Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias

Abstract

Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements. Two main categories of PMDs are recognized based on the phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs). From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are known. Recognition and diagnosis of PMDs is based on personal and familial medical history, physical examination, detailed reconstruction of ictal phenomenology, neuroimaging, and genetic analysis. Neurophysiological or laboratory tests are reserved for selected cases. Genetic knowledge of PMDs has been largely incremented by the advent of next generation sequencing (NGS) methodologies. The wide number of genes involved in the pathogenesis of PMDs reflects a high complexity of molecular bases of neurotransmission in cerebellar and basal ganglia circuits. In consideration of the broad genetic and phenotypic heterogeneity, a NGS approach by targeted panel for movement disorders, clinical or whole exome sequencing should be preferred, whenever possible, to a single gene approach, in order to increase diagnostic rate. This review is focused on clinical and genetic features of PMDs with the aim to (1) help clinicians to recognize, diagnose and treat patients with PMDs as well as to (2) provide an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders.

Keywords: acetazolamide; ataxia; basal ganglia; cerebellum; dyskinesia; epilepsy; functional movement disorders; hyperkinetic movement disorders; therapy; whole exome sequencing.

Figure 1

Onset of different paroxysmal movement disorders (PMDs) according with age. BNSM: benign neonatal sleep myoclonus; BMEI: benign myoclonus of early infancy; BPTI: Benign paroxysmal torticollis of infancy; PEM: Paroxysmal eye movements; PED: Paroxysmal exercise-induced dyskinesia; PKD: Paroxysmal kynesigenic dyskinesia; PNKD: Paroxysmal non-kynesigenic dyskinesia.

Figure 2

Schematic representation of synaptic neurotransmission mechanisms affected in PMDs in basal ganglia circuits. For simplicity, two hypothetical striatal synapses are shown: The synapse between a cholinergic interneuron and a medium spiny neuron (top), and the synapse between a dopaminergic neuron from the substantia nigra pars compacta and a striatal medium spiny neuron (bottom). Both these types of synapses are critical for control of volitional movements in humans. Red rectangles indicate genes involved in PMDs. Calcium channels are depicted in red, sodium channels in grey, potassium channels in blue. PMD: Paroxysmal movement disorders, GTPCH: GTP cyclohydrolase I, PTS: 6-Pyruvoyl Tetrahydrobiopterin Synthase, SR: sepiapterin reductase, BH4: Tetrahydrobiopterin; PCBD: pterin-4α-carbinolamine, PCD: pterin-4α-carbinolamine dehydratase, qBH2: quinonoid dihydrobiopterin; DHPR2: dihydropteridine reductase; TH: Tyrosine Hydroxylase; AADC: Aromatic l-amino acid decarboxylase, B6: pyridoxal phosphate (active form of vitamin B6); VMAT2: Vesicular monoamine transporter 2 (encoded by the SLC18A2 gene), (c)AMP: (cyclic) adenosine monophosphate. DR1: dopamine receptor type 1; Dopamine receptor type 2.

Figure 3

Schematic representation of synaptic neurotransmission mechanisms affected in PMDs in cerebellar circuits. For simplicity, two hypothetical synapses are shown: The GABAergic synapse between a Purkinje cell and a neuron of deep cerebellar nuclei (top), and the synapse between a glutamatergic cerebellar afferent (mossy fiber) and a neuron of deep cerebellar nuclei (bottom). Both these types of synapses are critical for cerebellar integration and coordination of movements. Red rectangles indicate genes involved in PMDs. Calcium channels are depicted in red, sodium channels in grey, potassium channels in blue.

Figure 4

Molecular mechanisms causing brain energy failure and mitochondrial dysfunction in PMDs. Red rectangles indicate genes involved in PMDs. Expression and function of GLUT-1 on membrane surface of endothelial cells of the brain vasculature is illustrated on the top. Mitochondrial energy production and BCAA (leucine, isoleucine, and valine) catabolism are illustrated on the bottom. PDHC converts pyruvate into acetyl-CoA, regulating its entry into the tricarboxylic acid (TCA) cycle and the activity of the oxidative phosphorylation. PDHC deficiency decreases the availability of acetyl-CoA for the TCA cycle promoting the reduction of pyruvate to lactate, determining intracellular energy failure and impaired redox state. Metabolic defects in BCAA metabolism cause the production of toxic compounds, that alter mitochondrial function. In addition, in the central nervous system transamination of BCAA is a source of glutamate, that can be use as neurotransmitter or for further production of GABA. In ECSH1 and HIBCH deficiencies, the accumulation of methacrylyl-CoA and acryloyl-CoA and their sulphurated conjugates probably leads to secondary decreased activity of PDHC and mitochondrial respiratory chain complexes. In BCKD complex deficiency, the elevated leucine levels alter water homeostasis causing cerebral edema and dysmyelination and displace other essential amino acids impairing neurotransmission. In addition, α-ketoisocaproic acid (not shown), an intermediate in leucine metabolism, has toxic effects in the central nervous system. ‡ Acryloyl cysteine, Acryloyl N-acetylcysteine, Acryloyl cysteamine, Methacryl-cysteamine, Methacryl-l-cysteine, N-acetyl-acryloyl-cysteine. † The increase of 3-hydroxy-isobutyryl-carnitine distinguishes HIBCH from ECSH1 deficiency. ¹ Detectable in plasma. ² Detectable in urines A-KG: α-ketoglutarate; BCAA: branched-chain amino acids BCKA: branched-chain ketoacids; BCHA: branched chain hydroxyacids. BCAT: branched-chain amino acid aminotransferases; BCKDC: branched-chain α-keto acid dehydrogenase enzyme complex; IBD: Isobutyryl-CoA dehydrogenase; ECSH1: short-chain enoyl-CoA hydratase; HIBCH: 3-Hydroxyisobutyryl-CoA hydrolase; 3-HBDH: 3-Hydroxyisobutyrate-CoA dehydrogenase; MMSDH: Methylmalonic semialdehyde dehydrogenase. PDHC: Pyruvate dehydrogenase complex.

Figure 5

Operative flowchart for pediatric-onset PMDs. DPMDs: developmental PMDs; EAs episodic ataxias; FMDs: functional movement disorders; LTM: long term EEG monitoring; PxDx paroxysmal dyskinesias; vEEG: video electroencephalogram; WES: whole exome sequencing; WGS: whole genome sequencing. * Please refer to Table 3 for specific diagnostic algorithm for DPMs.