Arthrogryposis Multiplex Congenita, Neurogenic Type

A number sign (#) is used with this entry because of evidence that neurogenic-type arthrogryposis multiplex congenita (AMCN) is caused by homozygous mutation in the ERGIC1 gene (617946) on chromosome 5q35. One such family has been reported.

Clinical Features

Weissman et al. (1963) described an arthrogryposis-like picture consisting of flexion contractures at the elbows or knees and no dislocation of the hips. Lebenthal et al. (1970) reported further observations of the kindred studied by Weissman et al. (1963). They found 23 cases in an inbred Arab group. In a repeat study of this kindred, Jaber et al. (1995) identified 40 affected individuals. Five of the 6 individuals who were originally reported as having congenital and lethal heart defects were limited to one sibship. None of the newly identified cases had heart defect or any associated malformation. Neurologic examination and electrophysiologic studies demonstrated a neuropathic (i.e., nonmyopathic) type of arthrogryposis. Penetrance may be incomplete in females. Shohat et al. (1997) found that the most common clinical features in this family were flexion contractures of the elbows and knees and marked equinovarus. Many patients learned how to cope adequately with their handicap, and most of the adult patients were employed, some as carpenters (a common profession in this clan). Females were less affected than males; the male/female ratio was 2 to 1 and the authors concluded that there is incomplete penetrance of the disorder in females.

From Israel, Krugliak et al. (1978) presented 3 autopsies of neuropathic AMC in Bedouin Arabs and commented on 2 other cases. This is presumably the same disorder as that reported by Lebenthal et al. (1970). One infant showed, in addition to depletion of spinal motor neurons, total absence of muscle spindles.

Heterogeneity

Burglen et al. (1996) found evidence suggesting that arthrogryposis multiplex congenita of neurogenic origin is genetically heterogeneous, with a subgroup being allelic to spinal muscular atrophy type I, or Werdnig-Hoffmann disease (SMA1; 253300). The evidence they presented came from a study of 12 patients with AMC, 6 of whom showed a deletion of SMN (600354), the survival motor neuron gene, which is implicated in SMA1. Neither point mutation in the SMN gene nor evidence for linkage to 5q13 was found in the other 6 patients. They suggested that the absence or interruption of the SMN gene would make arthrogryposis multiplex congenita-spinal muscular atrophy (AMC-SMA) easier to diagnose and would make genetic counseling feasible. Previously, one of the exclusion criteria for SMA had been arthrogryposis with severe and generalized contractures; now it is clear that some of these cases are in fact a form of SMA.

Mapping

In a large inbred Israeli-Arab kindred with autosomal recessive AMC of the neurogenic type, Magal et al. (1997) mapped the disease locus to the terminal part of 5q. Homozygosity testing pointed to linkage with D5S1456. Formal linkage studies showed a maximum lod of 5.3 at theta = 0.001 for linkage between AMC and this marker. No recombinations were observed between D5S394 and the disease locus, which is presumably located in 5q35. Lotan et al. (1997) pointed out that the kindred studied by Magal et al. (1997) was that originally described by Weissman et al. (1963) and updated by Lebenthal et al. (1970), as mentioned earlier. Shohat et al. (1997) indicated that the AMCN locus in this family was located between markers D5S1456 and D5S498. Further fine mapping of this region allowed Tanamy et al. (2001) to narrow the critical region to a distance of 0.442 Mb between markers D5S394 and D5S2069.

Molecular Genetics

In affected members of a highly consanguineous Arab kindred (Lebenthal et al., 1970) with AMCN, Reinstein et al. (2018) identified a homozygous missense mutation in the ERGIC1 gene (V98E; 617946.0001). The mutation was located within the previously defined linked region in this family. The mutation, which was found by exome sequencing, segregated with the disorder in the kindred and was not found in the ExAC database or in 212 ethnically matched controls. Functional studies of the variant and studies of patient cells were not performed.

Animal Model

Arthrogryposis, apparently recessively inherited, is known in sheep (Roberts, 1929) and in cattle (Hutt, 1934), although this designation is not used.

History

Like the terms 'cerebral palsy' and 'autism,' the term 'arthrogryposis' refers not to a distinct syndrome or single entity, but instead to a symptom complex that, in the case of the neurogenic type of AMC, is characterized by congenital contractures. Genetic forms seem to be rare. Several discordant monozygotic twin pairs have been described. The possibility of infection of the fetus by a virus with neuromyal tropism (e.g., coxsackie) should be investigated epidemiologically, virologically and immunologically.

Frischknecht et al. (1960) described 3 affected sibs and suggested the designation 'neuroarthromyodysplasia' rather than arthrogryposis because at autopsy changes were found to involve the spinal cord and the Betz cells. Ek (1958) reported affected sisters. In addition to the forms of arthrogryposis due to loss of motor neurons in the anterior horn of the spinal cord and to congenital muscular dystrophy, Bargeton et al. (1961) described a third type which is familial and characterized by focal collagenous proliferation in the anterior spinal roots. They reported autopsy findings in 1 of 2 brothers, the offspring of first-cousin parents. The primary lesion was neurologic. Swinyard (1963) also reported familial cases.

Laitinen and Hirvensalo (1966) observed affected sibs. Pena et al. (1968) studied 2 Puerto Rican families, each with affected children. At least 1 of the 4 affected children was female. Histologic abnormalities were found in the spinal cord.

Gustavson and Jorulf (1976) observed a case in which the parents were second cousins. The Drachman hypothesis that arthrogryposis is caused by immobilization of fetal limbs during the period of formation of joints received support from the finding of arthrogryposis in the offspring of a woman who received tubocurarine in early pregnancy for treatment of tetanus (Jago, 1970).