History :
Our patient was transferred to our NICU from an outside hospital at 3 weeks of age for intractable seizures since birth. She was a 37-week female infant born to non-consanguineous parents. There was no family history of seizures, and the patient had a one-year-old sibling with no medical problems.
Physical examination findings (including vital signs):
She was a symmetric SGA infant. On admission, she was noted to have microcephaly with a closed anterior fontanelle, microphthalmia, hypotelorism, high arched palate, and central hypotonia with hypertonia of bilateral upper extremity. Seizures were described as tonic-clonic movements in the left arm, which then generalized to the rest of the body. She had constant twitching movements of the face and tongue. In the NICU, she was treated with high doses of fosphenytoin, phenobarbital, levetiracetam, and later with Lacosamide. As she did not respond to anti-epileptic drugs, she was started on a ketogenic diet at about 6 weeks of life; however, this did not lead to an improvement in seizures. She continued to have frequent seizures despite a ketogenic diet and 4 seizure medications. She required respiratory support throughout life, including intubation, but was extubated to NIV which she remained on until death.
Laboratory or Diagnostic imaging or Procedures:
Initial EEG was abnormal, suggestive of a moderate to severe epileptic encephalopathy. The interictal record was consistent with severe diffuse cerebral dysfunction. A head ultrasound done around one month of age was unremarkable, and a brain MRI around the same time showed mild enlargement of the subarachnoid spaces with prominent Sylvian fissures. The corpus callosum was small in size, measuring 1.5 mm in thickness. Genetic testing was found to have a microdeletion of the LiNGO1 gene in addition to biallelic deletions of exon 1-2 of the BRAT1 gene.
Final diagnosis:
Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL) was our final diagnosis caused by BRAT1 mutation. We discussed this lethal mutation with the family, and the decision was made to provide comfort care while withdrawing respiratory support. The infant died shortly after with parents at the bedside.
Discussion:
Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL) is a severe epileptic encephalopathy characterized by the onset of rigidity and pharmacoresistant seizures at, or shortly after, birth. RMFSL is a recently discovered autosomal recessive disease caused by mutations in the BRAT1 gene. The first cases of RMFSL were reported by Puffenberger et al in 2012, who found a homozygous variant in the BRAT1 gene in two of the three cases. The disease presents as drug-resistant seizures with axial and extremity rigidity, lack of psychomotor development, and small or absent fontanelles, which were all features seen in our patient. Also, they display focal jerking movements of the tongue, face, and arms almost continuously throughout life.
