pISSN 1738-6586   eISSN 2005-5013
Open Access, Peer-reviewed
    J Clin Neurol. 2021 Oct;17(4):534-540. English.
    Published online Sep 17, 2021.
    https://doi.org/10.3988/jcn.2021.17.4.534
    Copyright © 2021 Korean Neurological Association
    Original Article

    A Compound Heterozygous Pathogenic Variant in B4GALNT1 Is Associated With Axonal Charcot-Marie-Tooth Disease

    Ji-Man Hong,a,* Hyeonjin Jeon,b,c,* Young-Chul Choi,d Hanna Cho,d Young Bin Hong,b,c and Hyung Jun Parkd
      • aDepartment of Neurology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea.
      • bDepartment of Biochemistry, College of Medicine, Dong-A University, Busan, Korea.
      • cDepartment of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan, Korea.
      • dDepartment of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
    • Correspondence: Hyung Jun Park, MD, PhD. Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Korea. Tel +82-2-2019-3329, Fax +82-2-3462-5904, Email: hjpark316@yuhs.ac
      Correspondence: Young Bin Hong, PhD. Department of Biochemistry, College of Medicine, Dong-A University, 32 Daesingongwon-ro, Seo-gu, Busan 49201, Korea. Tel +82-51-240-2762, Fax +82-51-240-2971, Email: ybhong@dau.ac.kr

      *These authors contributed equally to this work.
    Received March 16, 2021; Revised June 08, 2021; Accepted June 08, 2021.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Background and Purpose

    Pathogenic variants in B4GALNT1 have been reported to cause hereditary spastic paraplegia 26. This study has revealed that a novel compound heterozygous pathogenic variant in B4GALNT1 is associated with axonal Charcot-Marie-Tooth disease (CMT).

    Methods

    Whole-exome sequencing (WES) was used to identify the causative factors and characterize the clinical features of a Korean family with sensorimotor polyneuropathy. Functional assessment of the mutant genes was performed using a motor neuron cell line.

    Results

    The WES revealed a compound heterozygous pathogenic variant (c.128dupC and c.451G>A) in B4GALNT1 as the causative of the present patient, a 53-year-old male who presented with axonal sensorimotor polyneuropathy and cognitive impairment without spasticity. The electrodiagnostic study showed axonal sensorimotor polyneuropathy. B4GALNT1 was critical to the proliferation of motor neuron cells. The compensation assay revealed that the pathogenic variants might affect the enzymatic activity of B4GALNT1.

    Conclusions

    This study is the first to identify a case of autosomal recessive axonal CMT associated with a compound heterozygous pathogenic variant in B4GALNT1. This finding expands the clinical and genetic spectra of peripheral neuropathy.

    Keywords
    Charcot-Marie-Tooth disease; whole-exome sequencing; B4GALNT1

    INTRODUCTION

    A hereditary motor and sensory neuropathy commonly known as Charcot-Marie-Tooth disease (CMT) is a heterogeneous disorder of the peripheral nervous system.1, 2 CMT is mainly divided into demyelinating and axonal types according to the location of the main pathogenesis.3, 4, 5 The former is associated with demyelination in the Schwann cells and the latter is caused by aberrations in the integrity of peripheral axons. The main symptoms of CMT are motor deficit and sensory loss due to peripheral degeneration, gait disturbance, and walking disability. More than 100 genes have been reported to be associated with the CMT phenotype, and their number continues to increase with the application of efficient analysis tools such as whole-exome sequencing (WES).6, 7

    The beta-1,4-N-acetyl galactosaminyltransferase 1 gene (B4GALNT1) transfers GalNAc to LacCer, GM3, GD3, or GT3 to generate GA2, GM2, GD2, and GT2, respectively.8, 9, 10 Gangliosides are glycosphingolipids that are highly expressed in the nervous system and are involved in various critical roles such as synaptic plasticity and signal transduction.11, 12, 13 Alterations in ganglioside metabolism affect neuronal function and are associated with neurodegenerative diseases.14 Changes in the concentrations of gangliosides are involved in the pathogenesis of Alzheimer's disease, Huntington's disease, and gangliosidosis.15, 16, 17

