Richter, John E.

ABSTRACTBackgroundDespite the general perception of minimal donor‐site morbidity associated with scapular free flaps, the surgical harvest of scapular bone and subsequent reattachment of parascapular muscle have the potential to compromise postoperative shoulder function. A comprehensive assessment of functional impairment remains undocumented in the literature. Therefore, this systematic review was conducted to thoroughly explore both subjective and objective donor‐site morbidity following free flap surgery.MethodsSearches were conducted on PubMed, Embase, and CENTRAL to locate articles addressing functional donor‐site morbidity after the transfer of scapular bone. Qualifying articles reported scapular free flaps which utilized bone, including lateral border, medial border, and scapular tip. Each measured donor‐site morbidity using at least one of these measures: Constant‐Murley score (CM), Disabilities of Arm, Shoulder, and Hand questionnaire (DASH), shoulder range of motion (ROM), and shoulder strength.ResultsThe search culminated in 16 eligible studies, incorporating data from 316 cases. The CM was employed in five studies, yielding mean values from 60.6 to 95, while the DASH was utilized in nine studies, with means ranging from 10.44 to 46.7. Compared to normative values, these CM and DASH scores reflected negligible to mild impairment in shoulder function. Additional evaluations of shoulder ROM, conducted in four studies, revealed modest yet statistically significant reductions in flexion, abduction, and external rotation. Three studies measuring shoulder strength reported associated mild weakening of these motions.ConclusionsThis systematic review enables healthcare providers to characterize the probable scope of shoulder dysfunction following scapular bone harvest. Patient‐reported outcomes imply a high tolerance for the procedure, while objective measures denote the potential for substantial restoration of shoulder function approaching preoperative levels. To augment the understanding of functional recovery, future research should incorporate a comparative analysis of preoperative and postoperative functional metrics for each subject.

Objective To report a fatal case of Susac syndrome in a congenitally deaf patient with a cochlear implant and a history of migraines, emphasizing the diagnostic challenges in patients with preexisting conditions. Patient A 33-year-old male with congenital hearing loss, a cochlear implant, and chronic migraines who presented with mild subacute auditory disturbance and headaches that later progressed to severe encephalopathy. Intervention Explantation of a non–magnetic resonance imaging (MRI) compatible cochlear implant followed by MRI, fundoscopy, and the administration of immunosuppressive medications. Main Outcome Measures Diagnosis was confirmed by characteristic MRI appearance and the presence of a hemi-retinal artery occlusion. Results After weeks of immunosuppressive treatment, the patient died of a global cerebral ischemic event of unknown origin. Conclusions For patients with preexisting sensorineural hearing loss and cochlear implants, Susac syndrome poses a diagnostic challenge. Auditory disturbances in the absence of cochlear implant failure should prompt further evaluation for visual disturbances and encephalopathy. MRI and fundoscopy should be performed to detect other features of the disease.

Background. The ATP-binding cassette, subfamily D, member 1 (ABCD1) protein is a peroxisomal half-transporter that allows for very long chain fatty acid (VLCFA) degradation. Pathogenic variants of ABCD1 cause VLCFAs to build up in various tissues and bodily fluids, resulting in a disorder called X-linked adrenoleukodystrophy (X-ALD). This disorder is most commonly marked by adrenocortical insufficiency and high VLCFA concentration, and has varying levels of neurological involvement depending on phenotype. For example, the Addison-only form of X-ALD has no neurological impact, while the cerebral form of X-ALD often causes severe sensory loss, motor function impairment, cognitive decline, and death. Methods. A newly characterized and suspected pathogenic variant in ABCD1 was analyzed using our protein informatics platform (PIP). Personalized protein-level molecular studies were completed on genetic testing data, complementing the analysis and clinical study. Results. A case of adult onset adrenomyeloneuropathy (AMN) and a novel ABCD1 variant are presented. The unique ABCD1 protein is discussed, and the proband’s case is compared to existing reports of AMN. Conclusions. Data fusion from multiple sources was combined in a comprehensive approach yielding an enriched assessment of the patient’s disease and prognosis. Molecular modeling was performed on the variant to better characterize its clinical significance and confirm pathogenicity.

AbstractBiallelic pathogenic variants in AARS2, a gene encoding the mitochondrial alanyl‐tRNA synthetase, result in a spectrum of findings ranging from infantile cardiomyopathy to adult‐onset progressive leukoencephalopathy. In this article, we present three unrelated individuals with novel compound heterozygous pathogenic AARS2 variants underlying diverse clinical presentations. Patient 1 is a 51‐year‐old man with adult‐onset progressive cognitive, psychiatric, and motor decline and leukodystrophy. Patient 2 is a 34‐year‐old man with childhood‐onset progressive tremor followed by the development of polyneuropathy, ataxia, and mild cognitive and psychiatric decline without leukodystrophy on imaging. Patient 3 is a 57‐year‐old woman with childhood‐onset tremor and nystagmus which preceded dystonia, chorea, ataxia, depression, and cognitive decline marked by cerebellar atrophy and white matter disease. These cases expand the clinical heterogeneity of AARS2‐related disorders, given that the first and third case represent some of the oldest known survivors of this disease, the second is adult‐onset AARS2‐related neurological decline without leukodystrophy, and the third is biallelic AARS2‐related disorder involving a partial gene deletion.

