A Case of Genetically Confirmed Chorea-Acanthocytosis: Brain [18F]FDG-PET and [18F]FP-CIT-PET Findings.

Sir,

Chorea-acanthocytosis (ChAc, OMIM #200150), a rare autosomal recessively inherited disorder, has been known to be the most core form of neuroacanthocytosis syndrome.[1] Neurological symptoms comprise chorea, dystonia, parkinsonism, tics, seizure, cognitive impairment, and psychiatric illness, rendered by the central nervous system involvement. These symptoms are mostly presented in early adulthood. In addition, it can accompany the involvement of systemic organs, namely, the peripheral nerve, muscle, liver, and heart.[1] ChAc can be an important differential diagnosis of progressive heredodegenerative illness.

A 47-year-old man presented with progressive involuntary movements for 9 years. Initially, tongue protrusion and neck forward flexion occurred intermittently. Subsequently, he complained of sudden trunk lateroflexion while walking and lying down. He could not maintain his job because of the gradually worsening severity and frequency of these involuntary movements. Although he was administered various medications for symptomatic treatment, the involuntary movements were not well-controlled. He had no remarkable past medical history or family history. At the time of admission to our hospital, he could not perform daily living activities without assistance. He could not vocalize words appropriately. He continuously opened his mouth and only swallowed soft food materials without orolingual movement in the lying position. Upon motor examination, parkinsonian symptoms including decreased eye blinking, decreased facial expression, and bradykinesia were observed. Muscle wasting with weakness (4+/5) and decreased deep tendon reflexes were also observed on four limbs.

Complete blood count, liver function test, random blood sugar, renal function test, thyroid function test, antinuclear antibody, serum ferritin, serum ceruloplasmin, VDRL, HIV, chest X-ray radiography, and electrocardiography were normal. Peripheral blood smear examination showed 25% of acanthocytes [Figure 1] and the serum creatine kinase level (CK, 1382 U/L, normal range 39–308 U/L) was increased. Results of nerve conduction study and electromyography showed mainly peripheral neuropathy combined with myopathy. Brain magnetic resonance imaging (MRI) showed atrophy of bilateral putamen and caudate nuclei [Figure 2a]. The results of [18F] fludeoxyglucose (FDG)-positron emission tomography (PET), [18F] F-N-(3-fluoropropyl)-2β-carboxy methoxy-3β-(4-iodophenyl) nortropane (FP-CIT)-PET, and early perfusion image of [18F] FP-CIT-PET are described in Figure 2b-d.

Figure 1

Peripheral blood smear shows many acanthocytes characterized by their thorn-like protrusions (Wright stain, ×1,000)

Figure 2

Brain magnetic resonance imaging of the patient shows the decreased volume of bilateral caudate nuclei and putamen on T1 and T2 weighted image (a). Brain [18F]fludeoxyglucose-positron emission tomography (PET) of the patient shows hypometabolism of the caudate nuclei, putamen on both sides, and frontal cortex (arrows) (b). Early perfusion image of [18F]F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (FP-CIT)-PET showed mildly decreased blood flow at both caudate nuclei (c). Brain [18F]FP-CIT PET showed mildly decreased dopamine transporter binding at the bilateral caudate nuclei (arrows) (d)

Whole exome sequencing (WES) revealed pathogenic compound heterozygote variants in the VPS13A gene resulting in premature truncation. The allele c.4411C>T (p. Arg1471Ter, NM_033305.3) was found, which has been reported previously.[2] A novel deletion variant, c.7736_7739del (p. Arg2579AsnfsTer26), shared by the patient's mother, not listed in the LVOD (http://www.lovd.nl/VPS13A), was detected. Both variants were assessed as pathogenic according to the 2015 American College of Medical Genetics and Association for Molecular Pathology guideline and were confirmed by the Sanger sequence.

We could diagnose this patient as ChAc successfully by means of WES, which has been known to be a strong tool to differentiate the diagnosis among various neurologic disorders. A novel mutation of the other allele, c.7736_7739del (p. Arg2579AsnfsTer26), also results in premature truncation. This variant was also found in the patient's mother as a single heterozygote, which warrants the loss of function in the VPS13A gene and that the pathogenic variants of this patient are trans-compound heterozygous.

Lack of functional chorein is the molecular basis of ChAc. Chorein is expressed ubiquitously but is highly expressed in the brain, testis, kidney, and spleen. It has been reported that chorein is located in the terminal of neurites in rat PC12 cells and is involved in dopamine release and exocytosis of dense-core vesicles, which is associated with involuntary movements of the limbs.[3] Many explanations, including altered Lyn kinase activity, the composition of the junctional complexes involved in anchoring the membrane to the cytoskeleton, or decreased protein level of β-adducin, have been proposed in attempt to understand the dysmorphic features of the erythrocyte membrane regarding the acanthocytosis.[34] Chorein also participates in the regulation of diverse functions, including cytoskeletal architecture, exocytosis, and cell survival.[5]

The brain MRI appears generally similar to that of Huntington's disease [Figure 2a]. Recently, functional neuroimaging has been widely used, but the role of a differential diagnosis of ChAc has not been elucidated due to limited reports. The previous reports have shown that patients with chorea demonstrated progressive glucose hypometabolism in the striatum on [18F] FDG-PET.[6] Our case demonstrated marked hypometabolism at both putamen and caudate nuclei, which suggests the postsynaptic neuronal loss of the striatum in this patient. In addition, mild hypometabolism in the frontal lobe was also observed in this case, as in the previous report.[7] These findings represent functional connectivity of the frontostriatal circuit, which is usually involved in other neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

Only a few cases of ChAc with presynaptic dopamine neurons were evaluated. It seems that dopamine neuronal functions are related to the duration of symptoms, and a shift of clinical phenotypes from hyperkinetic syndrome to parkinsonism in ChAc after a disease course of more than 10 years.[8] One ChAc patient with 6 years of disease duration revealed normal presynaptic dopamine neuronal function on [18F] F-DOPA-PET.[9] The monozygotic twins with 4 years of disease course underwent [123 I]-β-CIT-SPECT and one of them showed asymmetricity in the striatum, but dopamine transporter (DAT) binding of the striatum was within normal limit.[10] The two patients, with a 20- and 17-year disease course, demonstrated decreased DAT binding using [123I]-FP-CIT-SPECT.[8] In this case, the patient suffered for 9 years and showed mildly decreased but relatively preservation of presynaptic dopamine neuron at striatum. Interestingly, perfusion images, acquired for the first 5 min after intravenous injection of [18F] FP-CIT, showed preserved blood flow at both the putamen and mildly decreased blood flow at both caudate nuclei. This perfusion/metabolism mismatch at striatum maybe associated with perfusion demand of relatively preserved presynaptic neurons.

In conclusion, functional images using PET suggest that the loss of postsynaptic neurons combined with relatively preserved presynaptic neurons. And degree of presynaptic neuronal loss may be associated with duration and severity of symptoms in patients with genetically confirmed ChAc. We expect that these findings could provide useful information on understanding the clinical features in patients with ChAc.

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