    Pathogenic variants in B4GALNT1 are involved in hereditary spastic paraplegia subtype 26 (SPG26) in an autosomal recessive manner. The clinical symptoms of SPG26 caused by pathogenic variants in B4GALNT1 include lower extremity spasticity, muscle weakness, and gait abnormality, while extrapyramidal and cerebellar signs, intellectual disability, and dysarthria have also been reported.18, 19, 20

    Here we report the clinical features of an autosomal recessive CMT patient with a novel compound heterozygous pathogenic variant in B4GALNT1.

    METHODS

    Clinical and electrophysiological assessments

    The clinical information used in the phenotype assessment included age at symptom onset, age at examination, family history, muscle impairments, joint contracture, sensory deficit, and deep tendon reflexes. Physical disability was quantified by scoring the patient on two scales. Disease severity was assessed according to the 9-point Functional Disability Scale (FDS) from 0 to 8 as follows: 0=normal; 1=normal except for cramps and fatigability; 2=inability to run; 3=difficulty walking unaided, but still possible; 4=can walk with a cane; 5=can walk with crutches; 6=can walk with a walker; 7=wheelchair-bound; and 8=bedridden.21 The CMT neuropathy score was determined based on the symptoms as well as the results of a neurological examination and nerve conduction study (NCS).22 NCS and needle electromyography were performed at both 41 and 53 years of age. The Mini-Mental State Examination (MMSE) and neuropsychological tests were performed at 53 years of age. This research protocol was approved by the Institutional Review Board of Gangnam Severance Hospital, Korea (IRB No: 3-2021-0014). Written informed consent was exempted by the board because this was a retrospective study.

    Isolation of genetic cause

    The genetic cause of peripheral neuropathy was determined by applying WES to the patient (III-2). The total sequencing yield was 18.87 Gbp/sample, and the coverage rate of the targeted exon regions (≥10×) was 99.0%. The average read depth of the target regions was 253.0 reads. The total number of single-nucleotide variants (SNVs) and indels was 111,802 per sample, of which 43,662 SNVs were coding variants. We identified seven functionally significant variants of neuromyopathy-relevant genes (Table 1).

    Table 1
    Functionally significant variants of neuromyopathy-relevant genes

    Generation of B4GALNT1 mutant

    The plasmid containing human B4GALNT1, pCMV6-myc-B4GALNT1, was obtained from OriGene (Rockville, MD, USA). Site-directed mutagenesis was performed to generate c.128dupC and c.451G>A using the following primers: B4GALNT1 forward, 5′-GGA GAT CTG CCG CCG CGA TCG CCA TGT GGC TGG GCC GCC GGG CCC-3′; B4GALNT1 reverse, 5′-CTG CTC GAG CGG CCG CGT ACG CGT CTG GGA GGT CAT GCA CTG-3′; B4GALNT1-128dupC forward, 5′-CTT GCG CCG TGG GCG CCC CCC GCA AAG CCC CCG CAG-3′; B4GALNT1-128dupC reverse, 5′-CTG CGG GGG CTT TGC GGG GGG CGC CCA CGG CGC AAG-3′; B4GALNT1-451G>A forward, 5′-CTC CAG TAC CCC CTA CAG AGT GTG GAA GTT CAG CCC C-3′; and B4GALNT1-451G>A reverse, 5′-GGG GCT GAA CTT CCA CAC TCT GTA GGG GGT ACT GGA G-3′. All pathogenic variants were confirmed using capillary sequencing.

    Cell viability assay

    The NSC34 mouse motor neuron cell line was used to monitor the effect of B4galnt1 knockdown as described previously.23, 24 To determine cell proliferation, cells (4×104) were transfected using Lipofectamine 3000 reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's protocol with the following B4galnt1-specific siRNAs (Bioneer, Daejeon, Korea): B4galnt1-siRNA#1, 5′-CAG UUC UGG AUA AAC UCA A-3′; B4galnt1-siRNA#2, 5′-CUU CUG UCC AGG AGA UAU A-3′; and B4galnt1-siRNA#3, 5′-CUG AUA GCU CCC GCC AAC U-3′. After 3 days of knockdown, cell proliferation was quantified by direct counting under a microscope.

