Primary degeneration of oculomotor, motor, and somatosensory systems and auditory and visual pathways in spinocerebellar ataxia type 7: A clinicopathological study in a Japanese autopsy case.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia associated with retinal degeneration. The disease is rare in Japan, and this is the first full description of clinicopathological findings in a Japanese autopsy case of genetically confirmed SCA7 having 49 cytosine-adenine-guanine (CAG) trinucleotide repeats in the ataxin 7 gene. A 34-year-old Japanese man with no family history of clinically apparent neurodegenerative diseases presented with gait disturbance, gradually followed by truncal instability with progressive visual loss by the age of 42 years. He became wheelchair-dependent by 51 years old, neurologically exhibiting cerebellar ataxia, slow eye movement, slurred and scanning speech, lower limb spasticity, hyperreflexia, action-related slowly torsional dystonic movements in the trunk and limbs, diminished vibratory sensation in the lower limbs, auditory impairment, and macular degeneration. Brain magnetic resonance imaging revealed atrophy of the brainstem and cerebellum. He died of pneumonia at age 60 with a 26-year clinical duration of disease. Postmortem neuropathological examination revealed pronounced atrophy of the spinal cord, brainstem, cerebellum, external globus pallidus (GP), and subthalamic nucleus, microscopically showing neuronal cell loss and fibrillary astrogliosis with polyglutamine-immunoreactive neuronal nuclei and/or neuronal nuclear inclusions (NNIs). Degeneration was also accentuated in the oculomotor system, auditory and visual pathways, upper and lower motor neurons, and somatosensory system, including the spinal dorsal root ganglia. There was a weak negative correlation between the frequency of nuclear polyglutamine-positive neurons and the extent of neuronal cell loss. Clinicopathological features in the present case suggest that neurological symptoms, such as oculomotor, auditory, visual, and sensory impairments, are attributable to degeneration in their respective projection systems affected by SCA7 pathomechanisms and that dystonic movement is related to more significant degeneration in the external than internal GP.

[A case of anti-SRY-Related HMG-Box Gene 1 (SOX1) antibody-positive chorea].

A 77-year-old man with a history of lung cancer at the age of 71 developed involuntary right leg movement for a month. Neurological examination revealed a right-sided hemi-chorea. Autoimmune disease was suspected owing to the presence of oligoclonal bands and the elevated IgG-index in the cerebrospinal fluid. We detected anti-SRY-Related HMG-Box Gene 1 (SOX1) antibodies, known to be serological markers of Lambert-Eaton syndrome with small cell lung cancer, but not tumors. The results of tests for antiphospholipid, anti-LGI1, and anti-CASPR2 antibodies associated with non-paraneoplastic autoimmune chorea were all negative. This is the first suggestive case of autoimmune chorea in which anti-SOX1 antibodies were detected.

Primary Position Upbeat Nystagmus with Low Serum Vitamin B12.

A 38-year-old man presented with primary position upbeat nystagmus accompanied by peripheral neuropathy. The serum vitamin B12 level was low along with high plasma homocysteine level, indicating vitamin B12 deficiency. Cyanocobalamin supplementation showed partial clinical and electrophysiological improvement. Although brain magnetic resonance imaging did not show any abnormal intensity lesions, the electrophysiological findings suggested that a pontomedullary medial lesion was responsible for the upbeat nystagmus. To our knowledge, this is the first case of upbeat nystagmus with low serum vitamin B12. Physicians need to recognize the possibility of vitamin B12 deficiency as a cause of upbeat nystagmus.

Colostral and foal serum immunoglobulin G levels and associations with perinatal abnormalities in heavy draft horses in Japan.

