INTRODUCTION — Movement disorders are characterized by either reduced or slow (bradykinetic) or excessive (hyperkinetic) activity. Bradykinetic movement disorders frequently are accompanied by rigidity, postural instability, and loss of automatic associated movements. Diagnosis of the specific condition depends primarily upon careful observation of the clinical features [1].
Bradykinetic disorders are reviewed here. Many such disorders, mostly rare, exist and only four are discussed here:
●Parkinson disease (PD)
●Wilson disease
●Huntington disease (HD)
●Neurodegeneration with brain iron accumulation (NBIA)
Hyperkinetic disorders are discussed separately. (See "Hyperkinetic movement disorders in children".)
ANATOMY OF THE BASAL GANGLIA — A brief review of the anatomy of the basal ganglia is appropriate because this site is involved in many of the bradykinetic disorders. The basal ganglia regulate the initiation, scaling, and control of the amplitude and direction of movement. Movement disorders can result from biochemical or structural abnormalities in these structures.
The basal ganglia are a complex of deep nuclei that consist of the corpus striatum, globus pallidus, and substantia nigra. The corpus striatum, which includes the caudate nucleus and the putamen, receives input from the cerebral cortex and the thalamus and, in turn, projects to the globus pallidus.
The substantia nigra is divided into the dopamine-rich pars compacta and the less dense pars reticularis. The pars reticularis is similar histologically and chemically to the medial segment of the globus pallidus, and both project via the thalamus to the premotor and motor cortex. The substantia nigra pars compacta gives rise to the nigral-striatal pathway, which is the main dopaminergic tract.
The output of the basal ganglia projects by way of the thalamus to the cerebral cortex and then to the pyramidal system. Basal ganglia output is sometimes referred to as the extrapyramidal system, a term now less commonly used, because it was once thought to be in parallel with the pyramidal system. Integration of the basal ganglia with the cortex facilitates motor control.
PARKINSON DISEASE — Bradykinetic movement disorders are characterized by slowness of movement and consist predominantly of conditions with features of parkinsonism, of which Parkinson disease (PD) is the most prominent example (table 1). Other characteristic motor findings of PD include tremor at rest, rigidity, and gait disturbance. In addition, nonmotor symptoms are also increasingly recognized components of PD. These include olfactory deficit; behavioral, cognitive, and sleep deficits; and dysautonomia. (See "Clinical manifestations of Parkinson disease".)
PD typically presents in middle and late life. However, early-onset disease can occur before age 40 years, and a juvenile form presents before age 21 [2]. Dystonia (often involving the legs), levodopa-induced dyskinesia, and levodopa-related motor fluctuations (eg, "wearing off" and "on-off" responses several hours following a dose) are common in the young-onset and juvenile forms of PD [3]. (See "Hyperkinetic movement disorders in children", section on 'Dystonia'.)
Most cases of PD are sporadic, but genetic loci (PARK1 through PARK23) have been associated with autosomal-dominant or -recessive PD or parkinsonism [2]. The genetic causes of PD are discussed separately. (See "Epidemiology, pathogenesis, and genetics of Parkinson disease", section on 'Genetics'.)
The diagnosis of juvenile parkinsonism is based on clinical signs beginning before the age of 21 years, while young-onset parkinsonism refers to cases presenting between 21 and 40 years of age [3,4]. Patients have gradual onset of slowness of movement, tremors in the hands or legs (but not the head), rigidity of muscles, shuffling gait, and postural instability. Other signs include lack of facial expression (hypomimia), drooling, dysarthria, and dystonia (involuntary spasms and abnormal postures of hands and feet).
Levodopa is the most effective drug in the treatment of PD [5]. However, most patients develop abnormal involuntary movements (dyskinesia) and unpredictable fluctuations in motor functioning within three years of treatment. Patients with onset before age 40 years are most likely to be affected. As a result, particularly in young patients, therapy is often initiated with other drugs that will control the symptoms and delay the need for levodopa. They include anticholinergic drugs (eg, trihexyphenidyl, amantadine) and dopamine agonists (eg, pramipexole and ropinirole). (See "Initial pharmacologic treatment of Parkinson disease".)
Complications of levodopa are managed by adjusting the dose and frequency of administration. If these changes do not alleviate symptoms, surgical treatment, such as high-frequency stimulation of the subthalamic nucleus or globus pallidus, is considered.
WILSON DISEASE — Wilson disease is a treatable cause of juvenile parkinsonism, dystonia, tremor, and other movement disorders. This rare disorder has an estimated prevalence of 30 per million.
