Introduction

The term “movement disorders” encompasses a wide group of neurological conditions characterized by abnormal increased movements (hyperkinesias) or reduced and slowed movements (hypokinesias). The association between movement disorders and peripheral neuropathy (PN) is poorly highlighted in literature. Since movement disorders and neuropathy share the same pathophysiological mechanism in various neurological syndromes, they may coexist or be a continuum of the same clinical spectrum. Furthermore, both may add to comorbidity and disability independently of the primary neurological manifestation, contributing to pain, reduced motor performance, falls and disability. Therefore, it is important to consider that neuropathy associated with a movement disorder may be not only a useful telltale in the diagnosis of complex syndromes but also a predictor of frailty. Furthermore, an increased awareness of overlapping pathologies presenting to movement disorders or neuromuscular clinics should be warranted, since atypical presentations may overcome classic boundaries between the two fields [1], as well as there may be occasions in which some neurological signs may be misinterpreted or overlooked due to the risk of restricted view in the ultra-specialty setting [2]. Finally, advancing technologies allowed the phenotypic spectrum expansion of numerous hereditary neurological disorders and the availability of next-generation sequencing (NGS) techniques is rapidly changing the way we approach genetic disorders. In this review, we aim to provide a guide for the differential diagnoses and potential causes in patients with concomitant neuropathy and movement disorders, offering a dual clinical approach according to the predominant neurological feature (Fig. 1). Pathogenic mechanisms will be further discussed to serve as cues of potential genotype–phenotype correlations, which will steer diagnostic workup and subsequent therapeutic management (Tables 1, 2).

Fig. 1
figure 1

Clinical approach to patients with movement disorder and peripheral neuropathy. It may be useful to divide the list of differential diagnosis according to the predominant neurological feature, whether it be movement disorder, peripheral neuropathy or other neurological signs. For sake of simplicity, we further categorized disorders on acquired or hereditary aetiologies. AD, autosomal dominant; APS/SLE, antiphospholipid syndrome/systemic lupus erythematosus; AR, autosomal recessive; CANVAS, cerebellar ataxia, neuropathy and vestibular areflexia syndrome; CKD, chronic kidney disease; HSMN, hereditary sensory and motor neuropathy; MDS, movement disorder; PN, peripheral neuropathy; SBMA, spinal and bulbar muscular atrophy

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Table 1 Acquired and hereditary MDS with peripheral neuropathy
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Table 2 Acquired and hereditary peripheral neuropathies associated with MDS
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Methods

Research strategies included screening literature on PubMed and Google Scholar databases updated until 30th April 2022. The search keywords were (“neuropathy” or “polyneuropathy” or “coronavirus”) AND (“movement disorder” or “tremor” or “chorea” or “parkinsonism” or “myoclonus” or “dystonia”). Two authors (F.G. and A.B.) screened records of search outputs for pertinence to the topic and English language only. After data review and summary, we drew a simplified diagnostic algorithm for the approach of patients with concomitant peripheral neuropathy and movement disorders according to the predominant clinical presentation (Fig. 1).

