Dados do Trabalho

Título

LATE-ONSET GM2 GANGLIOSIDOSIS DUE TO MUTATIONS IN GM2A GENE MIMICKING SPINAL MUSCULAR ATROPHY TYPE 3

Apresentação dos casos

Case 1. Male, 36 years old, history of parental consanguinity.
Started progressive proximal muscular weakness in lower limbs at ten years old—weakness presented with slow progression over the years to the scapular girdle. Clinical evaluation at that time with 15 years old showed a motor neuron disease, being diagnosed as Kugelberg Welander disease (SMA type 3). At that time, neurological evaluation was remarkable for the presence of preserved tendon reflexes in 4 limbs. Weakness progressed slowly, and the patient lost his gait around the third decade of life. At the age of 35, he presented proximal and distal muscle atrophy, and tendon reflexes are now abolished, with exuberant polyminimyoclonus on examination. Cognitive is normal. Molecular investigation for deletions in the SMN1 gene ruled out that it was 5q SMA - it had 02 SMN1 copies and 00 SMN2 copies.
Exome sequencing revealed a homozygous missense mutation at position c.428G>A (p.Gly143Glu) in the GM2A gene.
Case 2. A female, 43 years old, started muscle weakness of proximal predominance, exclusively affecting the lower limbs, around ten years ago and with electroneuromyography indicating a neurogenic process restricted to the quadriceps femoris and gastrocnemius muscles bilaterally. MRI of the thighs and legs showed exclusive involvement of the quadriceps femoris and gastrocnemius muscles, with a neurogenic pattern. Exome NGS showed two variants in compound heterozygosity (p.Gly143Glu and p.Gly166Arg) in the GM2A gene.
Case 3. Male, 40 years old, adult-onset muscle weakness of the lower limbs, mimicking SMA type 3, and investigation with NGS also showed two variants in the GM2A gene (p.Gly166Arg and p.Asp116His).

Discussão

Non-5q Spinal Muscular Atrophy presents a diversity of genes described in the literature. Previously, GM2 gangliosidosis mimicking spinal muscular atrophy (related to mutations in the HEXA gene) was described. However, motor neuron disease related to mutations in the GM2A gene, which encodes a ganglioside activator protein, has not yet been described. Here, we describe a late-onset motor neuron disease phenotype mimicking SMA type 3 or 4, whose genetic investigation resulted in the finding of GM2A gene mutations.

Comentários finais

Conclusion: The three cases presented here have in common a late-onset motor neuron disease mimicking SMA 3, with preferential involvement of the quadriceps and recessive mutations in the GM2A gene.

Referências

Hölzer HT, Boschann F, Hennermann JB, Hahn G, Hermann A, von der Hagen M, Tüngler V. Cerebellar atrophy on top of motor neuron compromise as indicator of late-onset GM2 gangliosidosis. J Neurol. 2021 Jun;268(6):2259-2262. doi: 10.1007/s00415-021-10492-y. Epub 2021 Mar 9. PMID: 33751187; PMCID: PMC8179894.
Scarpelli M, Tomelleri G, Bertolasi L, Salviati A. Natural history of motor neuron disease in adult onset GM2-gangliosidosis: A case report with 25 years of follow-up. Mol Genet Metab Rep. 2014 Jul 2;1:269-272. doi: 10.1016/j.ymgmr.2014.06.002. PMID: 27896099; PMCID: PMC5121317.

Palavras Chave

Spinal muscular atrophy; gangliosidosis; motor neuron disease