Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: A case report and literature review.

Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, ß-glucocerebrosidase. Enzyme replacement therapy is ineffective for neuronopathic Gaucher disease (nGD). High-dose ambroxol has been administered as an alternative treatment for a group of patients with nGD. However, little is known about the clinical indication and the long-term outcome of patients after ambroxol therapy. We herein report a case of a female patient who presented with a progressive disease of GD type 2 from 11 months of age and had the pathogenic variants of p.L483P (formerly defined as p.L444P) and p.R502H (p.R463H) in GBA1. A combined treatment of imiglucerase with ambroxol started improving the patient's motor activity in 1 week, while it kept the long-lasting effect of preventing the deteriorating phenotype for 30 months. A literature review identified 40 patients with nGD, who had received high-dose ambroxol therapy. More than 65% of these patients favorably responded to the molecular chaperone therapy, irrespective of p.L483P homozygous, heterozygous or the other genotypes. These results highlight the long-lasting effect of ambroxol-based chaperone therapy for patients with an expanding spectrum of mutations in GBA1.

High-Titer Anti-ZSCAN1 Antibodies in a Toddler Clinically Diagnosed with Apparent Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Syndrome.

Severe obesity in young children prompts for a differential diagnosis that includes syndromic conditions. Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) syndrome is a potentially fatal disorder characterized by rapid-onset obesity associated with hypoventilation, neural crest tumors, and endocrine and behavioral abnormalities. The etiology of ROHHAD syndrome remains to be established, but recent research has been focusing on autoimmunity. We report on a 2-year-old girl with rapid-onset obesity during the first year of life who progressed to hypoventilation and encephalitis in less than four months since the start of accelerated weight gain. The patient had a high titer of anti-ZSCAN1 antibodies (348; reference range < 40), and the increased values did not decline after acute phase treatment. Other encephalitis-related antibodies, such as the anti-NDMA antibody, were not detected. The rapid progression from obesity onset to central hypoventilation with encephalitis warns about the severe consequences of early-onset ROHHAD syndrome. These data indicate that serial measurements of anti-ZSCAN1 antibodies might be useful for the diagnosis and estimation of disease severity. Further research is needed to determine whether it can predict the clinical course of ROHHAD syndrome and whether there is any difference in antibody production between patients with and without tumors.

Long-lasting pain and somatosensory disturbances in children with myelin oligodendrocyte glycoprotein antibody-associated disease.

Myelin oligodendrocyte glycoprotein antibody (MOG-Ab) is an autoantibody associated with acquired demyelinating syndrome (ADS) in childhood and adults. The pathogenic roles of MOG-Ab and long-term outcomes of children with MOG-Ab-associated disease (MOGAD) remain elusive. We investigated the clinical features of children with ADS during follow-up in our institute. Clinical data were retrospectively analyzed using medical charts of patients managed in Kyushu University Hospital from January 1st, 2001, to March 31st, 2022. Participants were children of < 18 years of age when they received a diagnosis of ADS in our hospital. Cell-based assays were used to detect MOG-Ab in serum or cerebrospinal fluid at the onset or recurrence of ADS. The clinical and neuroimaging data of MOG-Ab-positive and MOG-Ab-negative patients were statistically analyzed. Among 31 patients enrolled in this study, 22 (13 females, 59%) received tests for MOG antibodies. Thirteen cases (59%) were MOG-Ab-positive and were therefore defined as MOGAD; 9 (41%) were MOG-Ab-negative. There were no differences between MOGAD and MOG-Ab-negative patients in age at onset, sex, diagnostic subcategories, or duration of follow-up. MOGAD patients experienced headache and/or somatosensory symptoms more frequently than MOG-Ab-negative patients (12/13 (92%) vs. 3/9 (22%); p = 0.0066). Somatosensory problems included persistent pain with hyperesthesia in the left toe, perineal dysesthesia, and facial hypesthesia. No specific neuroimaging findings were associated with MOGAD or the presence of somatosensory symptoms. CONCLUSIONS: Long-lasting somatosensory disturbances are prominent comorbidities in children with MOGAD. Prospective cohorts are required to identify molecular and immunogenetic profiles associated with somatosensory problems in MOGAD. WHAT IS KNOWN: • Recurrence of demyelinating events occurs in a group of children with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). WHAT IS NEW: • Long-lasting headache and somatosensory problems are frequent comorbidities with pediatric MOGAD. Pain and somatosensory problems may persist for more than 5 years. • Neuroimaging data do not indicate specific findings in children with somatic disturbances.

The earliest enzyme replacement for infantile-onset Pompe disease in Japan.

