A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis.

Background: Heterozygous variants of sequestosome-1 gene (SQSTM1) have been reported in patients with various neurological disorders, whereas biallelic pathogenic variants of SQSTM1 can cause child-onset and multisystem neurodegeneration, including cerebellar ataxia, dystonia, and vertical gaze palsy (NADGP). Here, we describe two cases of NADGP in a Japanese family.

Methods: We performed clinical and genetic laboratory evaluations of the two patients and their healthy parents.

Genetic counselling for at-risk family members with hereditary transthyretin amyloidosis: data from a single-centre study.

Background: Hereditary transthyretin-related amyloidosis is an autosomal dominant disorder. Recently, disease-modifying therapies (DMTs) have been developed. For at-risk individuals, genetic analysis aids in the early administration of medical care; however, few studies have evaluated the current status of genetic counselling and management of presymptomatic carriers of amyloidogenic variants.

Functional analysis of pathogenic variants with a Noonan-like phenotype.

RRAS2, a member of the R-Ras subfamily of Ras-like low-molecular-weight GTPases, is considered to regulate cell proliferation and differentiation via the RAS/MAPK signaling pathway. Seven pathogenic variants have been reported in patients with Noonan syndrome; however, few functional analyses have been conducted. Herein, we report two patients who presented with a Noonan-like phenotype with recurrent and novel pathogenic variants (p.

Cause, severity, and efficacy of treatment for hearing loss in children with Trisomy 18: A single institution-based retrospective study.

Trisomy 18 is a common chromosomal aberration syndrome, characterized by variable clinical manifestations, including cardiovascular, pulmonary, genitourinary, and musculoskeletal findings, leading to a shorter survival and severe developmental delay in survivors. However, recently, intensive therapeutic intervention has allowed for prolonging survival. In terms of otological complications, only a limited number of relevant reports have been published.

Lysinuric protein intolerance exhibiting renal tubular acidosis/Fanconi syndrome in a Japanese woman.

Lysinuric protein intolerance (LPI), caused by pathogenic variants of is characterized by protein aversion, failure to thrive, hyperammonemia, and hepatomegaly. Recent studies have reported that LPI can cause multiple organ dysfunctions, including kidney disease, autoimmune deficiency, pulmonary alveolar proteinosis, and osteoporosis. We report the case of a 47-year-old Japanese woman who was initially diagnosed with renal tubular acidosis (RTA), Fanconi syndrome, and rickets.

A MinION-based Long-Read Sequencing Application With One-Step PCR for the Genetic Diagnosis of 21-Hydroxylase Deficiency.

Context: Recently developed long-read sequencing (LRS) technology has been considered an option for CYP21A2 analysis. However, the clinical use of LRS for CYP21A2 analysis is limited.

Objective: This study's objective is to develop an efficient and low-cost LRS system for CYP21A2 screening.

Clinical features and morphology of collagen fibrils in patients with vascular Ehlers-Danlos based on electron microscopy.

Vascular-type Ehlers-Danlos syndrome (vEDS) is caused by collagen III deficit resulting from heterogeneous mutations in , which occasionally causes sudden death due to arterial/visceral rupture. However, it is difficult to conduct basic research on the pathophysiology of vEDS. Moreover, the number of patients with vEDS is small, limiting the number of available samples.

Otological Features of Patients with Musculocontractural Ehlers-Danlos Syndrome Caused by Pathogenic Variants in (mcEDS-).

Musculocontractural Ehlers-Danlos syndrome (EDS) caused by pathogenic variants in (mcEDS-) is a subtype of EDS characterized by multisystem malformations and progressive fragility-related manifestations. A recent international collaborative study showed that 55% of mcEDS- patients had hearing loss (HL), more commonly of the high-frequency type. Here, we report the first systemic investigation of the otological features of patients with this disorder based on the world's largest cohort at Shinshu University Hospital.

Spinal Deformity in Ehlers-Danlos Syndrome: Focus on Musculocontractural Type.

Spinal deformity in Ehlers-Danlos syndrome (EDS) is an important symptom that can lead to trunk balance deterioration, respiratory dysfunction, and digestive disorders as the deformity progresses, thereby reducing a patient's quality of life and activities of daily living. The severity of the deformity varies widely, with treatment depending on the extent and the presence of associated complications. The present review addressed the current state of clinical research and treatment of spinal deformities in EDS with a specific focus on the musculocontractural type.

Homozygous splice site variant affecting the first von Willebrand factor A domain of COL12A1 in a patient with myopathic Ehlers-Danlos syndrome.

