Brain

Kaur,, Parneet;Kadavigere,, Rajagopal;Girisha, Katta, Mohan;Shukla,, Anju

doi: 10.1093/brain/awaa046pmid: 32125366

Sir, The recent article by Van Bergen et al. described seven individuals from three families of different ethnicities with syndromic intellectual disability caused by the same pathogenic variant, NM_016146.6: c.454+3A>G in TRAPPC4 (MIM* 610976) (Van Bergen et al., 2020). All affected individuals had history of seizures and developmental delay, spastic quadriplegia, microcephaly and facial dysmorphism. Dystonia, tremors, joint contractures, vision impairment and hearing loss were noted in some of them. Neuroimaging data available for four individuals showed cerebral and cerebellar atrophy. Herein, we describe another individual of Indian origin manifesting progressive encephalopathy and muscle involvement with the same underlying pathogenic variant, c.454+3A>G in TRAPPC4. The study was approved by the institutional ethics committee and written informed consents were obtained from the family in accordance with the Declaration of Helsinki. We ascertained a 1 year and 7-month old female second born to a non-consanguineously married couple (Fig. 1A). She was born at term via normal vaginal delivery with birth weight of 2.4 kg [−2 standard deviations (SD)]. She did not attain any developmental milestones. She was irritable and had excessive crying since neonatal life. On examination, her weight was 6.5 kg (−5 SD), total length 56 cm (−8 SD) and occipito-frontal circumference 38.5 cm (−6 SD). On follow-up visit at 2 years and 3 months of age, her weight was 7.4 kg (−4 SD), total length 72 cm (−5 SD) and occipito-frontal circumference 40 cm (−8 SD). She had bitemporal narrowing, prominent nasal tip, full cheeks, long philtrum, tented and thin upper lip, open and wide mouth and pointed chin. She had persistent dystonic posturing, spasticity in all four limbs and clonus (Fig. 1B). Spasticity and dystonia were noted to progress with time. The rest of the systemic examination was unremarkable. Neuroimaging of the brain at 6 months of age showed significant cerebral atrophy, white matter volume loss and thinning of corpus callosum (Fig. 1C). Hearing evaluation was unremarkable. Ophthalmological examination revealed a normal fundus and possibility of cortical visual impairment. She had markedly increased plasma lactate (51.9 mg/dl), creatine phosphokinase (CPK, 1964 U/l), serum glutamic oxaloacetic transaminase (SGOT, 90 IU/l) and pyruvic transaminase (SGPT, 114 IU/l) at 1 year and 7 months. Repeat CPK levels at 2 years and 3 months of life reduced to 444 U/l. Figure 1 Open in new tabDownload slide Pedigree and clinical details of the proband. (A) Pedigree of the family. (B) Proband at 2 years and 3 months of age had had bitemporal narrowing, prominent nasal tip, full cheeks, long philtrum, tented and thin upper lip, open and wide mouth and pointed chin (left) and dystonic posturing (right). (C) T1 axial (left) and T1 sagittal (right) MRI of brain at 6 months of age shows gross cerebral atrophy secondary to paucity of white matter with sparing of basal ganglia and hypoplasia of corpus callosum (arrow). (D) Sanger validation and bi-allelic segregation analysis of the variant c.454+3A>G demonstrates mendelian segregation. Figure 1 Open in new tabDownload slide Pedigree and clinical details of the proband. (A) Pedigree of the family. (B) Proband at 2 years and 3 months of age had had bitemporal narrowing, prominent nasal tip, full cheeks, long philtrum, tented and thin upper lip, open and wide mouth and pointed chin (left) and dystonic posturing (right). (C) T1 axial (left) and T1 sagittal (right) MRI of brain at 6 months of age shows gross cerebral atrophy secondary to paucity of white matter with sparing of basal ganglia and hypoplasia of corpus callosum (arrow). (D) Sanger validation and bi-allelic segregation analysis of the variant c.454+3A>G demonstrates mendelian segregation. Singleton exome sequencing and autozygosity mapping were performed for the proband as described previously (Shukla et al., 2017; Girisha et al., 2019). The variant filtering and prioritization strategy is outlined in Supplementary Table 1. We identified a homozygous splicing