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Heterozygous variants in BICD2 cause autosomal dominant spinal muscular atrophy with lower extremity predominance. These variants are also identified in individuals with severe forms of congenital muscle atrophy representing arthrogryposis multiplex.
Case report
A girl was born with severe muscle weakness and respiratory distress. A fetal ultrasound had detected polyhydramnios and multiple joint contractures in utero. She was born with severe muscle weakness and respiratory distress. Bilateral hip joint dislocation and multiple bone fractures were also present at birth. Although she depends on medical care, including assisted ventilation and tube feeding, she has reached eight years of age. Her motor developmental skills were reduced owing to muscle weakness and deformity of her lower extremities, whereas her cognitive development slowly but steadily grew. Whole exome sequencing revealed a novel de novo missense BICD2 variant (c.1625G > A, p.(Cys542Tyr)), which was evaluated as likely pathogenic.
Conclusion
This is the first case report of a severe form of spinal muscular atrophy with lower extremity predominance caused by a de novo BICD2 variant in Japan.
Arthrogryposis multiplex congenita (AMC), or simply arthrogryposis, is a clinically heterogeneous disorder characterized by congenital multiple joint contractures [
]. AMC originates from a secondary effect of decreased fetal movement, which can arise due to various etiologies, an underlying genetic cause and/or environmental defects in utero. Abnormalities of all pathways involving movement, including the nervous system from the brain to the peripheral nerves, muscle, and connective tissue can be causative. Recently, many kinds of genetic variants in more than 200 genes have been identified as causative for arthrogryposis [
Heterozygous mutations in BICD2 (bicaudal D homolog 2, MIM 609797, NM_015250.3) cause autosomal dominant spinal muscular atrophy with lower extremity predominance (SMA-LED2, MIM 615290), which is known to have a childhood onset and mildly progressive phenotype [
Here, we report an eight-year-old girl, clinically diagnosed with AMC, who needs careful medical care, including continuous assisted ventilation and tube feeding through a gastrostomy. Whole exome sequencing revealed a novel de novo missense BICD2 variant, which was evaluated as pathogenic. To our knowledge, this is the first case report of a patient with a severe form of SMA-LED, clinically diagnosed with AMC, caused by a de novo BICD2 mutation in the Japanese population.
Genetic analysis was performed after obtaining written informed consent from her parents. They also gave written permission to publish this case report and use her photograph.
2. Case report
This girl was the second child born to healthy unrelated Japanese parents. Polyhydramnios and multiple joint contractures were detected on ultrasound at 27 weeks gestation. Her mother required repetitive therapeutic amniocenteses. The girl was born by caesarean section at 37 weeks gestation with mild asphyxia, weighing 2796 g, with a length of 49.5 cm. Her head circumference was 35.6 cm, which was normal upper range for her gestational age, but relatively large for her body size. She had multiple joint contractures with remarkable hip dislocation and multiple fractures of her extremities were detected by X-ray (Figure 1). Her muscle tone was weak and she showed severe respiratory insufficiency and needed intubation with assisted ventilation. At five months she had a tracheostomy, but weaning off assisted ventilation was difficult. She also had feeding difficulties and dysphagia of her saliva. Both tube feeding and continuous oral suction were needed. She had a gastrostomy at three years of age. Brain magnetic resonance imaging showed mild cerebral atrophy but no apparent structural abnormality. Further examinations, such as nerve conduction studies, electromyography and muscle biopsy, were not performed.
Fig. 1Images and clinical pictures. (A) X-ray just after birth showed bilateral hip dislocation with extreme extension (white arrow) and fractures of the bilateral humerus (black arrowheads). (B) Brain T2-weighted magnetic resonance images at the age of two years. Slightly dilated lateral ventricles bilaterally represented mild cerebral atrophy. No apparent cortical malformation was detected. (C) A clinical picture at the age of five years. She needed a reclining bed-wheelchair to move and continuous assisted ventilation via tracheostomy. Multiple joint contractures were predominant in the lower extremities, with equinovarus deformity in the foot.