    The knockdown of B4galnt1 in NSC34 cells was confirmed using the reverse-transcription polymerase chain reaction (RT-PCR). Total mRNA was purified using the RNeasy Mini Kit (Qiagen, Hilden, Germany). The cDNA obtained by applying reverse transcription using SuperScript™ II reverse transcriptase (Invitrogen) was used as a template for PCR amplification. Transfections of human wild-type and c.128dupC and c.451G>A mutant B4GALNT1 plasmids were performed in combination with B4galnt1-siRNA#3. After overexpression and knockdown for 3 days, the total number of NSC34 cells was counted.

    RESULTS

    Clinical manifestations

    A 53-year-old male (Fig. 1A, III-2) presented to our neurological clinic with gait disturbance. He did not have diabetes mellitus or alcohol abuse, and was only a carrier of hepatitis B. He first noticed a steppage gait at an age of 20 years, after which his muscle weakness progressed very slowly. When he was first examined at the age of 41 years, he displayed motor weakness and hypesthesia of the distal leg muscles. At the last examination at 53 years of age, he was able to ambulate independently. A neurological examination revealed motor weakness and atrophy of the bilateral distal leg muscles. Ankle contractures were also observed. Pain sensation was preserved, but the vibration and position senses were reduced. Knee and ankle jerks were absent, as were Babinski's sign and ankle clonus. The patient did not exhibit facial weakness or a higharched palate. He had an FDS score of 4 and a CMT neuropathy score of 6, and was categorized as having mild disability. He had received 12 years of education and scored 25 of 30 on the Korean version of the MMSE. Neuropsychological tests revealed cognitive impairments in multiple domains (language, ideomotor praxis, calculation, visuospatial, and memory) without any limitation in performing the activities of daily living.

    Fig. 1
    Pedigree and B4GALNT1 variants in the family with axonal Charcot-Marie-Tooth disease. A: Alleles of two pathogenic variants of B4GALNT1. Open symbols, unaffected; filled symbol, affected; arrow, proband. B: Sequencing chromatograms of c.128dupC and c.451G>A variants. Arrows indicate the pathogenic variant sites. C: Conservation analysis for amino acid sequences of B4GALNT1 among species. Yellow highlighting indicates the variant-site p.Gly151Ser (c.451G>A); blue text indicates completely conserved amino acids.

    Electrodiagnostic studies were performed at ages of 41 and 53 years (Table 2). NCSs showed reduced sensory nerve action potentials in the median, ulnar, superficial peroneal, and sural nerves. Needle electromyography showed mild denervation potentials in the bilateral tibialis anterior and gastrocnemius muscles at 53 years of age. These findings were consistent with axonal sensorimotor polyneuropathy. MRI of the brain and spinal cord did not reveal any parenchymal abnormalities.

    Table 2
    Electrophysiological features of patients with compound heterozygous B4GALNT1 variants

    Identification of a compound heterozygous pathogenic variant in B4GALNT1

    From the unreported functionally significant SNVs in dbSNP138 and the Genome Aggregation database (gnomeAD, https://gnomad.broadinstitute.org), we identified a pair of compound heterozygous pathogenic variants transmitted from each of the parents: c.128dupC and c.451G>A in B4GALNT1 (NM_001478.5) (Fig. 1A and B). Although the parents carried a copy of each mutant allele, they did not exhibit an axonal CMT phenotype. The siblings carried wild-type alleles. The c.128dupC variant was classified as a pathogenic variant based on the following evidence: 1) it is a null variant of a gene where loss of function is a known disease mechanism, 2) the variant is not found in gnomAD exomes and genomes, 3) there are multiple lines of computational evidence for a deleterious effect on the gene or protein, and 4) an in vitro functional study supports a damaging effect on the gene. The c.451G>A change causes the p.Gly151Ser variant. Gly151 is located in a highly conserved region among different species (Fig. 1C), and in silico analyses (using SIFT and PolyPhen2) predict that it affects functional integrity. This missense variant was classified as a likely pathogenic variant based on the following evidence: 1) the variant is not found in gnomAD exomes and genomes, 2) the variant is detected in trans with a pathogenic variant, 3) there are multiple lines of computational evidence for a deleterious effect on the gene or protein, and 4) an in vitro functional study supports a damaging effect on the gene.

