Bachmann-Bupp syndrome and treatment

Abstract

Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia. The condition is caused by 3'-end mutations of the ornithine decarboxylase 1 (ODC1) gene, which produce carboxy (C)-terminally truncated variants of ODC, a pyridoxal 5'-phosphate-dependent enzyme. C-terminal truncation of ODC prevents its ubiquitin-independent proteasomal degradation and leads to cellular accumulation of ODC enzyme that remains catalytically active. ODC is the first rate-limiting enzyme that converts ornithine to putrescine in the polyamine pathway. Polyamines (putrescine, spermidine, spermine) are aliphatic molecules found in all forms of life and are important during embryogenesis, organogenesis, and tumorigenesis. BABS is an ultra-rare condition with few reported cases, but it serves as a convincing example for drug repurposing therapy. α-Difluoromethylornithine (DFMO, also known as eflornithine) is an ODC inhibitor with a strong safety profile in pediatric use for neuroblastoma and other cancers as well as West African sleeping sickness (trypanosomiasis). Patients with BABS have been treated with DFMO and have shown improvement in hair growth, muscle tone, and development.

FIGURE 1

Polyamine pathway and associated genetic syndromes. The polyamine pathway is shown, highlighting five gene products (green colored) that are associated with known genetic syndromes and disorders (green boxes). The three principal polyamines putrescine, spermidine, and spermine are synthesized from ornithine by the subsequent catalytic actions of ODC, SRM, and SMS respectively, as well as the catalytic action of AMD1. Both ODC1 and AMD1 genes are direct transcriptional targets of MYC. In addition, polyamines are transported into and out of cells by polyamine transporters, including solute carriers and P5B-ATPases. Polyamines can be acetylated by the action of SSAT-1 and either exported by polyamine transporters or reconverted by PAOX. Alternatively, reconversion may occur directly by SMOX. Polyamines are tightly regulated to maintain cellular homeostasis required to regulate key physiological functions including embryogenesis and organogenesis. If the fine-tuned balance of polyamines is altered, it can result in tumorigenesis. Spermidine is the sole substrate for the post-translational hypusine modification (activation) of eIF5A (at amino-acid residue lysine-50) which requires the consecutive catalytic action of DHPS and DOHH. Therefore, spermidine directly controls eIF5A-dependent protein translation. In addition to SMS, ODC, DHPS, DOHH, and eIF5A, mutations in other polyamine-associated gene products (blue colored) might also be involved in related human genetic disorders, all leading to an imbalance (increase or decrease) of intracellular putrescine, spermidine, and/or spermine pools. Collectively, they present a new group of polyamine-associated neurodevelopmental disorders we have named polyaminopathies. Abbreviations: Amd1, S-Adenosylmethionine Decarboxylase; Arg1, Arginase 1; Az, Antizyme; Azin, Antizyme Inhibitor; Babs, Bachmann–Bupp Syndrome; Dcsam, Decarboxylated S-Adenosylmethionine; Dfmo, α-Difluoromethylornithine; Dhps, Deoxyhypusine Synthase; Dohh, Deoxyhypusine Hydroxylase; Eif5a, Eukaryotic Translation Initiation Factor 5a; Fabas, Faundes–Banka Syndrome; Mat1, Methionine Adenosyltransferase 1; Myc, Myelocytomatosis Oncoprotein; Odc, Ornithine Decarboxylase; Paox, Polyamine Oxidase; Sam, S-Adenosylmethionine; Smox, Spermine Oxidase; Srs, Snyder–Robinson Syndrome; Ssat-1, Spermidine/Spermine N1-Acetyltransferase 1; Srm, Spermidine Synthase; Sms, Spermine Synthase.

FIGURE 2

Representation of the ubiquitin-independent and antizyme-stimulated degradation of ODC by the 26S proteasome. ODC is a short-lived homodimer protein and regulated by a process that does not require ubiquitination to stimulate its proteasomal degradation. Antizyme binds to transient ODC monomer, which results in the exposure of the ODC carboxy (C)-terminal tail that is subsequently recognized by the 26S proteasome for degradation. Antizyme also binds AZIN, but with greater affinity than ODC, thus sequestering antizyme into a stable complex, which reduces its ability to regulate ODC. If the C-terminal tail of ODC is truncated in the final 37-amino acid residue destabilization region (yellow oval), ODC is not presented to the 26S proteasome, which leads to accumulation of ODC that remains catalytically active, thus producing increased amounts of putrescine, suggesting a gain-of-function situation. The underlying mechanisms by which increased ODC protein and elevated putrescine levels lead to BABS remain to be explored. Abbreviations: AZ, antizyme; AZIN, antizyme inhibitor; BABS, Bachmann–Bupp syndrome; CT, C-terminal tail; ODC, ornithine decarboxylase.

FIGURE 3

Clinical photography. The first patient diagnosed with Bachmann–Bupp syndrome at (a) birth, (b) 2 years 8 months, (c) 4 years 8 months (taken day of α-difluoromethylornithine [DFMO] initiation), (d) 5 years 6 months (11 months into DFMO treatment), and (e) 7 years 11 months. At birth, the patient had a full head of silver/blonde hair which fell out shortly after birth. Before treatment, the patient had complete alopecia with no hair, eyebrows, or eyelashes. After initiation of treatment, hair fully regrew, and the patient had significant improvement in muscle tone and development.