Wilson disease is an autosomal-recessive defect of cellular copper export. The major abnormality is reduced biliary excretion of copper that leads to its accumulation, initially in the liver and then in other tissues, particularly the brain. Tissue copper deposition causes a multitude of signs and symptoms that reflect hepatic, neurologic, hematologic, and renal impairment. The incorporation of copper into ceruloplasmin is also impaired.
Clinical aspects of Wilson disease are discussed in detail separately. (See "Wilson disease: Epidemiology and pathogenesis" and "Wilson disease: Diagnostic tests" and "Wilson disease: Treatment and prognosis".)
JUVENILE HUNTINGTON DISEASE — Huntington disease (HD) typically presents during the fourth and fifth decades of life; however, onset occurs during childhood or adolescence in approximately 5 to 7 percent of affected patients.
Genetics — The genetics and pathogenesis of HD are discussed in detail separately. (See "Huntington disease: Genetics and pathogenesis".)
Reviewed briefly, HD is transmitted as an autosomal-dominant trait with the affected gene being on the short arm of chromosome 4. Juvenile-onset disease shows a major transmitting parent effect, as approximately 80 percent of symptomatic patients inherit the mutant HD gene from their father [6]. The high number of cellular divisions that occur during spermatogenesis likely accounts for the pronounced paternal-repeat instability.
HD is one of a number of disorders that are associated with expansion of unstable trinucleotide (cytosine-adenine-guanine [CAG]) repeats that encode for polyglutamine tracts in the protein products. There is mounting evidence that fragments of the huntingtin protein containing expanded polyglutamine tracts may be neurotoxic. The greater the number of CAG repeats on expanded alleles, the earlier the age of onset and more severe the disease [7].
Demonstration of more than 36 CAG repeats in one of the alleles in the HD gene confirms the diagnosis of HD. Alleles with 27 to 35 CAG repeats are termed "intermediate alleles." An individual with an allele in this range is not at risk of developing symptoms of HD but may be at risk of having a child with an allele in the disease range. Juvenile forms are associated with alleles containing more than 60 to 70 repeats and, in some patients, more than 100 repeats.
The inverse relationship between age of onset and number of CAG repeats was confirmed in a Dutch cohort of 755 affected patients [8]. The correlation was stronger for paternal than maternal inheritance.
Clinical features — Patients with juvenile HD develop dystonia, ataxia, and seizures. Most of them have the akinetic-rigid parkinsonian syndrome termed the "Westphal variant." Only a minority have the classic feature of chorea seen in adults.
One retrospective study reported longitudinal data for 36 patients with juvenile HD and 197 with adult-onset HD [7]. The study examined presentation, progression, and survival for two subgroups of juvenile HD defined by CAG repeat length [7]. The high-expansion subgroup (n = 10; median CAG repeat length of 86) had a younger median age of symptom onset than the low-expansion subgroup (n = 26; median CAG repeat length of 61). Dystonia and parkinsonism were the main motor symptoms at onset in both subgroups. With disease progression, severe gait impairment, seizures, and developmental delay were more common in the high-expansion subgroup, while chorea developed only in the low-expansion subgroup. Overall, patients with juvenile HD had more rapidly progressive disease than those with adult-onset HD. Of 121 deceased patients (17 with juvenile and 104 with adult-onset HD), median survival from study enrollment was shorter in the juvenile HD cohort compared with the adult-onset HD cohort (hazard ratio 2.18, 95% CI 1.08-4.40).
Biochemical changes observed in the brains of adults with HD may explain the neurologic features. Glutamic acid decarboxylase activity is reduced, especially in the corpus striatum, substantia nigra, and other basal ganglia. By contrast, thyrotropin-releasing hormone, neurotensin, somatostatin, and neuropeptide Y are increased in the corpus striatum. The depletion of gamma-aminobutyric acid in the corpus striatum may result in disinhibition of the nigral-striatal pathway. Coupled with the accumulation of somatostatin, the net result may be the release of striatal dopamine, which results in chorea.
The pattern of brain abnormality depends upon the age of onset. The characteristic pathologic change in adults with HD is diffuse, marked atrophy of the neostriatum that may be worse in the caudate than in the putamen. The changes are more dramatic in early-onset HD. (See "Huntington disease: Genetics and pathogenesis", section on 'Neuropathology'.)
The reasons for the selective vulnerability of the medium spiny neurons in the striatum is not known, but some insight may be gained from the study of Rhes (Ras homolog enriched in striatum), a small guanine nucleotide-binding protein that is selectively localized to the striatum and to a much lesser extent in the cortex, but not in the cerebellum. Rhes binds physiologically to mutated huntingtin and leads to selective cytotoxicity. (See "Huntington disease: Genetics and pathogenesis", section on 'Rhes'.)