    Mutant protein inhibits cell proliferation and viability

    To investigate the role of B4GALNT1 in motor neurons, we measured its effect on cell proliferation after abrogation. Transfection of mouse B4galnt1-specific siRNAs for 72 h affected the number of NSC34 cells (Fig. 2A). RT-PCR showed that all of the B4galnt1-specific siRNAs were effective in reducing the mRNA levels in NSC34 cells (Fig. 2B). Direct cell counting showed that abrogation of B4GALNT1 significantly reduced the proliferation of NSC34 cells (Fig. 2C). The cell numbers were reduced to 50.6% in B4galnt1-siRNAs#3 treated cells compared with negative-control siRNA (NC-siRNA) treatment. This implies that B4GALNT1 is crucial for the proliferation of motor neurons.

    Fig. 2
    Knockdown of B4GALNT1 and cell proliferation. A: Representative images of cells from the NSC34 mouse motor neuron cell line, after mouse B4galnt1-specific siRNAs. B: Confirmation of B4galnt1 knockdown in NSC34 by reverse-transcription polymerase chain reaction. C: Proliferation changes after B4galnt1 knockdown. D: Compensation of B4galnt1 knockdown with overexpression with human B4GALNT1 (wild type and mutants). Data are mean and standard-error-of-the-mean values. Student's t-test: **p<0.01. Con, control; NC, negative control; WT, wild type.

    We next investigated the function of mutant B4GALNT1 after the generation of two mutants of B4GALNT1 (c.128dupC and c.451G>A) from the wild-type gene. After the knockdown of endogenous B4galnt1 in NSC34, human B4GALNT1 plasmids were introduced. Overexpression of wild-type and mutant (c.128dupC and c.451>A) B4GALNT1 did not affect cell proliferation in combination with NC-siRNA transfection, indicating that the mutant proteins did not show a dominant-negative effect. In the B4galnt1 cells knocked down by B4galnt1-siRNAs#3, overexpression of wild-type B4GALNT1 significantly increased cell proliferation to the control level, whereas overexpression of the mutant genes had no effect (Fig. 2D). These results are consistent with the reduced expression of B4GALNT1 in affected patients.

    DISCUSSION

    This study has identified a compound heterozygous pathogenic variant in B4GALNT1 that is associated with axonal sensorimotor polyneuropathy and mild cognitive impairment without spasticity. Pathogenic variants in B4GALNT1 has usually been reported to cause SPG26, which is associated with early-onset spastic paraplegia, intellectual disability, cerebellar ataxia, and peripheral neuropathy.18, 19, 20, 25 It has recently been reported that patients with a novel homozygous pathogenic variant (c.263dupG) in B4GALNT1 exhibit glutaric acidemia type II, which results in a sudden metabolic crisis that includes acidosis and hypoglycemia.26 The clinical findings of our patient have not been reported previously in other patients with pathogenic variants in B4GALNT1. However, many SPG-related genes, including ATL1, KIF1A, KIF5A, SACS, SPG11, and TFG, are also associated with spastic paraplegia, hereditary sensory neuropathy, or CMT diseases.27, 28, 29, 30, 31, 32

