An unusual cause of non-5q spinal muscular atrophy: DYNCH1-related disease

Case presentation: This is a five-year-old boy, admitted with global development delay associated with limb deformities. He was born prematurely at 35 weeks, by cesarean delivery due to pelvic presentation. During pregnancy, the mother noticed reduced fetal movements, and at birth, neonatal resuscitation with hospitalization was required. He was born with congenital arthrogryposis (CA), with thumbs in bilateral adduction, restricted plantar movement, global hypotonia, and facial dysmorphisms. Later, behavioral and cognitive changes became evident, leading to the diagnosis of autism spectrum disorder. Laboratorial work-up revealed mild CPK elevation. Genetic testing identified a heterozygous DYNCH1 pathogenic variant (p.Arg1201Ser), confirming the diagnosis of Spinal Muscular Atrophy Lower Extremity - predominant (SMALED – OMIM: 158600).

Discussion: CA is diagnosed in the presence of joint contractures in at least two areas of the body from birth with muscle wasting and abnormal joint configuration. The most common causes for this condition are disorders of the neuromuscular junction, congenital muscular dystrophies, congenital infections, and causes of fetal intrauterine immobility. There is, however, a smaller group referred to as neurogenic CA in which there is loss of motor neurons and subsequent denervation of muscle. Although the most frequent cause of neurogenic CA is 5q spinal muscular atrophy (SMA), SMN1-related, there is another group of diseases referred to as non-5q SMA, which include SMALED. This is a rare autosomal dominant condition caused by pathogenic DYNC1H1 variants. Mutations in this last gene are associated with three different phenotypes: Charcot Marie-Tooth disease, axonal, type 2O, intellectual developmental disorder, and SMALED. Patients with SMALED typically present muscle weakness, symmetric proximal and predominantly of the lower limbs, muscle atrophy, and deformities of joints. Cognitive delay can be present but is usually mild.

Final comments: This case describes DYNCH1-related SMALED, an unusual cause of non-5q SMA, in a Brazilian patient. This mutation is associated with variable phenotypes, leading to motor and cognitive disabilities. Neuropediatricians should be aware of this rare entity in the differential diagnosis of CA and/or SMA. Proper diagnosis enables adequate management and genetic counseling of the family.