Objective: We report the significative improvement on both movement disorder and neurodevelopment in a 5-year-old CLTC deficient patient treated with selegiline.

Background: In 2019 we described a 30-year-old woman harbouring the p.Pro890Leu aminoacid substitution in CLTC, who presented with intellectual disability and early-onset parkinsonism associated with low levels of homovanillic and 5-hydroxyindolacetic acids in CSF [1]. Interestingly, treatment with biogenic amine precursors was ineffective, while the inhibitor of MAO-B selegiline resulted in persistent clinical improvement.
The CLTC gene encodes for the clathrin heavy chain polypeptide, which plays a key role in neurotransmitters endocytosis, recycling, and trafficking as well as the generation of synaptic vesicles. Defects in this protein are responsible for a variable phenotype that includes neurodevelopmental and movement disorders, epilepsy, microcephaly, structural brain abnormalities, a various spectrum of additional neurologic problems, ophthalmologic and gastrointestinal abnormalities.

Method: We describe the case of a 5-year-old girl born at 35 weeks of gestational age for preterm premature rupture of membranes. She early presented with psychomotor delay, generalized rigidity, difficulties in latching, chewing and swallowing, with gastro-oesophageal reflux. On examination at the age of 4 she showed severe global development delay, trunk and limbs postural and action dystonia, severe sight and supranuclear oculomotor impairment. Trio-based exome sequencing revealed a de novo heterozygous likely pathogenetic variant (p.Ile675Phe) in CLTC gene. At the age of 4.5 she was prescribed with 5 mg/day of selegiline. Functional studies were performed aimed at dissecting the pathogenic mechanism in CLTC defect.

Results: After 6 months of this treatment there was a significative improvement on both movement disorder and neurodevelopment. Our recent in vitro and in vivo studies on the p.Pro890Leu variant demonstrated defective intracellular trafficking, which resulted in neurotransmitter depletion in the brain due to aberrant synaptic vesicles formation/turnover.

Conclusion: Defective CLTC protein may result in imbalance of biogenic amines in the synaptic cleft by altering their synaptic turnover. The striking improvement of the movement disorder and the neurodevelopment under the irreversible MAO-B inhibitor and functional studies support this hypothesis.

References: 1. Manti F, Nardecchia F, Barresi S, Venditti M, Pizzi S, Hamdan FF, Blau N, Burlina A, Tartaglia M, Leuzzi V. Neurotransmitter trafficking defect in a patient with clathrin (CLTC) variation presenting with intellectual disability and early-onset parkinsonism. Parkinsonism Relat Disord. 2019 Apr;61:207-210. doi: 10.1016/j.parkreldis.2018.10.012.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/improvement-of-movement-disorder-and-neurodevelopment-under-selegiline-in-a-cltc-deficient-patient/