    Sphingolipids or gangliosides play a series of important functions in neurons, such as proliferation, differentiation, and synaptic transmission.33, 34, 35, 36 To date, the most well-described diseases with sphingolipid metabolism are lysosomal storage disorders such as Tay-Sachs disease and Niemann-Pick C disease.37, 38 Recent advances in causative gene isolation have revealed that sphingolipid metabolism is associated with various types of neurodegenerative diseases, including peripheral neuropathy. Pathogenic variants in SPTLC1 (Serine palmitoyltransferase) and longchain base subunit and SPTLC2 are associated with hereditary sensory and autonomic neuropathy.39, 40 Mutant HSPB1, a causative gene of CMT2F and distal hereditary motor neuropathy type IIB, was recently reported to decrease mitochondrial ceramide levels and modify the structural and functional changes in mitochondria via interactions with ceramide synthase 1.41 Therefore, dysregulation of sphingolipid metabolism also affects neuronal activity in the peripheral nerves.

    Previous studies have found that B4galnt1 disruption in mice does not severely affect the nervous system, except for a slight reduction in neural conduction velocity from the tibial nerve to the somatosensory cortex, which suggests that complex gangliosides are predominantly required in synaptic transmission.42, 43 These features are very similar to those observed in humans, such as reduced sensory nerve function, abnormal gait, tremor, and ataxia in age-related neurodegeneration. Eleven pathogenic variants in B4GALNT1 have been reported, including two nonsense and three frameshift variants.18, 19, 20, 26 Predictions of the tertiary structure of B4GALNT1 protein suggest that most missense variants will affect protein stability, which is also supported by immunostaining data.44, 45 Enzymatic assays have revealed that all of the pathogenic variants completely affect the activity, while two pathogenic variants (c.898C>T (p.Arg300Cys) and c.682C>T (p.Arg228)) show lower levels of enzymatic activity.45

    To determine the effect of the newly identified pathogenic variants (c.128dupC and c.451G>A) on peripheral neurons, we evaluated the proliferation of motor neurons after abrogation of mouse B4galnt1 and overexpression of human mutant B4GALNT1. Knockdown of B4galnt1 significantly reduced the proliferation of mouse motor neurons. In the absence of mouse B4galnt1, overexpression of human wild-type B4GALNT1 completely compensated for the cell proliferation. However, transfection of both mutant genes (c.128dupC and c.451G>A) did not affect cell proliferation, implying that these pathogenic variants might significantly affect the enzymatic activity of B4GALNT1. Collectively these data suggest that the loss-of-function variants in B4GALNT1 can play a role in peripheral neuropathy by disturbing ganglioside metabolism in neurons.

    In conclusion, here we report for the first time that a compound heterozygous pathogenic variant in B4GALNT1 is associated with axonal CMT. The present findings suggest that alterations in sphingolipid metabolism are widely associated with peripheral neuropathy, and they expand the clinical spectrum of both B4GALNT1-associated diseases and hereditary motor and sensory neuropathy.

    Notes

    Author Contributions:

    • Conceptualization: Young Bin Hong, Hyung Jun Park.

    • Data curation: Hyeonjin Jeon, Ji-Man Hong.

    • Formal analysis: Ji-Man Hong, Young Bin Hong, Hanna Cho, Hyung Jun Park.

    • Funding acquisition: Ji-Man Hong.

    • Supervision: Young-Chul Choi.

    • Writing—original draft: Young Bin Hong, Hyung Jun Park.

    • Writing—review & editing: Young Bin Hong, Hyung Jun Park.

    Conflicts of Interest:The authors have no potential conflicts of interest to disclose.

    Funding Statement:This study was supported by NRF grants funded by MSIP, Republic of Korea (2016R1A5A2007009 and NRF-2019R1F1A1060313) and faculty research grant of Department of Neurology of Yonsei University College of Medicine (2019).

    Availability of Data and Material

    All data generated or analyzed during the study are included in this published article (and its supplementary information files).

    Acknowledgements

    The authors would like to thank the patient and his family for their help with this work.