variant c.454+3A>G in TRAPPC4. Segregation analysis by Sanger sequencing confirmed bi-allelic segregation of this variant (Fig. 1D). This variant is observed in heterozygous state in 68 individuals in gnomAD but was not observed in our in-house exome sequencing database of 693 individuals. On autozygosity mapping, a total of 123 Mb of region of homozygosity by descent was identified. The variant c.454+3A>G lies in a region of homozygosity of 2.24 Mb (Chr11:118500744-120742453) in the proband. In silico analysis tools (Human Splicing Finder version 3.1 and MutationT@ster) predict this variant to disrupt splicing. TRAPPC4 (also known as synbindin) is highly expressed in brain and is essential for dendritic spine morphogenesis in neurons (Ethell et al., 2000). Synbindin acts as physiological syndecan 2 (MIM* 142460) ligand and induces dendritic spine formation by recruiting intracellular vesicles towards postsynaptic sites. Severe neurological manifestations observed in paediatric patients with loss of function of this protein supports its essentiality in early neurodevelopment. The longest isoform (NM_016146.6) of TRAPPC4 encodes 219 amino acids of which amino acids 3–209 constitute the essential synbindin family domain (Uniprot: Q9Y296), as 31 healthy homozygotes were reported with a truncating variant in gnomAD (Chr11:118895635G>A; p.Trp217*) that does not affect this domain. Van Bergen et al. demonstrated c.454+3A>G results incomplete penetrant splice defect and over-expression of aberrant transcripts with premature termination (p.Leu120Aspfs*9), thus resulting in decreased protein level of TRAPPC4, affecting the functional domain and defective traffic protein particle (TRAPP) complex assembly, in affected cells. The TRAPP complex is composed of highly conserved protein subunits. TRAPPC4-encoded trafficking protein particle complex subunit 4 assembles with TRAPPC1, C2, two copies of C3, C5, C6 and C2L to form the stable core of the TRAPP complex (Sacher et al., 2019). The TRAPP core interacts with either TRAPPC9 or C10 to form TRAPP complex II or with TRAPPC8, C11, C12 and C13 to form TRAPP complex III. Hence, TRAPPC4 protein is part of a core protein complex of both TRAPP complexes II and III. TRAPP complex II localizes at early Golgi, COP I-coated vesicles, and centrosomal vesicles and plays a vital role in the secretory pathway (Scrivens et al., 2011). TRAPP complex III in addition to early Golgi also localizes at endoplasmic reticulum exit sites and tubulated recycling endosomes, and has recently been reported to function in secretory pathways and autophagy (Behrends et al., 2010; Lamb et al., 2016). Defects in several of the TRAPP complex subunits are known to cause a spectrum of neurodegenerative conditions namely early-onset progressive encephalopathy with episodic rhabdomyolysis (MIM# 618331, TRAPPC2L), neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy (MIM# 617862 TRAPPC6B), autosomal recessive mental retardation 13 (MIM# 613192 TRAPPC9) (Mir et al., 2009), autosomal recessive limb-girdle muscular dystrophy 18 (MIM# 615356 TRAPPC11) (Bogershausen et al., 2013), early-onset progressive encephalopathy with brain atrophy and spasticity (MIM# 617669 TRAPPC12) (Milev et al., 2017) and TRAPPC6A-related neurodevelopmental syndrome with dysmorphic features. These conditions, along with spondyloepimetaphyseal dysplasia tarda (MIM# 313400, TRAPPC2) (Gedeon et al., 1999) have been collectively referred to as TRAPPopathies. To date, defects in TRAPPC1, C3, C5, C10 and C13 have not been reported to cause any human disease. The clinical findings observed in the present proband reiterate the phenotype and genotype observed by Van Bergen et al. (2020). Additionally, we also observed elevated CPK and blood lactate levels indicating muscle involvement in the proband. All TRAPPopathies present with common findings of significant intellectual impairment, seizures, abnormal brain imaging findings, visual and hearing defects. Of note, muscle involvement has been observed in two of these disorders. In early-onset progressive encephalopathy with episodic rhabdomyolysis, two individuals from two unrelated families were noted to have febrile illness induced encephalopathy (Milev et al., 2018). These individuals had episodic rhabdomyolysis during periods of acute illness resulting in elevated levels of CK, lactate dehydrogenase, SGOT and SGPT. Although delayed membrane trafficking was observed in fibroblasts of affected individuals, the cause of recurrent episodes of rhabdomyolysis and muscle involvement could not be ascertained. The second TRAPPopathy with muscle involvement is autosomal recessive limb-girdle muscular dystrophy 18 due to pathogenic variants in TRAPC11. This disorder has significant phenotypic variability (Bogershausen et al., 2013; Liang et al., 2015; Fee et al., 2017; Koehler et al., 2017; Matalonga et al., 2017; Larson et al., 2018; Wang et al., 2018; Milev et al., 2019). The clinical findings range from predominant muscle involvement to multisystem involvement with cerebral and cerebellar atrophy, seizures, hepatomegaly, steatosis and spinal deformities. Elevated CPK has been observed in 18 of 23 individuals with pathogenic variants in TRAPPC11 (Bogershausen et al., 2013; Liang et al., 2015; Fee et al., 2017; Larson et al., 2018; Wang et al., 2018; Milev et al., 2019). CPK levels were not reported in four individuals of two families. However all four had myopathic changes on muscle biopsy (Koehler et al., 2017). A single case has been reported to have congenital disorder of glycosylation (CDG) with glycosylation pattern of CDG type II on isoelectric focusing (Matalonga et al., 2017). TRAPPC11 has been reported to be essential for normal N-linked glycosylation in human cells and zebrafish (DeRossi et al., 2016). Defects in TRAPPC11 have recently been shown to result in hypoglycosylation of alpha-dystroglycans, which elucidates phenotypic resemblance to limb girdle and congenital muscular dystrophy similar to other dystroglycanopathies (Larson et al., 2018). The phenotype in the present proband appears similar to TRAPPC2L-related disorder with episodic muscle damage as the CPK levels noted at different intervals varied widely. Also, high levels of blood lactate and liver enzymes were noted suggesting possible episodic rhabdomyolysis. The individuals reported by Van Bergen et al. (2020) did not have any evidence of muscle involvement. However, our findings warrant biochemical evaluation of individuals with TRAPPC4-related neurodegenerative disease for evaluation of possible muscle involvement. Further report of individuals with this condition and investigation of TRAPP4C in muscle disease would lead to a better understanding of this disorder. This would further aid in prognostication, therapeutic management and informed genetic counselling for these families. Data availability The data providing the evidence of the study are available from the corresponding author upon reasonable request. Acknowledgements We thank the patient and her family for participating in this study. Funding We thank the Department of Health Research, Ministry of Health and Family Welfare, Government of India for funding the project entitled ‘Clinical and Molecular Characterization of Leukodystrophies in Indian Children’ (V.25011/379/2015‐GIA/HR). Competing interests The authors report no competing interests. References Behrends C , Sowa ME , Gygi SP , Harper JW. Network organization of the human autophagy system . Nature 2010 ; 466 : 68 – 76 . Google Scholar Crossref Search ADS PubMed WorldCat Bogershausen N , Shahrzad N , Chong JX , von Kleist-Retzow JC , Stanga D , Li Y , et al. Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability . Am J Hum Genet 2013 ; 93 : 181 – 90 . Google Scholar Crossref Search ADS PubMed WorldCat DeRossi C , Vacaru A , Rafiq R , Cinaroglu A , Imrie D , Nayar S , et al. trappc11 is required for protein glycosylation in zebrafish and humans . Mol Biol Cell 2016 ; 27 : 1220 – 34 . Google Scholar Crossref Search ADS PubMed WorldCat Ethell IM , Hagihara K , Miura Y , Irie F , Yamaguchi Y. Synbindin, A novel syndecan-2-binding protein in neuronal dendritic spines . J Cell Biol 2000 ; 151 : 53 – 68 . Google Scholar Crossref Search ADS PubMed WorldCat Fee DB , Harmelink M , Monrad P , Pyzik E. Siblings with mutations in TRAPPC11 presenting with limb-girdle muscular dystrophy 2S . J Clin Neuromuscul Dis 2017 ; 19 : 27 – 30 . Google Scholar Crossref Search ADS PubMed WorldCat Gedeon AK , Colley A , Jamieson R , Thompson EM , Rogers J , Sillence D , et al. Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda . Nat Genet 1999 ; 22 : 400 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat Girisha KM , von Elsner L , Neethukrishna K , Muranjan M , Shukla A , Bhavani GS , et al. The homozygous variant c.797G>A/p.(Cys266Tyr) in PISD is associated with a Spondyloepimetaphyseal dysplasia with large epiphyses and disturbed mitochondrial function . Hum Mutat 2019 ; 40 : 299 – 309 . Koehler K , Milev MP , Prematilake K , Reschke F , Kutzner S , Juhlen R , et al. A novel TRAPPC11 mutation in two Turkish families associated with cerebral atrophy, global retardation, scoliosis, achalasia and alacrima . J Med Genet 2017 ; 54 : 176 – 85 . Google Scholar Crossref Search ADS PubMed WorldCat Lamb CA , Nuhlen S , Judith D , Frith D , Snijders AP , Behrends C , et al. TBC1D14 regulates autophagy via the TRAPP complex and ATG9 traffic . EMBO J 2016 ; 35 : 281 – 301 . OpenURL Placeholder Text WorldCat Larson AA , Baker PR 2nd , Milev MP , Press CA , Sokol RJ , Cox MO , et al. TRAPPC11 and GOSR2 mutations associate with hypoglycosylation ofalpha-dystroglycan and muscular dystrophy . Skelet Muscle 2018 ; 8 : 17 . Google Scholar Crossref Search ADS PubMed WorldCat Liang WC , Zhu W , Mitsuhashi S , Noguchi S , Sacher M , Ogawa M , et al. Congenital muscular dystrophy with fatty liver and infantile-onset cataract caused by TRAPPC11 mutations: broadening of the phenotype . Skelet Muscle 2015 ; 5 : 29 . Google Scholar Crossref Search ADS PubMed WorldCat Matalonga L , Bravo M , Serra-Peinado C , Garcia-Pelegri E , Ugarteburu O , Vidal S , et al. Mutations in TRAPPC11 are associated with a congenital disorder of glycosylation . Hum Mutat 2017 ; 38 : 148 – 51 . Google Scholar Crossref Search ADS PubMed WorldCat Milev MP , Graziano C , Karall D , Kuper WFE , Al-Deri N , Cordelli DM , et al. Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts . J Med Genet 2018 ; 55 : 753 – 64 . Google Scholar Crossref Search ADS PubMed WorldCat Milev MP , Grout ME , Saint-Dic D , Cheng YH , Glass IA , Hale CJ , et al. Mutations in TRAPPC12 manifest in progressive childhood encephalopathy and golgi dysfunction . Am J Hum Genet 2017 ; 101 : 291 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Milev MP , Stanga D , Schanzer A , Nascimento A , Saint-Dic D , Ortez C , et al. Characterization of three TRAPPC11 variants suggests a critical role for the extreme carboxy terminus of the protein . Sci Rep 2019 ; 9 : 14036 . Google Scholar Crossref Search ADS PubMed WorldCat Mir A , Kaufman L , Noor A , Motazacker MM , Jamil T , Azam M , et al. Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-binding protein, in nonsyndromic autosomal-recessive mental retardation . Am J Hum Genet 2009 ; 85 : 909 – 15 . Google Scholar Crossref Search ADS PubMed WorldCat Sacher M , Shahrzad N , Kamel H , Milev MP. TRAPPopathies: an emerging set of disorders linked to variations in the genes encoding transport protein particle (TRAPP)-associated proteins . Traffic 2019 ; 20 : 5 – 26 . Google Scholar Crossref Search ADS PubMed WorldCat Scrivens PJ , Noueihed B , Shahrzad N , Hul S , Brunet S , Sacher M. C4orf41 and TTC-15 are mammalian TRAPP components with a role at an early stage in ER-to-Golgi trafficking . Mol Biol Cell 2011 ; 22 : 2083 – 93 . Google Scholar Crossref Search ADS PubMed WorldCat Shukla A , Hebbar M , Srivastava A , Kadavigere R , Upadhyai P , Kanthi A , et al. Homozygous p.(Glu87Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome . J Hum Genet 2017 ; 62 : 723 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Van Bergen NJ , Guo Y , Al-Deri N , Lipatova Z , Stanga D , Zhao S , et al. Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability . Brain 2020 ; 143 : 112 – 30 . Google Scholar Crossref Search ADS PubMed WorldCat Wang X , Wu Y , Cui Y , Wang N , Folkersen L , Wang Y. Novel TRAPPC11 mutations in a Chinese pedigree of limb girdle muscular dystrophy. Case Rep Genet 2018; 2018: 8090797. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected] This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)