Arthrogryposis multiplex congenita, distal, type 1 (DA1) is the prototypic form of distal arthrogryposis and as such is largely characterized by camptodactyly (permanently bent fingers and toes) and clubfoot (inward- and upward-turning foot). Recent evidence suggests that DA1A due to TPM2 mutations results from muscle dysfunction, although distal arthrogryposis was originally defined as being without overt neurologic or muscle disease. Hypoplasia and/or absence of some interphalangeal creases is common. In distal arthrogryposes visceral anomalies are absent and intelligence is normal. Another form of type 1 DA is caused by mutation in the MYBPC1 gene (DA1B).
Detailed clinical description
In the upper extremities, ulnar deviation, camptodactyly, absent flexion creases, and overriding fingers can be found. In the lower extremities, metatarsus varus, talipes equinovarus, vertical talus, hip dislocation, and calcaneovalgus deformity can be seen. Intrafamilial variability is typical of DA1A. Limited range of motion at the shoulders can be observed. Some individuals may have a small mouth and mild limitation in opening of the mouth. Distal arthrogryposis type 1 affects an estimated 1 in 10,000 people worldwide. DA1A is certainly compatible with adult life, as large multigenerational families with the syndrome have been reported.
Prenatal diagnosis of distal arthrogryposis type I by ultrasound can be possible as early as the 18th week of gestation. Signs include the wrist blocked in extension and the fingers remaining ‘fisted’ throughout a period of ultrasonic observation.
DA1A is caused by one heterozygous mutations in the TPM2 and the transmission is autosomal dominant. Other mutations in the same gene can also cause arthrogryposis, distal, type 2B (DA2B) and nemaline myopathy 4 (which is autosomal dominant). The DA1A causing mutation is c.271C>G transversion in exon 3, which is predicted to result in an amino acidic substitution (p.Arg91Gly, often written in the old nomenclature as R91G; reference sequence: NM_003289.3). Codon 91 is a highly conserved residue and c.271C>G (p.Arg91Gly) is a gain of function mutation, which leads to increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility. Another amino acid change at codon 133 causes DA2B: c.397C>T (p.Arg133Trp). Few other mutations cause nemaline myopathy 4. In some cases, the genetic cause of distal arthrogryposis type 1 remains unknown and scientists speculate that mutations in genes other than TPM2 or MYBPC1 may be causative.
Genetic testing strategy
Targeted mutation analysis can be done to detect the causative c.271C>G mutation. However, since arthrogryposes are genetically and clinically heterogeneous, full TPM2 gene sequencing (EXOME GENE) or panel testing (EXOME PANEL) is recommended.
Panel testing recommended at Breda Genetics for this condition: