of small vessel disease in AFD (16). A recent study showed that affected individuals have disturbances in gait and hand dexterity (17). Progressive renal dysfunction, characterized by a mixture of glomerulopathy and tubulopathy, leads to ESRD in the fourth or fifth decade of life (18). Enzyme replacement therapy may slow decline in renal function but does not prevent neurological complications (15).

Mitochondrial cytopathies (MCPs) MCPs involve the nervous system predominantly but several other organs can be affected, resulting in wide variability of clinical features. The overall prevalence of MCPs is estimated to be 1: 5,000 (19). The genetic causes are due to pathogenic variants in

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mitochondrial genes (i.e. mtDNA) or nuclear genes encoding proteins affecting mitochondrial respiratory chain function. The expression of a clinical phenotype is dependent upon several factors such as gene-gene interaction, heteroplasmy, threshold effect (mutation load and reliance of different tissues upon oxidative metabolism), mitochondrial fission and fusion, random segregation, genetic bottleneck, and positive selection (20). More than 40 clinical syndromes have been reported but patients frequently have overlapping features. Myoclonus and ataxia are the most frequently encountered movement disorders in MCPs. Additionally, parkinsonism, dystonia, chorea, spasticity, tremor, and tics have also been reported (21). Renal involvement is underreported because it may be subclinical or overshadowed by dysfunction of other organs. MCPs like Kearns-Sayre syndrome (KSS), Pearson syndrome (PS), Leigh syndrome (LS), neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) syndrome, and myoclonic epilepsy with ragged-red fibers (MERRF) are known to manifest movement abnormalities in children and young adults (see Table 1). KS and PS are multi-system disorders caused by large-scale deletions or duplications of mitochondrial genome. LS of variable severity is caused by pathogenic variants in several mitochondrial or nuclear genes encoding respiratory chain subunits. Heteroplasmic point mutations in the MT-ATP6 gene cause NARP syndrome. MERRF is most frequently caused by point mutations in the MT-TK gene. Renal dysfunction can occur in all of these MCPs. The predominant renal phenotype depends on the preferential involvement of the podocytes and the tubular cells. KSS, PS, LS, and MERRF are usually accompanied by renal tubular dysfunction, manifesting as de ToniDebré-Fanconi syndrome, renal tubular acidosis (RTA), Bartter-like phenotype, isolated

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hypomagnesemia, or hypocalciuria (22, 23). Rarely, proximal tubulopathy and RTA can be presenting features of KSS (24). Histopathological and ultrastructural studies often show abnormalities of proximal tubule epithelia and proliferation of abnormal mitochondria (23). Glomerular dysfunction in the form of FSGS leading to ESRD was reported in a patient with NARP syndrome. Electron microscopic examination of tubular cells and podocytes showed accumulation of swollen and pleomorphic mitochondria with disoriented cristae containing paracrystalline inclusions (25). Another patient with slowly progressive cerebellar ataxia and other neurological features was reported to develop FSGS leading to ESRD requiring renal transplantation. Electron microscopy did not show abnormal mitochondria but genomic analysis of a renal biopsy specimen revealed heteroplasmic m.13513G>A variant in the MTND5 gene, underlying the importance of having sequencing from kidney. The authors named the phenotype mitochondrial cerebellar ataxia, renal failure, neuropathy, and encephalopathy (MCARNE) syndrome (26). Primary coenzyme-Q10 (CoQ10) or ubiquinone deficiency is caused by biallelic pathogenic variants in nuclear genes involved in its synthesis and is potentially treatable with CoQ10 supplementation. This is a clinically heterogenous disorder that presents with distinct neurological phenotypes such as cerebellar ataxia, dystonia, encephalomyopathy, and severe infantile multi-system disorder. Childhood onset steroid-resistant nephrotic syndrome may be seen in CoQ10 deficiency from pathogenic variants in the COQ2, COQ6, and PDSS2 genes (2730). If not treated, there may be rapid progression to ESRD. Pathologically, there is FSGS or collapsing glomerulopathy. Electron microscopy shows dysmorphic mitochondria in the

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podocytes (31). Tubulopathy was reported in a child with encephalopathy, seizures, and dystonia due to a pathogenic variant in the COQ9 gene (32).

Organic acidurias and urea cycle disorders The neurological spectrum of the rare organic acidurias and urea cycle disorders encompasses a variety of movement disorders. Prominent renal involvement is seen commonly in glutaric aciduria, methylmalonic aciduria, and argininosuccinic aciduria, and rarely in propionic aciduria (33). Glutaric aciduria (GA) type 1 In GA type 1, deficiency of glutaryl-CoA dehydrogenase due to biallelic pathogenic variants in the GCDH gene results in impaired breakdown of lysine, hydroxylysine, and tryptophan, and accumulation of neurotoxic metabolites, 3-hydroxyglutaric acid, glutaric acid, glutaconic acid, and glutylcarnitine (34, 35). Affected individuals commonly have progressive macrocephaly at or shortly after birth. Later they develop dystonia with intermittent tonic posturing due to irreversible damage of the basal ganglia from encephalopathic crises in the setting of catabolic states or intercurrent illness in infancy or early childhood. Although many patients develop parkinsonism, chorea, and athetosis, dystonia remains the predominant movement disorder. Some children may remain asymptomatic or develop an insidious onset movement disorder or motor delay (36). Low lysine diet, carnitine supplementation and intensive management of intercurrent illness are recommended to prevent damage to the basal ganglia (35).

