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Título

PLEKHG5 MUTATION: A RARE CAUSE OF CHARCOT-MARIE-TOOTH DISEASE

Apresentação do caso

Fifteen year-old male, brown skin, with non consanguineous parents and a previous
diagnosis of intellectual deficiency and attention deficit hyperactivity disorder. When the
patient was ten years old the symptoms began with gait impairment, bilateral foot drop and
calf pain. The symptoms progressed and 7 months before our clinical evaluation the patient
also started presenting muscle contracture in both upper limbs with no sensitive complaints.
In the physical exam there was distal limb muscle weakness in the regions from ulnar,
mediane and fibular nerve and bilateral claw hand. There was no muscle atrophy and the
only area with sensitive impairment was apalesthesia on the left hallux. Bilateral slapping
gait was also noticed.
The findings included a brain MRI with a discreet prominence in the lateral ventricles
and elevated serum creatine kinase (1400mg/dl). Needle electromyography showed a
chronic sensory-motor polyneuropathy affecting all four limbs with a myelin-axonal pattern.
The genetic painel presented a pathogenic mutation in heterozygous on the HINT1 and in
homozygous on PLEKHG5, both associated with an intermediary type C form of Charcot-
Marie-Tooth (CMT).

Discussão

CMT comprises a clinically and genetically heterogeneous group of peripheral
neuropathies characterized by progressive distal limb weakness, atrophy, foot deformities,
sensory impairment and hypo or areflexia. The two main clinical forms, demyelination and
axonal, were described based on electromyographic findings. There is also the intermediary
group that combines findings from the above.
Mutations on PLEKHG5 can lead to a wide set of manifestations, such as
intermediary CMT. The clinical manifestation is typically associated with missense mutations
in homozygous. Our patient presented similar symptoms even though the mutation was
heterozygous.
The second mutation found on the HINT1 gene is correlated with axonal neuropathy
associated with neuromyotonia. However, the patient's electromyographic study showed a
myelinic-axonal form, which is not present on the classic manifestations of this disease.
Therefore, our patient's diagnosis would not be completely explained by this variant alone.

Comentários finais

The case addressed a heterozygous mutation of the PLEKHG5 gene as a cause of
CMT. There are rare descriptions of such an association in the literature, as well as a well-
established genotype-phenotypic correlation.

Referências (se houver)

1. Pipis M, Rossor AM, Laura M, Reilly MM. Next-generation sequencing in Charcot-Marie-Tooth disease: opportunities and challenges. Nat Rev Neurol. 2019 Nov;15(11):644-656.
2. Azzedine, H., Zavadakova, P., Plante-Bordeneuve, V., Vaz Pato, M., Pinto, N., Bartesaghi, L., Zenker, J., Poirot, O., Bernard-Marissal, N., Arnaud Gouttenoire, E., Cartoni, R., Title, A., and 18 others. PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease. Hum. Molec. Genet. 22: 4224-4232, 2013.
3. Kim, H. J., Hong, Y. B., Park, J.-M., Choi, Y.-R., Kim, Y. J., Yoon, B. R., Koo, H., Yoo, J. H., Kim, S. B., Park, M., Chung, K. W., Choi, B.-O. Mutations in the PLEKHG5 gene is relevant with autosomal recessive intermediate Charcot-Marie-Tooth disease. Orphanet J. Rare Dis. 8: 104, 2013. Note: Electronic Article. Erratum: Orphanet J. Rare Dis. 8: 165, 2013.

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Doenças neuromusculares