Supplementary table 1: Syndromes and disorders associated with achalasia and their key features
Syndrome / MIM / Key features / Reference(s)Triple A syndrome
(Allgrove syndrome) / 231550 / Achalasia, ACTH-resistant adrenal insufficiency, alacrima, occasional additional neurological and dermatological abnormalities / Allgrove et al. 1978; Gazarian et al. 1995; Grant et al. 1993; Hirano et al. 2006; Houlden et al. 2002; Huebner et al. 2002; Huebner et al. 2004; Khelif et al. 2003; Kiriyama et al. 2008; Murphy et al. 1989; Prpic et al. 2003; Toromanovic et al. 2009; Tullio-Pelet et al. 2000; Weber et al. 1996
Down syndrome
(Trisomy 21) / 190685 / Most frequent form of mental retardation (MR); combination of phenotypic features including MR, characteristic facies, and multiple congenital abnormalities, in particular of the GI / Moore 2008; Nakazato and Landing 1986; Okawada et al. 2005; Spahis and Wilson 1999; Wallace 2007
Familial visceral neuropathy / 609629
(autosomal dominant)
243180
(autosomal recessive) / Intestinal dysmotility and pseudo-obstruction, achalasia, peripheral neuropathy, dysarthria, and pupillary defects, occasionally with neuronal eosinophilic intranuclear inclusions / Barnett et al. 1992; Camilleri et al. 1991; Faber et al. 1987; Mayer et al. 1986; Roper et al. 2005; Roy et al. 1980; Schuffler et al. 1978; Zannolli et al. 2002
Achalasia microcephaly syndrome / 200450 / Achalasia, microcephaly, and mental retardation / Dumars et al. 1980; Hernandez et al. 1989; Khalifa 1988; Kreuz et al. 1999; Williams et al. 1978
Parkinson’s disease / 168600 / Second most common neurodegenerative disease; several gene loci have been implicated in autosomal dominant forms / Johnston et al. 2001; Lesage and Brice 2009; Qualman et al. 1984
MEN 2B / 162300 / Cancer syndrome that includes medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia, multiple mucosal neuromata, and marfanoid body habitus / Carney et al. 1976; Carney and Hayles 1977; Carney et al. 1978; Cuthbert et al. 1978; Demos et al. 1983; Ghosh et al. 1994; Hirano 1999
Familial dysautonomia (Riley-Day syndrome) / 223900 / Autonomic neuropathy, occasionally including GI dysmotility / Maayan et al. 1990; Narcy et al. 1987; Nihoul-Fekete et al. 1991
Opitz-Frias syndrome / 145410 / Typical craniofacial features (hypertelorism, micrognathia, high arched palate), abnormalities of the cholinergic nervous system, malformation of the urinary tract / Bolsin and Gillbe 1985; Kien et al. 1981; Sauer et al. 1981
Neurofibromatosis type 1 (von Recklinghausen disease) / 162200 / Phacomatosis with multiple cutaneous manifestations (in particular cafe au lait spots and fibromatous tumors), tumors of the peripheral and central nervous system, and occasional skeletal features / Foster et al. 1987; Marshall et al. 1990b
Hereditary cerebellar ataxia / 208920 / Hereditary neuronal degeneration of the cerebellum / Murphy et al. 1989
Posterior column ataxia / 609033 / Severe sensory ataxia with retinitis pigmentosa, scoliosis / Higgins et al. 1997
Sandhoff disease (Type II GM2 gangliosidosis) / 268800 / Lysosomal storage disease, progressive CNS destruction, organomegaly and tissue damage / Pellegrini et al. 2006
Ectodermal dysplasia / 129500 (autosomal dominant)
224900
(autosomal recessive)
305100
(X-linked) / Dysplasia of two or more ectodermal structures such as the skin, teeth, nails, hair, cranial-facial structures, digits, and other body parts / Shimohashi et al. 1995