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About one-fourth of affected individuals develop chronic renal failure in the second or third decade of life (33). In GCDH-/- mice, metabolic crises induced by administration of highprotein diet cause thinning of brush border membranes and mitochondrial swelling in the renal proximal tubule cells through alteration of transporters and intracellular accumulation of glutaric acid and 3-hydroxiglutaric acid (37). Thus, it is speculated that chronic exposure to these excreted toxins impair mitochondrial function of the renal proximal tubules and make them susceptible to catabolic states (38). Methylmalonic aciduria (MMA) Defective breakdown of methylmalonyl-CoA causes MMA and secondarily hyperammonemia and ketoacidosis. Isolated MMA results from biallelic pathogenic variants in the gene encoding the apoenzyme methylmalonyl-CoA mutase (MMUT) or in the genes involved in the synthesis of its co-factor adenosylcobalamin (MMAA, MMAB, and MMADHC). Other disorders of cobalamin metabolism manifest as combined MMA and homocystinuria (39). Affected individuals present with metabolic crisis characterized by encephalopathy, hypotonia, vomiting, and sepsis-like picture in the neonatal period, childhood, or adolescence. Those who recover variably develop dystonia, chorea, myoclonus, tremor, ataxia pyramidal signs, intellectual disability, and dysfunction of other organs (40). Intercurrent illness or catabolic states can cause metabolic strokes involving the globus pallidus bilaterally. About one-third or more of patients with MMA develop chronic renal failure by the first or second decade, necessitating dialysis or renal transplantation in some (33, 41). Renal histopathology shows tubulointerstitial fibrosis and enlarged mitochondria in the proximal

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tubular cells (42). Mitochondrial dysfunction due to accumulation of toxic metabolites is the proposed mechanism for neuronal and renal injury (43). Management of MMA involves intensive treatment of metabolic crises, dietary changes, and carnitine supplementation. Liver transplantation or combined liver and renal transplantation may provide metabolic stability but not does prevent metabolic strokes. Patients with adenosylcobalamin synthesis defects may respond to treatment with vitamin B12 (40, 44). Argininosuccinic aciduria (ASA) ASA is caused by deficiency of the urea cycle enzyme argininosuccinate lyase from biallelic pathogenic variants in the ASL gene (45). Like other urea cycle disorders, affected neonates frequently have a severe presentation due to hyperammonemia characterized by lethargy, reduced consciousness, seizures, vomiting, and respiratory alkalosis. In those who survive and in late-onset forms, intercurrent illness or catabolic state can precipitate hyperammonemia lasting several days. During these episodes, patients may have signs of cerebellar ataxia (46). Mild cerebellar ataxia may persist without episodic hyperammonemia. Additionally, patients may have tremor, myoclonic and other types of seizures, episodic hypotonia and muscular weakness, and developmental delay. ASA is unique among the urea cycle disorders because of higher incidence of cognitive and behavioral abnormalities. Management strategies include treatment of hyperammonemia, dietary changes, arginine supplementation, nitrogen scavenging therapy, and liver transplantation (45). Patients may develop chronic renal failure by the second decade (33). Ultrasound shows nephromegaly and poor corticomedullary differentiation. Patients often have hypokalemia

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perhaps as a result of renal potassium wasting. Hyperammonemia, deficiency of arginine and downstream metabolites like nitric oxide, and toxicity of argininosuccinate are thought to play a role in the pathogenesis but the mechanism underlying renal involvement is not well established (47).

Other metabolic disorders Lesch-Nyhan disease (LND) LND is an X-linked recessive disorder caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase from pathogenic variants in the HPRT1 gene (48, 49). Affected infants have axial hypotonia and developmental delay. Subsequently they develop striking involuntary movements in the form of dystonic posturing of limbs and episodes of torticollis, retrocollis, or opisthotonus. There may be superimposed athetotic, choreic, or ballistic movements. Intellectual disability, impaired language, dysarthria, dysphagia, and pyramidal signs are other neurological features. Typically, they have selfdirected aggressive and mutilating behavior such as biting of the lips and the fingers resulting in partial amputation (50). There are attenuated variants of LNS with mild motor abnormalities, absent self-destructive behavior and preserved cognitive function. The neurological features are due to biochemical abnormalities in the brain and there are no characteristic pathological findings. Cerebellar abnormalities have been found in some autopsy studies (51). Hyperuricemia results in the formation of renal stones manifesting as hematuria, renal colic, and obstructive uropathy in the setting of dehydration. There is diminished concentrating

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ability of the kidneys due to impaired tubular function. Later, there may be glomerular involvement and renal failure (52). Control of hyperuricemia and symptomatic treatment of movement disorders are important management strategies. Wilson’s disease (WD) The fundamental abnormality in WD is impaired biliary excretion of copper due to biallelic loss-of-function mutations in the ATP7B gene, resulting in accumulation of copper in different organs. Patients who manifest neurological features may have a combination of movement abnormalities such as tremor, dystonia, parkinsonism, chorea, myoclonus, and ataxia. Additionally, there may be dysarthria, cognitive decline, and psychiatric features. The usual age of presentation is the second or third decade (53). Accumulation or excretion of copper by the kidney usually causes subtle impairment in function of the renal tubules. Proteinuria, glucosuria, phosphaturia, uricosuria, aminoaciduria, and microscopic hematuria may be detected as biochemical abnormalities. Histopathological examination usually does not show tubular pathology, albeit calcium deposits can be found in the tubules. In some patients tubulopathy manifests as proximal or distal RTA, and partial or complete de Toni-DebréFanconi syndrome (54). Hypercalciuria secondary to distal RTA or as a result of calcium mobilization from bones to neutralize systemic acidosis, may result in nephrocalcinosis (55, 56). Vitamin D resistant rickets can be the presenting feature of WD secondary to RTA and is commonly reported from the Indian subcontinent (57). In addition to awareness of the renal complications of WD, routine monitoring of renal function is important in patients treated with D-penicillamine as it may result in nephrotoxicity in about 7-11% of them, heralded by

