A number sign (#) is used with this entry because of evidence that arthrogryposis multiplex congenita-5 (AMC5) is caused by homozygous or compound heterozygous mutation in the TOR1A gene (605204) on chromosome 9q34.

Arthrogryposis multiplex congenita-5 (AMC5) is an autosomal recessive disorder characterized by severe joint contractures apparent at birth. Affected individuals usually have hypertonia and abnormal movements suggestive of dystonia, as well as feeding and/or breathing difficulties. More variable features may include poor overall growth, strabismus, dysmorphic facies, and global developmental delay with impaired speech (summary by Kariminejad et al., 2017).

Kariminejad et al. (2017) reported 4 children from 3 unrelated consanguineous Iranian families with AMC5. The patients, who ranged in age from 2 to 4 years, presented at birth with severe contractures of the large and small joints, including elbows, wrists, fingers, hips, knees, ankles, and toes. Tremor of the hands, stereotypic hand movements, facial grimacing, and neck extension were also observed in some patients. Additional features included rocker-bottom feet, hammertoes, camptodactyly, hip dislocation (2 patients), increased muscle tone, and strabismus. The contractures and tremor tended to resolve with time; strabismus worsened over time. The patients had poor overall growth, and some had dysmorphic features, such as prominent occiput, deep-set eyes, ptosis, upslanting palpebral fissures, short upturned nose, large, low-set and posteriorly rotated ears, retrognathia, wide mouth, high-arched palate, and short neck. All patients had global developmental delay with variably impaired intellectual development. Two sibs in family 1 and the patient in family 2 were the most severely affected: none could sit, walk, or speak. The 2-year-old patient in family 3 was beginning to crawl and babble. The unaffected carrier parents did not have signs of dystonia, consistent with incomplete penetrance of the dominant phenotype.

Reichert et al. (2017) reported a 7-month-old male infant, born of Mexican parents, with AMC5. The pregnancy was complicated by intrauterine growth retardation and decreased fetal movements. He was born with AMC, including contractures of all extremities, hip dislocation, clubfeet, 11 sets of ribs, and scoliosis. He developed restrictive lung disease requiring tracheostomy, and uncoordinated swallowing difficulties requiring tube feeding. The infant had no spontaneous or involuntary movements, but responded to voices and could make eye contact.

Isik et al. (2019) reported a 4.5-month-old boy with AMC5. The pregnancy was complicated by decreased fetal movements and polyhydramnios. At birth, he showed severe arthrogryposis with hip dislocation, joint contractures, adducted thumbs, camptodactyly, pes valgus, rocker-bottom feet, and hammertoes. He also had increased muscle tone. Soon after birth, he developed bradycardia necessitating resuscitation and apneic episodes and respiratory failure requiring mechanical ventilation. The infant had poor overall growth with microcephaly and dysmorphic features, including prominent occiput, round face with full cheeks, broad nasal bridge, anteverted nares, long philtrum, micrognathia, large ears, short neck, kyphoscoliosis, and umbilical and inguinal hernia. He did not have strabismus, but retinal examination showed pale optic discs. At 4 months of age, he had severe hypotonia with inability to lift his head or swallow. He had daily dystonic movements associated with apnea, and he died at 4.5 months of age during one of these episodes. Two prior pregnancies of the mother miscarried in the first trimester.

The transmission pattern of AMC5 in the families reported by Kariminejad et al. (2017) was consistent with autosomal recessive inheritance.

In 4 patients from 3 unrelated consanguineous Iranian families with AMC5, Kariminejad et al. (2017) identified homozygous mutations in the TOR1A gene (E303del, 605204.0001 and G318S, 605204.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all 3 families. None of the carrier parents had evidence of torsion dystonia, consistent with incomplete penetrance of the dominant phenotype. In vitro expression studies in cells transfected with the G318S mutation showed abnormal localization of the mutant protein from the endoplasmic reticulum to the nuclear envelope, as well as the formation of spheroid bodies.

In a 7-month-old boy, born of Mexican parents, with AMC5, Reichert et al. (2017) identified compound heterozygous mutations in the TOR1A gene (605204.0001 and 605204.0007). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.

In a 4.5-month-old boy, born of reportedly unrelated Bulgarian parents, with AMC5, Isik et al. (2019) identified a homozygous nonsense mutation in the TOR1A gene (R288X; 605204.0008). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. The variant was found at a low frequency in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.