Background and objectives: Loeys–Dietz syndrome 3, also known as aneurysms-–osteoarthritis syndrome, is an autosomal dominant genetic connective tissue disease caused by pathogenic variants in SMAD3, a transcription factor involved in TGF-β signaling. This disorder is characterized by early-onset osteoarthritis and arterial aneurysms. Common features include scoliosis, uvula abnormalities, striae, and velvety skin. Materials and Methods: The pathogenicity of a variant of uncertain significance in the SMAD3 gene was evaluated (variant c.220C > T) through personalized protein informatics and molecular studies. Results: The case of a 44-year-old male, who was originally presumed to have Marfan syndrome, is presented. An expanded gene panel determined the probable cause to be a variant in SMAD3, c.220C > T (p.R74W). His case was complicated by a history of stroke, but his phenotype was otherwise characteristic for Loeys–Dietz syndrome 3. Conclusion: This case emphasizes the importance of comprehensive genetic testing to evaluate patients for connective tissue disorders, as well as the potential benefit of utilizing a protein informatics platform for the assessment of variant pathogenicity.

AbstractBackgroundTransient receptor potential cation channel subfamily V member 4 (TRPV4) is an ion channel permeable to Ca2+ that is sensitive to physical, hormonal, and chemical stimuli. This protein is expressed in many cell types, including osteoclasts, chondrocytes, and sensory neurons. As such, pathogenic variants of this gene are associated with skeletal dysplasias and neuromuscular disorders. Pathogenesis of these phenotypes is not yet completely understood, but it is known that genotype–phenotype correlations for TRPV4 pathogenic variants often are not present.MethodsNewly characterized, suspected pathogenic variant in TRPV4 was analyzed using protein informatics and personalized protein‐level molecular studies, genomic exome analysis, and clinical study.ResultsThis statement is demonstrated in the family of our proband, a 47‐year‐old female having the novel c.2401A>G (p.K801E) variant of TRPV4. We discuss the common symptoms between the proband, her father, and her daughter, and compare her phenotype to known TRPV4‐associated skeletal dysplasias.ConclusionsProtein informatics and molecular modeling are used to confirm the pathogenicity of the unique TRPV4 variant found in this family. Multiple data were combined in a comprehensive manner to give complete overall perspective on the patient disease and prognosis.

AbstractBackgroundBeta‐galactosidase‐1 (GLB1) is a lysosomal hydrolase that is responsible for breaking down specific glycoconjugates, particularly GM1 (monosialotetrahexosylganglioside). Pathogenic variants in GLB1 cause two different lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB. In GM1 gangliosidosis, decreased β‐galactosidase‐1 enzymatic activity leads to the accumulation of GM1 gangliosides, predominantly within the CNS. We present a 22‐month‐old proband with GM1 gangliosidosis type II (late‐infantile form) in whom a novel homozygous in‐frame deletion (c.1468_1470delAAC, p.Asn490del) in GLB1 was detected.MethodsWe used an experimental protein structure of β‐galactosidase‐1 to generate a model of the p.Asn490del mutant and performed molecular dynamic simulations to determine whether this mutation leads to altered ligand positioning compared to the wild‐type protein. In addition, residual mutant enzyme activity in patient leukocytes was evaluated using a fluorometric assay.ResultsMolecular dynamics simulations showed the deletion to alter the catalytic site leading to misalignment of the catalytic residues and loss of collective motion within the model. We predict this misalignment will lead to impaired catalysis of β‐galactosidase‐1 substrates. Enzyme assays confirmed diminished GLB1 enzymatic activity (~3% of normal activity) in the proband.ConclusionsWe have described a novel, pathogenic in‐frame deletion of GLB1 in a patient with GM1 gangliosidosis type II.

AbstractBackgroundHaploinsufficiency of TAB2 is known to cause congenital heart defects and cardiomyopathy due to its important roles in cardiovascular tissue, both during development and through adult life. We report a sibling pair displaying adult‐onset cardiomyopathy, hypermobility, and mild myopia. Our proband, a 39‐year‐old male, presents only with the above symptoms, while his 36‐year‐old sister was also notable for a ventricular septal defect in her infancy.MethodsWhole‐exome sequencing was utilized to identify the molecular basis of the phenotype found in two siblings. A molecular modeling technique that takes advantage of conformational sampling advances (Maxwell's demon molecular dynamics and Monte Carlo) were used to make a model of the mutant variant for comparative analytics to the wild‐type.ResultsExome sequencing revealed a novel, heterogeneous pathogenic variant in TAB2, c.1039 C>T (p.R347X), that was present in both individuals. This pathogenic variant removes just over half the residues from the TAB2 protein and severely impacts its functional ability, which we describe in detail.ConclusionsAnalysis of the proband's family showed a history of cardiomyopathy, but no congenital heart defects or connective tissue disease. We highlight the heterogeneity in phenotype of TAB2 pathogenic variants and confirm the pathogenicity of this new variant through neoteric protein modeling techniques.

Chronic urticaria is a common condition characterized by recurrent hives lasting several weeks or months and is usually idiopathic. Approximately half of the individuals with chronic urticaria will present with episodes of angioedema that can be severe and debilitating. In this report, we describe a 47-year-old Hispanic male who presented initially for an evaluation of chronic hives following hospitalization due to hive-induced anaphylaxis. The individual had a history significant for urticaria and angioedema beginning in his early 30s. Interestingly, both the individual’s 41-year-old sister and 12-year-old daughter were also affected with chronic urticaria and severe angioedema. Whole exome sequencing of the proband and several family members revealed a heterozygous variant of uncertain significance in exon 2 of TNFAIP3, denoted as c.65G>A (p.R22Q), in all affected members. Variants in TNFAIP3 have been associated with multiple autoimmune diseases, susceptibility to allergy and asthma, and periodic fever syndromes, suggesting that this variant could potentially play a role in disease.