A Novel Homozygous Mutation in the COL4A4 Gene (Gly1436del) Causing Alport Syndrome Exposed by Pregnancy: A Case Report and Review of the Literature.

BACKGROUND: Alport syndrome results from a hereditary defect of collagen IV synthesis. This causes progressive glomerular disease, ocular abnormalities, and inner ear impairment. Case Presentation. Herein, we present a case of Alport syndrome in a 28-year-old woman caused by a novel mutation (Gly1436del) in the COL4A4 gene that was not unveiled until her first pregnancy. Within the 29th pregnancy week, our patient presented with massive proteinuria and nephrotic syndrome. Light microscopic examination of a kidney biopsy showed typical histological features of segmental sclerosis, and electron microscopy revealed extensive podocyte alterations as well as thickness of glomerular basement membranes with splitting of the lamina densa. One and a half years after childbirth, renal function deteriorated to a preterminal stage, whereas nephrotic syndrome subsided quickly after delivery. CONCLUSION: This case report highlights the awareness of atypical AS courses and emphasizes the importance of genetic testing in such cases.

Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and PEX26 mutated in Heimler syndrome.

BACKGROUND: Combined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome (USH1: congenital deafness, early retinitis pigmentosa (RP); USH2: progressive hearing impairment, RP). METHODS: Sanger sequencing and NGS of 112 genes (Usher syndrome, nonsyndromic deafness, overlapping conditions), MLPA, and array-CGH were conducted in 138 patients clinically diagnosed with Usher syndrome. RESULTS: A molecular diagnosis was achieved in 97% of both USH1 and USH2 patients, with biallelic mutations in 97% (USH1) and 90% (USH2), respectively. Quantitative readout reliably detected CNVs (confirmed by MLPA or array-CGH), qualifying targeted NGS as one tool for detecting point mutations and CNVs. CNVs accounted for 10% of identified USH2A alleles, often in trans to seemingly monoallelic point mutations. We demonstrate PTC124-induced read-through of the common p.Trp3955* nonsense mutation (13% of detected USH2A alleles), a potential therapy target. Usher gene mutations were found in most patients with atypical Usher syndrome, but the diagnosis was adjusted in case of double homozygosity for mutations in OTOA and NR2E3, genes implicated in isolated deafness and RP. Two patients with additional enamel dysplasia had biallelic PEX26 mutations, for the first time linking this gene to Heimler syndrome. CONCLUSION: Targeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.

Surgical treatment in a patient with Klippel-Feil syndrome and anterior cervical meningomyelocele: a case report and review of literature.

INTRODUCTION: Klippel-Feil syndrome (KFS) is considered a rare developmental disorder characterized by mono- or multisegmental fusion of the cervical vertebrae which is frequently associated with diverse non-osseous, e.g. neural, visceral, cardiopulmonary and genitourinary development anomalies. Anterior cervical meningomyelocele (MMC) in KFS has only been described in two previous patients, both with non-surgical treatment. CLINICAL PRESENTATION: We present the case of a 26-year-old female suffering from KFS, presenting with progressive bilateral C6 paraesthesias, C7 and C8 motor weakness and myelopathy. Radiological imaging revealed incomplete osseous fusion of the vertebrae C2-Th1. The spinal cord was displaced ventro-caudally through a large anterior MMC, apparently fixed at the dorsal oesophagus, severely stretching the cervical nerve roots. Surgery was indicated due to progression of the symptoms and was performed through a combined partial sternotomy and ventral anterolateral cervical approach. Intraoperatively, both division of oesophago-dural adhesions and intradural untethering of adhesions of the myelon with caudal parts of the cele were performed. Evoked somatosensory potentials improved immediately and 6-day postoperative MRI revealed a nearly complete reposition of the spinal cord in its physiological position. Genetic sequence analyses ruled out mutation of the growth and differentiation factor 6 (GDF6). Apart from slight intermittent paraesthesia, symptoms resolved almost completely within weeks after operation. Both radiological and neurological improvement remained stable at 16 months of follow-up. CONCLUSION: KFS with anterior cervical MMC is rarely seen and may require surgery in case of clincial signs of nerve root compression or myelopathy. Osseous decompression, untethering and adhesiolysis under electrophysiological monitoring can provide sufficient radiological and clinical improvement.