Complete nanopore repeat sequencing of SCA27B (GAA-FGF14 ataxia) in Japanese.

BACKGROUND: Although pure GAA expansion is considered pathogenic in SCA27B, non-GAA repeat motif is mostly mixed into longer repeat sequences. This study aimed to unravel the complete sequencing of FGF14 repeat expansion to elucidate its repeat motifs and pathogenicity. METHODS: We screened FGF14 repeat expansion in a Japanese cohort of 460 molecularly undiagnosed adult-onset cerebellar ataxia patients and 1022 controls, together with 92 non-Japanese controls, and performed nanopore sequencing of FGF14 repeat expansion. RESULTS: In the Japanese population, the GCA motif was predominantly observed as the non-GAA motif, whereas the GGA motif was frequently detected in non-Japanese controls. The 5'-common flanking variant was observed in all Japanese GAA repeat alleles within normal length, demonstrating its meiotic stability against repeat expansion. In both patients and controls, pure GAA repeat was up to 400 units in length, whereas non-pathogenic GAA-GCA repeat was larger, up to 900 units, but they evolved from different haplotypes, as rs534066520, located just upstream of the repeat sequence, completely discriminated them. Both (GAA)≥250 and (GAA)≥200 were enriched in patients, whereas (GAA-GCA)≥200 was similarly observed in patients and controls, suggesting the pathogenic threshold of (GAA)≥200 for cerebellar ataxia. We identified 14 patients with SCA27B (3.0%), but their single-nucleotide polymorphism genotype indicated different founder alleles between Japanese and Caucasians. The low prevalence of SCA27B in Japanese may be due to the lower allele frequency of (GAA)≥250 in the Japanese population than in Caucasians (0.15% vs 0.32%-1.26%). CONCLUSIONS: FGF14 repeat expansion has unique features of pathogenicity and allelic origin, as revealed by a single ethnic study.

Radial nerve palsy caused by a rapidly growing intramuscular hematoma in an infant with biliary atresia: a case report.

BACKGROUND: Biliary atresia (BA) is a rare cause of persistent jaundice in infants that can result in vitamin K malabsorption and vitamin K deficiency bleeding (VKDB). We present an infant with BA who developed a rapidly growing intramuscular hematoma in her upper arm after a vaccination which caused a radial nerve palsy. CASE PRESENTATION: An 82-day-old girl was referred to our hospital because of a rapidly growing left upper arm mass. She had received three doses of oral vitamin K before age 1 month. At age 66 days, she received a pneumococcal vaccination in her left upper arm. On presentation, she showed no left wrist or finger extension. Blood examination revealed direct hyperbilirubinemia, liver dysfunction, and coagulation abnormalities, indicating obstructive jaundice. Magnetic resonance imaging showed a hematoma in the left triceps brachii. Abdominal ultrasonography revealed an atrophic gallbladder and the triangular cord sign anterior to the portal vein bifurcation. BA was confirmed on cholangiography. VKDB resulting from BA in conjunction with vaccination in the left upper arm were considered the cause of the hematoma. The hematoma was considered the cause of her radial nerve palsy. Although she underwent Kasai hepatic portoenterostomy at age 82 days, the obstructive jaundice did not sufficiently improve. She then underwent living-related liver transplantation at age 8 months. The wrist drop was still present at age 1 year despite hematoma resolution. CONCLUSIONS: Delayed detection of BA and inadequate prevention of VKDB can result in permanent peripheral neuropathy.

Serum free carnitine levels in children with Kawasaki disease.

BACKGROUND: Carnitine plays an essential role in the transfer of long-chain fatty acids to the mitochondria for ß-oxidation. No study has characterized carnitine in children with Kawasaki disease (KD). The objective of this study was to elucidate the characteristics of serum free carnitine (FC) in hospitalized pediatric patients with KD. METHODS: We retrospectively analyzed 45 patients with KD in whom serum FC levels were measured. We investigated the clinical and laboratory parameters before intravenous immunoglobulin was administered, including serum FC levels, according to the response to intravenous immunoglobulin (IVIG). We also analyzed the relationship among serum FC, laboratory data, and clinical variables. RESULTS: IVIG was effective in 33 children (responders) and was ineffective in 12 children (non-responders). Serum FC levels were higher in non-responders than in responders: 35.3 µmol/L (range, 26.8-118.4 µmol/L) vs 31.4 µmol/L (range, 20.9-81.2 µmol/L), P <0.05. FC levels before IVIG in 80% of responders were below the normal range. The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and FC were higher in non-responders than in responders. FC levels were correlated with AST (R2 = 0.364, P = 0.0015) and ALT (R2 = 0.423, P < 0.001) levels. CONCLUSIONS: Free carnitine levels were elevated in some patients with KD, especially in those who were refractory to IVIG. Additionally, FC levels in children with KD correlated with ASL and ALT levels.

