Chorea-acanthocytosis with upper motor neuron degeneration and 3419_3420 delCA and 3970_3973 delAGTC VPS13A mutations

Abstract

Chorea-acanthocytosis (ChAc) is caused by loss of function mutations of VPS13A gene encoding the large disease protein named chorein [8, 10]. However, McLeod syndrome, Huntington’s disease-like 2, and pantothenate kinase-associated neurodegeneration also present with choreic movements and acanthocytosis. To our knowledge, only five autopsy cases of genetically proven ChAc have been reported [1, 6, 7, 9, 11]. Here, we report an autopsy case of ChAc with upper motor neuron degeneration and with novel VPS13A mutations. A Japanese man developed generalized tonic-clonic seizure at age of 35. At age of 37, he presented with postural instability due to lapse of knees, self-mutilation, orofacial dyskinesia with tongue-biting, involuntary vocalization, and pill-rolling tremor in the left hand. Blood smear showed that 30% of erythrocytes were acanthocytes after 5 min of incubation in normal saline (normal, less than 1%) [5]. Neurological examination showed that deep tendon reflexes in all limbs were absent. Brain CT and MRI revealed mild atrophy of the bilateral caudate nuclei. Genetic analysis revealed no expansion of CAG repeats in the genes of Huntington’s disease and dentatorubral-pallidoluysian atrophy. Expression of Kell antigen of erythrocytes was normal. At age of 42, he was bound to a wheelchair and gradually unable to move his left upper and lower extremities. At age of 47, congestive heart failure became apparent and he died suddenly. Postmortem examination revealed severe degeneration of the neostriatum (Fig. 1a, b). Moderate neuronal loss was found in the substantia nigra pars reticulata and mild in the spinal anterior horn. These findings were consistent with histopathological features of ChAc [12]. Furthermore, neuronal loss in the motor cortex with pyramidal tract degeneration, more severe on the right side, was evident (Fig. 1c–i). No Bunina bodies or TDP-43-positive inclusions were noted in the upper and lower motor neurons. Genetic analysis revealed two novel heterozygous mutations in exon 32 (c.3419_3420 delCA) and exon 35 (c.3970_3973 delAGTC) of the VPS13A gene (Fig. 2). Both mutations, which lead to premature stop codon further downstream resulting in truncated chorein, are considered to be pathogenic. Although epilepsy has been well recognized in patients with ChAc [2], the cortical degeneration in our case is not due to epilepsy, because of the absence of neuronal loss or gliosis in the medial temporal lobe. Moreover, no Bunina bodies or TDP-43-immunoreactive inclusions were noted in our case. Therefore, complication of neurodegenerative diseases causing bilateral pyramidal tract degeneration, such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration with motor neuron disease, appeared to be excluded. Although the inheritance of ChAc is widely known as autosomal recessive, single heterozygous VPS13A Y. Miki (&) F. Mori K. Wakabayashi Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan e-mail: yasuomiki@hotmail.com