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Management Of Syndromic Diarrhea/Tricho-Hepato-Enteric Syndrome

TTC37 is a protein coding gene, located on the long arm of chromosome 539. It consists of 43 exons and produces a product, previously known as thepsin. Thepsin/TTC37 is comprised of amino acid residues and 20 tetratricopeptide repeat (TPR) domains. It is widely expressed, with high levels observed in the intestine. TTC37 is considered to be the homolog of the yeast protein Ski341. Mutations have been described in multiple exons in TTC37, with recurrent mutations arising in exon 28. The missense mutation c.2808G>A was termed the ‘South Asian mutation’ by Hartley et al due to its frequency in patients of Indian and Pakistani origin.

SKIV2L is a gene located on the short arm of chromosome 633. It consists of 28 exons and produces the SKIV2L protein, a DExH box helicase that is 1246 amino acids in length. DexH box helicases are a family of proteins involved in RNA metabolism. The protein product of this gene is thought to be the homolog of the yeast protein Ski2, which along with Ski3 – yeast homolog of TTC37 and Ski8 – yeast homolog of WD Repeat Domain 61 (WDR61), form the Ski complex. SKIV2L protein is widely expressed, with particularly high levels of expression found in the stomach and brain. Loss of Skiv2l in mice can lead to a lack of negative regulation of the RIG-I receptor, resulting in upregulated receptor activity and subsequent type 1 interferon overproduction.

Mortality of patients suffering from THES has improved since it was first described in 1982, however it is still extremely high and approximately 1/3rd of patients die before the age of 1024. Death commonly results from hepatic failure or secondary to the complications associated with long term PN. As of yet, there have been no specific trials conducted into the treatment of THES given its rarity and it is normally managed on a case-by-case basis. Management of THES is normally supportive, consisting of PN and immunoglobulin supplementation, required by approximately 83% of patients. Other drugs such as steroids and antibiotics were often used, along with immunosuppressant drugs such as methotrexate and TNF blockers. Haematopoietic stem cell transplantation (HSCT) was conducted in 4 cases and successfully corrected reduced Ig production and response to vaccination. Unfortunately it did not appear to improve other problems, such as eczema and diarrhea, which suggests these symptoms may not be caused by dysfunction of the haematopoietic system. HSCT was also associated with a high mortality, with 2/4 patients dying due to complications of the treatment. It is evident that treatment of THES inadequate. Disease pathogenesis needs to be further investigated in order to improve treatment of THES in the future.

Few studies have investigated the effects of variants in SKIV2L and TTC37 on subsequent protein expression and function, therefore this remains to be fully elucidated. Heijima et al reported a reduction in SKIV2L protein expression as a result of variants in SKIV2L in one patient with THES, however no corresponding investigations have been carried out in TTC37 15. These proteins are thought to form part of the putative human Ski (Superkiller) complex, a cofactor of the cytosolic RNA exosome. As the phenotype can results from variants in either gene, it is presumed that the absence of the Ski complex is responsible for the disease. As the Ski complex is linked to the degradation of mRNA in yeast, THES may be caused by the accumulation of aberrant mRNA or the stabilization of transcripts that should be degraded. However, the mechanism by which a defect in the mRNA degradation system leads to this phenotype remains unclear. There is also uncertainty as to why certain systems such as the skin, gastrointestinal and immune system are predominantly affected.

Trichohepatoenteric syndrome (THES) is a rare autosomal recessive disorder that is characterized by early-onset intractable diarrhea as a result of enteropathy, hair dysmorphology, immunodeficiency and growth restriction. The first recorded cases of THES are thought to be those published by Stankler et al in 19826. His paper described 2 siblings who presented with low birth weight, dysmorphic features and abnormal ‘wooly’ hair6. Initially THES was considered a separate disorder from Syndromic Diarrhoea, a disorder where patients suffered from the same intractable diarrhea, however in 2007 Fabre et al proposed that these disorders were in fact the same recognizable phenotype. The incidence of THES is thought to fall between 1 in 400,000-500,000 live births and to date 80 patients have been described with the condition. It is caused by homozygous or compound heterozygous variants in the genes TTC37 or SKIV2L. Variants in either gene lead to an identical phenotype.

