Guillain-Barre Syndrome, Familial

A number sign (#) is used with this entry because a mutation in the PMP22 gene (601097) on chromosome 17 was identified in a single family with the acute (AIDP) and chronic (CIDP) forms of inflammatory demyelinating polyneuropathy.

Description

Guillain-Barre syndrome (GBS) is an acute inflammatory demyelinating polyneuropathy characterized most commonly by symmetric limb weakness and loss of tendon reflexes. It is a putative autoimmune disorder presenting after an infectious illness, most commonly Campylobacter jejuni, a gram-negative bacterium that causes acute enteritis (Yuki and Tsujino, 1995; Koga et al., 2005). Approximately 1 in 1,000 individuals develops GBS after C. jejuni infection (Nachamkin, 2001).

Although rare familial cases have been reported, GBS is considered to be a complex multifactorial disorder with both genetic and environmental factors rather than a disorder following simple mendelian inheritance (Geleijns et al., 2004).

Clinical Features

Davidson et al. (1992) reported the disorder in a father and son. The father's illness was at the age of 58 years. He recovered completely after a 2-month hospitalization during which he was treated with plasmapheresis. The son was hospitalized 9 years later at the age of 43 years; he also was treated with plasmapheresis, with complete recovery in 3 months. Davidson et al. (1992) commented on remarkably similar HLA typing results in the father and son.

Yuki and Tsujino (1995) reported 2 Japanese sisters who developed GBS following C. jejuni enteritis. The 19-month-old sister first developed flaccid tetraplegia and areflexia without sensory impairment and later showed esotropia, dysphagia, dysarthria, and nuchal weakness. All symptoms began to improve after about 2 weeks, and she was able to walk without support at day 117. Her 3.5-year-old sister developed similar clinical features, as well as respiratory failure and absence of corneal reflexes. She became comatose at day 7. She regained consciousness on day 22 and slowly recovered muscle function and the ability to walk without support at day 166. Both children met the clinical criteria for GBS following culture-confirmed C. jejuni enteritis.

Geleijns et al. (2004) reported 12 Dutch families in which at least 2 members had GBS. Clinical features were variable, even within families. The most common manifestations were motor deficits, including limb weakness, ataxia, ophthalmoplegia, bulbar weakness, dysphagia, and ptosis, although many patients also had sensory deficits. Almost all had a prodromal infectious illness. Among sibs, the observed incidence was increased 2.6-fold compared to the expected incidence. There was also a trend toward decreased age at onset in younger generations.

Inheritance

Saunders and Rake (1965) reported a brother and sister in whom muscle weakness developed 4 years apart. MacGregor (1965) reported a father with GBS whose daughter had an acute febrile illness with painful sensory neuropathy. Although these early reports suggested familial occurrence, Yuki and Tsujino (1995) noted that some of the patients reported by Saunders and Rake (1965) and MacGregor (1965) would not have fulfilled the accepted diagnostic criteria for GBS.

Bar-Joseph et al. (1991) reported 3 children, born of consanguineous parents in Israel, who all developed GBS before age 3 years.

Based on the observation of 12 Dutch families with at least 2 affected members, Geleijns et al. (2004) concluded that there may be a genetic component to increased susceptibility to GBS.

Molecular Genetics

Guillain-Barre syndrome has been associated with antecedent C. jejuni infections. Ma et al. (1998) found a higher frequency of a rare polymorphism in the TNFA gene (-308G-A; 191160.0004) in 43 Japanese patients with GBS who had had antecedent infection with C. jejuni compared to 85 community controls.

Despite the association of Guillain-Barre syndrome with antecedent C. jejuni infection, only a minority of infected individuals develop the disease, implying a role for genetic factors in conferring susceptibility. Pandey and Vedeler (2003) genotyped 83 patients and 196 healthy controls in Norway for immunoglobulin KM genes (genetic markers of the constant region of kappa immunoglobulin chains; 147200) by PCR-RFLP. The frequency of KM3 homozygotes was significantly increased in the patients compared with controls. Conversely, the frequency of KM1/KM3 heterozygotes was significantly decreased in patients compared with controls. The results suggested that KM genes may be relevant to the etiology of Guillain-Barre syndrome.

Korn-Lubetzki et al. (2002) described a family of Jewish Kurdish origin in which the father and 2 daughters were diagnosed with inflammatory demyelinating polyneuropathy within 10 years of each other. In the 2 patients tested, the father with the chronic form and a daughter with the acute form, a deletion in the PMP22 gene (601097.0004) typical of hereditary neuropathy with liability to pressure palsies (HNPP; 162500) was identified. The authors suggested that screening for the HNPP deletion in patients with atypical, recurrent, or familial inflammatory demyelinating polyneuropathy may be warranted.

Pathogenesis

The C. jejuni cst-II gene, which is involved in the biosynthesis of ganglioside-like lipooligosaccharides (LOS), has an asn51-to-thr (N51T) polymorphism that encodes a bifunctional alpha-2,3- and alpha-2,8-sialyltransferase and a monofunctional alpha-2,3-sialyltransferase, respectively. This polymorphism is assumed to affect autoantibody responses in the host through changes in the ganglioside epitope on the outer core of the organism. In a comparison of C. jejuni isolates from 105 patients with GBS, including 25 patients with similar neurologic variants, with 65 patients with uncomplicated enteritis, Koga et al. (2005) found that the neuropathic strains more frequently had the cst-II gene (85%), in particular the cst-II thr51 variant, compared to enteric strains (52%). C. jejuni strains with asn51 regularly expressed the GQ1b epitope (83%), those with thr51 had the GM1 (92%) and GD1a (91%) epitopes, and the presence of these strains in neuropathy patients corresponded to specific autoantibody reactivity. Koga et al. (2005) concluded that the genetic polymorphism of C. jejuni may determine autoantibody reactivity as well as clinical presentation of GBS, possibly through modification of host-mimicking molecules.

Hu et al. (2006) detected the IL23p19 protein (IL23A; 605580) in cerebrospinal fluid isolated from 5 patients with GBS. Sural nerve biopsies from these patients showed IL23p19 immunostaining in endoneurial macrophages. IL23A RNA was upregulated in sciatic nerve samples from 5 rats with experimental autoimmune neuritis (EAN), an animal model of GBS. Peak expression of IL23A RNA in the diseased animals occurred 2 days prior to peak clinical disease severity and then decreased to undetectable levels with clinical improvement. Hu et al. (2006) concluded that IL23 may play a role in the early effector phase of immune-mediated demyelination of the peripheral nerve.