A deleterious homozygous four-nucleotide deletion causing frameshift deletion in PANK2 gene (c.1426_1429delATGA, p.M476 fs) was identified in an 8 years old girl with dystonia, bone fracture, muscle rigidity, abnormal movement, lack of coordination and chorea.
In continuation with this observation, we analyzed a small cohort of 39 patients with HD phenocopy syndrome and detected the C9orf72 expansion in one female patient (2.6%) with two-year lasting mild generalized chorea and severe oro-bucco-lingual dyskinesia, who complained on forgetfullness (neuropsychological testing revealed dysexecutive syndrome with preserved episodic memory and recognition), unexplainable fears and increased appetite.
This is the first report of chorea in patients confirmed to have the FA genetic abnormality and broadens further the clinical phenotype associated with the FA genotype.
We excluded linkage to 11 regions containing genes associated with chorea and myokymia: 1) the Huntington disease gene on chromosome 4p; 2) the paroxysmal dystonic choreoathetosis gene at 2q34; 3) the dentatorubral-pallidoluysian atrophy gene at 12p13; 4) the choreoathetosis/spasticity disease locus on 1p that lies in a region containing a cluster of potassium (K+) channel genes; 5) the episodic ataxia type 1 (EA1) locus on 12p that contains the KCNA1 gene and two other voltage-gated K+ channel genes, KCNA5 and KCNA6; 6) the chorea-acanthocytosis locus on 9q21; 7) the Huntington-like syndrome on 20p; 8) the paroxysmal kinesigenic dyskinesia locus on 16p11.2-q11.2; 9) the benign hereditary chorea locus on 14q; 10) the SCA type 5 locus on chromosome 11; and 11) the chromosome 19 region that contains several ion channels and the CACNA1A gene, a brain-specific P/Q-type calcium channel gene associated with ataxia and hemiplegic migraine.
Expert commentary: Inhibitors of presynaptic vesicular monoamine transporter type 2 (VMAT2) that cause striatal dopamine depletion, such as tetrabenazine, deutetrabenazine, and valbenazine, are considered the treatment of choice in patients with chorea.
Oral deutetrabenazine (Austedo™), a reversible inhibitor of vesicular monoamine transporter type 2 (VMAT2) that is structurally related to tetrabenazine is approved for the treatment of chorea symptoms associated with Huntington's disease (HD).
Areas covered: Deutetrabenazine is the first deuterated drug and second drug after tetrabenazine, the classic vesicular monoamine transporter type 2 (VMAT2) inhibitor, to receive approval for the treatment of chorea associated with HD.
The recent development of selective vesicular monoamine transporter blocking agents has allowed for targeted chorea management with minimal side effects.
The field of movement disorders with neuronal antibodies keeps expanding with the discovery for example of antibodies against leucine rich glioma inactivated protein 1 (LGI1) and contactin associated protein 2 (Caspr2) in chorea, or antibodies targeting ARHGAP26- or Na/K ATPase alpha 3 subunit (ATP1A3) in cerebellar ataxia.
Clinical manifestations included faciobrachial dystonic seizures (FBDS) in 11 of 35 (31.4%) patients, all with LGI1 antibodies; a combination of gait instability, brainstem dysfunction, and sleep disorder associated with IgLON5 antibodies in 10 (28.6%); acute confusion, memory loss, and behavioral changes suggesting autoimmune encephalitis (AE) in 9 (25.7%; 2 patients with AMPAR, 2 with NMDAR, 2 with GABAbR, 2 with LGI1, and 1 with CASPR2 antibodies); and rapidly progressive cognitive deterioration in 5 (14.3%; 3 patients with IgLON5 antibodies, 1 with chorea; 1 with DPPX antibody-associated cerebellar ataxia and arm rigidity; and 1 with CASPR2 antibodies).
The field of movement disorders with neuronal antibodies keeps expanding with the discovery for example of antibodies against leucine rich glioma inactivated protein 1 (LGI1) and contactin associated protein 2 (Caspr2) in chorea, or antibodies targeting ARHGAP26- or Na/K ATPase alpha 3 subunit (ATP1A3) in cerebellar ataxia.
Clinical manifestations included faciobrachial dystonic seizures (FBDS) in 11 of 35 (31.4%) patients, all with LGI1 antibodies; a combination of gait instability, brainstem dysfunction, and sleep disorder associated with IgLON5 antibodies in 10 (28.6%); acute confusion, memory loss, and behavioral changes suggesting autoimmune encephalitis (AE) in 9 (25.7%; 2 patients with AMPAR, 2 with NMDAR, 2 with GABAbR, 2 with LGI1, and 1 with CASPR2 antibodies); and rapidly progressive cognitive deterioration in 5 (14.3%; 3 patients with IgLON5 antibodies, 1 with chorea; 1 with DPPX antibody-associated cerebellar ataxia and arm rigidity; and 1 with CASPR2 antibodies).
AOA1 is associated with oculomotor apraxia, severe sensorimotor neuropathy, choreiform movements, cognitive impairment, and cerebellar atrophy at an early age.
The mutually exclusive appearance of lightning-like myoclonic jerks triggered by action in SGCE mutation carriers and of continuous chorea of all limbs in TITF-1 mutation carriers phenotypically discriminated both genetic disorders.
We identified a homozygous mutation affecting the GAF-B domain of the 3',5'-cyclic nucleotide phosphodiesterase PDE2A gene (c.1439A>G; p.Asp480Gly) as the candidate novel genetic cause of chorea in the proband.
These include anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis which may present with orolingual facial dyskinesia and stereotyped movements, CRMP-5 IgG presenting with chorea, anti-Yo paraneoplastic cerebellar degeneration presenting with ataxia, anti-VGKC complex (Caspr2 antibodies) neuromyotonia, opsoclonus-myoclonus-ataxia syndrome, and muscle rigidity and episodic spasms (amphiphysin, glutamic acid decarboxylase, glycine receptor, GABA(A)-receptor associated protein antibodies) in stiff-person syndrome.
Considering that chorea in this patient might be due to the disruption of a gene at either of the 4p15.32 or 4q33 breakpoints, CLCN3 was considered as a candidate gene.
Four strains demonstrated RDS that was less pronounced than in most AT cells: one was from a patient with Nijmegen breakage syndrome, one was from a patient without ataxia but with choreiform movement disorder, telangiectasia, and elevated concentrations of alpha-fetoprotein in the blood, and two were from AT patients.