Defective phosphatidylethanolamine biosynthesis leads to a broad ataxia-spasticity spectrum

Kaiyrzhanov, Rauan; Wortmann, Saskia B.; Reid, Taryn R.; Dehghani, Mohammadreza; Mehrjardi, Mohammad Yahya Vahidi; Alhaddad, Bader; Wagner, Matias; Deschauer, Marcus; Cordts, Isabell; Fernández-Murray, J. Pedro; Treffer, Veronika; Metanat, Zahra; Pitman, Alan; Houlden, Henry; Meitinger, Thomas; Carroll, Christopher J.; McMaster, Christopher R.; Maroofian, Reza

doi:10.1093/brain/awaa442

Cited by 14 publications

(11 citation statements)

References 13 publications

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“…Previously, we established that the enzymatic activity of Pcyt2 is drastically reduced through the induction of mutations at PKC phosphorylation sites 8 and two catalytic sites 13 . Severe consequences of PCYT2 mutation and resultant diminished enzymatic activity we recently demonstrated in patients with multiple mutations that caused autosomal spastic paraplegia and profound lipid abnormalities 14 , 15 . According to dbSNP database PCYT2 is heavily mutated, with over 4400 single nucleotide polymorphisms identified and 60 allele mutations within the gene coding region 16 .…”

Section: Introductionmentioning

confidence: 88%

Pcyt2 deficiency causes age-dependant development of nonalcoholic steatohepatitis and insulin resistance that could be attenuated with phosphonoethylamine

Grapentine

Singh

Basu

et al. 2022

Sci Rep

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The mechanisms of NASH development in the context of age and genetics are not fully elucidated. This study investigates the age-dependent liver defects during NASH development in mice with heterozygous deletion of Pcyt2 (Pcyt2+/−), the rate limiting enzyme in phosphatidylethanolamine (PE) synthesis. Further, the therapeutic potential of Pcyt2 substrate, phosphoethanolamine (PEtn), is examined. Pcyt2+/− were investigated at 2 and 6–8 months (mo) of age and in addition, 6-mo old Pcyt2+/− with developed NASH were supplemented with PEtn for 8 weeks and glucose and fatty acid metabolism, insulin signaling, and inflammation were examined. Heterozygous ablation of Pcyt2 causes changes in liver metabolic regulators from young age, prior to the development of liver disease which does not occur until adulthood. Only older Pcyt2+/− experiences perturbed glucose and fatty acid metabolism. Older Pcyt2+/− liver develops NASH characterized by increased glucose production, accumulation of TAG and glycogen, and increased inflammation. Supplementation with PEtn reverses Pcyt2+/− steatosis, inflammation, and other aspects of NASH, showing that was directly caused by Pcyt2 deficiency. Pcyt2 deficiency is a novel mechanism of metabolic dysregulation due to reduced membrane ethanolamine phospholipid synthesis, and the metabolite PEtn offers therapeutic potential for NASH reversion.

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Section: Introductionmentioning

confidence: 88%

Pcyt2 deficiency causes age-dependant development of nonalcoholic steatohepatitis and insulin resistance that could be attenuated with phosphonoethylamine

Grapentine

Singh

Basu

et al. 2022

Sci Rep

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“…Recently, biallelic pathogenic variants in PCYT2 have been reported in 10 members of 9 independent families. [2][3][4][5][6] Two patients, a 32-year-old and a 59-year-old man, had a pure form of spastic paraparesis 4,6 ; all the others presented with a complex spastic paraplegia syndrome. The individuals reported here share several phenotypic features, including short stature, spastic tetraparesis, cerebellar ataxia, epilepsy, and cognitive decline (Table ).…”

Section: Discussionmentioning

confidence: 99%

“…1 Biallelic pathogenic variants in PCYT2 encoding CTP:phosphoethanolamine cytidylyltransferase (ET), the rate-limiting enzyme in phosphoethanolamine biosynthesis, have recently been associated with a clinical spectrum ranging from pure to complex spastic paraplegia syndrome, characterized by spastic tetraparesis, intellectual disability, short stature, progressive cerebral and cerebellar atrophy, epilepsy, and ophthalmologic abnormalities. 2-6…”

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confidence: 99%

Axonal Polyneuropathy in 2 Brothers With a Homozygous Missense Variant in the First Catalytic Domain of PCYT2

et al. 2022

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Background and ObjectivesTo expand the phenotype and genotype associated with PCYT2-related disorder.MethodsExome sequencing data from a patient with molecularly undiagnosed complex spastic paraplegia and axonal motor and sensory polyneuropathy were analyzed. Clinical data and nerve conduction studies of the patient and his affected brother were collected, and their phenotype and genotype were compared with previously reported patients with PCYT2-related disorder.ResultsA novel homozygous missense variant in PCYT2 (NM_001184917.2) c.88T>G; p.(Cys30Gly) was identified. This variant is located in a highly conserved tyrosine kinase site and is predicted damaging by several variant annotation tools. Both patients reported here and the previously published patients share several phenotypic features, including short stature, spastic tetraparesis, cerebellar ataxia, epilepsy, and cognitive decline. Axonal polyneuropathy, diagnosed in both brothers, was not previously reported.DiscussionThis family with a novel PCYT2 variant expands the clinical spectrum of PCYT2-related disorder to include axonal motor and sensory polyneuropathy and the genetic spectrum to include the variant located in the first catalytic domain, whereas all previously reported variants are located in the second catalytic domain. Further research is required to disentangle the underlying pathophysiologic mechanisms, leading to the complex phenotype of PCYT2-related disorder.

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“…The overlap between the phenotypes associated with CHKA, SELENOI, and PCYT2 comprises DD/ID, microcephaly, short stature, visual impairment, seizures, hyperreflexia, abnormalities of muscle tone, and movement disorder (Supplemental Table 3). 8,9,[24][25][26] Particularly noteworthy are the eye abnormalities observed in individual 3: nystagmus, diffuse retinal pigmentary epithelium, severe conduction dysfunction and moderate retinal dysfunction in both eyes. A retinal phenotype of cone-rod dystrophy and macular pigmentary changes was described for PCYT1A and SELENOI.…”

Section: Discussionmentioning

confidence: 99%

Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly

Kloeckner

Murray

Tavasoli

et al. 2021

Preprint

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The Kennedy pathways catalyze the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus since four out of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A), and spastic paraplegia (PCYT2, SELENOI).We identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders, and microcephaly. Using structural molecular modeling and functional testing of the variants in a in a cell-based S. cerevisiae model, we determined that these variants reduce the enzymatic activity of CHKA and confer a significant impairment of the first enzymatic step of the Kennedy pathway.In summary, we present CHKA as a novel autosomal recessive gene for a neurodevelopmental disorder with epilepsy and microcephaly.

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Defective phosphatidylethanolamine biosynthesis leads to a broad ataxia-spasticity spectrum

Cited by 14 publications

References 13 publications

Pcyt2 deficiency causes age-dependant development of nonalcoholic steatohepatitis and insulin resistance that could be attenuated with phosphonoethylamine

Pcyt2 deficiency causes age-dependant development of nonalcoholic steatohepatitis and insulin resistance that could be attenuated with phosphonoethylamine

Axonal Polyneuropathy in 2 Brothers With a Homozygous Missense Variant in the First Catalytic Domain of PCYT2

Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly

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