BACKGROUND: Infantile-onset Pompe disease (IOPD) is the most severe phenotype of a lysosomal storage disorder caused by acid alpha-glucosidase (GAA) deficiency. An enzymatic newborn screening (NBS) program started regionally in Japan in 2013 for early enzyme replacement therapy (ERT). We report the ERT responses of the first NBS-identified Japanese IOPD case and of another case diagnosed prior to NBS, to discuss the problems of promptly starting ERT in Japan. METHODS: Acid alpha-glucosidase activity was measured by fluorometric assay in both patients. The diagnosis of IOPD was confirmed by next-generation followed by Sanger-method sequencing (patient 1) or direct sequencing of polymerase chain reaction (PCR)-amplified products (patient 2) of the GAA gene. RESULTS: A female infant identified by NBS had a novel out-of-frame (p.F181Dfs*6) variant and a reported pathogenic (p.R600C) variant, along with two pseudodeficiency variants. Enzyme replacement therapy was started at age 58 days when the infant had increased serum levels of creatine kinase and slight myocardial hypertrophy. Clinical and biochemical markers improved promptly. She has been alive and well without delayed development at age 14 months. Patient 2, a Japanese male, received a diagnosis of IOPD at age 5 months before the NBS era. He had a homozygotic variant of GAA (p.R608X), later registered as a cross-reactive immunological material (CRIM)-negative genotype, and developed a high titer of anti-rhGAA antibodies. The patient has survived myocardial hypertrophy with continuous respiratory support for 12 years of ERT. CONCLUSIONS: Enzyme replacement therapy should not be delayed over the age of 2 months for reversible cardiac function, although CRIM-negative cases may hamper turnaround time reduction.

Hepatocyte polarity establishment and apical lumen formation are organized by Par3, Cdc42, and aPKC in conjunction with Lgl.

Hepatocytes differ from columnar epithelial cells by their multipolar organization, which follows the initial formation of central lumen-sharing clusters of polarized cells as observed during liver development and regeneration. The molecular mechanism for hepatocyte polarity establishment, however, has been comparatively less studied than those for other epithelial cell types. Here, we show that the tight junction protein Par3 organizes hepatocyte polarization via cooperating with the small GTPase Cdc42 to target atypical protein kinase C (aPKC) to a cortical site near the center of cell-cell contacts. In 3D Matrigel culture of human hepatocytic HepG2 cells, which mimics a process of liver development and regeneration, depletion of Par3, Cdc42, or aPKC results in an impaired establishment of apicobasolateral polarity and a loss of subsequent apical lumen formation. The aPKC activity is also required for bile canalicular (apical) elongation in mouse primary hepatocytes. The lateral membrane-associated proteins Lgl1 and Lgl2, major substrates of aPKC, seem to be dispensable for hepatocyte polarity establishment because Lgl-depleted HepG2 cells are able to form a single apical lumen in 3D culture. On the other hand, Lgl depletion leads to lateral invasion of aPKC, and overexpression of Lgl1 or Lgl2 prevents apical lumen formation, indicating that they maintain proper lateral integrity. Thus, hepatocyte polarity establishment and apical lumen formation are organized by Par3, Cdc42, and aPKC; Par3 cooperates with Cdc42 to recruit aPKC, which plays a crucial role in apical membrane development and regulation of the lateral maintainer Lgl.

Physical growth and neurodevelopment during the first year of life: a cohort study of the Japan Environment and Children's Study.

BACKGROUND: The association between a slower physical growth and poorer neurodevelopment has been established in infants born preterm or small for gestational age. However, this association is inconsistent in term-born infants, and detailed investigations in infancy, when intervention is most beneficial for improving outcomes, are lacking. We therefore examined this association separately by sex during the first year of life in term-born infants. METHODS: Using data collected until children reached 12 months old in an ongoing prospective cohort of the Japan Environment and Children's Study, we analyzed 44,264 boys and 42,541 girls with singleton term-birth. The exposure variables were conditional variables that disentangle linear growth from weight gain relative to linear growth, calculated from the length and weight at birth and 4, 7 and 10 months old. Neurodevelopmental delay was identified using the Japanese-translated version of Ages & Stages Questionnaires, third edition. RESULTS: A reduced risk of neurodevelopmental delay at 6 months old was observed in children with a higher birth weight (adjusted relative risks [aRRs]: 0.91 and 0.93, 95 % confidence intervals [95 % CIs]: 0.87-0.96 and 0.88-0.98 in boys and girls, respectively) and increased linear growth between 0 and 4 months old (aRRs: 0.85 and 0.87, 95 % CIs: 0.82-0.88 and 0.83-0.91 in boys and girls, respectively). A reduced risk at 12 months was found in children with an increased linear growth between 0 and 4 months (aRRs: 0.92 and 0.90, 95 % CIs: 0.87-0.98 and 0.84-0.96 in boys and girls, respectively), boys with an increased relative weight gain between 0 and 4 months (aRR: 0.90, 95 % CI: 0.84-0.97), and girls with a higher birth weight (aRR: 0.89, 95 % CI: 0.83-0.96). CONCLUSIONS: These results suggest that a slow physical growth by four months old may be a predictor of neurodevelopmental delay during infancy.