    References

      1. Harding AE, Thomas PK. Genetic aspects of hereditary motor and sensory neuropathy (types I and II). J Med Genet 1980;17:329–336.
      1. Klein CJ, Duan X, Shy ME. Inherited neuropathies: clinical overview and update. Muscle Nerve 2013;48:604–622.
      1. Züchner S, Vance JM. Mechanisms of disease: a molecular genetic update on hereditary axonal neuropathies. Nat Clin Pract Neurol 2006;2:45–53.
      1. Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol 2009;8:654–667.
      1. Pareyson D. Axonal Charcot-Marie-Tooth disease: the fog is only slowly lifting. Neurology 2007;68:1649–1650.
      1. Eggermann K, Gess B, Häusler M, Weis J, Hahn A, Kurth I. Hereditary neuropathies: clinical presentation and genetic panel diagnosis. Dtsch Arztebl Int 2018;115:91–97.
      1. Pipis M, Rossor AM, Laura M, Reilly MM. Next-generation sequencing in Charcot-Marie-Tooth disease: opportunities and challenges. Nat Rev Neurol 2019;15:644–656.
      1. Nagata Y, Yamashiro S, Yodoi J, Lloyd KO, Shiku H, Furukawa K. Expression cloning of beta 1,4 N-acetylgalactosaminyltransferase cDNAs that determine the expression of GM2 and GD2 gangliosides. J Biol Chem 1992;267:12082–12089.
      1. Ruan S, Raj BK, Furukawa K, Lloyd KO. Analysis of melanoma cells stably transfected with beta 1,4GalNAc transferase (GM2/GD2 synthase) cDNA: relative glycosyltransferase levels play a dominant role in determining ganglioside expression. Arch Biochem Biophys 1995;323:11–18.
      1. Yamashiro S, Haraguchi M, Furukawa K, Takamiya K, Yamamoto A, Nagata Y, et al. Substrate specificity of beta 1,4-N-acetylgalactosaminyltransferase in vitro and in cDNA-transfected cells. GM2/GD2 synthase efficiently generates asialo-GM2 in certain cells. J Biol Chem 1995;270:6149–6155.
      1. Yu RK, Nakatani Y, Yanagisawa M. The role of glycosphingolipid metabolism in the developing brain. J Lipid Res 2009;50 Suppl:S440–S445.
      1. Russo D, Parashuraman S, D'Angelo G. Glycosphingolipid-protein interaction in signal transduction. Int J Mol Sci 2016;17:1732
      1. She JQ, Wang M, Zhu DM, Sun LG, Ruan DY. Effect of ganglioside on synaptic plasticity of hippocampus in lead-exposed rats in vivo. Brain Res 2005;1060:162–169.
      1. Ariga T. Pathogenic role of ganglioside metabolism in neurodegenerative diseases. J Neurosci Res 2014;92:1227–1242.
      1. Ariga T, McDonald MP, Yu RK. Thematic review series: sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review. J Lipid Res 2008;49:1157–1175.
      1. Desplats PA, Denny CA, Kass KE, Gilmartin T, Head SR, Sutcliffe JG, et al. Glycolipid and ganglioside metabolism imbalances in Huntington’s disease. Neurobiol Dis 2007;27:265–277.
      1. Kolter T, Sandhoff K. Sphingolipid metabolism diseases. Biochim Biophys Acta 2006;1758:2057–2079.
      1. Boukhris A, Schule R, Loureiro JL, Lourenço CM, Mundwiller E, Gonzalez MA, et al. Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. Am J Hum Genet 2013;93:118–123.
      1. Harlalka GV, Lehman A, Chioza B, Baple EL, Maroofian R, Cross H, et al. Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis. Brain 2013;136:3618–3624.
      1. Wakil SM, Monies DM, Ramzan K, Hagos S, Bastaki L, Meyer BF, et al. Novel B4GALNT1 mutations in a complicated form of hereditary spastic paraplegia. Clin Genet 2014;86:500–501.