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proteinuria after about eight months of therapy (54). Rarely D-penicillamine can trigger immune-mediated glomerulonephritis and nephrotic syndrome (58). Hartnup disease This disorder, named after the Hartnup family of London, is characterized by impaired renal and intestinal absorption of neutral amino acids which can lead to deficiency of niacin and serotonin and manifest as neurological, psychiatric, and dermatological abnormalities (5961). Most of the affected individuals have a benign course or may remain asymptomatic because intact absorption of peptides compensates for lack of amino acid transport. In symptomatic patients, clinical features include short stature, intermittent photosensitive pellagra-like skin rashes, and diarrhea. Intermittent cerebellar ataxia is the most common neurological manifestation. Incoordination, intention tremor, nystagmus, and diplopia may occur in bouts lasting several days, often precipitated by fever, infection, intercurrent illness, or inadequate diet. Some patients may have intermittent chorea and athetosis, spastic paraparesis, collapsing falls, seizure, headache, psychiatric symptoms and rarely, intellectual disability. Symptoms usually occur in children but presentation in adults has been reported. Hartnup disease is caused by biallelic loss-of-function variants in the SLC6A19 gene which encodes the neutral amino acid transporter B0AT1 found in the brush border of kidney and intestinal epithelial cells (62, 63). More than 20 pathogenic variants (missense, non-sense, splice-site, deletions) have been identified. B0AT1 requires heterodimerization with collectrin for surface expression and stability in the kidney. Deletions in the CLTRN gene (on Xp22.2) encoding collectrin, were recently associated with neuropsychiatric features, motor tics and

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neutral aminoaciduria (phenotype resembling Hartnup disease). However, the pathogenesis of these features is not clear since plasma amino acid levels were normal in the affected patients (64).

Channelopathies Epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST) syndrome In 2009, two groups independently identified a distinct autosomal recessive disorder due to homozygous or compound heterozygous pathogenic variants in the KCNJ10 gene, using the acronyms EAST (epilepsy, ataxia, sensorineural deafness, and tubulopathy) and SeSAME (seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance) to describe the phenotype (65, 66). More than 30 patients with 16 different mutations have been reported worldwide (67). The KCNJ10 gene encodes Kir4.1, an inwardly rectifying potassium channel located in the glial cells of the brain, intermediate cells of the stria vascularis of the inner ear, renal epithelial cells, and retina. Kir4.1 is involved in potassium spatial buffering which is necessary to maintain the resting membrane potential of neurons. Its dysfunction can cause accumulation of potassium in the extracellular space, leading to neuronal depolarization, hyperexcitability, and reduced seizure threshold (66). The disorder presents with infantile onset generalized tonic-clonic seizures that are easily controlled by anticonvulsants. About half of the patients subsequently develop focal seizures that may be drug-resistant. There is delay in development of speech and motor milestones. Ataxia, though non-progressive, is the most debilitating feature of this disorder.

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Ataxic gait is evident when the children learn to walk. Cerebellar signs such as intention tremor, dysdiadochokinesia, dysmetria, titubation, truncal ataxia, and scanning speech are usually present. Pyramidal signs and dystonic posturing of limbs and face may develop in older patients. Intellectual disability is difficult to assess due to impaired communication and ataxia in severely affected patients. MRI is often reported as normal but careful analysis may show subtle abnormalities in the brain and the spinal cord, such as T2 and FLAIR hyperintensity of cerebellar nuclei, cerebellar and brainstem hypoplasia, thin corpus callosum and thin spinal cord (68, 69). Hearing impairment can vary from mild (or subclinical) to severe. The renal manifestations are similar to Gitelman syndrome, with hypokalemic metabolic alkalosis, hypomagnesemia, hypocalciuria, activation of the renin-angiotensinaldosterone axis, and urinary loss of sodium, potassium, chloride, and magnesium due to defective transport in the distal convoluted tubule. Some patients may have salt craving, enuresis, polyuria, and polydipsia. Renal ultrasound does not show any abnormality (69). Electron microscopic examination of a renal biopsy has shown decreased basolateral infolding and reduced number of mitochondria in the distal convoluted tubule (70). Management is focused on controlling seizures, salt supplementation, and hearing aids. Use of potassium sparing diuretics to correct serum potassium levels may place the patients at risk of hypovolemia.

Ciliopathies and related disorders

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Ciliopathies are disorders caused by mutations in genes with products that localize to the cilium–centrosome complex (71). Cilia are organelles present on the apical surface of almost every cell type and are involved in a variety of cellular functions such as planar cell polarity, cell-cycle regulation and transduction of extracellular signals. They integrate multiple signaling pathways of critical importance for development and organ differentiation. There is broad genotype-phenotype overlap between ciliopathies which include Joubert syndrome and nephronophthisis (see below) among several disorders (72). Joubert syndrome (JS) JS is a clinically and genetically heterogeneous group of congenital ataxias with characteristic midbrain-hindbrain malformation comprising hypoplasia and dysplasia of the cerebellar vermis, thickening and elongation of the superior cerebellar peduncles, and deep interpeduncular fossa, giving the radiological appearance of a molar tooth in axial images of the brain. There may be additional brain malformations (73). There is absence of decussation of the superior cerebellar peduncles and the pyramidal tracts (74). Molecular diagnosis can be established in about two-thirds of the patients by identification of pathogenic variants in more than 30 genes, most with autosomal recessive inheritance (75). The prevalence rate of JS in the age group of 0-19 years was found to be 1.7 per 100,000 in a recent population-based study from Italy (76). The clinical features were first described in four French-Canadian siblings in 1969 (77). Patients variably have infantile onset hypotonia, abnormal respiratory pattern (episodes of apnea alternating with tachypnea), ocular motor apraxia, impaired smooth pursuit, nystagmus, strabismus, delayed developmental milestones, intellectual disability, polydactyly, and facial dysmorphisms. About half of the affected children learn to walk independently but