Usefulness of brain natriuretic peptide to distinguish Kawasaki disease from cervical lymphadenitis.

BACKGROUND: Cervical lymphadenitis (CL) cannot be easily distinguished from Kawasaki disease (KD). We therefore explored whether brain natriuretic peptide (BNP) levels are useful in this context. METHODS: We retrospectively analyzed 14 children with CL and 177 children with KD. Patients with KD were divided into three groups according to their clinical symptoms at hospitalization - 97 patients had typical KD, 35 had node-first KD (NFKD), and 45 had KD without lymphadenopathy. We reviewed data on clinical and laboratory parameters, including serum BNP levels, at hospitalization together with factors that might distinguish KD from CL. RESULTS: Patients with CL were older than those with KD. Serum BNP levels were higher in all the KD groups than in the CL group. Multivariate logistic regression analyses indicated that higher BNP levels were associated with NFKD (odds ratio: 1.12, 95% confidence interval: 1.01-1.25). The receiver operating characteristic curve yielded a BNP cutoff of 18.3 pg/mL, with a sensitivity of 0.680, a specificity of 0.857, and an area under the curve of 0.806 (95% confidence interval: 0.665-0.947). CONCLUSIONS: Serum BNP levels can be used to distinguish KD from CL, especially in patients with NFKD.

Risk factors for shoulder osteoarthritis with rotator cuff tear in the elderly general population.

HYPOTHESIS AND/OR BACKGROUND: The relationship between shoulder osteoarthritis (OA) and rotator cuff tear (RCT) is unclear. We hypothesized that there is a difference between the pathogenesis of OA complicating RCT and that of RCT complicating OA. In this study, our primary objective was to determine the prevalence of shoulder OA without RCT, RCT without OA, and OA with RCT in the general older population. Our secondary objective was to identify risk factors for the association with OA+RCT in shoulder OA alone or RCT alone, respectively. METHODS: We enrolled patients from the public health checkup conducted in Gunma prefecture (Japan) in 2014. Subjects' shoulder pain at rest, during motion, and at night was evaluated using a questionnaire. Moreover, active and passive range of motions (ROMs) in flexion, abduction, and external rotation were measured. For RCT parameters, we evaluated as no tear, partial-thickness supraspinatus (SSP) tear, full-thickness SSP tear, and SSP-infraspinatus tears. For further analysis, the shoulders were divided into three groups according to the presence of RCT and/or OA: OA, RCT, and OA + RCT groups. Risk factors for OA + RCT were identified in a logistic regression analysis. RESULTS: Overall, 944 of 1148 shoulders were eligible for inclusion. The prevalence rates of shoulder OA, RCT, and OA + RCT were 5.8%, 21.1%, and 4.2%, respectively. Furthermore, 650 shoulders were excluded, and 55, 199, and 40 shoulders had OA, RCT, and OA + RCT, respectively. There were significant differences for age, ROM of active external rotation, strength of abduction, external rotation, and morphology of the rotator tears. However, there were no significant differences for pain visual analog scale score, passive ROM, Simple Shoulder Test, and grades of OA. Older age decreased active ROM in external rotation, and the presence of both subscapularis and SSP-infraspinatus tears was a risk factor for the association of OA with an RCT shoulder. Older age, weaker power in external rotation, and affected dominant side were risk factors for the association of RCT with an OA shoulder. DISCUSSION AND/OR CONCLUSION: This study is the first to report risk factors by considering both shoulder OA and RCT in the general population. Our findings will be useful for the treatment and management of OA and RCT as well as for the prevention of these conditions in the older adults.

An autopsy report of a familial amyotrophic lateral sclerosis case carrying VCP Arg487His mutation with a unique TDP-43 proteinopathy.

