Galloway-Mowat syndrome (GAMOS) is a severe autosomal-recessive disease characterized by the combination of early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies. To date, mutations of WDR73 are the only known monogenic cause of GAMOS and in most affected individuals the molecular diagnosis remains elusive. We here identify recessive mutations of OSGEP, TP53RK, TPRKB, or LAGE3, encoding the 4 subunits of the KEOPS complex in 33 individuals of 30 families with GAMOS. CRISPR/Cas9 knockout in zebrafish and mice recapitulates the human phenotype of microcephaly and results in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibits cell proliferation, which human mutations fail to rescue, and knockdown of either gene activates DNA damage response signaling and induces apoptosis. OSGEP and TP53RK molecularly interact and co-localize with the actin-regulating ARP2/3 complex. Furthermore, knockdown of OSGEP and TP53RK induces defects of the actin cytoskeleton and reduces migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identify 4 novel monogenic causes of GAMOS, describe the first link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.
BackgroundInformation regarding the long-term outcome of enzyme replacement therapy (ERT) with recombinant human N-acetylgalactosamine 4-sulfatase (rhASB, galsulfase, Naglazyme®, BioMarin Pharmaceutical Inc.) for Taiwanese patients with mucopolysaccharidosis (MPS) VI is limited.MethodsNine Taiwanese patients with MPS VI (4 males and 5 females; age range, 1.4 to 21.1 years) treated with weekly intravenous infusions of galsulfase (1.0 mg/kg) in 5 medical centers in Taiwan were reviewed. A set of biochemical and clinical assessments were evaluated annually.ResultsAfter 6.2 to 11.2 years of galsulfase treatment, 6 patients experienced improvement over baseline in the 6-minute walk test by a mean of 150 m (59% change over time), and 3 patients also increased the 3-minute stair climb test by a mean of 60 steps (46%). In a manual dexterity test, 3 patients decreased the time required to pick up 10 coins and put the coins into a cup by 15 s (33%). Shoulder range of motion in all 9 patients improved, and Joint Pain and Stiffness Questionnaire scores improved by 0.42 points (21%). Four patients showed improved pulmonary function. Five patients had positive effects on cardiac-wall diameters. Four patients had improved cardiac diastolic function. Liver and spleen sizes as measured by abdominal ultrasonography remained the same or decreased in all 9 patients. However, the severity degree of valvular stenosis or regurgitation did not show improvement despite ERT. A mean overall 69% decrease in urinary glycosaminoglycan (GAG) excretion indicated a satisfactory biomarker response.ConclusionsLong-term ERT was beneficial and safe for Taiwanese patients with MPS VI. This treatment reduced urinary GAG and had positive effects on a wide range of clinical functional assessments including endurance, mobility, joint function, pulmonary function, liver and spleen size, cardiac hypertrophy and diastolic dysfunction.
Information regarding the clinical outcome of enzyme replacement therapy (ERT) with recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) for mucopolysaccharidosis (MPS) VI in Asian patients is limited. We reviewed nine Taiwanese patients with MPS VI (four males and five females; age range 1.4-21.1 years) treated with weekly intravenous infusions of rhASB (1.0 mg/kg) for at least 2 years. We assessed the biochemical and clinical response every 3 months. After 2 years of treatment, seven patients experienced improvement over baseline in the 6-min walk by a mean of 69.3 m (27.3%), and seven also increased the 3-min stair climb by a mean of 47 steps (35.7%). Shoulder range of motion in all patients improved, and Joint Pain and Stiffness Questionnaire scores improved by 0.597 points (30.5%). Four patients had improved pulmonary function [forced expiratory volume in 1 s increased by 0.130 L (26.3%) and forced vital capacity by 0.148 L (27.6%)]. The respiratory disturbance index decreased in the four patients who underwent polysomnography. A mean overall 51% decrease in urinary glycosaminoglycan excretion indicated a satisfactory biochemical response. ERT was well tolerated by all patients. This treatment is thus beneficial and appears to be safe for treatment of MPS VI in Taiwanese patients.
BackgroundMucopolysaccharidosis IVA (MPS IVA) is a rare lysosomal storage disorder caused by N-acetylgalactosamine-6-sulfatase deficiency, which catalyzes a step in the catabolism of glycosaminoglycans, keratan sulfate and chondroitin-6-sulfate. This disease has a variable age of onset and rate of progression.MethodsA retrospective analysis of medical records of 24 patients with MPS IVA (11 males, 13 females; current mean age ± SD, 12.6 ± 6.6 years; age range, 1.4-29.4 years) seen at 6 medical centers in Taiwan from January 1996 through June 2013 was performed.ResultsMean ages of onset of symptoms and confirmed diagnosis were 2.0 ± 1.6 and 5.7 ± 4.5 years, respectively. The most prevalent clinical manifestations were kyphosis (100%), pectus carinatum (96%), abnormal gait (93%), striking short trunk dwarfism (92%), genu valgum (92%), and valvular heart disease (91%). Eight patients (33%) experienced at least one surgical procedure with the most common being ear tube insertion (25%), adenoidectomy (17%), tonsillectomy (13%), supraglottoplasty (13%), spinal decompression (13%), and spinal fusion (13%). The most prevalent cardiac valve abnormalities were aortic stenosis (45%) and mitral regurgitation (45%). At the time of the study, 8 out of 24 patients (33%) have died at the mean age of 17.2 ± 7.7 years.ConclusionsAn understanding of the natural history involved in MPS IVA may allow early diagnosis of the disease. All affected Taiwanese patients experienced significant functional limitations. Adequate evaluations and timely management may improve clinical outcomes and quality of life.
Plasma lysoGb3 is a more sensitive and reliable biomarker than plasma Gb3. LysoGb3 also correlated with age and left ventricular mass index in Fabry patients with IVS4+919G>A mutation. Because lots of infants with the IVS4+919G>A mutation already had elevated lysoGb3 levels at birth, that indicates that the development of hypertrophic cardiomyopathy may require a long and insidious course after lysoGb3 accumulation.
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