Management — No cure or disease-modifying treatment is currently available for HD [9]. Therapy is focused on symptom management and supportive care in order to optimize quality of life. (See "Huntington disease: Management".)
The impact of chorea in patients with HD should be carefully assessed to determine whether any specific treatment is necessary, since it may not be a debilitating or bothersome symptom, particularly in early stages. Pharmacologic treatment of chorea may worsen other aspects of HD, including parkinsonism, cognition, and mood. When chorea does become severe, padded reclining chairs and bed padding are recommended to reduce the risk of injury.
Tetrabenazine, a dopamine depleting agent that acts by inhibiting presynaptic vesicular monoamine transporter type 2 (VMAT2), can be useful for controlling chorea in patients with HD. Compared with the typical neuroleptics, one of the advantages of tetrabenazine is that it does not cause tardive dyskinesia. However, tetrabenazine treatment was associated with significantly more adverse events than placebo treatment in randomized trials. Dose-limiting symptoms with tetrabenazine included sedation, akathisia, parkinsonism, and depressed mood; these generally resolved with dose adjustments. Two other VMAT2 inhibitors approved by the US Food and Drug Administration (FDA) are deutetrabenazine (for chorea associated with HD and for tardive dyskinesia in adults) and valbenazine (for tardive dyskinesia in adults) [10]. Both have a longer duration of action and improved side effect profile compared with tetrabenazine. (See "Huntington disease: Management", section on 'Tetrabenazine' and "Huntington disease: Management", section on 'Deutetrabenazine'.)
For patients with HD who have moderately severe chorea that does not respond to nonpharmacologic intervention, we suggest initial treatment with tetrabenazine or deutetrabenazine rather than dopamine receptor blocking drugs (neuroleptics) [10,11]. For chorea that does not respond to VMAT2 inhibitors, additional treatment options include atypical and typical neuroleptics. Beyond these, alternatives include amantadine, levetiracetam, and topiramate. (See "Huntington disease: Management", section on 'Management of chorea'.)
Levodopa may provide symptomatic relief of the parkinsonian features of childhood HD.
Future directions — Many different potential therapies have shown some promise in animal models of HD, and some are being evaluated in early clinical trials [12-14]. (See "Huntington disease: Management", section on 'Investigational therapies'.)
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION — Neurodegeneration with brain iron accumulation (NBIA) is a rare progressive neurodegenerative syndrome that causes parkinsonism, dystonia, cognitive decline, and other neurologic deficits. NBIA is now considered a spectrum of phenotypically overlapping disorders, with several subtypes defined by differences at the molecular genetic level [15-19]. These subtypes are:
●Pantothenate kinase-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz disease, caused by mutations in the gene encoding pantothenate kinase 2 (PANK2) [20,21].
●Infantile neuroaxonal dystrophy (INAD), an autosomal-recessive disorder, caused by mutations in the phospholipase A2 group VI (PLA2G6) gene. (See "Neuropathies associated with hereditary disorders", section on 'Infantile neuroaxonal dystrophy'.)
●Mitochondrial membrane protein-associated neurodegeneration (MPAN), caused by homozygous or compound heterozygous genetic mutations in the chromosome 19 open reading frame 12 (C19orf12) gene [22-25].
●Beta-propeller protein-associated neurodegeneration (BPAN) [26,27], also known as static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) [16,28], caused by de novo mutations in the WD repeat domain 45 (WDR45) gene [27,29]. This disorder presents with global developmental delay in childhood followed by deterioration in early adulthood with progressive dystonia, parkinsonism, and cognitive decline [26]. Although WDR45 is located on Xp11.23 and undergoes inactivation, the clinical features of this form of NBIA do not follow a pattern typical of an X-linked disorder [27]. The phenotype of affected males was indistinguishable from that of females, with a striking uniformity of the clinical features and natural history of the disease in all 20 study participants (17 females and 3 males).
●Fatty acid hydroxylase-associated neurodegeneration (FAHN), a childhood-onset disorder characterized by gait impairment, spastic paraparesis, ataxia, and dystonia caused by mutations in the fatty acid 2-hydroxylase (FA2H) gene [30].
●Kufor-Rakeb syndrome, an autosomal-recessive condition caused by mutations in the ATPase cation transporting 13A2 (ATP13A2) gene [31-33].