Movement disorders with neuropathy

Sporadic MDS with neuropathies

Parkinson disease

PD is the second most common neurodegenerative disorder in the elderly population after Alzheimer’s disease and typically characterized by asymmetric bradykinesia, rigidity and rest tremor. The relationship between PD and PN has gained attention in recent years. PN is relatively frequent in the general PD population, with an estimated prevalence of 16% [3], presenting as an axonal, predominantly sensory, neuropathy with neuropathic pain, tingling, numbness and sometimes ataxia. PN may add to PD comorbidity by affecting balance and gait, increasing risk of falls and cumulative disability [4, 5]. A multicentre case–control study provided evidence that the duration of levodopa exposure and the daily levodopa dose, instead of disease severity or duration, were strongly associated with the risk of developing medium–large fibre neuropathy in PD patients [6]. Prolonged levodopa exposure was strongly linked to reduced serum vitamin B12 levels and increased homocysteine (Hcy) and methylmalonic acid (MMA) levels [6,7,8], possibly due to depletion of methyl groups needed for levodopa metabolism and cobalamin malabsorption, which may underlie PN pathogenesis in these individuals [9]. This mechanism is supported by evidence that COMT inhibitors, which halt methylation of levodopa, were linked to higher vitamin B12 levels and lower neurotoxic metabolites [10]. A dose-dependent levodopa neurotoxicity was further supported by the description of PD patients on duodopa therapy, who may develop a chronic symptomatic PN or more rarely a subacute, severe, axonal neuropathy with tetraparesis resembling Guillain–Barré syndrome [11,12,13,14]. Multiple vitamin B deficiencies (B1, B6, B12) have been advocated as the trigger of this subacute neuropathy and their supplementation improves neuropathic symptoms [9]. Periodic Hcy, vitamin B12 and folate screening, together with serial clinical and neurophysiological assessment, may be advisable in patients receiving > 600 mg/day dose levodopa and in those treated for more than 3 years or on duodopa therapy. Rarely, autosomal-recessive juvenile parkinsonism due to parkin mutations may show a predominant sensory or sensorimotor neuropathy, which may precede overt parkinsonism [15, 16]. Beside levodopa therapy, an intrinsic, PD-related neurodegenerative process affects the peripheral nervous system, presenting as a small fibre neuropathy (SFN) leading to sensory and autonomic impairment [17, 18]. The clinical features (i.e. pinprick and thermal sensory loss, burning pain, hyperalgesia and allodynia), associated with abnormal selected investigations (i.e. quantitative sensory testing, laser-evoked potentials) [19] and normal conduction studies suggest a diagnosis of SFN. Pathological confirmation is generally required with evidence of a reduced intraepidermal nerve fibre density (IENFD) on skin biopsy, which has been detected in several cohorts of PD patients. About 60–70% of PD patients suffer from mild to moderate autonomic dysfunction such as orthostatic hypotension, bladder and bowel disturbances, sudomotor abnormalities and sexual dysfunction due to small fibre involvement [20]. An intrinsic pathology is supported by evidence of α-synuclein deposition in the skin and sensory nerve fibres of both sporadic and genetic PD patients [21,22,23,24,25], raising as a potential biomarker for early diagnosis. A peripheral α-synuclein deposition in the skin has also been demonstrated in other α-synucleinopathies such as Lewy body dementia [26] and multiple system atrophy (MSA) [27], proving skin biopsy to be a valuable tool for the distinction of parkinsonism related to synucleinopathies compared to tauopathies, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) [27].

Paraneoplastic disorders

Neurological manifestations in cancer are common, disabling and often underdiagnosed. The concomitant presence of a specific movement disorder associated with neuropathy may be the result of a paraneoplastic syndrome, and unmasking the underlying malignancy proves effective for the resolution of neurologic symptoms. Choreic movements and peripheral neuropathy are associated, respectively, with 11% and 42% of CRMP5-IgG antibodies paraneoplastic syndromes as part of a more extensive involvement of the nervous system that may include limbic encephalitis and cerebellar ataxia [28]. Peripheral neuropathy precedes the cancer diagnosis in more than 90% of cases; axonal sensorimotor neuropathy is more frequent than pure sensory neuropathy (50% vs. 25%). Dysautonomia is uncommon. Small cell lung cancer (SCLC), the most common malignancy, is diagnosed in 75% of CRMP5-IgG paraneoplastic syndromes and thymoma in 15% of the cases. Clinical manifestation associated with ANNA1/anti-Hu antibodies in SCLC are ataxia, choreoathetoid movements, dystonia and a sensory neuronopathy with neuropathic pain and ataxia due to degeneration of the dorsal root ganglia neurons [29]. Dysautonomia is present in more than 70% of cases. In anti-Ma2 encephalitis, neuropathy is often associated with parkinsonian features such as bradykinesia, masked faces, hypophonia and rigidity; tremor is less frequent [30]. In male patients up to 50 years, there is a strong association with germ cell tumours of the testis [31]. In women and in men more than 50 years, the associated tumours include non-SCLC, breast cancer, colon cancer and lymphoma. Ataxia associated with neuropathy has been described in patients with Hu-Ab and PCA2-Ab and SCLC, Yo-Ab and gynaecologic cancers, DNER-Ab and Hodgkin lymphoma [32, 33]. Neuromyotonia, peripheral neuropathy, hyperhidrosis, tachycardia, insomnia and urinary dysfunction, especially in males, are typical of Morvan’s syndrome [34]. Needle EMG examination detects myotonic discharges, with the characteristic wax and wane pattern. When associated with neoplasms, especially thymoma, CASPR2 and LGL1 should be investigated for [35].