Malignant transformation of phosphaturic mesenchymal tumor: a case report and literature review.

Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMT-MCT) causes tumor-induced osteomalacia (TIO). Most cases follow a benign clinical course, with rare occurrences of malignant transformation. We report a case of malignant PMT-MCT and review previous malignant cases to identify predictive factors for transformation. A 13-yr-old female, who presented with hypophosphatemic rickets, elevated serum intact fibroblast growth factor 23 (FGF23) levels, and a nodule in the back, received a diagnosis of TIO because of the benign PMT histopathology. After resection of the primary tumor, regular imaging analyses did not indicate any relapse. At 17 years of age, a tumor developed in the left leg and increased in size. The resected tumor showed a histopathology of pleomorphic sarcoma positive for the TP53 mutation. Despite amputation of the affected leg, the patient died due to multiple metastases at 18 years of age. A literature review revealed that 14 out of 15 reported malignant PMT-MCT tumors occurred in adults, and found no predictive factors for malignant transformation and treatment outcome. Changes in size or number of the tumors along with intact FGF23 levels have been considered as the only sign of malignant transformation. This pediatric case report and literature review indicate the need for prolonged regular monitoring for PMT-MCT.

The expanding phenotype of hypokalemic periodic paralysis in a Japanese family with p.Val876Glu mutation in CACNA1S.

BACKGROUND: Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disease characterized by the episodic weakness of skeletal muscles and hypokalemia. More than half patients with HypoPP carry mutations in CACNA1S, encoding alpha-1 subunit of calcium channel. Few reports have documented the non-neuromuscular phenotypes of HypoPP. METHODS: The proband is a Japanese woman who developed HypoPP at 6 years of age. An excessive insulin secretion with the oral glucose tolerance test rationalized that she had experienced frequent attacks of paralysis on high-carbohydrate diets. RESULTS: Voglibose and acetazolamide effectively controlled her paralytic episodes. Her 8-year-old son and 2-year-old daughter started showing the paralytic symptoms from 4 and 2 years of age, respectively. Laboratory tests revealed high concentrations of creatinine kinase in serum and elevated renin activities in plasma of these children. The targeted sequencing confirmed that these three patients had an identical heterozygous mutation (p.V876E) in CACNA1S. CONCLUSION: Our data indicate that the p.V876E mutation in CACNA1S contributes to the early onset of neuromuscular symptoms and unusual clinical phenotypes of HypoPP.

Metabolic and immunological assessment of small-for-gestational-age children during one-year treatment with growth hormone: the clinical impact of apolipoproteins.

Children born small for gestational age (SGA) are at a higher risk for metabolic disorders later in life. In this study, we aimed to characterize young SGA children without catch-up growth and evaluate the effects of GH treatment on endocrinological, metabolic, and immunological parameters. Study design is a one-year single hospital-based study included prospective observation of SGA patients during 12 months of GH treatment. Clinical and laboratory profiles of SGA children at baseline were compared with controls born appropriate size for age. Twenty-six SGA children (median age, 3.4 years) and 26 control children (median age, 3.8 years) were enrolled. Anthropometric, hematologic, biochemical, immunological, and endocrinological parameters were assessed at baseline and 1, 3, 6, 9, and 12 months after the start of GH treatment. As a result, median height SD score (SDS) of SGA children increased by +0.42 with 12-month GH treatment. Body mass index SDS was lower in SGA children than in controls. Serum apolipoprotein A1 increased, whereas apolipoprotein B decreased during GH treatment. Serum leptin and resistin levels, which were lower in SGA children than in controls at baseline, did not change remarkably with GH treatment. Monocyte counts, which were lower in SGA patients at baseline, increased after GH treatment. Neutrophil counts significantly increased after GH treatment. Natural killer cell ratios, which were higher in SGA patients, decreased after GH treatment. In conclusion, there was no evidence suggesting metabolic abnormalities in SGA children. Serum apolipoprotein changes might predict the beneficial role of GH treatment in lowering cardiometabolic risk.

Severe Hemolytic Anemia Following Intravenous Immunoglobulin in an Infant With Kawasaki Disease.

Severe hemolytic anemia (HA) is an uncommon adverse reaction of intravenous immunoglobulin (IVIg) administration. Previous reports assume that antibodies contained in IVIg preparations are the cause of hemolysis. We report a 10-month-old infant with Kawasaki disease who was treated with high-dose IVIg and developed severe HA. The patient's Rh blood type was D+C+c+E-e+. He developed anti-C and anti-e antibodies following treatment with IVIg, and, after considering all possible causes of hemolysis, we concluded that this was a case of autoimmune HA induced by immunoglobulin treatment. The hyperinflammatory condition associated with Kawasaki disease may have contributed to the severity of anemia.