Dados do Trabalho

Título

Increasing genetic and phenotypic variability of PRPS1 gene mutations: a new mutation associated to a complex hereditary motor neuropathy

RESUMO

Case Presentation
Two male siblings from non-consanguineous parents presented in their first decade of life with a complex phenotype including delayed motor milestones, dysarthria and deafness. Ataxic gait was noted at age of three in both. Symptoms worsened over the years, mainly gait, with frequent falls. Their mother presented hypoacusia by the age of 54, with no other symptoms. Brain MRI revealed cerebellar atrophy. Nerve conduction studies revealed motor axonal neuropathy in both siblings. WES revealed a class 5 variant on the PRPS1 gene: (NM_002764.4) c.894A>C. Hence, a diagnosis within the spectrum of Arts syndrome and PRPS1-related disorders was made.

Discussion
Arts syndrome is a rare entity described in 1993. Twelve young boys of a family presented sensorineural hypoacusia, ataxia, delayed motor milestones and tendency to upper respiratory tract infections. Later, an autopsy showed absence of myelinated axons in the posterior column of the spinal cord.
It is an X-linked condition caused by a loss-of-function mutation on the PRPS1 gene leading to decreased enzyme function. Besides Arts syndrome, mutations in PRPS1 have been associated with a large spectrum of manifestations, as X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5) and X-linked deafness-1 (DFNX1). Adult female carriers can present isolated hypoacusia, as did the mother of our patients.
We found description of 22 pathogenic variants in this gene, apart from the aforementioned new variant. Clinical features of this case showed the presence of motor neuropathy, sensorineural hypoacusia and delayed motor milestones, which have been described in some loss-of-function mutations. Gain-of-function mutations described so far are mostly related to hyperuricemia and gout arthritis. This is of great importance as a minor study has shown benefit from providing S-adenosylmethionine (SAM) to some patients.
Description of a novel variant in the PRPS1 gene may support the impression that according to the mutation and residual enzyme function, different clinical features are seen.

Final Comments
We present a new variant in the PRPS1 gene related to Arts syndrome, and a pure motor neuropathy could be a new finding that had not been described so far. Segregation analysis suggests an X-linked inheritance. PRPS1 gene is related to nucleotide metabolism and the synthesis of purines, and identification of this mutation is of practical relevance as SAM supplementation may be beneficial to these patients.

Palavras Chave

Sensorineural hypoacusia; Ataxia; Motor neuropathy; Neuromuscular disorders; PRPS-1 gene; Arts syndrome.