The purpose of this study was to elucidate the colostral and foal serum immunoglobulin G (IgG) concentration values in heavy draft horses in Japan and to examine the effects of peripartum mare condition on colostral immunity. Colostrum was obtained 1 hr after foaling (pre-suckling; n=178). Blood was collected from the jugular vein of the foals (n=147) at 24 to 48 hr after birth. The foaling statuses of 73 mares were recorded. The average colostral IgG concentration was 10,540 ± 3,190 mg/dl (median=10,928; range 1,434-17,514 mg/dl). The average serum IgG concentration obtained from neonatal foals 24 to 48 hr after birth was 1,750 ± 919 mg/dl (median=1,890; range 0-3,510 mg/dl). Although colostral IgG did not differ between the normal foaling mare (n=59) and dystocial mare (n=14), foal serum IgG was lower in foals born in dystocia than in foals in normal foaling (P<0.05). This study demonstrates reference values for colostral and foal serum IgG specific to heavy draft horses in Japan and suggests that dystocia may interfere with the acquisition of colostral immunity in neonatal foals.

[Reversible Cerebral Vasoconstriction Syndrome (RCVS) Induced by a Chinese Herbal Medicine; Tokishigyakukagoshuyushokyoto].

A 52-year-old woman taking a Chinese herbal medicine for 10 months was admitted to our hospital for recurrent severe headaches, nausea and vomiting. Brain magnetic resonance imaging revealed convexity subarachnoid hemorrhage in the left occipital and parietal lobes. Brain magnetic resonance angiography (MRA) showed multifocal segmental stenosis of cerebral arteries. Clinical symptoms resolved after treatments with nicardipine and verapamil. Follow-up MRA at 31 days after the onset showed complete disappearance of multifocal stenosis of cerebral arteries, confirming the diagnosis of reversible cerebral vasoconstriction syndrome (RCVS). It was suggested that licorice and evodia fruit, which were components of a Chinese herbal medicine named tokishigyakukagoshuyushokyoto were the precipitating factors of vasoconstriction. It is important for physicians to recognize that herbal supplements could be one of the causes of RCVS. (Received January 22, 2019; Accepted April 3, 2019; Published July 1, 2019).

Novel pathogenic VPS13A gene mutations in Japanese patients with chorea-acanthocytosis.

OBJECTIVE: To identify mutations in vacuolar protein sorting 13A (VPS13A) for Japanese patients with suspected chorea-acanthocytosis (ChAc). METHODS: We performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis of the VPS13A gene, and chorein Western blotting of erythrocyte ghosts. As the results of the analysis, 17 patients were molecularly diagnosed with ChAc. In addition, we investigated the distribution of VPS13A gene mutations and clinical symptoms in a total of 39 molecularly diagnosed Japanese patients with ChAc, including 22 previously reported cases. RESULTS: We identified 11 novel pathogenic mutations, including 1 novel CNV. Excluding 5 patients with the unknown symptoms, 97.1% of patients displayed various neuropsychiatric symptoms or forms of cognitive dysfunction during the course of disease. The patients carrying the 2 major mutations representing over half of the mutations, exon 60-61 deletion and exon 37 c.4411C>T (R1471X), were localized in western Japan. CONCLUSIONS: We identified 13 different mutations in VPS13A, including 11 novel mutations, and verified the clinical manifestations in 39 Japanese patients with ChAc.

Thyrotoxicosis Presenting as Unilateral Drop Foot.

Neuromuscular disorders associated with hyperthyroidism have several variations in their clinical phenotype, such as ophthalmopathy, periodic paralysis, and thyrotoxic myopathy. We herein report an unusual case of thyrotoxic myopathy presenting as unilateral drop foot. Histopathological examinations of the left tibialis anterior muscle showed marked variation in the fiber size, mild inflammatory cell infiltration, and necrotic and regenerated muscle fibers with predominantly type 1 fiber atrophy. Medical treatment with propylthiouracil resulted in complete improvement of the left drop foot. This case expands the phenotype of thyrotoxicosis and suggests that thyrotoxicosis be considered as a possible cause of unilateral drop foot.