Although she was clinically diagnosed with AMC, general laboratory findings and her other clinical signs were not specific for an accurate diagnosis. Chromosomal analysis demonstrated a normal female karyotype, 46XX, and microarray analysis showed no pathological findings. We performed whole exome sequencing using the “Initiative on Rare and Undiagnosed Diseases in Pediatrics” system in Japan. Whole exome sequencing revealed a heterozygous BICD2 missense variant (NM_015250.3: c.1625G > A, p.(Cys542Tyr)). This variant was not listed in the gnomAD database, and was predicted to be a protein-damaging mutation by in silico analyses, SIFT, PolyPhen2 and Mutation Taster. This variant was not detected in either of her parents and was considered de novo. According to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines, the variant was classified as likely pathogenic.
Now she is eight years old. She still needs medical care, including continuous assisted ventilation, continuous oral suction, and tube feeding via gastrostomy. She lies on her bed and has difficulty sitting or standing voluntarily. She can turn her head and has limited movement of her upper limbs. Deep tendon reflexes are absent and she has no apparent plantar response, while sensory responses to pain and temperature are intact. Compared to her poor physical development, her cognitive development continues slowly but steadily. She can communicate with others by eye contact and smile back. She can express her emotions by facial changes. She also recognizes her parents and her favorite care givers, and likes to watch children’s television programs.
3. Discussion
BICD2 is a cargo protein and essential for intracellular transport through microtubules. The BICD2 protein binds the dynein-dynactin motor protein complex, and plays the role of a linker between the motor protein complex and various cargoes [
]. Individuals carrying heterozygous BICD2 missense variants present with muscle weakness and atrophy of the proximal lower limbs. Mostly the onset is congenital or during childhood and the clinical course is benign and slowly progressive.
] first reported the severe clinical course of two individuals with onset in utero. They presented with reduced fetal movement and were born with AMC and severe hypotonia. Two more case reports were published after their article [
]. We have summarized the clinical findings of our present case and the affected individuals previously reported in Table 1. In these reports, hip dislocation was one of the common features, and while muscle weakness involved the whole body resulting in respiratory insufficiency, the lower extremities were predominantly affected, with equinovarus deformity in the foot. Half of the individuals unfortunately died during the perinatal period or in early infancy. In the remaining individuals still living, a high degree of medical care and careful management was essential for life. Delayed cognitive development was also common, although it was preserved and not progressively impaired, compared to physical impairment. Cortical malformations or cerebral atrophy were sometimes present on magnetic resonance imaging. The extent of impairment of BICD2 function might be associated with neuronal proliferation and migration.
Table 1Clinical findings in affected individuals with a BICD2-related severe form of SMA-LED.
Our present patient has the novel mutation, p.(Cys542Tyr), which was not listed in the gnomAD database. The mutation was predicted to be damaging by in silico prediction programs, and classified as likely pathogenic by the ACMG-AMP guidelines. We concluded that this mutation affects the patient. The cysteine at position 542 (Cys542) is highly conserved in species from Drosophila to primates. Besides, a different substitution, p.(Cys542Thr), reported by Storbeck et al [
], affects a patient with severe SMA-LED (Patient No. 5 in Table 1), suggesting that Cys542 is important for BICD2 protein function.
Cys542 is located in coiled-coil domain 2 of the BICD2 protein. This domain interacts with kinesin-1, a representative motor protein, as well as dynein. According to a recent review, Cys542 is included in one of the hotspot domains of the BICD2 variants in SMA-LED [
]. They examined the relationship between variant location and clinical features. Individuals with variants in the coiled-coil domain 2 tended to be more likely to show signs of severe disease than those with variants in other domains. Disrupting interactions between the partner proteins could lead to a more severe influence.
Another type of SMA-LED is caused by mutations of DYNC1H1, encoding cytoplasmic dynein heavy chain 1, a binding partner of BICD2. Notably DYNC1H1-related SMA-LED also presents a clinical spectrum, with some individuals having the congenital onset of arthrogryposis with cognitive impairment and cortical malformations [
]. Axonal transport is essential for nerve development, activity and survival. Many kinds of mutations in genes encoding involvement in intracellular transport mechanisms have been discovered to cause neurological disease [
]. They are promising for potential therapeutic targets. Further accumulation of knowledge involving intracellular transport and function of motor protein families is greatly needed.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We sincerely thank the patient and her family members for participation in this study. This work was supported in part by a grant for Initiative on Rare and Undiagnosed Diseases in Pediatrics from the Japan Agency for Medical Research and Development.
References
Hall J.G.
Arthrogryposis (multiple congenital contractures): diagnostic approach to etiology, classification, genetics, and general principle.
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