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have ataxic gait. Some patients may present with head jerks as a compensatory phenomenon for ocular motor apraxia. The natural history of JS may be affected by involvement of the kidney and other organs at different ages (see Table 3). In a prospective study, about 30% of patients were found to have renal involvement in the form of nephronophthisis, mixed nephronophthisis and polycystic kidney disease, unilateral multi-cystic dysplastic kidney, or indeterminate cystic kidney disease. Renal involvement was commonly associated with mutations in the CEP290, TMEM67, and AHI1 genes. Of the patients with renal involvement, 24% had hypertension before decrease in renal function and 45% developed ESRD between 6-24 years of age (78). Pathologically, nephronophthisis is characterized by thickening and disintegration of the tubular basement membrane, atrophy of renal tubular structure, and tubulointerstitial fibrosis. There may be infantile, juvenile, or adolescent onset of symptoms such as polyuria, enuresis, polydipsia, anemia, and growth retardation. There is progression to ESRD in the first three decades, necessitating dialysis or renal transplantation. Ultrasound may show small or normalsized kidneys, small cysts, loss of corticomedullary differentiation, and increased echogenicity (72). Timely diagnosis of nephronophthisis is essential to initiate supportive treatment of chronic renal failure and to ensure appropriate fluid intake. Such measures can prevent the development of complications, such as renal osteodystrophy and poor growth (79). von Hippel-Lindau (VHL) disease Ataxia can be a manifestation of cerebellar hemangioblastoma in VHL disease caused by heterozygous germline inactivation of the VHL tumor-suppressor gene. Cerebrovascular

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complications of VHL disease due to polycythemia or hypertension from pheochromocytoma rarely may present with secondary movement disorders. Renal cysts and renal cell carcinoma are components of the many visceral features of this disease (71, 80). Oculocerebrorenal syndrome of Lowe (OCRL) OCRL is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, intellectual disability, and proximal renal tubular dysfunction due to pathogenic variants in the OCRL1 gene encoding enzyme phosphatidylinositol 4,5-bisphosphate localized to the Golgi apparatus. Loss of OCRL1 function results in several cellular defects including impaired formation of cilia and endocytic trafficking (81). Affected individuals are symptomatic from birth with hypotonia and diminished tendon reflexes (82). Children may have behavioral abnormalities including irritability, stubbornness, obsessions, and stereotypy. Choreoathetoid movements have been reported but they are considered secondary to visual impairment and sensory deprivation.

Miscellaneous inherited disorders Nephrocerebellar syndrome Galloway-Mowat syndrome (GMS), first described in 1968, is the combination of infantile-onset steroid-resistant nephrotic syndrome and central nervous system abnormalities (neuronal migration defects, cerebellar atrophy, hypomyelination) clinically manifesting as microcephaly, psychomotor delay, intractable epilepsy, and mild dysmorphic features (83, 84). It is caused by biallelic pathogenic variants in the WDR73 gene encoding a protein that is

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expressed in the embryonic brain and kidneys and associates with the mitotic microtubules during cell division. It is thought to participate in cellular functions such as cell division, signal transduction, vesicle trafficking, cytoskeletal dynamics, DNA excision repair, nuclear envelope transport, and autophagy (85, 86). Recently the spectrum of GMS was expanded by description of a nephrocerebellar syndrome characterized by progressive microcephaly, visual impairment, congenital roving nystagmus, stagnant psychomotor development, multifocal seizures, hypotonia, axial dystonia, chorea, and steroid-resistant nephrotic syndrome or renal failure in 30 children of Amish populations (86). Neuroimaging showed diffuse cerebral atrophy, thinning of the corpus callosum, and hypoplasia and progressive atrophy of the cerebellum. About 50% of the patients died in the first three decades of life from renal failure. Brain pathology included profound loss of cerebellar granule cells, cerebellar gliosis, and selective loss of striatal cholinergic interneurons. Marked effacement and microvillus transformation of podocyte foot processes, and FSGS were found in renal tissues. Congenital nephrotic syndrome of the Finnish type This disorder is caused by biallelic pathogenic variants in the NPHS1 gene which encodes nephrin, a cell adhesion molecule expressed in the slit diaphragm of glomerular podocytes. About 9% of affected children may develop dystonia, athetosis, and hypotonia during the first year of life. MRI of the brain shows hyperintensity of the globus pallidus in T2weighted and FLAIR images. Secondary mitochondrial dysfunction and chronic bilirubin encephalopathy (with hypoalbuminemia as a risk factor) have been speculated as pathogenic mechanisms, yet the association remains obscure (87).

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Neuronal intranuclear inclusion disease (NIID) It was recently discovered that sporadic as well as familial NIID is caused by heterogenous GGC repeat expansions in the 5’ untranslated region of the human-specific NOTCH2NLC gene which is highly expressed in various radial glia populations and may have a role in neurogenesis through Notch signaling (88). The expansions neither change the gene expression nor cause hypermethylation (gene silencing) but may result in abnormal antisense transcripts (88-90). NIID is a slowly progressive neurodegenerative disorder manifesting with broad clinical manifestations such as dementia, cerebellar ataxia, extrapyramidal symptoms, seizures, pyramidal signs, neuropathy, and autonomic dysfunction (91). There is scarce evidence of organ dysfunction outside the nervous system despite the widespread presence of characteristic anti-ubiquitin and anti-p62 reactive eosinophilic hyaline inclusions in various tissues including renal tubular cells (91). Two patients were reported with glomerulonephritis before the onset of neurological symptoms (92, 93) and few other patients had biochemical evidence of renal dysfunction (91). It is not clear if renal involvement is part of the disease process.