●Neuroferritinopathy, an adult-onset autosomal-dominant basal ganglia disease characterized by variable symptoms that include parkinsonism, chorea, and dystonia [34]. The disorder is caused by mutations in the ferritin light chain (FTL) gene [35]. Serum ferritin levels are normal or low.
●Aceruloplasminemia, an adult-onset autosomal-recessive disorder caused by mutations in the ceruloplasmin gene and characterized by ceruloplasmin deficiency, diabetes, dementia, parkinsonism, chorea, and ataxia [36,37].
●Woodhouse-Sakati syndrome [38], a progressive extrapyramidal syndrome characterized by dystonia, dysarthria, cognitive decline, and endocrine abnormalities such as hypogonadism, alopecia, and diabetes mellitus. It follows an autosomal-recessive inheritance pattern and is caused by biallelic mutations in the DDB1 and CUL4 associated factor 17 (DCAF17) gene [39].
●NBIA of unknown cause.
Of these, the most common genetic types of NBIA, in descending order, are PKAN, INAD, MPAN, and BPAN [18,40]. The other genetic types of NBIA listed above appear to be rare. Nevertheless, idiopathic NBIA and the minor genetic forms account for approximately 38 percent of cases.
The following discussion will focus on NBIA of childhood onset, particularly PKAN. INAD is reviewed elsewhere. (See "Neuropathies associated with hereditary disorders", section on 'Infantile neuroaxonal dystrophy'.)
Clinical features — Children with NBIA have posture and gait abnormalities, bradykinesia, rigidity, and other parkinsonian features, including tremor. Affected patients may also have hyperkinetic movement disorders, such as dystonia and choreoathetosis, as well as progressive dysarthria, dementia, ataxia, spasticity, epilepsy, optic atrophy, and retinitis pigmentosa.
As noted above, many patients with NBIA have mutations in the PANK2 gene and are said to have PKAN [18,20,41,42]. PKAN is inherited in an autosomal-recessive pattern, but NBIA also occurs sporadically, and some phenotypically similar cases appear to be transmitted in an autosomal-dominant fashion.
The relationship between genotype and phenotype was evaluated in a study of 123 patients from 98 families with NBIA [42]. Two variants were distinguished:
●Classic disease with early onset (typically in the first decade of life) and rapid progression
●Atypical disease with later onset (usually in the second or third decade of life) and slow progression
All patients with classic disease and one-third of those with atypical disease had PANK2 mutations [42]. In this series, abnormalities in classic NBIA were noted with the following frequencies:
●Movement disorders including dystonia, dysarthria, rigidity, and choreoathetosis – 98 percent
●Retinopathy – 68 percent
●Cognitive decline – 29 percent
●Corticospinal tract involvement, including spasticity, hyperreflexia, and extensor toe signs – 25 percent
●Few patients had optic atrophy (3 percent) and none had seizures
Prominent speech-related and psychiatric symptoms were common in patients with atypical disease and PANK2 mutations [42]. By contrast, these symptoms were unusual in those with atypical disease without the mutations and in those with classic disease. Limited retrospective data suggest that action-induced dystonic opisthotonus (ie, extensor truncal dystonia) may be a common manifestation of NBIA in patients with PANK2 and PLA2G6 mutations [43].
Neuroimaging — All patients with PANK2 mutations, whether classic or atypical, had the characteristic radiologic sign known as "eye of the tiger" on brain magnetic resonance imaging (MRI), with a central focus of increased T2 signal intensity in the medial globus pallidus surrounded by a zone of decreased signal [42]. This sign was not seen in patients without PANK2 mutations. While considered a characteristic feature of PKAN, the "eye of the tiger" sign has also been reported in a minority of patients with neuroferritinopathy [15].
In addition to iron distribution within the globus pallidus and substantia nigra, other typical MRI features vary according to the type of NBIA [18,40,44]:
●PKAN: "Eye of the tiger" sign
●Infantile neuroaxonal dystrophy (INAD): Cerebellar atrophy; some cases lack iron deposition
●Mitochondrial membrane protein-associated neurodegeneration (MPAN): Cerebellar and cortical atrophy and T2-weighted hyperintense streaking between the globus pallidus interna and externa
●Beta-propeller protein-associated neurodegeneration (BPAN): T1-weighted signal hyperintensity with a central band of hypointensity within the substantia nigra
Diagnosis — The diagnosis of NBIA is based upon clinical features. The diagnosis of PKAN is suspected when an MRI scan shows a central focus of increased T2 signal intensity surrounded by a zone of decreased signal in the region of the globus pallidus ("eye of the tiger" sign) [15].