Myopathic Ehlers-Danlos syndrome (mEDS) is a subtype of EDS that is caused by abnormalities in COL12A1. Up-to-date, 24 patients from 15 families with mEDS have been reported, with 14 families showing inheritance in an autosomal dominant manner and one family in an autosomal recessive manner. We encountered an additional patient with autosomal recessive mEDS.

Clinical utility of urinary mulberry bodies/cells testing in the diagnosis of Fabry disease.

Introduction: Variants in the galactosidase alpha () gene cause Fabry disease (FD), an X-linked lysosomal storage disorder caused by α-galactosidase A (α-GAL) deficiency. Recently, disease-modifying therapies have been developed, and simple diagnostic biomarkers for FD are required to initiate these therapies in the early stages of the disease. Detection of urinary mulberry bodies and cells (MBs/MCs) is beneficial for diagnosing FD.

A patient with pleuroparenchymal fibroelastosis carrying a novel gene variant.

Pleuroparenchymal fibroelastosis is a recently recognized clinical entity characterized by interstitial pneumonia with proliferating elastin in the upper lung regions. Pleuroparenchymal fibroelastosis is categorized as idiopathic or reported depending on the coexistent initiating factors; however, congenital contractural arachnodactyly, which is caused by abnormal production of elastin based on a mutation in the gene, is rarely reported with lung lesion resembling pleuroparenchymal fibroelastosis. We present a case of pleuroparenchymal fibroelastosis in a patient with a novel mutation in the gene, which encodes the prenatal fibrillin-2 protein as a scaffold for elastin.

Detailed Courses and Pathological Findings of Colonic Perforation without Diverticula in Sisters with Musculocontractural Ehlers-Danlos Syndrome Caused by Pathogenic Variant in (mcEDS-).

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a heritable connective tissue disorder characterized by multiple congenital malformations and progressive connective-tissue-fragility-related manifestations in the cutaneous, skeletal, cardiovascular, visceral, ocular, and gastrointestinal systems. It is caused by pathogenic variants in the carbohydrate sulfotransferase 14 gene (mcEDS-) or in the dermatan sulfate epimerase gene (mcEDS-). As gastrointestinal complications of mcEDS-, diverticula in the colon, small intestine, or stomach have been reported, which may lead to gastrointestinal perforation, here, we describe sisters with mcEDS-, who developed colonic perforation with no evidence of diverticula and were successfully treated through surgery (a resection of perforation site and colostomy) and careful postoperative care.

Case report: further delineation of -related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature.

The Ehlers-Danlos Syndromes (EDS), a group of hereditary connective tissue disorders, were classified into 13 subtypes in the 2017 International Classification. Recently, a new subtype of EDS called classical-like EDS type 2 (clEDS2), which is caused by biallelic variants in the adipocyte enhancer binding protein 1 () gene, was identified. We describe the 11th patient (9th family) with clEDS2, who was complicated by a critical vascular event (superior mesenteric artery aneurysm and rupture).

Pathophysiological Investigation of Skeletal Deformities of Musculocontractural Ehlers-Danlos Syndrome Using Induced Pluripotent Stem Cells.

Musculocontractural Ehlers-Danlos syndrome caused by mutations in the carbohydrate sulfotransferase 14 gene (mcEDS-) is a heritable connective tissue disorder characterized by multiple congenital malformations and progressive connective tissue fragility-related manifestations in the cutaneous, skeletal, cardiovascular, visceral, and ocular systems. Progressive skeletal deformities are among the most frequent and serious complications affecting the quality of life and activities of daily living in patients. After establishing induced pluripotent stem cells (iPSCs) from cultured skin fibroblasts of three patients with mcEDS-, we generated a patient iPSC-based human osteogenesis model and performed an in vitro assessment of the phenotype and pathophysiology of skeletal deformities.

Long-term Observation of a Japanese Patient with a Multiple-system Neurodegenerative Disorder with a Uniallelic de novo Missense Variant in KIF1A.

We encountered a 37-year-old Japanese man with KIF1A-associated neurological disorder (KAND) who exhibited motor developmental delay, intellectual disability, and slowly progressive cerebellar ataxia, hypotonia, and optic neuropathy. Pyramidal tract signs were evident late in this case. At 30 years old, the patient developed a neurogenic bladder.

Mouse Models of Musculocontractural Ehlers-Danlos Syndrome.

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a subtype of EDS caused by mutations in the gene for carbohydrate sulfotransferase 14 () (mcEDS-) or dermatan sulfate epimerase () (mcEDS-). These mutations induce loss of enzymatic activity in D4ST1 or DSE and disrupt dermatan sulfate (DS) biosynthesis. The depletion of DS causes the symptoms of mcEDS, such as multiple congenital malformations (e.