Objective: To describe a patient with a de novo NKX2-1 mutation and low CSF 5-methyltetrahydrofolate (5MTHF) who had mild improvement in fine motor control after initiating leucovorin treatment.

Background: NKX2-1 is a highly conserved transcription factor expressed during organogenesis of the lungs, thyroid and forebrain particularly the basal ganglia and hypothalamus [1]. NKX2-1-related disorders range from benign hereditary chorea to choreoathetosis, congenital hypothyroidism and neonatal respiratory distress.  While described as “benign,” chorea can cause significant motor impairment.  Cerebral folate deficiency has a variable clinical presentation including psychomotor retardation, dyskinesia, cerebellar ataxia, spastic diplegia.  It is diagnosed by low 5MTHF levels and is responsive to treatment with folinic acid [2].

Method: Case Study

Results: A 13-year-old female with congenital hypothyroidism, choreoathetosis, congenital myopathy, mild axial hypotonia, and asthma was found on exome testing to have a de novo heterozygous pathogenic variant (c.544_549delCAACAG) in the NKX2-1 gene. As part of her diagnostic evaluation, CSF studies were performed.  Her CSF neopterin and 5MTHF levels were slightly low at 5 (normal 8-33) and 38 (normal 40-120) respectively.  Leucovorin treatment was initiated at 1mg/kg/day and was well tolerated. The patient continued to have significant choreoathetosis but she aquired new fine motor skills such as tying her shoelaces and mild improvement in gait, allowing increased independent walking.

Conclusion: This is the first reported case of a patient with NKX2-1-related disorder and cerebral folate deficiency. Although cerebral folate deficiency is associated with a wide range of mechanisms, the exact mechanism leading to the low CSF 5MTHF in this patient is unclear.  The improvement in choreoathetosis with leucovorin therapy was modest; however, previous reports of cerebral folate deficiency suggest that outcome from treatment may be dependent on age of commencement of therapy [3]. This case introduces a new potential avenue of treatment. Further investigation into the relationship between NKX2-1-related disorders and cerebral folate deficiency and the potential efficacy of folinic acid treatment is needed.

References: 1. Gras D, Jonard L, Roze E, et al. Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow up in a large series with new mutations in the TITF1/NKX2- gene. J Neurol Neurosurg Psychiatry. 2012; 83(10): 956-62. 2. Hyland K, Shoffner J, Heales, S. Cerebral folate deficiency. J Inherit Metab Dis (2010) 33:563. 3. Ramaekers VT, Sequeira JM, Quadros EV. Clinical recognition and aspects of the cerebral folate deficiency syndromes. Clin Chem Lab Med. 2013; 51 (3): 497-511n

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MDS Abstracts - https://www.mdsabstracts.org/abstract/nkx2-1-related-disorder-with-cerebral-folate-deficiency/