Chapter 2 AN OvERvIEw AND ONLINE REGIStRy OF MICROvILLuS INCLuSION DISEASE PAtIENtS AND tHEIR MYO 5 B MutAtIONS

Microvillus inclusion disease (MVID) is one of the most severe congenital intestinal disorders and is characterized by neonatal secretory diarrhea and the inability to absorb nutrients from the intestinal lumen. MVID is associated with patient-, familyand ancestry-unique mutations in the MYO5B gene, encoding the actin-based motor protein myosin Vb. Here we review the MYO5B gene and all currently known MYO5B mutations and for the first time methodologically categorize these with regard to functional protein domains and recurrence in MYO7A associated with Usher syndrome and other myosins. We also review animal models for MVID and the latest data on functional studies related to the myosin Vb protein. To congregate existing and future information on MVID geno-/phenotypes and facilitate its quick and easy sharing among clinicians and researchers, we have constructed an online MOLGENIS-based international patient registry (www.MVID-central. org). This easily accessible registry currently contains detailed information of 137 MVID patients together with reported clinical/phenotypic details and 41 unique MYO5B mutations, of which several unpublished. The future expansion and prospective nature of this registry is expected to improve disease diagnosis, prognosis and genetic counseling. An introduction to microvillus inclusion disease Microvillus inclusion disease (MVID; Online Mendelian Inheritance In Man 251850), previously known as familial protracted enteropathy (Davidson’s disease) or congenital microvillus atrophy, is a rare but life-threatening autosomal recessive enteropathy (Davidson et al, 1978; Cutz et al, 1989; Ruemmele et al, 2006). MVID is associated with patientor family-specific mutations in the MYO5B gene, encoding the ubiquitously expressed myosin Vb protein (Erickson et al, 2008; Müller et al, 2008; Ruemmele et al, 2010; Chen et al, 2011; Szperl et al, 2011). The clinical presentation of MVID is characterized by intractable, severe, watery diarrhea beginning in early infancy, failure to absorb nutrients, and failure to thrive. The prognosis is generally poor and depends on total parenteral nutrition (TPN) and bowel transplantation. MVID is the leading cause of neonatal secretory diarrhoea and accounts for ~7% of paediatric bowel transplantations worldwide. Most patients die at a young age as a consequence of total parenteral nutrition-induced liver failure or sepsis. Histological hallmarks of MVID small intestinal biopsies are hypoplastic atrophic or disorganized villi without crypt hypertrophy or immune cell infiltrate and, at the intestinal cellular level, microvillus atrophy, intracellular accumulation of brush border enzymes, and microvillus inclusions in the cytoplasm (Cutz et al, 1989; Ruemmele et al, 2006). Each of these hallmarks severely limits the absorptive capacity of the intestine. Diagnosis is established with light microscopy showing accumulation of periodic acid Schiff (PAS) reactivity and/or the brush border enzyme CD10 in the cytoplasm of the enterocytes (Groisman et al, 2002; Koepsell and Talmon, 2010) and, ultimately, with electron microscopy showing microvillus inclusions (Phillips et al, 1985). Two forms of MVID are distinguished: an early-onset and late-onset form in which symptoms start within hours or 1-3 months after birth, respectively. Notably, considerable enterocyte-to-enterocyte variation exists with respect to the extent of microvillus atrophy, number of microvillus inclusions, and the accumulation of electron-dense ‘granules’, AN OVERVIEW AND ONLINE REGISTRY OF MICROVILLUS INCLUSION DISEASE PATIENTS AND THEIR MYOSIN VB MUTATIONS 33 without a clear correlation between these phenotypes (Iancu et al, 2007). It is also relevant to note that the percentage of enterocytes with microvillus inclusions varies greatly between patients and in single patients as a function of time. An atypical form of MVID, i.e., without detectable microvillus inclusions, has been proposed (Mierau et al, 2001; Weeks et al, 2003). However, because of the sparse distribution of microvillus inclusions and sampling issues, the absence of microvillus inclusions is difficult to confirm (Cutz et al, 1997). A useful marker for these inclusions at the light microscopic level is villin (Sherman et al, 2004). In one patient spontaneous passage of detached long bowel segments has been reported (Chiang et al, 2013). Furthermore, extra-intestinal manifestations have been reported in MVID patients, including obesity and cushingoid fat distribution without demonstrated endocrine disease (Gambarara et al, 2003), hematuria (Siahanidou et al, 2013), pneumocystis jiroveci pneumonia (Siahanidou et al, 2013), dihydropyrimidinase deficiency (Assmann et al, 1997), autosomal dominant hypochondroplasia (Heinz-Erian et al, 1999), microcephaly, renal Fanconi syndrome (Golachowska et al, 2012) or other renal problems (Halac et al, 2011), hypophosphatemic rickets (Kagitani et al, 1998), diabetes (Oatman et al, 2013), cardiac (Gathungu et al, 2008) and pulmonary (Halac et al, 2011) problems, and liver dysfunction (Halac et al, 2011; Siahanidou et al, 2013) including multiple hepatic adenomas (Burgis et al, 2013). Several children with MVID have been reported to require special education care or display psychiatric problems (Halac et al, 2011). It is unclear to what extent these extra-intestinal phenotypes may be iatrogenic or linked to the MYO5B mutations, and patient-specific disease model are eagerly awaited. In some patients non TPN-related liver dysfunction presented only after intestinal transplantation (Halac et al, 2011). It can thus be anticipated that more complex phenotypic manifestations will evolve with therapeutic interventions and, as improved health care will increase the life span of children with MVID, also with age. An online registry for MvID patients and their MyO5B mutations To gain insight in the intestinal and extra-intestinal clinical manifestations of MVID and how these evolve with therapeutic interventions and age, a detailed understanding of the spectrum of MYO5B mutations, and the ability to establish genotype-phenotype correlations as a function of time is needed. Therefore, we have thoroughly reviewed the literature on MVID and MYO5B and constructed an international Microvillus Inclusion Disease (MVID) Patient Registry, accessible at http://www.MVID-central.org, to aid all clinicians and scientists working in the field of Microvillus Inclusion Disease and the MYO5B gene. The registry, the initiative of which is supported by the International Transplantation Association, contains all MVID patients who have been published in the medical literature. Information has been collected with regard to 1) patient/family details (including gender, consanguinity, and ancestry), 2) genetic details (including MYO5B cDNA change, paternal origin, exon/intron, homozygous/(compound) heterozygous, type of mutation), 3) protein