Objective: to present four cases (two families) with a likely diagnosis of spastic paraplegia type 64 (SPG 64), broadening this disease phenotype.

Background: SPG64 is an ultra rare autosomal recessive complicated form of hereditary spastic paraplegia (HSP) caused by pathogenic variants in ENTPD1. Currently, three families with SPG64 has been described in the literature, presenting with microcephaly, intellectual disability, dysarthria, abnormal gait and spasticity.

Method: Case series from a single neurogenetics center.

Results: Patient 1 (Family 1) is a 26yo female, born to consanguineous parents, who presented intellectual disability with speech regression at 2yo, imbalance, seizures, scoliosis and ankle contracture. Her phenotype have also included flaccid paraparesis, arreflexia, Babinski sign, and minor facial dysmorphisms. Nerve conduction studies were normal, and thin corpus callosum was present on brain MRI. Whole exome sequencing (WES) showed a homozygous likely pathogenic variant (c.769_770delGG, p.Gly257Glu fs*18) in ENTPD1. Her sister (Patient 2), currently with 32 yo, presented mild developmental delay and pyramidal signs, bilateral hearing impairment, microcephaly, mild intellectual disability and velopharyngeal insufficiency. Patient 3 (Family 2) is a 16yo female, born to consanguineous parents, with a Rett-like phenotype characterized by regression of developmental milestones, intellectual disability (marked in speech), stereotypies, seizures,  hyporreflexia, and Babinski sign. Her sister (Patient 4) presented a very similar clinical picture, associated to feet contractures. WES revealed a homozygous likely pathogenic variant in ENTPD1 (c.574-8_574-5delTCTT) in both sisters.

Conclusion: We have presented 4 cases from 2 families with the core feature of intellectual disability with mild pyramidal signs associated to likely pathogenic variants in ENTPD1. Functional and pathophysiological studies are paramount to establish and understand better this nosological entity, which up to now was based only on clinical and genetic data. ENTPD1 variants should be considered in the differential diagnosis of patients with intellectual disability or suspicion of complicated forms of HSP with or without thin corpus callosum.

References: 1- Novarino, G., Fenstermaker, A. G., Zaki, M. S., Hofree, M., Silhavy, J. L., Heiberg, A. D., Abdellateef, M., Rosti, B., Scott, E., Mansour, L., Masri, A., Kayserili, H., and 41 others. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343: 506-511, 2014. 2- Jean Mamelona, Nicolas Crapoulet and Alier Marrero. A new case of spastic paraplegia type 64 due to a missense mutation in the ENTPD1 gene. Hum Genome Var. 2019; 6: 5. Published online 2019 Jan 11. doi: 10.1038/s41439-018-0036-4.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/spastic-paraplegia-type-64-a-case-series/