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Título

POLR3B variant causing an axonal Charcot-Marie-Tooth disease

RESUMO

Case presentation: An 18-years-old male patient presented with a history of daily
vomiting, delayed puberty, and weakness. He complained of gastrointestinal tract
symptoms since his first year of life. Frequent falls were noted when learning to walk.
At age seven, he could no longer handle small objects, and was unable to climb stairs.
The patient also complained of painful paresthesia. On physical examination, muscle
atrophy was perceived, strength in opposition had a MRC grade 4 in proximal muscles
and MRC grade 0 in distal muscles. Deep tendon reflexes were absent. Pinprick and
vibration were reduced in upper and lower extremities. Electrodiagnostic studies (EDX)
revealed a severe axonal sensory-motor polyneuropathy. Median and ulnar motor
conductions studies were within normal range. Neuromuscular ultrasound showed
neurogenic changes in distal muscles. Whole-exome sequencing identified an
heterozygous de novo mutation in POLR3B - chr12:106.444.552 G>A
(p.Arg682Lys). A final diagnosis of Charcot-Marie-Tooth type 2 (axonal) was made.
Discussion: Polymerase RNA 3 B is the largest subunit of RNA polymerase III,
an enzyme involved in transcription of small non-conding RNA. Classical disease
descriptions were related bi-allelic mutations causing leukodystrophy. In 2021 this gene
was associated with peripheral neuropathy. To our knowledge, only nine patients
presenting with this pathogenic variant were described worldwide (six in original
publication, two in Japan, and one in China). There are no descriptions of this variant
causing neuropathy in Latin America. Although all cases reported had a EDX with
predominantly demyelinating features, the case here presented is of a clear axonal
phenotype, as demonstrated by EDX and nerve ultrasound. Delayed puberty was present
in our patient, like classical leukodystrophy type. Other features such as abnormal
dentition and ataxia were not present.
Conclusions: Despite widespread use of Next Generation Sequencing in
Hereditary Neuropathies, many patients remain without a final genetic diagnosis. This
number is even larger in axonal types. Newly described variants associated with disease
as the one here presented are of great interest in improving diagnostic rates and
expanding phenotypes.