Acquired disorders Several vascular, immune-mediated, neoplastic, and toxic disorders which involve both the kidneys and the nervous system are associated with movement disorders. Immunological and vasculitic processes in autoimmune disorders of the kidneys may affect the basal ganglia. Chorea and ballism (hemi or bilateral) are known complications of systemic lupus

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erythematosus that may be associated with nephritis and antiphospholipid antibodies (94). Parkinsonism can also be a rare manifestation of central nervous system vasculitis associated with lupus nephritis (95). These are potentially reversible with appropriate immunotherapy. Sydenham’s








glomerulonephritis (96). Vasculitic infarcts in the basal ganglia causing contralateral choreoathetoid movements have been reported in some patients with hemolytic uremic syndrome (97). Chorea, ballism, and opsoclonus-myoclonus may occur as paraneoplastic syndromes antedating the detection of renal cell carcinoma (98, 99). Mercury toxicity can present with tremor, cerebellar ataxia, neuropsychiatric symptoms, and renal tubular dysfunction. Organ susceptibility depends on the form of exposure (100). Intoxication with ethylene glycol and methanol rarely results in parkinsonism through necrosis of the basal ganglia (predominantly putamen) from metabolic acidosis and metabolites such as oxalic acid and formic acid respectively (101). Necrosis of the renal proximal tubular cells can occur from internalized calcium oxalate monohydrate crystals in ethylene glycol toxicity and secondarily from hypotension, myoglobinuria, and hemoglobinuria in methanol toxicity (102, 103). A variety of drugs may result in movement disorders combined with renal dysfunction. For example, lithium toxicity manifests with action tremor, cerebellar ataxia, and renal involvement in the form of nephrogenic diabetes insipidus and reduction in glomerular filtration rate (104). Several other drugs (acyclovir, cephalosporin, etc.) may cause tremor, myoclonus, chorea, and ataxia in the setting of renal dysfunction (105, 106).


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There are several inherited and acquired disorders in which involvement of the nervous system and the kidneys gives rise to movement disorders and renal dysfunction, typically independent of each other (with some exceptions such as Hartnup disease and rhabdomyolysis related acute kidney injury). It is important to recognize these disorders because their management is challenging and needs targeted approach. Although treatment of renal dysfunction may have a positive impact on morbidity and mortality, it generally does not improve neurological outcome. In contrast, a variety of movement disorders occur more commonly as direct or indirect consequences of renal dysfunction and its management (Tables 4 and 5), and are potentially reversible with appropriate treatment. We acknowledge that there are some limitations of this review. Not all case reports and series provide detailed description of movement disorder phenomenology and severity. It is difficult to draw conclusions from case reports mentioning renal involvement in some disorders as this could be a chance occurrence. For instance, paroxysmal kinesigenic dyskinesia and cerebellar ataxia have been reported in patients with cystinuria, a relatively common hereditary disorder characterized by impaired tubular transport of cysteine and dibasic amino acids but the pathophysiology of neurological involvement has not been delineated clearly (107, 108). Cerebellar ataxia and other movement disorders may be part of the complex phenotype of several hereditary disorders which involve the nervous system and other visceral organs including, rarely, the kidneys, such as congenital disorders of glycosylation and peroxisomal disorders (109-111). The discussion of all of these disorders is beyond the scope of this review.

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Author Roles

1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique; SSB: 1B, 1C, 3A AEL: 1A, 3B

Disclosures Funding sources and conflict of interest: We did not receive specific funding for this work. We declare that there are no conflicts of interest relevant to this work. Financial disclosures for previous 12 months: We declare that there are no additional disclosures to report.

Ethical Compliance Statement Approval from institutional review board or ethics committee was not required for this work. Informed patient consent was not necessary 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.


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Figure legends Figure 1. Manifestations of glomerulopathy in disorders with movement abnormalities (163) Figure 2. General and site-specific manifestations of tubulopathy in disorders with movement abnormalities (164) Abbreviations: EAST = epilepsy, ataxia, sensorineural deafness, and tubulopathy, KSS = Kearns-Sayre syndrome, MERRF = myoclonic epilepsy with ragged-red fibers, MMA = methylmalonic aciduria, mtDNA = mitochondrial deoxyribonucleic acid, nDNA = nuclear deoxyribonucleic acid, OCRL = oculocerebrorenal syndrome of Lowe, PS = Pearson syndrome, RTA = renal tubular acidosis a

Mechanism of renal dysfunction is not clearly known but there is indirect evidence of

tubulopathy. b

There is dysfunction of specific neutral amino acid transporter in the proximal convoluted

tubule. c

Rhabdomyolysis can be caused by acquired and inherited movement disorders (see

Supplementary Table 1)

Supplementary Table 1. Renal dysfunction due to movement disorders or their treatment

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Table 1. Inherited lysosomal and mitochondrial disorders with movement abnormalities and renal involvement Disorder (gene) and movement abnormalities Lysosomal disorders Action myoclonus renal failure syndrome (SCARB2) Myoclonus (cortical), tremor, cerebellar ataxia (10)

Anderson-Fabry disease (GLA) Parkinsonism (16), reduced hand dexterity, gait disturbances (17)

Mitochondrial cytopathies Kearns-Sayre syndrome (large scale deletions or duplications in mtDNA) Cerebellar ataxia

Renal phenotypea and other systemic features

Additional features and comments

Seizures, slow horizontal saccades, sensorineural hearing loss, peripheral neuropathy (usually subclinical, demyelinating) (112-114)

Renal phenotype: glomerulopathy Other features: dilated cardiomyopathy (115)

AOO: adolescence, adulthood Tremor is likely rhythmic cortical myoclonus Atypical: prominent cognitive decline (11) MRI: usually normal EEG: generalized spike and wave discharges with background slowing

Neuropathic pain, transient ischemic attack or stroke, sensorineural hearing loss, tinnitus (15)

Renal phenotype: glomerulopathy Other features: angiokeratoma, cornea verticillata, abdominal pain, diarrhea, constipation, cardiomyopathy, arrhythmias (15)

AOO: variable Parkinsonism is due to basal ganglia infarcts (16) Enzyme replacement therapy may slow progression of renal disease

Progressive external ophthalmoplegia, pigmentary retinopathy, sensorineural hearing loss, myopathy (116)

Renal phenotype: tubulopathy Other features: diabetes mellitus, short stature (116)

AOO: childhood, adolescence Tubulopathy can be presenting feature (24) MRI: cerebellar or global atrophy, T2W hyperintensities in the deep gray matter nuclei, cerebellar white matter, subcortical white matter (116) Muscle biopsy: ragged-red fibers CSF protein > 100 mg/dL

