COL12A1 Gene Variant and a Review of the Literature: A Case Report of Ullrich Congenital Muscular Dystrophy.

Introduction: Mutations in collagen type IV-associated genes lead to Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM). COL12A1 gene mutations have rarely been reported in patients with UCMD- and BM-like disorders not involving COL6 mutations. UCMD-2 results from homozygous mutations in the COL12A1 gene on the long arm of chromosome 6. Pathogenic variants in COL12A1 result in a rare congenital connective tissue/myopathy overlap syndrome under the heading of myopathic Ehlers-Danlos syndrome. COL12A1 dominant pathogenic variants have been rarely reported, and the phenotypic spectrum has not yet been identified. Case Presentation: We describe a female patient aged 2 years and 10 months exhibiting a milder phenotype who presented due to pronounced joint hyperlaxity, frequent falls, and skin lesions. Genetic analysis revealed a homozygous c.8903C>T (p.Pro2968Leu) missense variant that had previously been described but concerning which there had been no clinical report, in the COL12A1 gene. Discussion/Conclusion: This report is presented in order to raise awareness of rare mutations in the COL12A1 gene that affect muscle and connective tissue and to add to the literature in defining the phenotypic spectrum.

Case Report of Two Siblings Diagnosed with Osteogenesis Imperfecta Type XV with a New Mutation in the WNT1 Gene and Review of the Literature.

Introduction: Osteogenesis imperfecta (OI) is a heritable disorder characterized by bone fractures and low bone mass. Recently, mutations of the WNT1 gene have been reported to be causative in OI. The mutation in WNT1 causes autosomal-recessive OI due to its critical role in bone formation. WNT1 mutations cause varying degrees of clinical severity, ranging from moderate to progressively deforming forms. In addition to the OI phenotype, our cases also had extra-skeletal findings. Case Presentation: We describe two siblings with multiple fractures and developmental delay. A novel homozygous frameshift WNT1 mutation was detected in this family, and we reviewed the literature for WNT1-related OI cases. Discussion: We report a novel variant with a clinical diagnosis of severe OI, and this review will provide a comprehensive overview of previously published cases of OI type XV. With a better understanding of disorders associated with WNT1 mutations, therapies targeting Wnt1 signaling pathway may contribute therapeutic benefits.

Pyridoxine-dependent Epilepsy caused by a Novel homozygous mutation in PLPBP Gene.

Seizures in newborn infants may be the first finding of hereditary metabolic diseases. Pyridoxine-dependent epilepsy (PDE) is a treatable disorder associated with defects in the one of ALDH7A1, PNPO, or PLPBP genes and it is uncommon but progresses with persistent seizures in the neonatal and infancy period. The seizures are generally resistant to traditional antiepileptic drugs and show a dramatic response to high-dose pyridoxine. In 2016, mutations were reported in PLPBP (previously known as PROSC) gene, which encodes pyridoxal phosphate homeostatic protein (PLPHP).When early-onset antiepileptic resistant seizures are not treated, clinical findings emerge including the development of encephalopathy, congenital microcephaly, and subsequent retardation of psychomotor development. The present case is a 33-month-old female infant with seizures starting from postnatal day 1, who did not respond to traditional anti-epileptic drugs but responded to pyridoxine treatment. In the genetic tests, homozygote c.695 C > T (p.Ala232Val) mutation was determined in the PLPBP gene, which has not been previously identified. Since a specific treatment was found, this case is reported with the aim of emphasizing the need to consider pyridoxine dependence, which is one of the vitamin-dependent metabolic encephalopathies, in the differential diagnosis of epilepsy patients.

X-Linked Spinal Muscular Atrophy 2 due to a Synonymous Variant in the UBA1 Gene in a Family with Novel Findings from Turkey.

Spinal muscular atrophy, X-linked 2 (SMAX2) is a rare type of spinal muscular atrophy characterized by muscle weakness, hypotonia, areflexia, myopathic face, tongue fibrillations, contractures, bone fractures, and cryptorchidism. Variants of the UBA1 gene lead to SMAX2. The UBA1 gene encodes a protein that activates the ubiquitin pathway which is responsible for protein degradation. Here, we describe a family presenting with hypotonia, muscle weakness, areflexia, contractures, weak cry, in association with other anomalies including myopathic face, scoliosis, tongue fibrillations, and cryptorchidism. Molecular analysis in 2 patients revealed a hemizygous pathogenic variant in the UBA1 gene (NM_153280.3, NP_695012.1: c.1731C>T [p.Asn577Asn]) inherited from their carrier mothers. Our study presents the first patients from Turkey, widening the phenotypic spectrum of SMAX2 by pectus carinatum, medullary sponge kidney, and frontal cyst.