Ann Clin Neurophysiol.  2024 Apr;26(1):26-29. 10.14253/acn.23004.

A case of a missense DYNC1H1 mutation causing spinal muscular atrophy with lower limb predominance concurrent with germ cell tumor

• Lee MA
• Kim M
• Lee JH

• KMID: 2554851
• DOI: http://doi.org/10.14253/acn.23004

Abstract

We report a patient diagnosed with a germ-cell tumor presenting with spinal muscular atrophy with lower limb predominance (SMA-LED) caused by a DYNC1H1 genetic variant. His clinical and electrophysiologic phenotype was compatible with SMA-LED. We identified a heterozygous missense variant (c.1793G>T) of DYNC1H1. This report expands the clinical spectrum of DYNC1H1-related disorders, and reinforces the importance of DYNC1H1 in both central and peripheral neuronal functions. We suggest that germ-cell tumors should be considered as a possible phenotype of DYNC1H1-related disorders.

Keyword

Germ cell tumor; DYNC1H1 protein; Spinal muscular atrophy; Germ cell tumor; protein; Spinal muscular atrophy

Figure

• 

  Fig. 1. Pedigree and clinical features of the patient. (A) Pedigree of the three-generation family with dominant spinal muscular atrophy with lower extremity predominance. Filled symbol pointed by the arrow indicates the affected patient. There were no affected individuals other than our patient. (B) A heterogeneously enhanced mass of size 9.3×7.6×8.9 cm was found in the right mediastinum, and diagnosed as a mixed germ-cell tumor (arrow). (C) Foot deformity (talipes). (D) Distal wasting in lower limbs.

Reference

1. Fleury P, Hageman G. A dominantly inherited lower motor neuron disorder presenting at birth with associated arthrogryposis. J Neurol Neurosurg Psychiatry. 1985; 48:1037–1048.

2. Harms MB, Ori-McKenney KM, Scoto M, Tuck EP, Bell S, Ma D, et al. Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy. Neurology. 2012; 78:1714–1720.

3. Scoto M, Rossor AM, Harms MB, Cirak S, Calissano M, Robb S, et al. Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy. Neurology. 2015; 84:668–679.

4. Punetha J, Monges S, Franchi ME, Hoffman EP, Cirak S, Tesi-Rocha C. Exome sequencing identifies DYNC1H1 variant associated with vertebral abnormality and spinal muscular atrophy with lower extremity predominance. Pediatr Neurol. 2015; 52:239–244.

5. Cheng J, Randall A, Baldi P. Prediction of protein stability changes for single-site mutations using support vector machines. Proteins. 2006; 62:1125–1132.

6. Capriotti E, Fariselli P, Casadio R. I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res. 2005; 33:W306–W310.

7. Giannakakou P, Sackett DL, Ward Y, Webster KR, Blagosklonny MV, Fojo T. p53 is associated with cellular microtubules and is transported to the nucleus by dynein. Nat Cell Biol. 2000; 2:709–717.

8. Lee Y, Lee JS, Kim SY, Cho J, Yoo Y, Lee S, et al. Comprehensive genetic analysis by whole exome sequencing in 352 Korean pediatric patients with unknown neurodevelopmental disorders. bioRxiv. 2018; Nov. 18. [Epub]. DOI: 10.1101/472803.

9. Gong LB, Wen T, Li Z, Xin X, Che XF, Wang J, et al. DYNC1I1 promotes the proliferation and migration of gastric cancer by up-regulating IL-6 expression. Front Oncol. 2019; 9:491.

10. Sucularli C, Arslantas M. Computational prediction and analysis of deleterious cancer associated missense mutations in DYNC1H1. Mol Cell Probes. 2017; 34:21–29.