Supravalvular aortic stenosis (SVAS) is a rare left ventricular outflow tract obstruction, most commonly caused by pathogenic variants in ELN. Truncating variants in exons 1-29 typically produce non-syndromic SVAS through elastin haploinsufficiency, whereas C-terminal variants are linked to autosomal dominant cutis laxa. However, clinically and mechanistically well-characterized variants in the distal part of this "stenotic zone," such as exon 28, remain uncommon. We conducted a retrospective family-based case report with standardized clinical evaluation, serial echocardiography, and trio whole-exome sequencing with Sanger confirmation and conservation analysis. A female infant presented at 1 month with severe sinotubular junction narrowing (Z-score -4.8, peak gradient 24 mmHg), severe peripheral pulmonary artery stenosis, a small atrial septal defect, and moderate mitral regurgitation. Her father had severe SVAS with mild PPAS and prior aortic root enlargement, without syndromic features. Trio sequencing identified a novel heterozygous ELN exon 28 frameshift variant, c.1879_1883dup (p.Ala629LeufsTer15), inherited from the father. Ala629 is fully conserved, and the duplication introduces a premature stop codon, consistent with nonsense-mediated decay and elastin haploinsufficiency. At 9 months, SVAS progressed (peak gradient 35 mmHg), while PPAS gradients regressed by >40%. This novel exon 28 ELN frameshift expands the non-syndromic SVAS spectrum and illustrates a characteristic pattern of progressive aortic stenosis with improving PPAS, supporting ELN testing and targeted longitudinal surveillance in similar patients and families. Neurocutaneous disorders due to mitochondrial proline synthesis defects comprise PYCR1-related autosomal recessive cutis laxa (ARCL), ALDH18A1-related ARCL, and ALDH18A1-related autosomal dominant cutis laxa (ADCL). These disorders are characterized by thin, translucent skin with wrinkles (especially on the hands and feet); typical facial characteristics including a triangular face with a progeroid appearance, a broad forehead (prominent-appearing neurocranium due to small viscerocranium), convex nasal ridge, full or sagging cheeks, and pointed chin; moderate-to-severe intellectual disability or mild intellectual disability with additional neurodiverse phenotypes including autism spectrum disorder or attention-deficit/hyperactivity disorder; and pre- and postnatal growth deficiency. Additional features can include joint laxity, congenital hypotonia, progressive increased lower limb reflexes/spasticity, congenital hip dislocation, adducted thumbs, corneal clouding, and lens opacities. The diagnosis of a neurocutaneous disorder due a to mitochondrial proline synthesis defect can be established in a proband with characteristic clinical findings and identification of biallelic ALDH18A1 or PYCR1 pathogenic variants or a de novo ALDH18A1 pathogenic variant associated with ALDH18A1-related ADCL. Treatment of manifestations: Prelingual speech therapy to improve swallowing and speech development; routine treatment of epilepsy; in those with abnormal serum amino acids (low ornithine, citrulline, arginine), supplementation with arginine has been described in a limited number of individuals, but clinical benefit remains to be confirmed; physical therapy for motor delays and spastic diplegia; mobility devices for spastic diplegia; treatment of hip dislocation, scoliosis, and joint contractures per orthopedist; cervical spine fusion for atlantoaxial instability; palate enlargement as needed; correction of diffraction abnormalities and possible surgical correction in those with impaired vision due to clouding; management of hypertension; treatment of other cardiovascular manifestations per cardiologist. Surveillance: Neurologic exam initially every six months then annually; EEG as clinically indicated; brain MRI every ten years or more frequently in those with imaging abnormalities or new neurologic concerns; monitor developmental progress and educational needs every six months initially then annually; assess growth at each visit; assess for orthopedic manifestations every six months until age one year then annually; anterior chamber evaluation to assess for corneal clouding and cataract annually; echocardiogram every three years or more frequently in those with abnormal findings; brain MR angiogram every ten years or more frequently in those with abnormal findings; peak flow measurements or pulmonary function tests every three years beginning at age eight years. Agents/circumstances to avoid: Contact sports; prolonged fasting; activities requiring hyperbaric pressure; aesthetic surgical intervention; activities with high acceleration or that increase the risk for seizures; smoking; sunbathing. Neurocutaneous disorders due to mitochondrial proline synthesis defects are inherited in an autosomal recessive (PYCR1- and ALDH18A1-related ARCL) or an autosomal dominant (ALDH18A1-related ADCL) manner. Autosomal recessive inheritance: The parents of a child with PYCR1- or ALDH18A1-related ARCL are presumed to be heterozygous for a pathogenic variant. If both parents are known to be heterozygous for a pathogenic variant, each sib of an individual with PYCR1- or ALDH18A1-related ARCL has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not a carrier. Heterozygous sibs of a proband with PYCR1-related ARCL are asymptomatic. To date, heterozygous carriers of pathogenic variants causative for ALDH18A1-related ARCL are reported to be asymptomatic. Carrier testing for at-risk relatives requires prior identification of the PYCR1 or ALDH18A1 pathogenic variants in the family. Autosomal dominant inheritance: All probands reported to date with ALDH18A1-related ADCL whose parents have undergone molecular genetic testing have the disorder as the result of a de novo ALDH18A1 pathogenic variant. If the ALDH18A1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism. Once the PYCR1 or ALDH18A1 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Cutis laxa is a highly heterogeneous connective tissue disorder characterized by progressively loose skin, often accompanied by systemic involvement. Autosomal dominant cutis laxa (ADCL) has been linked to variants in several genes, including ALDH18A1, which encodes Δ1-pyrroline-5-carboxylate synthetase, a key enzyme in proline and collagen metabolism. We report a novel case of ADCL in a 1.6-year-old patient presenting with growth delay, hypotonia, joint laxity, lax skin, cataract, dysmorphic features, microcephaly, cranial vessel tortuosity, hip dislocation, and psychomotor retardation. Whole-exome sequencing revealed a de novo heterozygous c.400 T > C (p.Ser134Pro) substitution in the ALDH18A1 gene. This variant has not been previously reported, and it is the first report of an individual with ALDH18A1-ADCL due to a substitution at a highly conserved residue, p.Ser134 of the P5CS protein. Our findings expand the mutational spectrum of ALDH18A1-related ADCL and highlight the importance of genetic testing in diagnosing rare disorders.