Genetic sequence analysis for PANK2 mutations is recommended by some experts to confirm the diagnosis in those with suspected NBIA and the "eye of the tiger" MRI sign [19]. Options include single gene testing, when clinical features point strongly a specific NBIA type, or screening by gene panel, which includes multiple genes known to be associated with NBIA [40].
Pathology — Increased iron uptake is confirmed by postmortem examination, which reveals the characteristic pigmentary degeneration of the basal ganglia, particularly the internal segment of the globus pallidus and the zona reticularis of the substantia nigra. The pigmentary changes result from marked iron accumulation in these areas [21].
The mechanism by which basal ganglia iron uptake is increased in NBIA is not well understood. Systemic and cerebrospinal fluid iron levels, as well as plasma ferritin, transferrin, and ceruloplasmin, are all normal [21]. Furthermore, disorders of systemic iron overload, such as hemochromatosis, are not associated with increased brain iron.
Marked neuroaxonal degeneration with the formation of ubiquitinated deposits and spheroids is another distinctive pathologic feature of PKAN [45]. These glycoprotein-containing axonal swellings have been attributed to abnormal lipid membrane peroxidation. It may result from chelation of ferrous iron caused by increased cysteine (demonstrated in one patient with NBIA), leading to the accelerated generation of free hydroxyl radicals in the presence of non-protein-bound iron.
Treatment — Treatment of NBIA, including iron chelation with deferoxamine and antioxidant therapy, is ineffective. A small randomized controlled trial of patients with PKAN found that treatment with the iron chelator deferiprone lowered iron content in the basal ganglia (measured by MRI) compared with placebo [46]. However, deferiprone treatment led to only a slight trend towards slowing disease progression, which did not reach statistical significance. A randomized trial of fosmetpantotenate, developed to reverse the biochemical defect in PKAN, found no clinical benefit [47]. Levodopa and anticholinergic drugs may provide modest relief of parkinsonian symptoms.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Huntington disease".)
SUMMARY
●Bradykinetic movement disorders frequently are accompanied by rigidity, postural instability, and loss of automatic associated movements. The basal ganglia are a complex of deep nuclei that consist of the corpus striatum, globus pallidus, and substantia nigra. These nuclei regulate the initiation, scaling, and control of the amplitude and direction of movement. Movement disorders can result from biochemical or structural abnormalities in these structures. (See 'Anatomy of the basal ganglia' above.)
●Bradykinetic movement disorders are characterized by slowness of movement and consist predominantly of conditions with features of parkinsonism, of which Parkinson disease (PD) is the most prominent example (table 1). Other characteristic motor findings of PD include tremor at rest, rigidity, and gait disturbance. Nonmotor symptoms include olfactory deficit; behavioral, cognitive, and sleep deficits; and dysautonomia. PD typically presents in middle and late life. However, early-onset disease can occur before age 40 years, and a juvenile form presents before age 20. (See 'Parkinson disease' above.)
●Wilson disease (hepatolenticular degeneration) is a treatable cause of juvenile parkinsonism, dystonia, tremor, and other movement disorders. Clinical aspects of Wilson disease are discussed in detail separately. (See "Wilson disease: Epidemiology and pathogenesis" and "Wilson disease: Diagnostic tests" and "Wilson disease: Treatment and prognosis".)
●Huntington disease (HD) typically presents during the fourth and fifth decades of life; however, onset occurs during childhood or adolescence in approximately 5 to 7 percent of affected patients. Patients with juvenile-onset HD develop dystonia, ataxia, and seizures. Most of them have the akinetic-rigid syndrome termed the "Westphal variant." Approximately one-fourth have the classic feature of chorea seen in adults. Children also have more rapidly progressive disease than adults. (See 'Juvenile Huntington disease' above.)
●Neurodegeneration with brain iron accumulation (NBIA) is a rare progressive neurodegenerative syndrome that causes parkinsonism, dystonia, cognitive decline, and other neurologic deficits. NBIA is now considered a spectrum of phenotypically overlapping disorders, with several subtypes defined by differences at the molecular genetic level, including the following (see 'Neurodegeneration with brain iron accumulation' above):
•Pantothenate kinase-associated neurodegeneration (PKAN)
•Infantile neuroaxonal dystrophy (INAD)
•Mitochondrial membrane protein-associated neurodegeneration (MPAN)
•Beta-propeller protein-associated neurodegeneration (BPAN)
•Fatty acid hydroxylase-associated neurodegeneration (FAHN)
•Kufor-Rakeb syndrome
•Neuroferritinopathy
•Aceruloplasminemia
•Woodhouse-Sakati syndrome
•NBIA of unknown cause