Most human diseases have genetic components, frequently single nucleotide variants (SNVs), which alter the wild type characteristics of macromolecules and their interactions. A straightforward approach for correcting such SNVs-related alterations is to seek small molecules, potential drugs, that can eliminate disease-causing effects. Certain disorders are caused by altered protein-protein interactions, for example, Snyder-Robinson syndrome, the therapy for which focuses on the development of small molecules that restore the wild type homodimerization of spermine synthase. Other disorders originate from altered protein-nucleic acid interactions, as in the case of cancer; in these cases, the elimination of disease-causing effects requires small molecules that eliminate the effect of mutation and restore wild type p53-DNA affinity. Overall, especially for complex diseases, pathogenic mutations frequently alter macromolecular interactions. This effect can be direct, i.e., the alteration of wild type affinity and specificity, or indirect via alterations in the concentration of the binding partners. Here, we outline progress made in methods and strategies to computationally identify small molecules capable of altering macromolecular interactions in a desired manner, reducing or increasing the binding affinity, and eliminating the disease-causing effect. When applicable, we provide examples of the outlined general strategy. Successful cases are presented at the end of the work.

Identification of the first pathogenic branch point variant in the SMS gene in a large French non-consanguineous family with a phenotype retrospectively consistent with Snyder-Robinson syndrome. RT-PCR analysis followed by RNA-sequencing demonstrated that this variant, lead to the synthesis of a predominant aberrant transcript with complete intron 6 retention.

Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder-Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.

Spermine synthase (Sms), a key enzyme in polyamine biosynthesis, catalyzes the conversion of spermidine to spermine using decarboxylated S-adenosylmethionine (dcAdoMet) as an aminopropyl donor. Although Sms is well-characterized in eukaryotes, it is relatively rare in bacteria, where spermine in some species is probably produced by non-specific aminopropyltransferases. In humans, SMS mutations cause Snyder-Robinson syndrome (SRS), an X-linked disorder characterized by intellectual disability, osteoporosis, and neurological dysfunction due to disrupted polyamine homeostasis. Structural studies reveal that Sms functions as a dimer, with its N-terminal domain essential for enzymatic activity. Loss of Sms leads to spermine deficiency, elevated spermidine levels, and metabolic imbalances, contributing to SRS pathology. Therapeutic strategies under investigation include rebalancing spermidine/spermine ratio, polyamine biosynthesis inhibitors (e.g., DFMO), antioxidants and gene therapy using AAV vectors. Conversely, in multiple cancer types, Sms overexpression promotes tumor progression by altering polyamine metabolism, activating oncogenic pathways (e.g., AKT, mTOR), and facilitating immune evasion. Elevated Sms expression correlates with poor prognosis in colorectal, pancreatic, hepatocellular, and head and neck cancers, highlighting its potential as a therapeutic target. However, spermine's role is context-dependent, exhibiting both pro-tumorigenic and cytotoxic effects. While inhibition of Sms may suppress cancer growth, its deficiency in SRS underscores the delicate balance required in polyamine regulation. Insights from SRS and cancer studies highlight Sms as a critical enzyme in cellular homeostasis, with therapeutic implications for both degenerative and proliferative diseases. Further research is needed to elucidate its complex role and optimize targeted interventions. Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome characterized by facial dysmorphism, asthenic build, progressive kyphoscoliosis, early-onset osteoporosis, and seizures. To date, only affected males have been reported. Developmental delay usually presents as failure to meet early developmental milestones and then evolves to mild-to-profound intellectual disability (which appears to remain stable over time) and variable motor disability. Asthenic habitus and low muscle mass usually develop during the first year. Seizure onset varies but typically occurs in early childhood. During the first decade, males with SRS develop osteoporosis, resulting in fractures in the absence of trauma. Rare findings may include nonspecific kidney manifestations. The diagnosis of SRS is established in a male proband with a hemizygous loss-of-function SMS pathogenic variant identified by molecular genetic testing. Treatment of manifestations: Developmental and educational support; treatment of seizures per neurologist; calcium supplementation has slightly improved bone mineral density in a few individuals; standard management of kyphoscoliosis and contractures by orthopedics; standard surgical treatment by craniofacial team for those with cleft palate; treatment of genitourinary and kidney manifestations per urologist and/or nephrologist; develop transitional care plan in adolescence; social work and family support. Surveillance: Monitor developmental progress and educational needs at each visit; monitor those with seizures as clinically indicated; clinical examination and DXA scans to evaluate for progression of osteoporosis and investigate for factures if medically indicated; while receiving calcium supplementation, individuals should be evaluated regularly for ectopic calcification by endocrinologist; clinical examinations for kyphoscoliosis and assessment of mobility and self-help skills at each visit; monitor for nephrocalcinosis and renal cysts and kidney function per nephrologist, considering creatine levels in the context of low muscle mass; assess family needs at each visit. Agents/circumstances to avoid: Assess the risk vs benefit of medications associated with increased osteoporosis (e.g., anticonvulsants), particularly when alternative treatments are limited. SRS is inherited in an X-linked manner. If the mother of the proband has an SMS pathogenic variant, the chance of transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (to date, features of SRS have not been observed in heterozygous females). Affected males are not known to reproduce. The risk to other family members of a male proband depends on the status of the proband's mother: if the mother has the SMS pathogenic variant, the maternal aunts and maternal cousins of the proband may be at risk of having an SMS pathogenic variant. Once an SMS pathogenic variant is identified in an affected family member, carrier testing for at-risk female relatives and prenatal/preimplantation genetic testing are possible.

Polyaminopathies are a relatively new family of rare genetic syndromes recently described in the literature. These syndromes are involved in the biosynthesis of polyamines, which include putrescine, spermidine, and spermine. Polyamines are aliphatic molecular that are found in most life forms, including humans, and are essential for embryogenesis, organogenesis, and tumorigenesis. The five known polyaminopathies that have been described to date include Snyder-Robinson Syndrome (SRS), Bachmann-Bupp Syndrome (BABS), Faundes-Banka Syndrome (FABAS), as well as neurodevelopmental disorders associated with variants in DHPS and DOHH. These syndromes share many overlapping clinical phenotypes, including developmental delay, hypotonia, and intellectual disability. Here we describe details for identifying and obtaining high-quality biological samples from patients with polyaminopathies. This includes special considerations for the informed consent process and the collection and shipment of biological samples for patients with rare diseases, many of whom live in countries around the world. We also detail the technical protocols for the collection, processing, storage, and tracking of biological samples for downstream research analysis specific to research in polyaminopathies, as well as biobanking for future use.