Novel mosaic TRAF7 likely pathogenic variant in an African American family.

Pathogenic variants in TRAF7 are often de novo and features of individuals harboring these variants are characterized by neurodevelopmental delay, ptosis, cardiac defects, limb anomalies, and dysmorphic features. We present a familial case in two African American patients with a novel, likely pathogenic c.1936G>A variant in TRAF7. Patient 1 is a 31-year-old female with a patent ductus arteriosus (PDA), intellectual disability, ptosis, and other dysmorphic features. She was identified to harbor this likely pathogenic variant in a mosaic (33.89%) state in leukocytes. Her son, Patient 2, is a 10-month-old male with a PDA, atrial septal defect, ptosis, developmental delay, history of feeding difficulties, congenital maxillary frenulum, and malrotation of the intestine. He has the same variant in a non-mosaic state. These cases demonstrate the variable expressivity observed with variants in TRAF7 within the same family and expand upon current understanding of mosaic TRAF7 variants. They also provide phenotypic data on genetic variation in individuals with African American ancestry, a population who has been underrepresented in the literature and may be less frequently referred to genetic specialists.

An exploration of knowledge, risk perceptions, and communication in a family with multiple genetic risks for Parkinson's disease.

Genomic testing increasingly challenges health care providers and patients to understand, share, and use information. The provision of polygenic risks is anticipated to complicate comprehension, communication, and risk perception further. This manuscript aims to illuminate the challenges confronting families with multiple genetic risks for Parkinson's disease. Identifying and planning for such issues may prove valuable to family members now and in the future, should neuroprotective or genotype-specific therapies become available. We present qualitative data from interviews with a multi-generational family carrying pathogenic variants in the glucocerebrosidase (GBA1) and leucine-rich repeat kinase 2 (LRRK2) genes which are associated with an increased risk for developing Parkinson's disease (PD). The family includes two brothers (heterozygous for LRRK2 p.G2019S and homozygous for GBA1 p.N409S) and their four descendants. The brothers were concordant for GD and discordant for PD. Genetic counseling and testing were provided to four of the six participants. Two years later, semi-structured interviews were conducted with the initial participants (n = 4) and two additional first-degree relatives. Interviews were transcribed and thematically analyzed, providing the basis for this report. Illuminated topics include the perceived risk of developing PD, recall of genetic information, and family communication. With the expanding use of exome and genome sequencing, we anticipate that genetic counselors will increasingly face the challenges demonstrated by this case involving multiple genetic risks for PD, limited data to clarify risk, and the inherent variability of family communication, genetic knowledge, and risk perception. This clinical case report provides a compelling narrative demonstrating the need for additional research exploring these multifaceted topics relevant to both families facing these challenges and providers striving to assist, support and guide their journey.

Investigation of a dysmorphic facial phenotype in patients with Gaucher disease types 2 and 3.

Gaucher disease (GD) is a rare lysosomal storage disorder that is divided into three subtypes based on presentation of neurological manifestations. Distinguishing between the types has important implications for treatment and counseling. Yet, patients with neuronopathic forms of GD, types 2 and 3, often present at young ages and can have overlapping phenotypes. It has been shown that new technologies employing artificial intelligence and facial recognition software can assist with dysmorphology assessments. Though classically not associated nor previously described with a dysmorphic facial phenotype, this study investigated whether a facial recognition platform could distinguish between photos of patients with GD2 and GD3 and discriminate between them and photos of healthy controls. Each cohort included over 100 photos. A cross validation scheme including a series of binary comparisons between groups was used. Outputs included a composite photo of each cohort and either a receiver operating characteristic curve or a confusion matrix. Binary comparisons showed that the software could correctly group photos at least 89% of the time. Multiclass comparison between GD2, GD3, and healthy controls demonstrated a mean accuracy of 76.6%, compared to a 37.7% chance for random comparison. Both GD2 and GD3 have now been added to the facial recognition platform as established syndromes that can be identified by the algorithm. These results suggest that facial recognition and artificial intelligence, though no substitute for other diagnostic methods, may aid in the recognition of neuronopathic GD. The algorithm, in concert with other clinical features, also appears to distinguish between young patients with GD2 and GD3, suggesting that this tool can help facilitate earlier implementation of appropriate management.

Current and emerging pharmacotherapy for Gaucher disease in pediatric populations.

INTRODUCTION: The past decades have witnessed a remarkable improvement in the health of patients with Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase, resulting from the availability of enzyme replacement and substrate reduction therapies. Especially in pediatric populations, early diagnosis and initiation of treatment is essential to achieving optimal outcomes. AREAS COVERED: The authors review the literature pertaining to the effectiveness of currently available therapies and describe new pharmacotherapies under development, especially for young patients. EXPERT OPINION: For pediatric patients with non-neuronopathic Gaucher disease, there may be new therapeutic options on the horizon in the form of gene therapy or small molecule glucocerebrosidase chaperones. These have the potential to result in a cure for systemic disease manifestations and/or to reduce the cost and convenience of treatment. For children with neuronopathic Gaucher disease, the challenge of targeting therapy to the central nervous system is being explored through new modalities including brain-targeted gene therapy, in-utero therapy, brain-penetrant small molecule chaperones, and other methods that convey enzyme across the blood-brain barrier. Indeed, these are exciting times for both pediatric patients with Gaucher disease and those with other lysosomal storage disorders.

Diagnosing neuronopathic Gaucher disease: New considerations and challenges in assigning Gaucher phenotypes.

Gaucher disease (GD), resulting from biallelic mutations in the gene GBA1, is a monogenic recessively inherited Mendelian disorder with a wide range of phenotypic presentations. The more severe forms of the disease, acute neuronopathic GD (GD2) and chronic neuronopathic GD (GD3), also have a continuum of disease severity with an overlap in manifestations and limited genotype-phenotype correlation. In very young patients, assigning a definitive diagnosis can sometimes be challenging. Several recent studies highlight specific features of neuronopathic GD that may provide diagnostic clues. Distinguishing between the different GD types has important therapeutic implications. Currently there are limited treatment options specifically for neuronopathic GD due to the difficulty in delivering therapies across the blood-brain barrier. In this work, we present both classic and newly appreciated aspects of the Gaucher phenotype that can aid in discriminating between acute and chronic neuronopathic GD, and highlight the continuing therapeutic challenges.

Pregnancy-associated plasma protein-aa supports hair cell survival by regulating mitochondrial function.

To support cell survival, mitochondria must balance energy production with oxidative stress. Inner ear hair cells are particularly vulnerable to oxidative stress; thus require tight mitochondrial regulation. We identified a novel molecular regulator of the hair cells' mitochondria and survival: Pregnancy-associated plasma protein-aa (Pappaa). Hair cells in zebrafish pappaa mutants exhibit mitochondrial defects, including elevated mitochondrial calcium, transmembrane potential, and reactive oxygen species (ROS) production and reduced antioxidant expression. In pappaa mutants, hair cell death is enhanced by stimulation of mitochondrial calcium or ROS production and suppressed by a mitochondrial ROS scavenger. As a secreted metalloprotease, Pappaa stimulates extracellular insulin-like growth factor 1 (IGF1) bioavailability. We found that the pappaa mutants' enhanced hair cell loss can be suppressed by stimulation of IGF1 availability and that Pappaa-IGF1 signaling acts post-developmentally to support hair cell survival. These results reveal Pappaa as an extracellular regulator of hair cell survival and essential mitochondrial function.