Dados do Trabalho

Título

MUTATION IN DYNC1H1 GENE CAUSING DOMINANT SPINAL MUSCULAR ATROPHY WITH LOWER EXTREMITY PREDOMINANCE AND COGNITIVE DYSFUNCTION: A CASE REPORT IN A CHILD

Apresentação do caso único

G.L.S.A, male, 10 years old, evaluated by neuropediatrics for cognitive dysfunction and maternal report of incoordination and lower limb weakness noticed by 8 years old, with adequate neuropsychomotor development until then. Parent with difficulty to walking since 6 years old, due to distal weakness in the lower limbs and the presence of left tendon retraction. A genetic test was performed in the parent for progressive spinal amyotrophy and showed no deletions in the SMN1 gene. The investigation was continued in the father with hereditary neuropathy panel and evidenced a heterozygous mutation in the DYNC1H1 gene autosomal dominant (OMIN* 600112). This variant is associated with axonal type 2O Charcot-Marie-Tooth disease, spinal muscular atrophy with lower limb predominance (SMALED) and cortical dysplasia complex. Patient does not present changes in physical examination and has normal copies of SMN1 gene. The hereditary neuropathy panel is no longer available. However, due to dominant genetic inheritance and a electroclinical dyscorrelation at this age, electroneuromyography was performed with mild reduced recruitment and motor unit potencials of increased duration and amplitudes in quadriceps and tibialis anterior muscles point a neuronopathy type, compatible with SMALED. A brain magnetic resonance imaging was performed, with normal results. Patient was referred for motor physiotherapy, pedagogical follow-up and cognitive evaluation.

Discussão

Spinal muscular atrophies (SMAs) are hereditary disorders characterized by degeneration of spinal cord motor neurons. The majority of SMA cases show autosomal recessive inheritance and are caused by homozygous deletion or mutation of the SMN1 gene on 5q. The non-5q SMAs with distal-predominant weakness show phenotypic overlap with the distal hereditary motor neuropathies. The DYNC1H1 mutation causing SMALED with the main clinical features of congenital hip dislocation, talipes, delayed motor development, atrophy and weakness in the lower limbs with relative sparing of the upper limbs and very slow progression of the disease. The role of DYNC1H1 has thus seen an expansion in its phenotypic spectrum encompassing development of both the central and peripheral nervous systems.

Comentários finais

SMALED is extremely rare and only a handful of families have been reported. The advancement of genetic testing allowed new mutations to be discovered and the distal spinal muscular atrophies remains challenging because of clinical and genetic heterogeneity.

Referências

Das J, Lilleker JB, Jabbal K, Ealing J. A missense mutation in DYNC1H1 gene causing spinal muscular atrophy - Lower extremity, dominant. Neurol Neurochir Pol. 2018 Mar;52(2):293-297. doi: 10.1016/j.pjnns.2017.12.004. Epub 2017 Dec 14. PMID: 29306600.

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 Feb;52(2):239-44. doi: 10.1016/j.pediatrneurol.2014.09.003. Epub 2014 Oct 5. PMID: 25484024; PMCID: PMC4351714.

Palavras Chave

spinal muscular atrophy with lower extremity predominance; SMALED; DYNCH1