Autoimmune disorders

Although peripheral neuropathy in antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) underlies immune and vascular mechanisms [36], the pathophysiology of movement disorders is not completely understood, and multiple mechanisms may play a role. Classically, antiphospholipid antibody–antigen complex affects coagulation to result in thrombosis. Some patients who develop movement disorders in the context of APS and SLE have ischaemic-appearing lesions on neuroimaging [37]; however, in the majority of them, there are no specific imaging findings suggesting a different aetiology. Chorea is the most common movement disorder in APS and SLE, with a prevalence between 1 and 4.3% [38,39,40]. Men are scarcely involved. In most cases, the episode is single, the onset bilateral and the prognosis good, but sometimes there may be relapses (2–6 episodes). Immunologic testing often reveals positive lupus anticoagulant and anticardiolipin antibodies in blood. Less frequent manifestations are ataxia, dystonia and myoclonus. A sensorimotor axonal polyneuropathy is diagnosed in approximately 6% of patients with SLE, while rarely it may present with isolated motor involvement [41]. Small fibre involvement is uncommon [42]. Moreover poorly levodopa-responsive parkinsonism is more often associated with neuropsychiatric lupus (NPSLE), both in patients with an established diagnosis of SLE and as a presenting subacute manifestation of NPSLE [43]. Parkinsonism associated with peripheral neuropathy has been also described in Sjogren’s syndrome and rheumatoid arthritis, both due to a prothrombotic aetiology [44]. In most cases, brain MRI shows hyperintensity on T2 and FLAIR in the striatum or in the globus pallidus nucleus.

Heavy metals

A number of heavy metals have been described in association with parkinsonism and neuropathy, comprising manganese (Mn), mercury and carbon disulphide (CS2; Table 1).

In particular, the exposure to high concentrations of Mn dust and fumes in mining workers leads to an increased risk of manganism, defined as a complex clinical entity characterized by parkinsonism, behavioural changes and neuropathy [45,46,47]. Mn crosses the blood–brain barrier and accumulates in the mitochondria within the globus pallidus [48]. Patients usually develop bradykynesia, rigidity, action tremor and dystonia, more pronounced in the lower limbs, leading to the typical “cock gait” [46]. The therapeutic effect of levodopa is usually unsatisfactory and the disease rapidly evolves within 5 years [49]. Conversely, neuropathy may arise either from a direct effect or by disrupting the dopaminergic modulation of thyroid hormone synthesis, likely accounting also for neurodevelopmental effects as observed in chronic Mn exposure [50].

Conversely, mercury is usually associated with hyperkinetic features (tremor, ataxia) and a subacute sensory and motor neuropathy, closely mimicking Guillain–Barré SYNDROME and acute axonal polyneuropathies [51] (Table 1).

Hereditary MDS with neuropathy

Neuroacanthocytosis

Core neuroacanthocytosis syndromes (NA syndromes) encompasses a heterogeneous group of genetic syndromes characterized by the coexistence of acanthocytes on blood smear and neurological symptoms. Among them, the so-called "core" NA syndromes are characterized by movement disorders due to basal ganglia degeneration, peripheral nervous system involvement, cognitive impairment and psychiatric features. However, only chorea acanthocytosis (ChAc) and McLeod syndrome (MLS) show extrapyramidal features along with a peripheral involvement. Patients with ChAc, caused by VPS13A gene mutation, develop generalized chorea in the majority of cases and parkinsonism in the minority [52]. Other extrapyramidal features in these patients include peculiar “feeding dystonia” with tongue protrusion, orofacial dyskinesias limb and trunk dystonia [53]. Even if most patients have neuromuscular involvement, myopathic changes are rare at EMG examination despite muscle atrophy, weakness and a typical elevation of creatine phosphokinase (CK) [54]. Axonal neuropathy is frequent, but usually mild to moderate. MLS is defined as the absence of Kx red blood cell (RBC) protein and weak expression of Kell antigens on RBCs. Compared to ChAc, MLS is characterized by more consistent neuromuscular manifestations due to a severe myopathic and axonal neuropathic involvement. In most cases CK elevation is severe, however, typically < 4000 U/L [55, 56]. Patients usually develop chorea, while parkinsonism and dystonia are uncommon. Generalized seizures occur in about half of the patients. MLS presents in young-to-middle adulthood, even though MLS typically has a later onset of neurological symptoms.