Humeral fracture in a Japanese Black calf repaired by closed approach and two methods of external skeletal fixation.

A healthy 71-day-old female Japanese Black calf was evaluated for fracture of the left humerus. The left humeral fracture was treated by closed repair and unilateral external skeletal fixation (ESF) with an epoxy putty fixator. The calf was active, and eight days after surgery slipped and fell, resulting in breakage of the ESF. The calf underwent repair by transfixation pinning and casting (TPC), which is an alternative to the ESF method. The TPC was removed 37 days after the first surgery, and the calf could bear weight on the left forelimb while walking. This case suggests that recovery after closed repair with TPC for a humeral fracture in an active calf can be successfully managed on the farm.

[A case of vascular parkinsonism associated with hyperhomocysteinemia and methylenetetrahydrofolate reductase gene variant (C677T)].

A 56-year-old man, who presented with 6 years history of difficulty in walking, was diagnosed as having vascular parkinsonism on the basis of the clinical findings of parkinsonism, pyramidal sign and the brain MRI findings of multiple lacunar infarction. Although he did not have hypertension, he had hyperhomocysteinemia and homozygous methylenetetrahydrofolate reductase (MTHFR) gene variant (C677T) as risk factors for ischemic stroke. Recent studies have shown that hyperhomocysteinemia and MTHFR gene variant are associated with small-vessel disease, suggesting that these risk factors may underlie vascular parkinsonism, particularly in patients lacking hypertension and in those with a relatively younger age at onset of this disease.

[Sporadic case of non-progressive neurogenic muscular atrophy localized in both calf muscles].

A 60-year-old woman was admitted to our hospital because of difficulty in standing on her toes. Neurological examination showed muscle weakness in both calf muscles. Her serum creatine kinase (CK) level was slightly elevated. MRI revealed hyper-intense signals localized in both the gastrocnemius and soleus muscles. Histological examinations of biopsied muscle specimens showed a marked variation in fiber size, small angular fibers, and hypertrophic and splitting fibers, but no muscle fiber necrosis or regeneration or inflammatory cell infiltration. ATPase stained sections showed small grouped atrophy of type 1 fibers. NADH-TR stained sections showed target/targetoid fibers predominantly in type 1 fibers. Dysferlin immunoreactivity was normal. Follow-up clinical evaluation for one year showed no progression. This patient was diagnosed as having an unknown type of spinal muscular atrophy or benign calf amyotrophy. Sporadic cases characterized by elderly-onset, neurogenic muscular atrophy localized in both calf muscles, and non-progressive course are extremely rare in Japan.

[Case of anti VGKC-complex antibody associated disorder presenting with severe pain and fasciculations predominant in unilateral upper extremity].

A 21-year-old man complained of severe pain and muscle twitching localized in his right arm. Neurological examination showed muscle fasciculations in his right forearm but no myokymia or myotonia. Needle electromyography revealed fibrillation potentials in his biceps brachii muscle and extensor carpi radialis muscle at rest but no myokymic discharges. His serum anti-voltage-gated potassium channel (VGKC)-complex antibody level was significantly high (194.2pM; controls <100pM). Although anticonvulsant therapy relieved his pain, he was readmitted to our hospital because of severe pain in his left arm and both thighs three months later. A high-dose intravenous immunoglobulin (IVIG) therapy followed by steroid pulse therapy relieved his pain. This case with neither muscle cramp nor myokymia expands the phenotype of anti VGKC-complex antibody associated disorder.

[A case of fasciitis localized in the calf muscles associated with Edwardsiella tarda sepsis].

A 49-year-old man presented with fever and pain, redness, swelling, and difficulty in walking. The serum C-reactive protein (CRP), creatin kinase (CK), and endotoxin levels were elevated. A blood culture revealed Edwardsiella tarda(E. tarda). Computed tomography (CT) showed subfascial and subcutaneous low-density areas in the lower legs, suggesting focal abscesses and edema. The patient was likely to have necrotizing fasciitis or cellulitis. He was successfully treated with several antibiotics and discharged after 43 days. Because E. tarda causes sepsis and fulminating necrotizing fasciitis with a high mortality rate in patients with an underlying illness, it should be considered a potentially important pathogen. The lack of an underlying illness may be a factor for a good outcome in this case.