Other neurological features

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Pearson syndrome (large scale deletions or duplications in mtDNA) Cerebellar ataxia

Progressive external ophthalmoplegia, pigmentary retinopathy, sensorineural hearing loss, myopathy (117)

Renal phenotype: tubulopathy Other features: sideroblastic anemia, neutropenia, thrombocytopenia, lifethreatening exocrine pancreatic dysfunction (117)

AOO: childhood Survivors may develop features of KearnsSayre syndrome (117)

Leigh syndrome (several genes for mitochondrial respiratory chain subunits) Dystonia (most common), ataxia, chorea, ballism, athetosis, myoclonus, parkinsonism

Subacute psychomotor retardation, dysarthria, ophthalmoparesis, abnormal respiration, seizures, optic atrophy, retinopathy (118)

Renal phenotype: tubulopathy Other features: short stature, anorexia, diarrhea, pancreatitis, cardiomyopathy, dysmorphic features

AOO: childhood, adolescence, adulthood MRI: bilateral symmetric T2W hyperintensities in basal ganglia, thalamus, substantia nigra, brainstem, and spinal cord (118)

Myoclonic epilepsy with raggedred fibers (MT-TK, MT-TL1, MTTH, MT-TS1) Myoclonus (cortical), cerebellar ataxia

Sensorineural hearing loss, optic atrophy, retinopathy, myopathy, exercise intolerance, peripheral neuropathy, cognitive decline (116, 119)

Renal phenotype: tubulopathy Other features: multiple lipomas

AOO: childhood, adolescence MRI: cerebellar or brainstem atrophy (116) EEG: generalized spike and wave discharges with background slowing (119) Muscle biopsy: ragged- red fibers

Neurogenic muscle weakness, ataxia, and retinitis pigmentosa (MT-ATP6) Cerebellar ataxia

Sensory neuropathy, retinitis pigmentosa, proximal muscle weakness (neurogenic); developmental delay, cognitive decline, seizures (116)

Renal phenotype: mixed glomerulopathy and tubulopathy (25)

AOO: adolescence, adulthood Maternally inherited Leigh syndrome can occur in other family members if heteroplasmy level is > 90%

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Mitochondrial cerebellar ataxia, renal failure, and encephalopathy (MT-ND5) Cerebellar ataxia

Peripheral neuropathy, sensorineural hearing loss (120)

Renal phenotype: glomerulopathy

AOO: adulthood MRI: cerebellar atrophy (120)

CoQ10 deficiency (COQ2, COQ6, PDSS2, COQ9) Cerebellar ataxia, dystonia

Pyramidal signs, myopathy, seizures, intellectual disability, encephalopathy (27-30)

Renal phenotype: glomerulopathy (COQ2, COQ6, PDSS2) Tubulopathy (COQ9) Other features: fatal multi-system disorder in infants (severe phenotype)

AOO: childhood Phenotypes: cerebellar ataxia, encephalomyopathy, Leigh syndrome MRI: T2W hyperintensities in basal ganglia and white matter (27), cerebellar and cortical atrophy (27, 32)

Abbreviations: AOO = age of onset, CoQ10 = coenzyme Q10, EEG = electroencephalography, MRI = magnetic resonance imaging, T2W = T2-weighted a Predominant renal phenotype is mentioned; long-standing glomerulopathy is accompanied by tubular dysfunction and atrophy

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Table 2. Inherited organic acidurias, urea cycle disorders and other metabolic disorders with movement abnormalities and renal involvement Disorder (gene) and movement abnormalities Organic acidurias Glutaric aciduria type 1 (GCDH) Dystonia, parkinsonism, chorea, athetosis

Methylmalonic aciduria (MMUT, MMAA, MMAB, MMADHC) Dystonia, chorea, myoclonus, tremor (123, 124)

Urea cycle disorders Argininosuccinic aciduria (ASL) Cerebellar ataxia (intermittent), tremor, myoclonus

Other neurological features

Renal phenotypea and other systemic features

Additional features and comments

Macrocephaly, acute encephalopathic crises, seizures, developmental delay, intellectual disability, subdural hematoma, retinal hemorrhage (121)

Renal phenotype: tubulopathyb

AOO: childhood MRI: widened Sylvian fissures with dilatation of the subarachnoid spaces surrounding underdeveloped frontotemporal lobes, subdural collections, T2W hyperintensities in globus pallidus, striatum, and white matter (122)

Encephalopathy (during metabolic crises), hypotonia, developmental delay, intellectual disability, seizures, optic atrophy, sensorineural hearing loss, supranuclear gaze palsy (40)

Renal phenotype: tubulopathy Other features: pancreatitis, recurrent vomiting, anorexia, cardiomyopathy, dermatitis (40)

AOO: childhood, adolescence MRI: T2W hyperintensities in bilateral globus pallidus (125)

Seizures, episodic hypotonia, episodic muscular weakness, developmental delay, intellectual disability, behavioral abnormalities (47, 126)

Renal phenotype: tubulopathyb Other features: trichorrhexis nodosa (coarse brittle hair), chronic diarrhea, chronic liver disease (47, 126)

AOO: childhood, adolescence Mild cerebellar ataxia may persist (127) MRI: generalized atrophy, focal infarcts, T2W basal ganglia and white matter hyperintensities, heterotopia (47, 126)

Other metabolic disorders

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Lesch-Nyhan disease (HPRT1) Dystonia, chorea, athetosis, ballism

Axial hypotonia, developmental delay, intellectual disability, impaired language, dysarthria, dysphagia, pyramidal signs, aggressive behavior, selfmutilating behavior (50)

Renal phenotype: tubulopathy, renal stones (orange crystals in baby diapers) Other features: gouty arthritis, subcutaneous tophi

AOO: childhood Mild variants may be seen in adults (128) MRI: normal in routine imaging; reduced basal ganglia and white matter volume in morphometric studies (129, 130)