We here report an autopsy case of familial amyotrophic lateral sclerosis (ALS) with p.Arg487His mutation in the valosin-containing protein (VCP) gene (VCP), in which upper motor neurons (UMNs) were predominantly involved. Moreover, our patient developed symptoms of frontotemporal dementia later in life and pathologically exhibited numerous phosphorylated transactivation response DNA-binding protein of 43 kDa (p-TDP-43)-positive neuronal cytoplasmic inclusions and short dystrophic neurites with a few lentiform neuronal intranuclear inclusions, sharing the features of frontotemporal lobar degeneration with TDP-43 pathology type A pattern. A review of previous reports of ALS with VCP mutations suggests that our case is unique in terms of its UMN-predominant lesion pattern and distribution of p-TDP-43 pathology. Thus, this case report effectively expands the clinical and pathological phenotype of ALS in patients with a VCP mutation.

"Burnt-out" progressive multifocal leukoencephalopathy in idiopathic CD4+ lymphocytopenia.

Progressive multifocal leukoencephalopathy (PML) is a fatal disease caused by John Cunningham virus (JCV) infection; however, a growing number of PML patients now survive longer and achieve remission, largely due to the advent of combination antiretroviral therapy. Several reports have suggested that the pathology in such patients presents only chronic demyelination without characteristic cellular changes, being referred to as "burnt-out" PML. On the other hand, our knowledge of "burnt-out" PML is still substantially limited, especially in patients with non-human immunodeficiency virus infection. Here, we report a case of PML associated with idiopathic CD4+ lymphocytopenia (ICL) who presented with spontaneous remission and survived for 11 years after onset. Notably, postmortem examination revealed surprisingly broad "burnt-out" lesions lacking the classic histopathological findings. However, pathogenic JCV-specific DNA sequences was still present in the autopsied brain tissue. This case suggests that complete remission can be achieved with a persistent presence of JCV-specific pathogenic sequences, even after a catastrophic infection. Considering that there have been a few reported cases of PML with ICL with long survival, the long-term survival of our case may share a favorable immunological response that is unique to a subgroup of ICL.

Neonatal intrahepatic cholestasis caused by citrin deficiency with no hepatic steatosis: a case report.

BACKGROUND: Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a common form of neonatal jaundice. Histopathological examination of the liver in patients with NICCD typically shows fatty liver, steatohepatitis, and liver fibrosis. Jaundice and fatty liver often improve by 1 year of age. We herein describe a girl who was diagnosed with NICCD based on an SLC25A13 mutation, although no fatty deposits were found on pathologic examination of the liver. CASE PRESENTATION: The patient in this case was a 3-month-old girl. At 2 months of age, she presented with jaundice, discolored stools, and poor weight gain and was found to have hyperbilirubinemia. Cholangiography revealed that she did not have biliary atresia. A laparoscopic liver biopsy was performed, and liver histopathology showed no fatty deposits. Genetic analysis revealed a compound heterozygous mutation in SLC25A13, and she was diagnosed with NICCD. She was given medium-chain triglyceride milk and gained weight. She resumed consumption of normal milk and breast milk, and her stool color improved. She was discharged at 4 months of age with adequate weight gain and a lower total bilirubin concentration. She was in good condition after discharge and showed normal development at the time of outpatient follow-up. CONCLUSIONS: We experienced a case of NICCD in a patient without fatty liver. This case illustrates that the absence of hepatic steatosis in neonatal cholestasis does not rule out NICCD.

A nationwide questionnaire survey on accidental magnet ingestion in children in Japan.

AIM: The aim is to investigate the actual situation of accidental ingestion of magnets in children in Japan and the clinical features of the resulting gastrointestinal damage. METHODS: We developed a questionnaire and sent it to 496 board-certified training hospitals nationwide. Information was collected on the number of children with accidental magnet intake from 2015 to 2017, witnesses of magnet intake, number and type of magnets, presence or absence of gastrointestinal injury, treatment, etc RESULTS: The number of cases of accidental ingestion of magnets within the study period was 104, with a median age of 2 years. About half of the incidents were unwitnessed. There were 33 cases of accidental ingestion of multiple magnets. Among them, oesophagogastroduodenoscopy was performed in 4 children and surgery in 10, and significantly invasive treatment was required in comparison with single-magnet ingestion. Gastrointestinal injury was observed in 11 cases, 10 of which were caused by multiple-magnet ingestion. All 10 of these patients underwent surgical treatment. There was no mortality. CONCLUSION: The incidence of accidental magnet ingestion in Japan is estimated to be 50-70 per year. Unwitnessed cases are not uncommon. Multiple magnet ingestion often causes gastrointestinal injury. Many cases of gastrointestinal injury are caused by ingestion of magnetic toys.