Treacher Collins syndrome / 154500 / Disorder of craniofacial development including antimongoloid slant of the eyes, coloboma of the lid, micrognathia, microtia and other deformities of the ears, hypoplastic zygomatic arches, and macrostomia / Schneider 1987
Goldenhar syndrome (Hemifacial microsomia) / 164210 / Oculo-Auriculo-Vertebral (OAV) syndrome, incomplete development of ear, nose, soft palate, lip, and mandible, usually on one side of the body / Shokeir 1977
Dubowitz syndrome / 223370 / Intrauterine growth retardation, short stature, microcephaly, characteristic facial appearance / Nowicki and Peterson 1998
Klein-Waardenburg syndrome (Waardenburg syndrome type III) / 148820 / Hearing loss, pigmentary anomalies (white forelock), and limb abnormalities / Piechowiak et al. 1985
Smith-Lemli-Opitz syndrome / 270400 / 7-DHC reductase deficiency with elevated cholesterol precursors, growth retardation, microcephaly, mental retardation, hypospadias, 2-3 toe syndactyly, dysmorphic features / Haas et al. 2005
Marfan syndrome / 154700 / Connective tissue disorder with typical habitus and cardinal features in cardiovascular, skeletal, and ocular systems / Rapeport and Bremner 1981
Binder syndrome / 155050 / Maxillo-nasal dysplasia, midfacial hypoplasia / Narcy et al. 1987
Shy-Drager syndrome / 146500 / Progressive multiple system atrophy with autonomic failure and features of Parkinson’s disease / Aubert et al. 1980
Fabry disease / 301500 / X-linked lysosomal storage disorder with angiokeratomas, anhidrosis, cardiovascular complications, and renal insufficiency / Roberts and Gilmore 1984
Alport syndrome / 308940 / Association of Alport syndrome (hereditary nephritis and hearing loss) with diffuse leiomyomatosis of the esophageal wall / Leichter et al. 1988; Marshall et al. 1990a
Hirschsprung disease / 142623 / Aganglionic megacolon; one major susceptibility gene, RET, contributes to HSCR1, and several other loci contribute to HSCR2-9 / Gupta and Hollander 1977; Jorge and Diaz 1976; Kelly et al. 1997; Kohler et al. 2005
Megacystis-microcolon-intestinal hypoperistalsis syndrome / 249210 / Hereditary hollow visceral myopathy with distended bladder, dilated small bowel, microcolon, decreased/absent peristalsis, with the presence of ganglion cells / Al Harbi et al. 1999
Situs inversus viscerum / 270100 / Reversed or mirrored positions of the major visceral organs / Spinelli et al. 1991
Sjögren syndrome (Sicca syndrome) / 270150 / Dry eyes and dry mouth, association with rheumatoid disorders / Koivukangas et al. 1973; Poglio et al. 2007; Simila et al. 1978; Weissmann 1958
Autoimmune polyendocrine syndrome type II / 269200 / Addison’s disease combined with hypothyroidism, diabetes mellitus type 1, and occasionally hypogonadism and vitiligo / Fritzen et al. 1996
Autoimmune thyropathies / Hashimoto thyroiditis (140300) or Graves disease (275000) / Hashimoto’s thyroiditis or Grave’s disease / Emami et al. 2007; Kroupa et al. 2008
Sarcoidosis / 181000 / Multisystem disorder with formation of non-caseating granulomas / Dufresne et al. 1983
Supplementary table 2: Genes implicated in achalasia and involvement in cellular pathways
AAAS / 12q13 / · autosomal recessive
· candidate gene / · Development of the peripheral and central nervous systems
· Nucleocyto-plasmic transport
· Impaired import of DNA repair proteins? / · Triple A (achalasia, addisonianism, alacrima) syndrome / Allgrove et al. 1978; Gazarian et al. 1995; Grant et al. 1993; Hirano et al. 2006; Houlden et al. 2002; Huebner et al. 2002; Huebner et al. 2004; Khelif et al. 2003; Kiriyama et al. 2008; Murphy et al. 1989; Prpic et al. 2003; Toromanovic et al. 2009; Tullio-Pelet et al. 2000; Weber et al. 1996