Spinocerebellar ataxias

Spinocerebellar ataxias (SCAs) represent progressive, autosomal dominant, neurodegenerative disorders involving the cerebellum-connected structures. Even though ataxia is the main feature in most cases, different phenotypes can be observed in the same SCA subtype due to the combined involvement of the brainstem, spinal cord and peripheral nervous system [57]. The coexistence of extrapyramidal symptoms and peripheral neuropathy is typical of numerous SCA subtypes. SCA can manifest as parkinsonism, especially in SCA2, SCA3 and SCA17, closely mimicking idiopathic PD, thus representing a not uncommon genetic cause of parkinsonism, even in apparently sporadic cases [58]. Dystonia is usually associated with it. Since mutation of SCA genes is considered positive in 0.5–8% of familial PD [59,60,61], the screening of SCA2, SCA3 and SCA17 is required in PD patients. Small expansions with interruption could explain the parkinsonian phenotype and genetic cases with relatively low penetrance. SCA3 is common in Western populations, while SCA2 and SCA17 are predominant in Asian populations; however, a sensory axonal mild polyneuropathy has been described only in SCA2 and SCA3, respectively, in 80% and 54% of patients. In SCA3, the fewer the CAG repetitions, the more is the peripheral involvement. Tremor is associated with polyneuropathy in SCA2, SCA8, SCA12 and SCA27. Tremor can be (a) a fast (6.5–8 Hz) action, postural or orthostatic tremor, becoming slower over time in case of association with parkinsonism or (b) slow action and intention tremor (3–4 Hz). Different features in SCA-related tremor likely depend on which pathway is mainly involved: the cerebello-thalamo-cortical loop or nigro-striatal dopaminergic pathway [62]. Chorea is uncommon, described mainly in SCA1 and SCA17. Since the more the CAG repetitions, the more is the disease severity in the SCA1 subtype, and co-presence between chorea and sensorimotor axonal polyneuropathy is not uncommon.

Inborn errors of copper metabolism: Wilson disease (WD)

Wilson disease (WD) is an autosomal-recessive disease caused by mutations in the ATP7B gene, encoding a copper-transporting ATPase, and clinically characterized by dysarthria, dystonia, tremor (the “wing-beating tremor”) and choreoathetosis [63, 64]. As the main criteria, the presence of Kayser–Fleischer rings (KFR) and serum ceruloplasmin (CP) < 10 mg/dL are sufficient per se to confirm the diagnosis [64]. A more detailed description of WD is beyond the aim of our paper, but sometimes mutations in a second, closely related copper-transporting ATPase, formally named ATP7A, induces a distal motor neuropathy (see Table 1). Although very rare, this neuropathic involvement can present alone, predominantly as a small fibre disease [65, 66], or along with an “atypical Menkes disease”, also comprising epilepsy, kinky hair, cerebellar ataxia and neurodevelopmental delay [67].

Neuropathy with MDS

Tremor is the most common movement disorder observed in patients with peripheral neuropathies, for whom the label neuropathic tremor is frequently used. It presents as a postural/action tremor, bilateral, commonly affecting the distal upper limbs and impairing the common activities of daily life, such as handwriting and drinking. It is more commonly observed in chronic demyelinating neuropathies rather than axonal neuropathies, as well as in patients with concomitant cerebellar dysfunction. Other movement disorders, such as dystonia, parkinsonism and myoclonus may be present in patients with other neuropathies, either acquired or inherited, usually in the context of complex disease phenotypes.