Pronation and palmar pinch improve the stability of the medial elbow joint space in high school baseball pitchers.

HYPOTHESIS: We aimed to investigate the contributions of grip, pronation, and pinch to stabilization of the medial elbow joint space; examine their relationship with muscle strength; and assess the effect of stabilization on the medial elbow joint space in baseball pitchers. METHODS: In this controlled laboratory study, we measured the medial elbow joint space using ultrasound during the following conditions: unloading; loading; and loading with grip, pronation, and pinch. To evaluate changes in the medial elbow joint space as a result of various conditions, 1-way repeated-measures analysis of variance and post hoc analysis for multiple comparisons were performed. To investigate whether strong or weak muscle strength improved the medial elbow joint space during the loaded condition, Pearson correlation analysis was performed. Finally, a post hoc power analysis was performed. RESULTS: We enrolled 121 pitchers. The medial elbow joint space in the loaded condition, loaded condition with full grip, and loaded condition with full pinch was significantly larger than that in the unloaded condition. The medial elbow joint space in the loaded condition with full grip, loaded condition with full pronation, and loaded condition with full palmar pinch was significantly smaller than that in the loaded condition. A post hoc power analysis showed that the power of the 1-way repeated-measures analysis of variance was 100%. The strengths of the full grip and palmar pinch were significantly correlated with a reduced gap distance of the medial elbow joint space (P < .001 for both). CONCLUSION: In high school baseball pitchers, pronation and palmar pinch contraction significantly improved the gap distance of the medial elbow joint space in the loaded condition and during grip contraction. Moreover, the grip and palmar pinch strengths were significantly correlated with stabilizing effects on the medial elbow joint space.

Middle-age-onset cerebellar ataxia caused by a homozygous TWNK variant: a case report.

BACKGROUND: The TWNK gene encodes the twinkle protein, which is a mitochondrial helicase for DNA replication. The dominant TWNK variants cause progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, while the recessive variants cause mitochondrial DNA depletion syndrome 7 and Perrault syndrome 5. Perrault syndrome is characterized by sensorineural hearing loss in both males and females and gonadal dysfunction in females. Patients with Perrault syndrome may present early-onset cerebellar ataxia, whereas middle-age-onset cerebellar ataxia caused by TWNK variants is rare. CASE PRESENTATION: A Japanese female born to consanguineous parents presented hearing loss at age 48, a staggering gait at age 53, and numbness in her distal extremities at age 57. Neurological examination revealed sensorineural hearing loss, cerebellar ataxia, decreased deep tendon reflexes, and sensory disturbance in the distal extremities. Laboratory tests showed no abnormal findings other than a moderate elevation of pyruvate concentration levels. Brain magnetic resonance imaging revealed mild cerebellar atrophy. Using exome sequencing, we identified a homozygous TWNK variant (NM_021830: c.1358G>A, p.R453Q). CONCLUSIONS: TWNK variants could cause middle-age-onset cerebellar ataxia. Screening for TWNK variants should be considered in cases of cerebellar ataxia associated with deafness and/or peripheral neuropathy, even if the onset is not early.

Serum Pepsinogen Values in Japanese Junior High School Students With Reference to Helicobacter Pylori Infection.

BACKGROUND: Distributions of serum pepsinogen (PG) values were assessed in Helicobacter pylori-infected and non-infected junior high school students (aged 12-15 years) in Japan. METHODS: All junior high school students (1,225 in total) in Sasayama city, who were basically healthy, were asked to provide urine and serum samples, which were used to measure urine and serum H. pylori antibodies using ELISA kits and PG values. The subjects, whose urine and serum antibodies were both positive, were considered H. pylori infected. RESULTS: Of the 187 subjects who provided urine and blood samples, 8 were infected, 4 had discrepant results, 4 had negative serum antibody titers no less than 3.0 U/ml, and 171 were non-infected. In the H. pylori non-infected subjects, the median PG I and PG II values and PG I to PG II ratio (PG I/II) were 40.8 ng/mL, 9.5 ng/mL, and 4.4, respectively, whereas in the infected subjects, these values were 55.4 ng/mL, 17.0 ng/mL, and 3.3, respectively (each P < 0.01). In the non-infected subjects, PG I and PG II were significantly higher in males than in females (P < 0.01). CONCLUSIONS: The PG I and PG II values were higher, and the PG I/II was lower in H. pylori infected students than in non-infected students. In H. pylori non-infected students, males showed higher PG I and PG II values than females. The distributions of PG values in junior high school students differed from those in adults.