Relationship between diarrhea and peripheral leukocyte population in neonatal Japanese black calves.

Neonatal Japanese Black (JB) calves show a high incidence of diarrhea. The objective of this study was to analyze the immune cell populations of neonatal JB calves in detail and examine its correlation with the incidence of diarrhea immediately after birth. Understanding the immune cell populations is helpful in clinics in order to determine the condition of the immune system for prevention of diseases. Blood samples were obtained from JB calves on the day of birth. The peripheral leukocyte populations were analyzed separately for calves that had diarrhea within 2 weeks after birth (diarrhea group; n = 26) and for calves without diarrhea (control group; n = 74). The numbers of the peripheral blood CD3(+)TcR1-N12(+) and CD8(+) T cells were significantly lower in the diarrhea group compared with the control group. These findings suggest that the congenital lower peripheral γδ and CD8(+) T cells results in a high risk of diarrhea in neonatal JB calves.

Whole genome characterization of new bovine rotavirus G21P[29] and G24P[33] strains provides evidence for interspecies transmission.

We have reported a novel bovine rotavirus, the AzuK-1 (G21P[29]) strain, isolated from an asymptomatic calf. We isolated another bovine rotavirus, the Dai-10 strain, bearing new G24P[33] genotypes, assigned by the Rotavirus Classification Working Group (RCWG), from an asymptomatic cow in Hyogo Prefecture, Japan in 2007. To gain an insight into the origins and evolution of these strains, we determined the complete ORF sequences of all 11 genes of the two strains. The NSP3 genes of both strains were confirmed to belong to a new NSP3 genotype, T9, by the RCWG. Genotype determination of AzuK-1 and Dai-10 strains revealed that eight gene segments of both strains possessed genotypes typically observed in bovine rotaviruses, with the exception of VP4, VP7 and NSP3 gene segments. Unexpectedly, phylogenetic analyses showed that VP6 and NSP2 gene segments of the AzuK-1 and Dai-10 strains were clustered with those of simian or canine/feline rotaviruses, rather than with those of bovine rotaviruses. These findings indicate the possibility that both strains originated by interspecies transmission and multiple reassortment events involving bovine, simian and canine/feline rotaviruses, resulting in the introduction of some genes into the genetic background of bovine rotaviruses.

Relationship between plasma vitamin C and serum diagnostic biochemical markers in lactating cows.

We investigated the relationship between plasma vitamin C concentration and serum levels of some diagnostic biochemical markers in 118 lactating Holstein cows. Blood sample was collected once from each cow and we measured the plasma vitamin C concentration and the serum levels of glucose, beta-hydroxybutyrate, free fatty acids, triacylglycerol, total cholesterol, albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase and gamma-glutamyltransferase. The regression of plasma vitamin C with each serum diagnostic biochemical marker indicated that the vitamin C concentration significantly decreased as glucose, alkaline phosphatase or aspartate aminotransferase level increased and as total cholesterol or albumin concentration decreased. Furthermore, the plasma vitamin C concentration was significantly lower in the cows showing that each of these marker levels was out of its reference interval than in the cows showing that the marker level was within its reference interval. The significant correlations were observed among total cholesterol, albumin, alkaline phosphatase and aspartate aminotransferase levels, to which the glucose concentration was not related. These results showed that the plasma vitamin C concentration was low in the cows that had concurrently low levels of total cholesterol and albumin, and high levels of alkaline phosphatase and aspartate aminotransferase. Therefore, a hepatic malfunction possibly decreases plasma vitamin C concentration through suppressing vitamin C production. On the other hand, the high level of glucose possibly decreases plasma vitamin C concentration through suppressing vitamin C recycling.