Elastin is a connective tissue protein, produced from the ELN gene, that provides elasticity and recoil to tissues that stretch, such as the large arteries of the body, lung parenchyma, skin, ligaments and elastic cartilages. It is produced as a soluble monomer, tropoelastin, that when cross-linked in the extracellular space generates a polymer that is extraordinarily stable, with a predicted half-life of >70 years. Although data suggest ongoing elastin transcription, it is rare to see new elastin deposited outside of its tight developmental window. Consequently, elastin-related disease comes about primarily in one of three scenarios: (1) inadequate elastin deposition, (2) production of poor-quality elastic fibers, or (3) increased destruction of previously deposited elastin. By understanding the pathways controlling elastin production and maintenance, we can design new therapeutics to thwart those abnormal processes. In this review, we will summarize the diseases arising from genetic and environmental alteration of elastin (Williams syndrome, supravalvar aortic stenosis, autosomal dominant cutis laxa, and ELN-related vascular and connective tissue dysfunction) and then describe the mechanisms controlling elastin production and maintenance that might be manipulated to generate novel therapeutics aimed at these conditions. We will end by summarizing existing therapeutic strategies targeting these disease mechanisms before outlining future approaches that may better solve the challenges associated with elastin based regenerative medicine.

Cutis laxa is a genetically heterogeneous disorder characterized primarily by loose, redundant skin with abnormal wrinkling and elasticity. It is an exceptionally rare condition, with an estimated prevalence of < 1 in 1,000,000 individuals. In addition to the distinctive cutaneous manifestations, cutis laxa can present with a constellation of other features, including progeroid appearance, growth retardation, and developmental delays. We report a case of a 26-month-old girl who presented with features similar to nutritional rickets with global developmental delay and some additional features of joint and skin hyper-laxity in the backdrop of severely low vitamin D levels. The patient, however, failed to respond to the conventional treatment for rickets. Subsequent genetic testing revealed an autosomal dominant form of cutis laxa caused by an exceedingly rare c.377G>A (p.Arg126His) substitution in the ALDH18A1 gene, which encodes the bifunctional enzyme catalyzing the final steps of de novo phospholipid biosynthesis. The present case highlights the diagnostic challenges posed by cutis laxa, as the clinical manifestations can overlap with other conditions, leading to potential misdiagnosis or delayed recognition. The rarity of this disorder, combined with its phenotypic variability, underscores the importance of raising awareness among clinicians and expanding the literature to encompass the full spectrum of presentations associated with cutis laxa.

Superoxide Dismutase 3 (SOD3) scavenges extracellular superoxide giving a hydrogen peroxide metabolite. Both Reactive Oxygen Species diffuse through aquaporins causing oxidative stress and biomolecular damage. SOD3 is differentially expressed in cancer and this research utilises Gene Expression Omnibus data series GSE2109 with 2,158 cancer samples. Genome-wide expression correlation analysis was conducted with SOD3 as the seed gene. Categorical SOD3 Pearson Correlation gene lists incrementing in correlation strength by 0.01 from ρ≥|0.34| to ρ≥|0.41| were extracted from the data. Positively and negatively SOD3 correlated genes were separated for each list and checked for significance against disease overlapping genes in the ClinVar and Orphanet databases via Enrichr. Disease causal genes were added to the relevant gene list and checked against Gene Ontology, Phenotype Ontology, and Elsevier Pathways via Enrichr before the significant ontologies containing causal and non-overlapping genes were reviewed with a literature search for possible disease and oxidative stress associations. 12 significant individually discriminated disorders were identified: Autosomal Dominant Cutis Laxa (p = 6.05x10-7), Renal Tubular Dysgenesis of Genetic Origin (p = 6.05x10-7), Lethal Arteriopathy Syndrome due to Fibulin-4 Deficiency (p = 6.54x10-9), EMILIN-1-related Connective Tissue Disease (p = 6.54x10-9), Holt-Oram Syndrome (p = 7.72x10-10), Multisystemic Smooth Muscle Dysfunction Syndrome (p = 9.95x10-15), Distal Hereditary Motor Neuropathy type 2 (p = 4.48x10-7), Congenital Glaucoma (p = 5.24x210-9), Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (p = 3.77x10-16), Classical-like Ehlers-Danlos Syndrome type 1 (p = 3.77x10-16), Retinoblastoma (p = 1.9x10-8), and Lynch Syndrome (p = 5.04x10-9). 35 novel (21 unique) genes across 12 disorders were identified: ADNP, AOC3, CDC42EP2, CHTOP, CNN1, DES, FOXF1, FXR1, HLTF, KCNMB1, MTF2, MYH11, PLN, PNPLA2, REST, SGCA, SORBS1, SYNPO2, TAGLN, WAPL, and ZMYM4. These genes are proffered as potential biomarkers or therapeutic targets for the corresponding rare diseases discussed.