Sporadic neuropathies with MDS

Chronic acquired demyelinating neuropathies

Neuropathic tremor is a prevalent feature in chronic acquired demyelinating neuropathies, such as paraproteinemic (IgM) polyneuropathy, with or without anti-myelin-associated glycoprotein (MAG) antibodies, chronic inflammatory demyelinating polyneuropathy (CIDP) and also multifocal motor neuropathy (MMN) with conduction blocks. Rarely, it rather occurs later in the disease course, with studies showing a median time interval from disease onset of 5.8 years [68]. Paraproteinemic IgM-associated neuropathy classically presents as a chronic progressive distal demyelinating neuropathy affecting mainly sensory function, with ataxia, distal sensory loss and mild lower limb muscle weakness being the main symptoms [69]. Neuropathic tremor is a classic feature, affecting up to 90% of cases and can be severely disabling in almost half of the cases with long-standing disease [68, 70]. Rarely, an additional resting component has been reported in patients with positive anti-MAG titres. Interestingly, detailed clinical and neurophysiological assessment revealed that a postural/action tremor may be found in more than half of the patients with CIDP or MMN [68]. Among CIDP subtypes, those with positive antibodies against neurofascin-155 (NF155) represent about 4–18%% of cases and show a peculiar phenotype characterized by sensory ataxia, tremor, neuropathic pain, autonomic and cranio-bulbar symptoms, sometimes associated with signs of cerebellar dysfunction (cerebellar ataxia, dysarthria, gaze-evoked nystagmus) and CNS demyelinating lesions [71,72,73]. Such diverging features led some authors to consider anti-NF155-associated demyelinating neuropathy as a separate disease entity, called “autoimmune nodopathy” [74], although the issue is still controversial. The pathogenesis of tremor in inflammatory neuropathies is poorly understood. Several studies failed to prove the correlation between tremor and other neuropathic features, such as proprioceptive loss or weakness [75, 76]. Nonetheless, despite no association with its occurrence, neurophysiological parameters of demyelination, such as slowed conduction velocities and prolonged distal and F-wave latencies, correlate with tremor severity [68, 77], suggesting the temporal dispersion of afferent inputs may be a necessary, but not sufficient condition to explain the phenomenology of neuropathic tremor. Interestingly, some studies showed that cerebellar dysfunction, as assessed through either through neurophysiological or imaging studies, may further underlie tremor pathogenesis in inflammatory neuropathies [78, 79]. Cerebellar ataxia may indeed be found in inflammatory neuropathies with sensory predominant phenotypes, such as in those with positive anti-NF155 and anti-MAG antibodies, the latter reported also in patients with isolated, late-onset cerebellar ataxia [80]. Lending support to these findings, genetic studies showed that patients with biallelic mutations in either the neurofascin or MAG genes are associated with early-onset cerebellar ataxia and demyelinating neuropathy, sometimes with additional manifestations, such as spasticity, myoclonus or dystonia [81, 82]. Besides tremor, other movement disorders have been rarely reported. Of note, a small case series described four patients with MMN, showing pathologic involuntary movements such as muscle spasms and abnormal posturing of the affected limb. Arguing against dystonia, there was an absence of classic features such as specific triggers and sensory tricks, as well as the strict link between the distribution of abnormal movements and sites of focal conduction block. This led the authors to define these clinical signs as “pseudo-dystonia”, probably due to local axonal hyperexcitability caused by loss of myelin sheath, a mechanism already known to cause other hyperexcitability-related symptoms, such as cramps and fasciculations [83].

Nutritional and metabolic disorders

Acquired toxic-metabolic disorders, typically associated with peripheral neuropathy, may show unusual presentations, including movement disorders. Vitamin B12 deficiency, commonly caused by dietary habits or malabsorption, may present with a myriad of neurologic manifestations [84]. Low vitamin B12 levels are diagnostic, but an increase in homocysteine and/or methylmalonic acid levels may precede overt B12 deficiency on routine laboratory tests [85]. Lack of vitamin B12 results in impaired myelination and axonal degeneration of long tract fibres, leading to a spectrum of clinical disorders ranging from sensorimotor axonal polyneuropathy to a subacute combined degeneration (SCD) involving the posterior and lateral columns. An acute/subacute onset of impaired vibration sense and proprioception in the legs with an ascending fashion resulting in sensory impairment and gait ataxia, together with pyramidal signs, is a classic clinical phenotype [86]. On MRI, T2 hyperintensities in the posterior columns of the cervical and upper thoracic cord may be diagnostic of SCD. Other classic findings may be cognitive and behavioural abnormalities, mood disorders and optic atrophy. Involuntary movements are rarely described in adults with vitamin B12 deficiency, including chorea, tremor, myoclonus and dystonia and may be found in combination with other B12-related manifestations, such as peripheral neuropathy, cognitive impairment or long tract signs [87, 88]. Depletion of vitamin B12 stores in the newborns, such as in those breastfed by B12-deficient mothers, may result in infantile tremor syndrome, a complex and severe disease characterized by developmental delay, lethargy, seizures and tremor, which may be reversible after cobalamin supplementation [88]. While diabetic peripheral neuropathy is the most prevalent complication of type 2 diabetes mellitus with an estimated prevalence that ranges from 21.3 to 34.5% [89], movement disorders are extremely rare. Transient chorea–ballism is a rare complication of non-ketotic hyperglyycaemia with an estimated prevalence of less than 1:100,000 [90]. In patients with decompensated diabetes, chorea/ballism, especially when occurring acutely and unilaterally, may mimic a stroke episode (and go into thrombolysis). According to a meta-analysis [91], the mean serum glucose level upon admission is higher than 400 mg/dL. The presentation is unilateral in 88% of patients and prognosis is often good. MRI shows hyperintensity of the putamen nucleus, both unilateral and bilateral. Chronic kidney disease commonly causes an axonal sensory neuropathy, due to the accumulation of toxic metabolites crossing the blood–nerve barrier [92]. Nonetheless, CNS toxicity may be observed in the acute setting leading to uremic encephalopathy, characterized by altered mental status, behavioural abnormalities, tremor, asterixis and myoclonic jerks. A reversible parkinsonism associated with the lentiform fork sign on MRI may be an unusual manifestation of uremic encephalopathy [93].