The age at presentation of THES varies between approximately 2 weeks and 7 months, however in many cases patients present with diarrhea within the first month of life. There is a high incidence of preterm delivery and during pregnancy, polyhydramnios and placentomegaly may be seen. The clinical presentation of THES can prove variable, with differences in both symptoms and disease severity. In particular, there is a large range in severity of gastrointestinal problems associated with THES; patients with mild symptoms need only oral enteral nutrition, while those with severe malnutrition require long-term total parenteral nutrition (TPN).

Immunodeficiency diseases occur when there is a defect in one or more components of the immune system. These diseases are classified as either primary or secondary immunodeficiencies1. Primary immunodeficiency (PID) diseases are defined as a “genetically heterogeneous group of disorders that affect distinct components of the innate and adaptive immune system”. Since the first report of PID in 1956, a boy with X-linked agammaglobulinaemia, over 354 distinct disorders have been described. Recently however, due to the expanding number and spectrum of phenotypes within PID diseases, the nomenclature has changed to “inborn errors of immunity”. Unlike PID, this new terminology facilitates the inclusion of diseases of immune dysregulation and autoinflammatory disorders. The following project will focus on one such inborn error of immunity, known as trichohepatoenteric syndrome. As well as the Ski complex, human diseases have been linked to variants in genes encoding proteins that form the RNA exosome. Pontocerebellar hypoplasia (PCH) is an autosomal recessive neurodegenerative condition. PCH types 1b and 1c have been linked to variants in EXOSC3 and EXOSC8 respectively. In addition, variants in EXOSC2 have been linked to a distinct phenotype consisting of retinitis pigmentosa and impairment of intellectual development.

The degradation of excess mRNA within the cell cytoplasm is key to maintaining cellular homeostasis. Accumulation of aberrant mRNA species is harmful as they may interfere with translation of properly processed mRNA. Excess aberrant mRNAs in the cytoplasm can also activate innate cytosolic antiviral defence mechanisms, leading to a subsequent production of interferon and pathogenic inflammation.

Type I interferons (IFN?/?) are major cytokines involved in the host response to viral infection and other intracellular pathogens50. They induce the expression of a group of several hundred ‘interferon-stimulated genes’ (ISGs), to induce the cellular antiviral state and promote apoptosis of infected cells to counter viral infection. In addition, they alert surrounding cells to the presence of a viral infection by facilitating antigen presentation, which leads to the maturation and proliferation of lymphocytes. The result is the restriction of viral spread and protection with minimum damage to the host.

Production of type I interferon is initiated by pattern recognition receptors (PRRs) of the innate immune system50. PRRs are cellular receptors that play a key role in innate immunity. They recognize regular patterns of molecular structure present on pathogens but not on the body’s own cells, termed pathogen-associated molecular patterns (PAMPs).

The host is alerted to the presence of a viral infection upon detection of viral nucleic acids within the cell cytoplasm by intracellular PRRs. There are multiple nucleic acid sensing pathways within the cell that trigger an innate immune response. RNA viruses are detected in the cytosol by two members of the cytosolic RIG-I like helicase family, Retinoic acid-inducible gene I (RIG-I) and Melanoma differentiation-associated 5 (MDA5).

MDA5 senses long dsRNA (>2kbp). RIG-I senses short dsRNA and ssRNA (<2kpb), with a di- or triphosphate moiety at the 5’end, allowing it to distinguish between host and viral mRNA. On transcription of eukaryotic RNA within the nucleus, a 7-methylguanosine is added to the 5-triphosphate group on its first nucleotide in a process known as capping. Most RNA viruses however, do not undergo this modification as they do not replicate in the nucleus. RIG-I utilizes this difference, sensing the uncapped 5-triphosphate end of the viral RNA. RIG-I receptors are widely expressed and serve as intra-cellular sensors for multiple types of viral infection. They are known to detect a variety of viruses including flavivirus, rhabdoviruses and paramoyxoviruses, such as Sendai virus. However, they are unable to detect picornaviruses such as Hepatitis A and Poliovirus as they both undergo capping. These viruses are instead sensed by MDA. In addition, RIG-I can detect viral DNA via the RNA polymerase III pathway, which transcribes DNA into 5’-triphosphate RNA. Stimulation of the RIG-I or MDA receptors, leads to the production of type I interferon and pro-inflammatory cytokines.

