Arthrogryposis, Distal, With Impaired Proprioception And Touch

A number sign (#) is used with this entry because of evidence that distal arthrogryposis with impaired proprioception and touch (DAIPT) is caused by homozygous or compound heterozygous mutation in the PIEZO2 gene (613629) on chromosome 18p11.

Heterozygous mutation in the PIEZO2 gene can cause distal arthrogryposis-5 (DA5; 108145), which shows some overlapping features.

Description

Distal arthrogryposis with impaired proprioception and touch is an autosomal recessive neurologic disorder characterized by loss of certain mechanosensation modalities resulting in ataxia, difficulty walking, dysmetria, muscle weakness and atrophy, and progressive skeletal contractures. Patients have onset of symptoms in early childhood (summary by Chesler et al., 2016 and Delle Vedove et al., 2016).

Clinical Features

Chesler et al. (2016) reported 2 unrelated patients with defects in touch and proprioception resulting in neuromuscular and skeletal abnormalities. The patients, who presented at 18 and 8 years of age, respectively, had congenital hip dysplasia, finger contractures, foot deformities, and severe progressive scoliosis. Both had a history of hypotonia, delayed head control, delayed walking until between 6 and 7 years of age, and impaired fine motor skills. Physical examination showed unsteady gait, inability to walk with eyes closed, and a positive Romberg sign, consistent with sensory ataxia. The patients had profoundly reduced touch discrimination, proprioception, and vibratory sense, more impaired on hairless glabrous skin than on hairy forearm skin. Electrophysiologic studies showed reduced amplitudes of sensory-nerve action potentials (SNAPs) and borderline, low-to-normal sensory-nerve conduction velocities, consistent with a mild sensory axonal neuropathy. There was no evidence of impaired cognition.

Delle Vedove et al. (2016) reported 10 patients from 4 unrelated consanguineous families with DAIPT. The families were of Turkish, Indian, Libyan, and Pakistani descent, and the patients ranged in age from 5 to 27 years. In the neonatal period, patients had hypotonia with poor feeding and they often had respiratory insufficiency that resolved spontaneously. The patients had delayed motor development with walking around age 5 years, although several patients never achieved independent ambulation. They had distal muscle weakness and atrophy primarily of the lower limbs, and about half also had distal muscle weakness and atrophy of the upper limbs. Additional features included dysarthria and areflexia. Skeletal features included scoliosis, 'duck-bill' deformity of the thumb, congenital pes equinovarus, pes planus, sandal gap deformity, arachnodactyly, and camptodactyly, consistent with contractures. Some patients had myopathic facies with long nose, wide nasal bridge, thin upper lip, and high-arched palate. Two of 4 patients studied had evidence of an axonal-demyelinating peripheral sensory neuropathy, and another reported decreased vibration sense. Three patients from 2 unrelated families had mild cognitive impairment.

Mahmud et al. (2017) reported 3 sibs, born of consanguineous Bangladeshi parents, with progressive contractures associated with impaired touch sensation and proprioception. The patients presented at 6 months of age with contractures of the hands and feet that worsened over time resulting in severe deformities. Two learned to walk at ages 6 and 9 years, but the third sib never achieved independent ambulation. Additional features included short stature, scoliosis, mildly decreased muscle strength, and absent reflexes. Mahmud et al. (2017) noted that the contractures in these sibs were more severe than those observed in DA5: the sibs had abduction of the first metacarpal bones, severe flexion contractures of the metacarpophalangeal and metatarsophalangeal joints, eversion of feet, and limited plantar flexion; one patient also had bilateral luxation of the radius.

Haliloglu et al. (2017) reported an 18-year-old boy, born of consanguineous Turkish parents, with DAIPT. At birth, he had hypotonia, hip dysplasia, distal laxity, contractures, and difficulty feeding. Head control was achieved at age 5 months and sitting without support at age 8 months. A muscle biopsy at age 3 years revealed mild myopathic changes, with predominant type I fibers. The patient started walking independently with an unsteady gait and coordination defects at age 16 years, following surgery for progressive scoliosis. At examination at age 18 years, he had an elongated face, high-arched palate, distal laxity, abduction in hands (prominently in the thumb), flexion contractures, left-sided scoliosis, asymmetric involvement of shoulder and trunk muscles, rigid spine deformity, and protruded calcaneus and eversion deformity of the feet. He showed slightly decreased lung function. Sensory examination showed a proprioception defect prominent in the upper extremity. He showed worsening of balance and coordination when he closed his eyes. Joint position sense was lost in the lower extremities and was present at ankle level. He was inconsistent in sensing during the light touch examination. Nerve conduction studies revealed a mild axonal neuropathy.

Inheritance

The transmission pattern of DAIPT in the families reported by Chesler et al. (2016) and Mahmud et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated patients with DAIPT, Chesler et al. (2016) identified compound heterozygous loss-of-function mutations in the PIEZO2 gene (613629.0010-613629.0012). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. In vitro functional expression studies in HEK293 cells showed that all 3 variants, including 2 nonsense variants and 1 missense variant, resulted in nonfunctional proteins. The findings suggested that PIEZO2 is required to transduce the mechanical forces at sensory afferent terminals.

In 3 sibs, born of consanguineous Bangladeshi parents, with DAIPT, Mahmud et al. (2017) identified a homozygous nonsense mutation in the PIEZO2 gene (S903X; 613629.0013). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a complete loss of function by abolishing the pore domain.

In 9 patients from 3 unrelated consanguineous families with DAIPT, Delle Vedove et al. (2016) identified homozygous loss-of-function mutations in the PIEZO2 gene (613629.0014-613629.0016). The mutations, which were found by whole-exome sequencing or homozygosity mapping and confirmed by Sanger sequencing, segregated with the disorder in the families. A tenth patient from another family with a similar phenotype was found to have 2 homozygous deletions encompassing the PIEZO2 gene. Delle Vedove et al. (2016) concluded that loss of PIEZO2 in afferent neurons in the dorsal root ganglia leads to disturbed proprioception causing aberrant muscle development and function.

By targeted gene-panel sequencing in an 18-year-old boy with DAIPT, who was born of consanguineous Turkish parents, Haliloglu et al. (2017) identified homozygosity for a nonsense mutation (R462X; 613629.0018) in the PIEZO2 gene. His parents, who were heterozygous for the mutation, were noted to have distal joint laxity.