Medication-induced disorders

Finally, medications may be responsible for a combined presentation of peripheral neuropathy and involuntary movements. Drugs such as amiodarone and traditional chemotherapeutics are common iatrogenic causes of peripheral neuropathy [94]. In some patients, toxicity may also present with a postural/action tremor, affecting up to a third of patients on long-term amiodarone treatment [95]. Rarely, chemotherapy may result in a levodopa-responsive parkinsonism, which may be reversible after suspension of treatment [96].

Hereditary neuropathies with MDS

Hereditary sensory and motor neuropathies

Hereditary motor and sensory neuropathies (HSMN), also known as Charcot–Marie–Tooth (CMT) disease, comprise a group of heterogenous disorders characterized by juvenile- or adult-onset peripheral neuropathy with slowly progressive distal amyotrophy, areflexia and sensory deficits. Various movement disorders have been described in the context of HMSN, such as tremor, parkinsonism and dystonia. A postural/action tremor in the upper limbs is commonly observed in patients with long-standing HSMN, reported in up to 40% of cases with CMT1A [97], the most common type of demyelinating CMT caused by duplication of the PMP22 gene. Furthermore, patients with axonal CMT (CMT2) may be tremulous, as up to 20% of cases with MFN2 or GDAP1 mutations may show hand tremor [98]. Tremor presentation is usually delayed compared to neuropathy onset, with a time lag of several years. It has apparently no relationship with the degree of muscle weakness and sensory deficits and a central mechanism has been suggested [97]. In comparison, parkinsonism is rare, although it has been reported in some HSMN patients with mutations in LRSAM1 [99], FIG4 [100, 101] and SLC25A46 [102] genes. In such cases, patients present with a juvenile- or adult-onset slowly progressive neuropathy, while parkinsonism either appears simultaneously or follow after a few years, being potentially responsive to levodopa treatment. Some clinical clues may help to clinch the diagnosis in such patients. For example, patients with early-onset parkinsonism and demyelinating neuropathy may suggest autosomal-recessive FIG4 mutations, further supported by the presence of a non-uniform demyelination in neurophysiological studies, resembling acquired demyelinating neuropathies [100]. The combination of a sensorimotor axonal neuropathy together with optic atrophy and parkinsonism/dystonia may point towards pathogenic variants in the SLC25A46, which encodes for a mitochondrial carrier protein involved in mitochondrial dynamics and responsible for a broad spectrum of neurodegenerative diseases, ranging from lethal congenital pontocerebellar hypoplasia (PCH) to the mildest phenotypes including optic atrophy, peripheral neuropathy, cerebellar ataxia and spasticity [102, 103]. Few reports have also described an association between movement disorders and other hereditary neuropathies, comprising hereditary neuropathy with liable pressure palsies (HNPP) and distal hereditary motor neuropathy (dHMN). Tremor, dystonia and myoclonus have been rarely reported in HNPP patients [104,105,106], primarily involving the limbs affected by pressure palsies then spreading over adjacent segments, suggesting the presence of an additional central mechanism responsible for the abnormal movements. Finally, mutations in the DCTN1 gene are responsible for several neurological disorders including CMT, dHMN-type VIIB, ALS and Perry syndrome, an adult-onset neurodegenerative disorder characterized by neuropsychiatric symptoms, parkinsonism and central hypoventilation. Recently, a common missense mutation has been reported in a large family pedigree presenting with either dHMN-VIIB or Perry syndrome, with some members showing overlapping features [107].