Candidate genes mediating autoimmune response / inflammatory processes
HLA class II DQ and DR / 6p21
MHC region / candidate gene / · Recognition of cell surface molecules
· Specific immune regulation / · Several autoimmune diseases
· Positive and negative associations of various DR and DQ alleles with idopathic achalasia / De la Concha et al. 2000; De la Concha et al. 1998; Di Nardo et al. 2005; Gebe et al. 2002; Latiano et al. 2006; Raymond et al. 1999; Ruiz-de-Leon et al. 2002; Verne et al. 1999; Wong et al. 1989
PTPN22 / 1p13 / candidate gene / · Gene product is lymphoid-specific phosphatase
· Down-regulation of T-cell activation / · Autoimmune diseases
· Gender-specific association of gene variants with achalasia (in females) / Bottini et al. 2006; Kahles et al. 2005; Pierer et al. 2006; Santiago et al. 2007; Vang et al. 2005
RASSF1A / 3p21 / candidate gene / · Tumor suppressor gene
· Possibly involved in immune-regulation / · Megaesophagus in aged RASSF1a-deficient mice
· Increased incidence of gastrointestinal tumors in RASSF1a-deficient mice / van der Weyden et al. 2009
Esophageal motor function
NOS1 (nNOS)
NOS2 (iNOS)
NOS3 (eNOS) / 12q24 (NOS1)
17q11 (NOS2)
7q36 (NOS3) / candidate genes / · NO-production / · Impaired nNOS synthesis of esophageal myenteric plexus in achalasia patients
· Achalasia in nNOS-deficient mice / De Giorgio et al. 1999; Gockel et al. 2008; Kim et al. 1999; Lefebvre 1995; Lui et al. 1997; Mearin et al. 2006; Mearin et al. 1993; Murray et al. 1991; Murray and Clark 1994; Sivarao et al. 2001; Takahashi 2003; Tottrup et al. 1991; Watanabe et al. 2002; Yamato et al. 1992
KIT / 4q11 / candidate gene / · Tyrosine kinase receptor expressed on interstitial cells of Cajal (ICC)
· KIT signalling is important for the development and maintenance of the ICC phenotype / · Gain of function mutations cause gastrointestinal stromal tumor and other tumors in humans
· W/Wv mutant mice with partial loss of KIT function display a variety of GI motility disorders
· Reduced numbers of ICC and reduced NO-dependent neurotransmission in the LES zone in W/Wv mice / De Giorgio and Camilleri 2004; Sanders et al. 2002; Ward et al. 1998
VIPR1 / 3p22 / candidate gene / · Mediation of VIP effects: smooth muscle relaxation and immune-modulation / · Rheumatoid arthritis
· Polymorphisms causing receptor down-modulation are associated with late onset achalasia in humans / Delgado et al. 2008; Paladini et al. 2009; Pozo and Delgado 2004; Sreedharan et al. 1995; Voice et al. 2002
GDNF-RET-signalling pathway
RET / 10q11 / · autosomal- dominant mutations with variable expression and penetrance in HSCR1
· candidate gene / · GDNF-RET signalling: development and function of the ENS / · Many different loss-of-function mutations in HSCR
· Gain-of-function mutations in MEN 2 syndromes
· Achalasia and MEN 2B in rare patients / Amiel and Lyonnet 2001; Barlow et al. 2003; Ceccherini et al. 1993; Moore and Zaahl 2008; Musholt et al. 1997
GDNF / 5p13 / · autosomal- dominant mutations in HSCR3
· candidate gene / · GDNF-RET signalling / · May act in concert to produce an enteric phenotype (HSCR) / Gianino et al. 2003; Moore et al. 1996; Pichel et al. 1996; Sanchez et al. 1996; Srinivasan et al. 2005
SPRY2
(SPROUTY2) / 13q31 / candidate gene / · Inhibitor of receptor tyrosine kinase signalling
· Negative regulator of GDNF-RET signalling / · Development of ENS hyperganglionosis with achalasia and megacolon in SPRY2-deficient mice / Dikic and Giordano 2003; Gross et al. 2001; Hanafusa et al. 2002; Lim et al. 2002; Yusoff et al. 2002