Co-morbidity of progressive supranuclear palsy and amyotrophic lateral sclerosis: a clinical-pathological case report.

BACKGROUND: The coexistence of distinct neurodegenerative diseases in single cases has recently attracted greater attention. The phenotypic co-occurrence of progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) has been documented in several cases. That said, the clinicopathological comorbidity of these two diseases has not been demonstrated. CASE PRESENTATION: A 77-year-old man presented with gait disturbance for 2 years, consistent with PSP with progressive gait freezing. At 79 years old, he developed muscle weakness compatible with ALS. The disease duration was 5 years after the onset of PSP and 5 months after the onset of ALS. Neuropathological findings demonstrated the coexistence of PSP and ALS. Immunohistochemical examination confirmed 4-repeat tauopathy, including globose-type neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies as well as TAR DNA-binding protein 43 kDa pathology in association with upper and lower motor neuron degeneration. Immunoblotting showed hyperphosphorylated full-length 4-repeat tau bands (64 and 68 kDa) and C-terminal fragments (33 kDa), supporting the diagnosis of PSP and excluding other parkinsonian disorders, such as corticobasal degeneration. Genetic studies showed no abnormalities in genes currently known to be related to ALS or PSP. CONCLUSIONS: Our case demonstrates the clinicopathological comorbidity of PSP and ALS in a sporadic patient. The possibility of multiple proteinopathies should be considered when distinct symptoms develop during the disease course.

Rapidly decreasing prevalence of Helicobacter pylori among Japanese children and adolescents.

BACKGROUND: The secular trend in the prevalence of Helicobacter pylori (H. pylori) infection among children and adolescents in Japan has not been well documented. MATERIALS AND METHODS: We reviewed all relevant literature published between 1991 and 2017, focusing on the relationship between the prevalence of H. pylori infection and birth year. Our literature search covered all journal articles, conference proceedings and meeting abstracts that reported the prevalence of H. pylori infection in Japanese subjects under 20 years of age. RESULTS: We examined the prevalence of H. pylori infection according to birth year on the basis of data points, which comprised 20,269 subjects of 81 groups. Three-coefficient logistic regression analysis was performed to examine the trend in H. pylori prevalence. The prevalence was approximately 10% in the individuals born in 1985, but it decreased to 3% in the individuals born in 2011. The plot of H. pylori prevalence against birth year clearly indicated a birth-cohort effect: the earlier the birth year, the higher the prevalence. CONCLUSIONS: Our analysis revealed a rapidly decreasing prevalence of H. pylori infection among Japanese children and adolescents over the past three decades.

Gastric cancer in children and adolescents in Japan.

BACKGROUND: Very limited data are available on childhood gastric cancer. Using a retrospective survey and literature review, we assessed the clinical features of gastric cancer in children and adolescents. METHODS: We collected information on childhood gastric cancer from pediatricians of 518 hospitals that issue the title of "certified board pediatrician" approved by Japan Pediatric Society, using a questionnaire on background, diagnosis year, onset symptoms, tumor location, histology, nodular gastritis, Helicobacter pylori testing, treatment, and prognosis. Studies were collected using PubMed and the NPO Japan Medical Abstracts Society database. Data for childhood gastric cancer were abstracted from the Japanese Vital Statistics database. RESULTS: Of the 518 hospitals, 349 returned the questionnaire, which identified four patients. Literature review identified 77 cases of gastric cancer, and we analyzed data for 80 children <16 years old. Most patients were >10 years old, and there were no sex differences. Onset symptoms ranged from abdominal pain to non-localized. Sixteen of 44 children had a family history of cancer; 10 had a family history of gastric cancer. Histologically, approximately 80% had undifferentiated-type carcinoma. Prognosis was extremely poor, and two of three tested children were positive for H. pylori infection. Childhood gastric cancer death has been declining. CONCLUSIONS: Childhood gastric cancer is rare in Japan, and information on H. pylori in childhood gastric cancer patients is limited. Declining childhood gastric cancer rates may reflect the decreasing prevalence of infection but further study is necessary to clarify the relationship between H. pylori and gastric cancer.