Motor neuron diseases

More rarely, lower motor neuron diseases have also been associated with concomitant peripheral neuropathy and CNS manifestations. For example, spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is a progressive lower motor neuron disorder caused by a CAG repeat expansion in the androgen receptor gene. A peripheral nerve involvement with small or absent SAPs is frequently encountered and highly diagnostic for SBMA [108]. Although rarely reported, tremor is the most common CNS manifestation of SBMA and is associated with other neurological features, such as cognitive impairment and white matter abnormalities in neuroimaging studies [109].

Mitochondrial disorders

Mitochondrial diseases (MIDs) represent a group of inherited neurometabolic disorders characterized by mitochondrial dysfunction and failure in multiple tissues, including the brain, peripheral nerves, muscle, heart, and visual and auditory pathways. Clinical phenotypes are highly heterogeneous, ranging from isolated manifestations, such as chronic progressive external ophthalmoplegia (CPEO) and myopathy, to multiple syndromic features, with variable combinations of psychomotor delay, epilepsy, CPEO, myopathy, neuropathy, optic atrophy, movement disorders, sensorineural hearing loss and stroke-like episodes [110, 111]. Peripheral neuropathy may be the predominant feature in selected MIDs, such as those associated with mutations in nuclear genes including POLG1, C10ORF2, TYMP and MPV17 [98]. POLG mutations are responsible for 10–25% of MIDs cases [112,113,114,115], commonly presenting with an adult-onset CPEO or showing early-onset multisystemic disorders, such as Alpers–Huttenlocher syndrome and mitochondrial recessive ataxia syndrome. POLG mutations are typically associated with a moderate-to-severe predominantly sensory axonal neuropathy, resulting in sensory loss, ataxia and neuropathic pain [98, 114]. Sensory neuronopathy is characteristic of POLG-related diseases and may also be found in more complex phenotypes such as sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO) or ataxia neuropathy spectrum. Sometimes, movement disorders such as dystonia and parkinsonism may present later in the disease course in patients with POLG mutations [116,117,118], usually mimicking classic PD with an asymmetric tremor-predominant form, presynaptic dopaminergic deficits on neuroimaging and response to levodopa. Parkinsonism may also be encountered in patients mutated in the C10ORF2, who frequently show a sensory-predominant neuropathy similar to POLG-related diseases [98]. Mutations in COX20 gene leads to mitochondrial complex IV deficiency, which manifests with early-onset cerebellar ataxia, sensory neuropathy and dystonia [119]. Recently, the mitochondrial UQCRC1 gene was found as a new cause of autosomal-dominant parkinsonism and polyneuropathy [120]. Peripheral neuropathy is common also in other MIDs, often sensory or sensorimotor and subclinical, representing a minor feature of more complex disorders, as it occurs in myoclonic epilepsy with red-ragged fibres (MERRF), Leigh syndrome, mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and Kearns–Sayre syndrome, which usually present during childhood or early adulthood [98, 121]. In such cases, dystonia is the most common movement disorder observed, usually generalized, followed by myoclonus and chorea while parkinsonism is rare [118].

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome

Peripheral neuropathy and movement disorders may also coexist in other hereditary disorders with common neuropathic features, although other neurological signs predominate the clinical picture, such as ataxia or spasticity. The discovery of a biallelic intronic (AAGGG)n expansion in the replication factor C subunit 1 (RFC1) gene as the major cause of cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS, 90% of cases) and late-onset cerebellar ataxia (from 6 to 22%) was a recent breakthrough in the field of adult-onset cerebellar ataxias [122,123,124]. CANVAS is a neurodegenerative disorder manifesting as a slowly progressive gait ataxia, beginning in the fifth to sixth decades, associated with a clinical or neurophysiological evidence of a sensory neuropathy/neuronopathy and bilateral vestibular areflexia [125]. A sensory neuronopathy is a major feature of the disease, detected in 100% of cases, and may be the sole clinical presentation, followed by a stepwise progression with vestibular and cerebellar dysfunction [124]. Loss of vibration sense and proprioception contribute to gait ataxia, while a clinical–electrodiagnostic dissociation may be observed between sensory symptoms, such as tingling, numbness and neuropathic pain, and the degree of axonal loss, with generalized loss of sensory action potentials in about half of the cases [126]. Vestibular areflexia can be witnessed by an abnormal head impulse test or video-oculography [127] and usually manifests with oscillopsia and non-specific visual disturbances, while vertigo is rare [124]. Patients with a biallelic RFC1 expansion more commonly develop a multisystemic disorder in which gait ataxia can be accompanied by autonomic dysfunction (62%) as well as extrapyramidal symptoms, such as bradykinesia, postural instability and slow vertical saccades, presenting overlapping phenotypes with either MSA-C or PSP in 19% and 9%, respectively [128]. Interestingly, genetic screening of the RFC1 expansion identified positive patients also in non-CANVAS cohorts, such as those with idiopathic sensory neuropathy (up to a third) [126] and rarely as a pure parkinsonism indistinguishable from idiopathic PD [129].

