Sedaghatian type Spondylometaphyseal Dysplasia (SSMD) is an extremely rare progressive disorder in which ends of the long bones (metaphyses) show cupping/flaring, flattening of the vertebrae (platyspondyly), cardiac arrhythmia, and central nervous system abnormalities including hypogenesis of corpus callosum and cerebellar hypoplasia. The disease is congenital, and the majority of patients die in the first days after birth due to respiratory distress. SSMD is an autosomal recessive disease caused by variants in both alleles of the glutathione peroxidase 4 (GPX4) gene (Smith et al.). GPX4 is a member of the family of antioxidant defense enzymes called glutathione peroxidases, and protects the cells against membrane lipid peroxidation.
SSMD was first reported by Sedaghatian (after which the disorder is eponymously named) in 1980, reporting two brothers in Iran who each died within the first week of birth, and finding ‘severe congenital metaphyseal involvement, mild rhizomelic shortness of upper limbs, and mild platyspondyly’. Since that time, a small number of further reports have been published describing patients with presumed SSMD (Table 1). In 2014, Smith et al. used whole exome sequencing of a child affected with SSMD (and unaffected parents) and found that mutations in GPX4 are likely responsible for SSMD. A small number of patient GPX4 sequences have been reported (shown in Table 2), and include both point mutations and missense mutations. The implications on GPX4 are discussed below.
At the time of writing, we know of four pediatric patients (3 male, 1 female, median age 31 months) living with this condition. Based on natural history data of these patients, other symptoms include severe hypotonia, global development delays, auditory neuropathy, cortical visual impairment, scoliosis, and hypertonia. The oldest patient developed intractable seizures at the age of 3 and continues to be treated with anticonvulsants to reduce the occurrence of breakthrough seizures. There is no current therapy to treat SSMD, except for physical and occupational therapies. Without treatment, babies born with this condition can never sit up, walk, have feeding difficulties, and significantly delay physical and cognitive development. They are at a high risk for premature death by cardiovascular, cerebrovascular, neuromuscular, or renal complications.
GPX4 is an antioxidant enzyme belonging to the family of mammalian isoenzymes called glutathione peroxidases produced by the gene gpx4. gpx4 gene consists of seven exons and six introns and produces three isoforms of the protein - mitochondrial (mGPX4 - UNIPROT P36969-1), cytosolic (cGPX4 - UNIPROT P36969-2) and nuclear (nGPX4). All three isoforms are ubiquitously expressed in all tissues. Cytosolic and mitochondrial isoforms are known to be essential in the neurons of the developing brain (Savaskan et al) and the nuclear isoform is predominantly synthesized during late spermatogenesis (Pfeifr et al). It is a selenoprotein whose catalytic activity is indispensable for normal embryogenesis, maintaining mitochondrial oxidative phosphorylation, preventing lipid peroxidation, and plays a part in combating increased oxidative damage due to injury or chemotherapy.
mGPX4 has been shown to protect mitochondrial ATP generation against oxidative damage (Liang et al). Knockdown studies of GPX4 show reduction in expression of genes encoding components of Complex I, IV, and V (Cole-Ezea et al). Overexpression of mGPX4 prevents release of the proapoptotic signalling molecule Cytochrome C from mitochondria and plays a key role as an anti-apoptotic agent in mitochondrial death pathways (Nomura et al). mGPX4 protects cardiac contractile function and preserves electron transport chain activities following ischemia/reperfusion (Dabkowski et al.)
Cytosolic isoform of GPX4 is capable of reducing complex lipid peroxides such as those present in lipid membrane bilayer of cells. Polyunsaturated-fatty-acid-containing phospholipids (PL-PUFAs) are the lipids most susceptible to peroxidation with the bis-allylic carbons being most susceptible to attack by reactive oxygen species (Feng et al). GPX4 localizes to lipid membranes and reduces PUFA hydroperoxides using Glutathione (GSH) as substrate.
Ferroptosis is a novel form of iron-dependent cell death. Loss of GPX4 results in peroxidation of the lipid cell membrane driven by an increase in reactive oxygen species (ROS). Depletion of the cell's intrinsic antioxidant Glutathione (GSH) also leads to ferroptosis. The presence of oxidizable phospholipids acylated with polyunsaturated fatty acid, presence of redox-active iron, and defective lipid peroxide repair are the hallmark features required for ferroptosis (Dixon et al). α-Tocopherol (Vitamin E) works with GPX4 and GSH to stop lipid peroxidation thereby halting ferroptosis.
Ferroptosis is emerging as a mechanism of cell death in various diseases including cardiovascular diseases (Kobayashi et al), acute kidney failure (Muller et al) and may also play a role in central degenerative brain disorders (Weiland et al, Yang et al.). Ferroptosis is driven by loss of activity of lipid repair enzyme GPX4 and subsequent accumulation of lipid hydroperoxides. Depletion of GPX4 in mice is known to induce ferroptotic cell death in embryo, testis, brain, liver, heart, and photoreceptor cells (Imai et al.), cause rapid motor neuron degeneration and paralysis (Chen L), promotes cognitive impairment (Hambright et al), triggers acute renal failure (Angeli et al), and results in impaired T-cell-mediated immune response (Matsushita et al). Mice with depleted GPX4 showed hallmarks of ferroptosis including an increase in lipid peroxidation in various cell types (Hambright et al).
Read more about GPX4, SSMD disease and animal models at: