Molecular and functional characterization of mutations in SPG4 and SPG7 gene

Die hereditären spastischen Paraplegien (HSP), auch hereditäre spastische Spinalparalysen oder spastische Paraplegien (SPG) genannt, stellen eine sehr heterogene Gruppe von Erkrankungen mit autosomal dominantem (70-80%), autosomal rezessivem (15-20%) oder X-chromosomal rezessivem Erbgang dar. Bis zum jetzigen Zeitpunkt konnten über 40 Loci bzw. 17 Gene für die Erkrankung identifiziert worden. Im Rahmen dieser kumulativen Doktorarbeit werden 3 Publikationen zum Thema HSP vorgestellt. In der ersten Publikation werden die Ergebnisse unserer molekulargenetischen Untersuchungen bei Patienten mit Mutationen im SPG4-Gen dargestellt (Shoukier et al. 2009). Ziel der Studie war die Erweiterung des Mutationsspektrums und die Etablierung einer aussagekräftigen Genotyp-Phänotyp-Korrelation. Weitere Ziele der Studie waren, eine mögliche mutation-cluster-region im SPG4-Gen zu identifizieren und den strukturellen und funktionellen Effekt der Missense-Mutationen in der AAA-Domäne au! f Proteinebene zu ermitteln. In der zweiten Arbeit (Klimpe et al. 2010) werden die Ergebnisse einer funktionellen Evaluation ausgewählter Splice-site-Mutationen im SPG4-Gen beschrieben. Mithilfe eines quantitativen Allel-spezifischen Expressionsassays gelang der Nachweis eines threshold-effect-models für die HSP4. Der threshold effect bedeutet, dass die Symptome der Erkrankung erst dann bei den Patienten auftreten, wenn der Prozentsatz des Wildtyp-Spastins (Wt-Spastin) unter einem Schwellenwert liegt. Das SPG7-Gen kodiert für das Protein Paraplegin, welches als eine Untereinheit der hetero-oligomeric-mAAA-Protease in den Mitochondrien fungiert. In der Hefe besteht die mAAA Protease aus den zwei Untereinheiten Yta10 und Yta12, und diese Protease ist essenziell für die Aufrechterhaltung der respiratorischen Aktivität (Arlt et al. 1998). In der dritten Publikation (Bonn et al. 2010) wird ein Hefe-Komplementations-Assay für den Nachweis der Pathogenität verschiedener Veränderungen im SPG7-Gen verwendet. Diese Methode kann weiterhin für die Beurteilung der klinischen Relevanz weiterer Mutationen im SPG7-Gen verwendet werden

Hereditary papillary renal cell carcinoma primarily diagnosed in a cervical lymph node: a case report of a 30-year-old woman with multiple metastases

Abstract Background Papillary renal cell carcinoma is a rare cancer. Some cases can be attributed to individuals with hereditary renal cell carcinomas usually consisting of the clear cell subtype. In addition, two syndromes with hereditary papillary renal cell carcinoma have been described. One is the hereditary leiomyomatosis and renal cell carcinoma, which is characterized by cutaneous and uterine leiomyomas and renal cell carcinoma mostly consisting of the papillary renal cell carcinoma type II with a worse prognosis. Case presentation We describe a case of a 30-year-old woman with hereditary leiomyomatosis and renal cell carcinoma syndrome with extensively metastasized papillary renal cell carcinoma, primarily diagnosed in a cervical lymph node lacking leiomyomas at any site. Conclusion Papillary renal cell carcinoma in young patients should be further investigated for a hereditary variant like the hereditary leiomyomatosis and renal cell carcinoma even if leiomyomas could not be detected. A detailed histological examination and search for mutations is essential for the survival of patients and relatives.</p

Prenatal Diagnosis of Fryns Syndrome through Identification of Two Novel Splice Variants in the <i>PIGN</i> Gene—A Case Series

Fryns syndrome (FS) is a multiple congenital anomaly syndrome with different multisystemic malformations. These include congenital diaphragmatic hernia, pulmonary hypoplasia, and craniofacial dysmorphic features in combination with malformations of the central nervous system such as agenesis of the corpus callosum, cerebellar hypoplasia, and enlarged ventricles. We present a non-consanguineous northern European family with two recurrent cases of FS: a boy with multiple congenital malformations who died at the age of 2.5 months and a female fetus with a complex developmental disorder with similar features in a following pregnancy. Quad whole exome analysis revealed two likely splicing-affecting disease-causing mutations in the PIGN gene: a synonymous mutation c.2619G>A, p.(Leu873=) in the last nucleotide of exon 29 and a 30 bp-deletion c.996_1023+2del (NM_176787.5) protruding into intron 12, with both mutations in trans configuration in the affected patients. Exon skipping resulting from these two variants was confirmed via RNA sequencing. Our molecular and clinical findings identified compound heterozygosity for two novel splice-affecting variants as the underlying pathomechanism for the development of FS in two patients

LMNA Mutation in a Family with a Strong History of Sudden Cardiac Death

We report a family with heterozygous deletion of exons 3&ndash;6 of the LMNA gene. The main presentation of affected family members was characterized by ventricular and supraventricular arrhythmias, atrioventricular (AV) block and sudden cardiac death (SCD) but also by severe dilative cardiomyopathy (DCM). We report on two siblings, a 36-year-old female and her 40-year-old brother, who suffer from heart failure with mildly reduced ejection fraction, AV conduction delays and premature ventricular complexes. Their 65-year-old mother underwent heart transplantation at the age of 55 due to advanced heart failure. Originally, the LMNA mutation was detected in one of the uncles. This index patient and three of his brothers died of SCD as well as their father and aunt. The two siblings were treated with implanted defibrillators in our specialized tertiary heart failure center. This case report places this specific genetic variant in the context of LMNA-associated familial DCM

Analyse systématique des anomalies retrouvées à l'IRM cérébrale chez les patients atteints d'une paraplégie spastique héréditaire associée aux mutations de l'AP4

peer reviewed[en] BACKGROUND AND OBJECTIVES: AP-4-associated hereditary spastic paraplegia (AP-4-HSP: SPG47, SPG50, SPG51, SPG52) is an emerging cause of childhood-onset hereditary spastic paraplegia and mimic of cerebral palsy. This study aims to define the spectrum of brain MRI findings in AP-4-HSP and to investigate radioclinical correlations. METHODS: We performed a systematic qualitative and quantitative analysis of 107 brain MRI studies from 76 individuals with genetically confirmed AP-4-HSP and correlation with clinical findings including surrogates of disease severity. RESULTS: We define AP-4-HSP as a disorder of gray and white matter and demonstrate that abnormal myelination is common and that metrics of reduced white matter volume correlate with severity of motor symptoms. We identify a common diagnostic imaging signature consisting of (1) a thin splenium of the corpus callosum, (2) an absent or thin anterior commissure, (3) characteristic signal abnormalities of the forceps minor ("ears of the grizzly sign"), and (4) periventricular white matter abnormalities. The presence of 2 or more of these findings has a sensitivity of ∼99% for detecting AP-4-HSP; the combination of all 4 is found in ∼45% of cases. Compared to other HSPs with a thin corpus callosum, the absent anterior commissure appears to be specific to AP-4-HSP. Our analysis identified a subset of patients with polymicrogyria, underscoring the role of AP-4 in early brain development. These patients displayed a higher prevalence of seizures and status epilepticus, many at a young age. DISCUSSION: Our findings define the MRI spectrum of AP-4-HSP, providing opportunities for early diagnosis, identification of individuals at risk for complications, and a window into the role of the AP-4 complex in brain development and neurodegeneration