Serum free amino acid concentration in hepatic lipidosis of dairy cows in the periparturient period.

Blood samples were taken from eight multiparous cows at a dairy farm on eight occasions between the prepartum period and peak lactation to study the serum concentrations of amino acids and biochemical constituents. The cows were classified as having either severe hepatic lipidosis (HL) or non-hepatic lipidosis (non-HL) according to their clinical condition after calving and changes in serum biochemical parameters. The serum concentrations of beta-hydroxybutyric acid were higher in the HL group than in the non-HL group (ANOVA: p<0.01). The serum concentrations of methionine (Met), phenylalanine, and arginine were significantly different between the two groups (ANOVA: p<0.05). In particular, the Met levels were significantly low for 14 days after calving in the HL group (p<0.05), although Met levels in the HL group tended to be lower than the values in the non-HL group until 30 days after calving, starting 14 days before calving. The results suggest that an insufficiency of Met during the periparturient period is related to the development of hepatic lipidosis.

Plasma vitamin C concentration is not related to the incidence of ketosis in dairy cows during the early lactation period.

Many animals including cattle can synthesize vitamin C from glucose. The objective of this study was to investigate plasma vitamin C concentration in ketotic cows during the early lactation period because glucose supply for vitamin C synthesis might be limited in these cows. We measured plasma beta-hydroxybutyrate (BHBA) concentration in 118 cows within 2 months after parturition. Subclinical/clinical ketosis was quantitatively determined using a plasma BHBA threshold of 1,200 microM. Plasma glucose concentration was lower in the ketotic cows than in the control cows but plasma vitamin C concentration did not differ between the control and the ketotic cows. Then we measured plasma vitamin C, BHBA and glucose levels in 7 cows during the periparturient period. Plasma BHBA increased and plasma glucose decreased after parturition but plasma vitamin C did not change. These results indicate that plasma vitamin C is not related to the incidence of ketosis in the early lactation period. We suggest that ketotic cows have the ability to produce vitamin C to meet its requirement in the early lactation period although glucose supply is not sufficient for milk production. Vitamin C synthesis is possibly given a high metabolic-priority for glucose in lactating cows.

[Evaluation of neurosonography for a case of brainstem transient ischemic attack (TIA) due to proximal subclavian artery stenosis, with favorable outcome after axillo-axillary bypass grafting].

We report an 82-year-old man with crescendo brainstem TIA and left upper-limb ischemia due to the left proximal subclavian artery stenosis. Angiography revealed that the left proximal subclavian artery was stenotic. The right vertebral artery was considered to be aplastic or occlusive. Neurosonography, especially the echo-Doppler study of the left vertebral artery, showed that the subclavian artery steal phenomenon did not occur. This study has enabled us to opt for axillo-axillary bypass. We preferred to avoid percutaneous transluminal angioplasty in order to avoid the risk of embolization. The patient received the axillo-axillary bypass operation. He has been free of TIAs and the left upper-limb ischemia since the surgery. We have evaluated his blood circulation fully, by comparing his state before and after the axillo-axillary bypass grafting.

The relationship between changes in serum glycine and alanine concentrations in non-essential amino acid and milk production in the transition period in dairy cows.

The serum concentration of non-essential amino acid (NEAA) was measured in ten Holstein dairy cows grouped as low production (n=5) and high production (n=5) from one month pre-partum through four months post-partum and the relationship between production and amino acid concentrations was studied. The glycine (Gly)/NEAA ratio and the glycine/alanine ratio of the high production group were significantly higher than the low production group (p<0.01). The observed decrease of the alanine (Ala)/NEAA ratio was more remarkable in the high production group than in the low production group. Measurement of Gly/Ala ratio in serum may be useful for evaluating the nutritional status of peri-parturient dairy cow.