Defects in nucleic acid sensing and degradation pathways are associated with a group of inborn errors of immunity known as type I interferonopathies. Type I interferonopathies are a group of auto-inflammatory disorders, caused by dysfunction of the innate immune system. This group exhibits significant phenotypic heterogeneity, with a unifying feature of persistent and abnormal upregulation of type 1 interferon. Symptoms are often due to systemic autoinflammation, at times overspilling into autoimmunity. Presentation often occurs in early life and may mimic congenital infection. Aicardi Goutieres Syndrome (AGS), like THES, may be caused by pathogenic variants in multiple genes involved in both DNA and RNA nucleic acid sensing pathways. AGS presents as an early onset progressive brain disease with symptoms mimicking those seen as a result of viral infection in utero. Other type I interferonopathies, such as STING-associated vasculitis with onset in infancy (SAVI), are characterized by systemic inflammation. SAVI is caused by gain-of-function variants in TMEM173, which encodes stimulator of interferon genes (STING), an adaptor molecule involved in the cytosolic DNA sensing pathway.

Type I interferonopathies result from a number of distinct mechanisms. Firstly, an abnormal metabolism of endogenous nucleic acids may lead to a pathogenic upregulation of interferon, as seen in TREX1 deficient AGS50. Enhanced sensitivity to nucleic acids or impaired negative regulation of nucleic acid PRRs may be also responsible, as seen in Singleton-Merton Syndrome caused by variants in DDX5850. Lastly, there may ligand-independent activation of these receptor or defects further downstream. As defects in nucleic acid degradation pathways have been associated with a pathogenic upregulation of type I interferon, it was hypothesized that variants in SKIV2L or TTC37, which may affect mRNA degradation within the cell, could also lead to heightened interferon production. Patients with pathogenic variants in SKIV2L, but not TTC37, have been reported to exhibit a strong type I interferon peripheral blood signature. This observation was linked mechanistically to heightened interferon response following RIG-I receptor stimulation in murine cells deficient in Skiv2l, but not Ttc37. On this basis, Stetson proposed that SKIV2L has an exosome-independent role regulating the RIG-I receptor. However this mechanism has not been investigated in human cells.

A potential endogenous source of cellular RIG-I ligand, is the Unfolded Protein Response (UPR). The UPR is a cellular stress response that regulates gene expression64. It is activated by an accumulation of unfolded proteins in the endoplasmic reticulum (ER), as a result of an overabundance of newly synthesized polypeptides, causing the ER to exceed its protein-folding capacity. Activation of the UPR stimulates the expression of genes that increase the size of the ER and its functional capacity. It also leads to the activation of Inositol-requiring enzyme 1 (IRE-1), which leads to the transcription of ER chaperones via splicing of XBP1 and degradation of mRNA66. The latter function is thought to create a source of endogenous RNA which can trigger RIG-I66. This was demonstrated by Stetson et al, who observed an upregulation of RIG-I receptor activity in SKIV2L deficient cells after stimulation of the UPR.

The findings of Stetson et all have led to the proposal that SKIV2L deficient THES is a type I interferonopathy. As discussed above, the precise pathomechanism in a human context is unknown. Nevertheless, if type I interferon plays a significant role in pathogenesis, this could revolutionise the treatment and potentially the prognosis of THES. Based on our current knowledge of type I interferonopathies, targeting type I interferon, the IFN? receptor (IFNAR), or the Janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) pathway to inhibit a pathogenic type I IFN response may be therapeutically effective. Clinical trials are currently underway, treating patients suffering from certain type I interferonopathies with the JAK inhibitor baracitinib, and initial observations seem promising. No clinical attempts to block the interferon signaling pathway in patients with SKIV2L deficient THES have been reported28.

However, there are significant questions regarding whether type I interferon plays a pathogenic role in SKIV2L deficiency. First, pathogenic variants in SKIV2L and TTC37 produce an identical clinical phenotype. Second, none of the clinical features of THES overlap with existing type I interferonopathies. Finally, a recent study of a novel SKIV2L deficient patient did not find any evidence of enhanced ISG responses, calling into question the original observation by the Stetson group15. The authors speculated that there may instead be a correlation between disease severity and type I interferon production and that determining ISG expression could assist in the prediction of the prognosis and severity of symptoms in patients with THES.

Nevertheless, given the current uncertainties, and in particular the absence of mechanistic data regarding the role of human SKIV2L in regulating RIG-I signaling, further research is warranted.

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