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Título

When a hint turns into a HINT - a rare case of an axonal sensory-motor neuropathy with neuromyotonia

RESUMO

Case presentation: A 17-year-old woman born from consanguineous parents presented to our neurogenetic outpatient clinic with a history of progressive unsteady gait since early childhood. She had normal milestones achievement and no significant medical history until the age of 6-year-old when she began to have frequent falls. For the subsequent years, she had worsening of symptoms with slowly progressive muscle weakness and sensory loss, especially at distal parts of the limbs. The patient was actively asked about difficulties in releasing grip after a strong voluntary hand contraction and reported distress doing this task since the beginning of the symptoms. In the neurological examination she had winged scapula, absent Achilles tendon reflexes, pinprick and vibration sense impairment with a length-dependent pattern and a slap gait with distal lower limbs weakness combined with fasciculations and action myotonia. Nerve conduction studies revealed an axonal motor-greater-than-sensory polyneuropathy and needle monopolar examination revealed increased insertional activity with myotonia and neuromyotonia (discharges of 90 to 120 Hz). The patient’s parents also performed nerve conduction and needle studies with normal results. On complementary investigation, no cardiologic or pulmonary involvement was detected. Initial molecular analysis ruled out MPZ, PMP22, GJB1, GDAP1 mutations. An American College of Medical Genetics and Genomics (ACMG) class 5 homozygous missense variant on histidine triad nucleotide binding protein 1 (HINT1) gene (c.110G>C,p.Arg37Pro) was found leading to the diagnosis of autosomal recessive neuromyotonia and axonal neuropathy (NMAN). Discussion: An early-onset (mostly around the age of 10-years-old) axonal form of motor-predominant peripheral neuropathy associated with neuromyotonia has been linked to loss of functional HINT1 gene. About 70-80% of patients present with neuromyotonia, which is a clinical hallmark for the diagnosis. Our case brings to light a classical presentation of a rare autosomal recessive mutation gene that produces a neuropathy within the Charcot–Marie–Tooth (CMT) spectrum. Final comments: Despite the increasing diagnosis of HINT1 patients world-wide, it remains a diagnostic challenge to assess the pathogenicity of novel variants. This reinforces the importance to recognize the clinical syndrome allowing for request exome sequencing, identify molecular etiology and define treatment strategies of this CMT subtype.

Palavras Chave

HINT1, Neuromyotonia and axonal neuropathy, Charcot-Marie-Tooth

Área

Neurogenética