Spinal Muscular Atrophy Type I With False Negative in Newborn Screening: A Case Report.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by the deletion or mutation of the survival motor neuron 1 (SMN1) gene. The establishment of effective newborn screening (NBS) for SMA is important for early diagnosis so that treatment can be administered in the pre-symptomatic or early disease stages. Polymerase chain reaction (PCR)-based genetic testing with dried blood spots has been used in NBS to detect the homozygous deletion of exon 7 in SMN1, however, this methodology is not able to detect newborn infants with heterozygous deletions and/or point mutations in SMN1. We report the case of a male infant who was diagnosed with SMA despite the NBS being negative for all conditions including SMA. The patient presented with severe hypotonia and muscle weakness from around 14 days of age. SMA was suspected and sequence analysis of SMN1 and SMN2 was conducted using the multiplex ligation-dependent probe amplification (MLPA) method, which revealed compound heterozygous mutations of SMN1. The patient was diagnosed with SMA and started on modulating agents including gene therapy. His motor function improved slightly with treatment, however, his motor development remained prominently retarded by 5 months of age. This case highlights the importance of investigating SMA as a potential diagnosis even when the NBS result is negative.

Assessment of type I interferon signatures in undifferentiated inflammatory diseases: A Japanese multicenter experience.

Purpose: Upregulation of type I interferon (IFN) signaling has been increasingly detected in inflammatory diseases. Recently, upregulation of the IFN signature has been suggested as a potential biomarker of IFN-driven inflammatory diseases. Yet, it remains unclear to what extent type I IFN is involved in the pathogenesis of undifferentiated inflammatory diseases. This study aimed to quantify the type I IFN signature in clinically undiagnosed patients and assess clinical characteristics in those with a high IFN signature. Methods: The type I IFN signature was measured in patients' whole blood cells. Clinical and biological data were collected retrospectively, and an intensive genetic analysis was performed in undiagnosed patients with a high IFN signature. Results: A total of 117 samples from 94 patients with inflammatory diseases, including 37 undiagnosed cases, were analyzed. Increased IFN signaling was observed in 19 undiagnosed patients, with 10 exhibiting clinical features commonly found in type I interferonopathies. Skin manifestations, observed in eight patients, were macroscopically and histologically similar to those found in proteasome-associated autoinflammatory syndrome. Genetic analysis identified novel mutations in the PSMB8 gene of one patient, and rare variants of unknown significance in genes linked to type I IFN signaling in four patients. A JAK inhibitor effectively treated the patient with the PSMB8 mutations. Patients with clinically quiescent idiopathic pulmonary hemosiderosis and A20 haploinsufficiency showed enhanced IFN signaling. Conclusions: Half of the patients examined in this study, with undifferentiated inflammatory diseases, clinically quiescent A20 haploinsufficiency, or idiopathic pulmonary hemosiderosis, had an elevated type I IFN signature.

Sudden out-of-hospital cardiac arrest in pediatric patients in Kyushu area in Japan.

BACKGROUND: It is well-known that a neurologically favorable outcome of out-of-hospital cardiac arrest (OHCA) is associated with the presence of bystander-initiated cardiopulmonary resuscitation (bystander CPR) and use of an automated external defibrillator. However, little is known about the effect of the presence of pre-existing conditions, prior activity, and locations on the outcome of pediatric OHCA. METHODS: We analyzed the data from questionnaires about pediatric patients with OHCA aged from 3 days to 19 years in the Kyushu area in Japan between 2012 and 2016. RESULTS: A total of 594 OHCA cases were collected. The numbers of OHCA cases and the rate of 1 month survival with a favorable neurological outcome during sleeping, swimming / bathing, and exercise were 192 (1.0%), 83 (32.5%), and 44 (65.9%), respectively. When an OHCA occurred at school (n = 56), 88% of children / adolescents received bystander CPR, but when it occurred at home (n = 390), 15% received bystander CPR. Cardiovascular (n = 61), suicide (n = 61), and neurological / neuromuscular (n = 44) diseases were three major pre-existing conditions. The OHCA of cardiovascular disease was associated with exercise (24/61) and mainly occurred at school (22/61). The OHCA of neurological / neuromuscular disease was associated with swimming/bathing (15/44) and mainly occurred during bathing at home (12/44). Multivariate regression analysis showed that the presence of bystander CPR (P < 0.001) and occurrence of OHCA at school (P < 0.001) were independently predictive of a favorable outcome in pediatric OHCA. CONCLUSION: The outcome was different among pre-existing conditions, prior activity, and location of OHCA. These findings might be useful for preventing OHCA and improving the outcome of pediatric OHCA.

Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation.

OBJECTIVES: To collect clinical information and NOD2 mutation data on patients with Blau syndrome and to evaluate their prognosis. METHODS: Fifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians. RESULTS: The study population comprised 26 males and 24 females aged 0-61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment. CONCLUSIONS: In patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.

Infliximab versus intravenous immunoglobulin for refractory Kawasaki disease: a phase 3, randomized, open-label, active-controlled, parallel-group, multicenter trial.

We compared the efficacy and safety of infliximab with intravenous immunoglobulin (IVIG), a standard therapy, in a phase 3 trial (NCT01596335) for Japanese patients with Kawasaki disease (KD) showing persistent fever after initial IVIG. Patients with initial IVIG-refractory KD, aged 1-10 years, received a single dose of IV infliximab 5 mg/kg or IV polyethylene glycol-treated human immunoglobulin (VGIH) 2 g/kg on day 0. Primary outcome was defervescence rate within 48 h after the start of treatment. Safety was evaluated through day 56. Overall, 31 patients were randomized (infliximab, n = 16; VGIH, n = 15); 31.3% and 60.0% patients discontinued due to worsening KD. Defervescence rate within 48 h was greater with infliximab (76.7%) than VGIH (37.0%) (p = 0.023), and defervescence was achieved earlier with infliximab (p = 0.0072). Coronary artery lesions occurred in 1 (6.3%) and 3 (20.0%) patients receiving infliximab and VGIH, respectively, up to day 21. Adverse events occurred in 15 (93.8%) and 15 (100.0%) patients in the infliximab and VGIH groups, respectively. No serious adverse events in the infliximab group and one in the VGIH group were observed. Infliximab improved the defervescence rate within 48 h and time to defervescence versus standard therapy, and was well tolerated in patients with IVIG-refractory KD.

Association of cord blood chemokines and other biomarkers with neonatal complications following intrauterine inflammation.

BACKGROUND: Intrauterine inflammation has been associated with preterm birth and neonatal complications. Few reports have comprehensively investigated multiple cytokine profiles in cord blood and precisely identified surrogate markers for intrauterine inflammation. AIM: To identify the cytokines and surrogate markers associated with intrauterine inflammation and subsequent neonatal complications. PATIENTS AND METHODS: We analyzed cord blood samples from 135 patients admitted to the neonatal intensive care unit at Sasebo City General Hospital. We retrospectively determined the associations between the presence of neonatal complications and cord blood cytokines, prenatal factors, and laboratory data at birth. A total of 27 cytokines in the cord blood were measured using a bead-based array sandwich immunoassay. RESULTS: Both Th1 and Th2 cytokine levels were low, whereas the levels of growth factors and chemokines were high. In particular, chemokines IL-8, MCP-1, and MIP-1α were significantly higher in very premature neonates when compared with more mature neonates. In addition, some have been shown to be associated with multiple neonatal complications, including patent ductus arteriosus (PDA), respiratory distress syndrome (RDS), and chronic lung disease (CLD). Similarly, the levels of N-terminal pro-brain natriuretic peptide, nucleated RBC, and urinary ß2-microglobulin were associated with these complications and chemokine levels. CONCLUSIONS: Our results suggest the association of inflammatory chemokines IL-8, MCP-1, and MIP-1α with intrauterine inflammation, premature birth, and neonatal complications in these perinatal subjects. Furthermore, the association of the aforementioned biomarkers with PDA, RDS, and CLD may help establish early diagnostic measures to predict such neonatal complications following intrauterine inflammation.

A long-term follow-up of Japanese mother and her daughter with Blau syndrome: Effective treatment of anti-TNF inhibitors and useful diagnostic tool of joint ultrasound examination.

Blau syndrome (BS) is an autosomal dominant autoinflammatory disease associated with NOD2 gene mutations. It is characterized by arthritis, skin rash, and uveitis. Here, we report contrasting outcomes of a daughter and her mother with BS. Their long-term follow-up revealed the efficacy of anti-tumor necrosis factor inhibitor (TNF) with respect to BS. Joint findings of BS feature tenosynovitis over articular synovitis on ultrasonography. BS might be one of the differential diagnoses of juvenile idiopathic arthritis and rheumatoid arthritis.