Extranodal NK/T-cell lymphoma, nasal type, manifesting as rapidly progressive dementia without any mass or enhancing brain lesion.

Among the many potential etiologies for rapidly progressive dementia (RPD), primary central nervous system extranodal NK/T-cell lymphoma, nasal-type (ENKL) is a rare entity. We present the first reported case of autopsy-proven RPD due to ENKL without any mass or enhancing lesion of the brain. A 54-year-old immunocompetent man presented with RPD, myoclonus and ataxia. The mini-mental state examination (MMSE) score was 22/30. His brain MRI revealed progressive brain atrophy without gadolinium enhancement or mass lesion. Five months after the initial evaluation, cognitive impairment further worsened with an MMSE score of 3/30. At the advanced stage, lumbar MRI showed swollen cauda equina with gadolinium enhancement. The number of Epstein-Barr virus (EBV) DNA in cerebrospinal fluid had gradually increased. Twelve months after onset, the patient died of respiratory failure. Pathological findings revealed that lymphoma cells had diffusely invaded the meninges, parenchyma of the brain, spinal cord and cauda equina. Cells were positive for CD3, CD56 and EBV-encoded small RNAs and negative for CD20. No evidence of malignancy was identified in the visceral organs. This report indicates that ENKL should be recognized as one of the rare causes of RPD. Early testing for EBV-DNA in cerebrospinal fluid and imaging of cauda equina would be useful diagnostic tools.

Exome sequencing reveals a novel TTC19 mutation in an autosomal recessive spinocerebellar ataxia patient.

BACKGROUND: Spinocerebellar ataxias (SCAs) are heterogeneous diseases characterized by progressive cerebellar ataxia associated with dysarthria, oculomotor abnormalities, and mental impairment. To identify the causative gene, we performed exome sequencing on a Japanese patient clinically diagnosed with recessive SCA. METHOD: The patient is a 37-year-old Japanese woman with consanguineous parents. The head magnetic resonance imaging (MRI) showed cerebellar atrophy and T1 low/T2 high intensity at the bilateral inferior olives. Single-nucleotide polymorphism (SNP) genotyping and next-generation sequencing were performed, and the variants obtained were filtered and prioritized. RESULTS: After these manipulations, we identified a homozygous nonsense mutation of the TTC19 gene (p.Q277*). TTC19 has been reported to be a causative gene of a neurodegenerative disease in Italian and Portuguese families and to be involved in the pathogenesis of mitochondrial respiratory chain complex III (cIII) deficiency. This report is the first description of a TTC19 mutation in an Asian population. Clinical symptoms and neuroimaging are consistent with previous reports. The head MRI already showed abnormal features four years before her blood lactate and pyruvate levels were elevated. CONCLUSIONS: We should consider the genetic analysis of TTC19 when we observe such characteristic MRI abnormalities. Genes associated with mitochondrial function cause many types of SCAs; the mutation we identified should help to elucidate the pathology of these disorders.

Deep brain stimulation of the thalamic ventral lateral anterior nucleus for DYT6 dystonia.

BACKGROUND: A missense mutation of the THAP1 gene results in DYT6 primary dystonia. While deep brain stimulation (DBS) of the internal globus pallidus (GPi) is effective in treating primary dystonia, recent reports indicate that GPi DBS is only mildly effective for DYT6 dystonia. OBJECTIVE: To describe a patient with DYT6 dystonia who underwent thalamic ventral lateral anterior (VLa) nucleus DBS. PATIENT: A 35-year-old Japanese man had been experiencing upper limb dystonia and spasmodic dysphonia since the age of 15. His dystonic symptoms progressed to generalized dystonia. He was diagnosed as having DYT6 dystonia with mutations in the THAP1 gene. Because his dystonic symptoms were refractory to pharmacotherapy and pallidal DBS, he underwent thalamic VLa DBS. RESULTS: Continuous bilateral VLa stimulation with optimal parameter settings ameliorated the patient's dystonic symptoms. At the 2-year follow-up, his Burke-Fahn-Marsden Dystonia Rating Scale total score decreased from 71 to 11, an improvement of more than 80%. CONCLUSIONS: The thalamic VLa nucleus could serve as an alternative target in DBS therapy for DYT6 dystonia.