Wilson disease (ATP7B) Tremor, dystonia, parkinsonism, chorea, myoclonus, cerebellar ataxia

Dysarthria, dysphagia, pyramidal signs, cognitive decline, psychiatric features, seizures (53)

Renal phenotype: tubulopathy Other features: chronic liver disease, arthropathy, osteomalacia, vitamin D resistant rickets, hemolytic anemia, Kayser-Fleischer ring, sunflower cataract (54)

AOO: childhood, adolescence, adulthood MRI: T2W hyperintensities in bilateral basal ganglia, brainstem, thalamus; ‘face of giant panda’ sign in midbrain, ‘face of miniature panda’ sign in pons, bright claustrum sign (53)

Hartnup disease (SLC6A19) Intermittent cerebellar ataxia, chorea, athetosis

Intermittent diplopia, nystagmus, spastic paraparesis, collapsing falls, headache, psychiatric features, intellectual disability (131)

Renal phenotype: tubulopathy Other features: photosensitive pellagra-like skin rashes, diarrhea, short stature

AOO: childhood, adolescence, adulthood Deletions in the CLTRN gene causes Hartnup disease-like phenotype (64) MRI: delayed myelination, generalized atrophy, thin corpus callosum (132)

Abbreviations: AOO = age of onset, MRI = magnetic resonance imaging, T2W = T2-weighted a Predominant renal phenotype is mentioned b Mechanism underlying renal involvement is not well-established

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Table 3. Inherited channelopathies, ciliopathies and miscellaneous disorders with movement abnormalities and renal involvement Disorder (gene) and movement abnormalities Channelopathies Epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST) syndrome (KCNJ10) Cerebellar ataxia, dystonia

Other neurological features

Seizures (generalized, focal), pyramidal signs, sensorineural hearing loss (subclinical or severe), impaired communication, intellectual disability (65, 66)

Ciliopathies and related disorders Joubert syndrome (CEP290, Hypotonia, abnormal respiration, TMEM67, AHI1, several other developmental delay, intellectual genes) disability ocular motor apraxia, Cerebellar ataxia, head jerks impaired smooth pursuit, nystagmus, strabismus, amaurosis, retinopathy, chorioretinal or optic nerve colobomas (79)

Oculocerebrorenal syndrome of Lowe (OCRL1)

Hypotonia, intellectual disability, diminished tendon reflexes (82)

Renal phenotypea and other systemic features

Additional features and comments

Renal phenotype: tubulopathy

AOO: childhood Cerebellar ataxia is non-progressive but most disabling feature MRI: normal or subtle abnormalities (T2W hyperintensities of cerebellar nuclei, cerebellar and brainstem hypoplasia, thin corpus callosum and thin spinal cord) (68)

Renal phenotype: tubulopathy Other features: polydactyly, facial dysmorphism, hepatic fibrosis, cardiac malformations, skeletal dysplasia, scoliosis (79)

AOO: childhood Head jerks compensatory for ocular motor apraxia may be mistaken as tics (133) Combinations of clinical features are known by several acronyms and eponymous syndromes MRI: ‘molar tooth’ sign in axial images due to combination of cerebellar vermis hypodysplasia, thickened, and elongated superior cerebellar peduncles, and deep interpeduncular fossa (79)

Renal phenotype: tubulopathy

AOO: childhood

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Stereotypy, chorea, athetosis (134, 135)

Miscellaneous disorders Nephrocerebellar syndrome (Galloway-Mowat syndrome) (WDR73) Dystonia, chorea Congenital nephrotic syndrome of the Finnish type (NPHS1) Dystonia, athetosis

Neuronal intranuclear inclusion disease (NOTCH2NLC)

Other features: congenital cataracts, glaucoma, arthropathy, rickets (82)

Chorea, athetosis are probably secondary to visual impairment and sensory deprivation (135) Dent disease type 2 is an allelic disorder with predominant renal phenotype (82) Ciliary dysfunction is one of the many cellular abnormalities (81) MRI: delayed myelination, ventriculomegaly; T2W hyperintensities (cystic lesions) in deep and periventricular white matter appear after myelination is complete; tigroid pattern (radially oriented hypointense strips within white matter hyperintensity) may be seen (82)

Congenital roving nystagmus, seizures, developmental delay, visual impairment (86)

Renal phenotype: glomerulopathy

AOO: childhood MRI: diffuse cerebral atrophy, thin corpus callosum, cerebellar hypoplasia

Hypotonia (87)

Renal phenotype: glomerulopathy

AOO: childhood Mechanism of basal ganglia involvement is not clearly known MRI: T2W hyperintensities in bilateral globus pallidus (87)

Dementia, seizures, pyramidal signs, peripheral neuropathy, autonomic dysfunction (91)

Renal phenotype: glomerulopathyb

AOO: variable Disease pathogenesis is yet to be determined

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Cerebellar ataxia, tremor, parkinsonism

Inclusions found in renal tubular cells; mechanism of podocyte damage not known MRI: T2W confluent hyperintensities involving the cerebral white matter (leukoencephalopathy); DWI hyperintensities in the corticomedullary junction (91)

Abbreviations: AOO: age of onset, DWI = diffusion weighted imaging, MRI = magnetic resonance imaging, T2W = T2-weighted a Predominant renal phenotype is mentioned; long-standing glomerulopathy is accompanied by tubular dysfunction and atrophy b Mechanism underlying renal involvement is not well-established

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Table 4. Movement disorders in renal failure (consequences of azotemia and electrolyte imbalance) Etiology or syndrome Movement abnormalities Direct consequences of renal failure Uremic encephalopathy Myoclonus, postural and kinetic tremors, ataxia, paratonia, opisthotonus and decorticate posturing (1-3) Types of myoclonus: asterixis (negative myoclonus), multifocal jerks, twitch convulsive syndrome (combination of fasciculations, intense asterixis, and multifocal jerks culminating in seizure), and epilepsia partialis continua; myoclonus can be spontaneous, with action or stimulus-sensitive, distal as well as proximal (2, 3, 136) Uremic striatopallidal syndrome

