Deterioration after Liver Transplantation and Transthyretin Stabilizer Administration in a Patient with ATTRv Amyloidosis with a Leu58Arg (p.Leu78Arg) TTR Variant.

We herein report a 44-year-old Japanese man with hereditary transthyretin amyloidosis (ATTRv amyloidosis) harboring the variant Leu58Arg (p.Leu78Arg) in TTR in whom we conducted an observational study with liver transplantation (LT) and transthyretin (TTR) stabilizers (tafamidis and diflunisal) for 9 years. This patient showed gradual deterioration of sensory, motor, and autonomic neuropathy symptoms after LT. Furthermore, cardiac amyloidosis gradually developed. Although the present case showed deterioration of the symptoms after disease-modifying treatments, LT might be suitable in patients with the same variant if they are young and in good condition due to a long survival after LT.

Accumulation of phosphorylated TDP-43 in the cytoplasm of Schwann cells in a case of sporadic amyotrophic lateral sclerosis.

We report for the first time the presence of phosphorylated transactivation response DNA-binding protein of 43 kDa (p-TDP-43)-immunoreactive cytoplasmic inclusions in Schwann cells in an autopsy case of sporadic amyotrophic lateral sclerosis (ALS). An 81-year-old woman with no family history of neuromuscular disorders noticed difficulty in handling chopsticks due to weakness of the hands. She then developed weakness of the lower and upper limbs and dyspnea. Neurological examination at the age of 83 years revealed disorientation, severe weakness of the facial muscles, tongue, neck and extremities, and fasciculations in the thighs. She exhibited hyperactive jaw jerk and lower limb deep tendon reflexes and normal upper limb deep tendon reflexes, and left extensor plantar response was observed. The patient was diagnosed as having sporadic ALS. An autopsy performed at the age of 84 years revealed widespread p-TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions in the cerebrum, brain stem, and spinal cord, in addition to some Bunina bodies. Moreover, a small number of p-TDP-43-immunoreactive inclusions were found in the facial or accoustic nerve (indistinguishable), spinal cord anterior roots, cauda equina, and peripheral nerves in the dorsal root ganglia. Immunohistochemical staining for p-TDP-43 revealed just a few p-TDP-43-immunoreactive inclusions surrounding axons in the cervical and lumbar anterior roots. Double immunofluorescence analysis revealed that these inclusions were co-localized with S-100 protein ß, suggesting that these inclusions were localized in the cytoplasm of Schwann cells. The peripheral nervous system including Schwann cells may be involved in TDP-43 pathology in ALS.

A novel mutation in the GBA2 gene in a Japanese patient with SPG46: A case report.

Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder characterized by pyramidal weakness and spasticity of the lower limbs. SPG46, one of autosomal recessive HSP, is clinically characterized by spasticity and pyramidal weakness of the lower limbs, mental retardation, congenital bilateral cataract, thin corpus callosum, and hypogonadism in males. Mutations in the nonlysosomal glucosylceramidase ß2 (GBA2) gene have been identified in patients with SPG46. A Japanese woman was identified with bilateral cataracts when she was in an elementary school. She felt falling easily, speaking unclearness, and difficulty in walking and raising her left leg in her 30s. Her neurological examination at the age of 44 revealed dysarthria, spasticity in the upper and lower extremities, increased jaw jerk and tendon reflexes in the extremities, bilateral extensor plantar reflexes, ataxia, and pollakiuria. Magnetic resonance imaging showed thinning of the corpus callosum body as well as atrophy in the pons and cerebellum. A novel homozygous c.1838A > G (p.D613G) missense mutation was detected at exon 12 in GBA2. We diagnosed her illness as an autosomal-recessive form of hereditary SPG46. The clinical features matched previously reported phenotype of SPG46. This is the first report of a Japanese patient with SPG46 with a novel mutation in GBA2. We presume that the novel GBA2 missense mutation found in our patient would cause loss of GBA2 activity, resulting in the neurological manifestations of SPG46.