Fragile X tremor/ataxia syndrome

Fragile X tremor/ataxia syndrome (FXTAS) is a rare late-onset neurodegenerative disorder due to the presence of a premutation size of 55–200 CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Core clinical features are cerebellar ataxia, tremor and nystagmus, but a great phenotypic variability is appreciated, with studies reporting a high prevalence of sensory neuropathy (up to 80%) and parkinsonism in 60% of cases, accompanied by abnormal dopaminergic transport deficits and response to levodopa [130, 131]. Importantly, up to 25% of cases may be initially diagnosed with idiopathic parkinsonism, although the presence of an underlying sensory neuropathy, which could be either non-length dependent (56%) or length dependent (25%), should alert the clinician towards an alternative diagnosis, including FXTAS [131]. Other characteristic features are autonomic dysfunction and psychiatric and cognitive abnormalities, frequently accompanied by radiological signs such as T2-hyperintensities of the middle cerebellar peduncles and splenium of the corpus callosum [132].

Autosomal-recessive cerebellar ataxias

The combination of cerebellar ataxia and a dorsal root ganglionopathy or polyneuropathy is an important diagnostic clue also for autosomal-recessive cerebellar ataxias (ARCAs), such as Friedreich’s ataxia (FA), ataxia-telangiectasia (AT) and ataxia with oculomotor apraxia 1 and 2 (AOA1 and AOA2). They can be recognized in cases showing an early age of onset (usually < 20 years) and peculiar signs, such as the combination of areflexia and extensor plantar responses (FA) or the combination of oculomotor apraxia and high levels of alpha-fetoprotein (AT, AOA1, AOA2) [133,134,135]. Furthermore, the presence of cutaneous telangiectasias, recurrent infections and sensitivity to ionizing radiation are essential clues for the diagnosis of AT [133]. Hyperkinetic movements, such as tremor, dystonia and chorea may be additional signs in these patients, although rarely observed in adult-onset cases [136,137,138,139].

Hereditary spastic paraplegias

Hereditary spastic paraplegias (HSPs) are a group of hereditary disorders characterized by lower limb weakness and spasticity. Both uncomplicated and complicated forms, with additional neurological signs, may occur and detect in many genetic HSP subtypes. Peripheral neuropathy is the most common non-pyramidal abnormality found in HSP [140], with axonal forms commonly described in both autosomal-dominant (SPG3A/atlastin, SPG6/NIPA1, SPG10/KIF5A, SPG30/KIF1A) and autosomal-recessive HSPs (SPG7/paraplegin, SPG11/spatacsin, SPG15/spastizin, SPG48/AP5Z1) [140,141,142], while demyelinating forms were only reported in autosomal-recessive SPG75 due to biallelic null MAG mutations [143]. Among these subtypes, extrapyramidal symptoms, including a dopa-responsive parkinsonism or dystonia, may occur in the context of multisystemic phenotypes, especially in cases with SPG7, SPG11, SPG15 [141, 144,145,146] as well as those with mutations in the kinesin genes, such as SPG10 and SPG30 [147, 148].

Conclusions

Movement disorders and peripheral neuropathy may coexist in several neurological disorders and both acquired and genetic causes should be accounted for. A careful neurological examination is necessary to identify multisystem pathology, as well the search for extra-neurological features, involving the skin, bones, heart and special senses, such as vision and hearing. Raising awareness of this potential relationship may help clinicians to unravel the final diagnosis and guide clinical management.