Parkinsonism or chorea depending on predominant involvement of the GPi or GPe respectively (137, 138) Parkinsonism: acute to subacute onset of bradykinesia, rigidity, and postural instability; tremor is typically absent; response to dopaminergic replacement therapy is poor (139, 140) Chorea: acute to subacute onset; may be generalized, focal, asymmetric, or unilateral; sometimes may be followed by parkinsonism (141, 142); can relapse with intercurrent illness or further renal decompensation (143)

Other features and comments Variable disturbances in consciousness, perception, and cognition, generalized tonic-clonic seizures, paratonia Myoclonus usually accompanies lethargy and obtundation; myoclonus can be of subcortical (brainstem reticular-reflex myoclonus) or cortical origin (130, 131) Opisthotonus and decorticate posturing are seen in advanced cases Clinical features are more pronounced in rapidly developing uremia

Mild encephalopathy, dysarthria, pyramidal signs Usually occurs in patients on hemodialysis for ESRD due to diabetic nephropathy; can occur without preceding dialysis (139, 144) and in ESRD due to another or unknown etiology (140, 145); hypoglycemic events, thiamine deficiency, and metformin can be triggers (138, 142, 146, 147) CT: nearly symmetric basal ganglia hypodensity with evidence of edema and mass effect ; MRI: basal ganglia hypointensity in T1W images, hyperintensity in T2W and FLAIR images, bright DWI and corresponding ADC (vasogenic edema); dark medial GP on ADC (cytotoxic edema); complete or partial lentiform fork sign in T2W and FLAIR images (148); MR angiogram: prominent lenticulostriate arteries in the symptomatic phase (140)

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Prognosis: parkinsonism may resolve partially or completely within weeks to months with intensification of hemodialysis or supportive treatment; radiological resolution occurs earlier; residual cystic changes in the GP and the putamen (bright signal in T2W and ADC) may be a marker for residual neurological impairment (149, 150); chorea usually improves within days to weeks with intensification of hemodialysis; use of dopamine receptor blockers for chorea may cause parkinsonism (143); neurological symptoms may persist despite radiological resolution (151) Uremic restless leg syndrome

More severe and less responsive to dopaminergic drugs in comparison to patients without kidney disease (152, 153)

Consequences of electrolyte imbalance in renal failure Hyponatremia Tremor, myoclonus, ataxia, rigidity (4)

Cramps, encephalopathy, seizures, hyporeflexia


Tremor, myoclonus, chorea, rigidity (4)

Encephalopathy, seizures, hyperreflexia


Tetany, trismus, opisthotonus (4)

Encephalopathy, seizures, Chvostek’s sign, Trousseau’s sign


Tremor, myoclonus, startle, tetany, chorea, downbeat nystagmus (4)

Encephalopathy, seizures, hyperreflexia, Chvostek’s sign, Trousseau’s sign, downbeat nystagmus (154)


Tremor, ataxia (4)

Weakness, areflexia, perioral paresthesia, ophthalmoparesis May mimic Wernicke’s encephalopathy

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Abbreviations: ADC = apparent diffusion coefficient, CT = computed tomography, DWI = diffusion weighted imaging, ESRD = end stage renal disease, FLAIR = fluid attenuated inversion recovery, GP = globus pallidus, GPe = globus pallidus externa, GPi = globus pallidus interna, MRI = magnetic resonance imaging, T1W = T1 weighted, T2W = T2 weighted

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Table 5. Movement disorders as consequences of treatment of renal failure Etiology or syndrome Movement abnormalities Other features and comments Consequences of dialysis in renal failurea Dialysis disequilibrium Myoclonus, tremor, rarely dystonia Acute onset or worsening of confusion, headache, nausea, cramps, seizures (generalized or syndrome (5, 155, 156) focal) Occurs near the end of rapid hemodialysis, due to disparity between the blood and the brain pH and urea concentration In current practice, this condition is rarely seen because of measures that slow down the disparity (5) Neuroimaging: diffuse or multi-focal cerebral edema Osmotic demyelination Parkinsonism, choreo-athetosis, Usually occurs as a complication of rapid correction of hyponatremia; rarely seen in ESRD syndrome focal or segmental dystonia, following hemodialysis myoclonus, tremor, ataxia, and Neuroimaging: features of demyelination catatonia (extrapontine Pathological hallmark of osmotic demyelination syndrome is loss of myelin (myelinolysis); myelinolysis) clinical phenotype the term has been loosely (or perhaps incorrectly) used in the literature in the setting of may evolve from one to another hemodialysis for cases with dialysis disequilibrium syndrome and uremic striatopallidal (157, 158) syndrome (158, 159), although it is known that uremia is protective (157); a subset of cases described may be true osmotic demyelination syndrome, while others are likely to be reversible vasogenic edema Dialysis dementia Myoclonus, tremor, ataxia, facial Subacute onset cognitive decline, personality change, apraxia, dysarthria, seizures grimacing Attributed to aluminum toxicity With current use of water purification and non-aluminum phosphate binders, this condition is not seen (5, 160) Thiamine deficiency Ataxia, chorea Confusion, ophthalmoparesis (components of Wernicke’s encephalopathy), psychosis Patients on chronic hemodialysis are at risk (146, 160) Consequences of renal transplantationb Calcineurin inhibitors Tremor, ataxia (161) Peripheral neuropathy

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Drugs used as immunosuppressive therapy Manganese accumulation in the GP has been reported in patients on hemodialysis (162) but this has not been investigated further; patients did not have typical clinical features of manganism. b Movement disorders may be presenting features of brain tumors or central nervous system infections, which often complicate patients on chronic immunosuppressive therapy following renal transplantation. a

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Movement Disorders and Renal Diseases Authors and affiliations: Suvorit S. Bhowmick, MD,1 Anthony E. Lang, MD, FRCPC1 1 Morton and Gloria Shulman Mov...
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