      1. Birouk N, Gouider R, Le Guern E, Gugenheim M, Tardieu S, Maisonobe T, et al. Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases. Brain 1997;120:813–823.
      1. Shy ME, Blake J, Krajewski K, Fuerst DR, Laura M, Hahn AF, et al. Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology 2005;64:1209–1214.
      1. Hong YB, Kang J, Kim JH, Lee J, Kwak G, Hyun YS, et al. DGAT2 mutation in a family with autosomal-dominant early-onset axonal Charcot-Marie-Tooth disease. Hum Mutat 2016;37:473–480.
      1. Choi YR, Hong YB, Jung SC, Lee JH, Kim YJ, Park HJ, et al. A novel homozygous MPV17 mutation in two families with axonal sensorimotor polyneuropathy. BMC Neurol 2015;15:179
      1. Wilkinson PA, Simpson MA, Bastaki L, Patel H, Reed JA, Kalidas K, et al. A new locus for autosomal recessive complicated hereditary spastic paraplegia (SPG26) maps to chromosome 12p11.1–12q14. J Med Genet 2005;42:80–82.
      1. Rose L, Hall K, Tang S, Hasadsri L, Kimonis V. Homozygous B4GALNT1 mutation and biochemical glutaric acidemia type II: a case report. Clin Neurol Neurosurg 2020;189:105553
      1. Guelly C, Zhu PP, Leonardis L, Papić L, Zidar J, Schabhüttl M, et al. Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I. Am J Hum Genet 2011;88:99–105.
      1. Rivière JB, Ramalingam S, Lavastre V, Shekarabi M, Holbert S, Lafontaine J, et al. KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2. Am J Hum Genet 2011;89:219–230.
      1. Liu YT, Laurá M, Hersheson J, Horga A, Jaunmuktane Z, Brandner S, et al. Extended phenotypic spectrum of KIF5A mutations: from spastic paraplegia to axonal neuropathy. Neurology 2014;83:612–619.
      1. Souza PVS, Bortholin T, Naylor FGM, Pinto WBVR, Oliveira ASB. Early-onset axonal Charcot-Marie-Tooth disease due to SACS mutation. Neuromuscul Disord 2018;28:169–172.
      1. Montecchiani C, Pedace L, Lo Giudice T, Casella A, Mearini M, Gaudiello F, et al. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. Brain 2016;139:73–85.
      1. Tsai PC, Huang YH, Guo YC, Wu HT, Lin KP, Tsai YS, et al. A novel TFG mutation causes Charcot-Marie-Tooth disease type 2 and impairs TFG function. Neurology 2014;83:903–912.
      1. Sohn H, Kim YS, Kim HT, Kim CH, Cho EW, Kang HY, et al. Ganglioside GM3 is involved in neuronal cell death. FASEB J 2006;20:1248–1250.
      1. Itokazu Y, Wang J, Yu RK. Gangliosides in nerve cell specification. Prog Mol Biol Transl Sci 2018;156:241–263.
      1. Zitman FM, Todorov B, Verschuuren JJ, Jacobs BC, Furukawa K, Furukawa K, et al. Neuromuscular synaptic transmission in aged ganglioside-deficient mice. Neurobiol Aging 2011;32:157–167.
      1. Ando S, Tanaka Y, Waki H, Kon K, Iwamoto M, Fukui F. Gangliosides and sialylcholesterol as modulators of synaptic functions. Ann N Y Acad Sci 1998;845:232–239.
      1. Walkley SU, Siegel DA, Dobrenis K, Zervas M. GM2 ganglioside as a regulator of pyramidal neuron dendritogenesis. Ann N Y Acad Sci 1998;845:188–199.
      1. Vance JE. Lipid imbalance in the neurological disorder, Niemann-Pick C disease. FEBS Lett 2006;580:5518–5524.
      1. Dawkins JL, Hulme DJ, Brahmbhatt SB, Auer-Grumbach M, Nicholson GA. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet 2001;27:309–312.
      1. Rotthier A, Auer-Grumbach M, Janssens K, Baets J, Penno A, Almeida-Souza L, et al. Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am J Hum Genet 2010;87:513–522.
      1. Schwartz NU, Linzer RW, Truman JP, Gurevich M, Hannun YA, Senkal CE, et al. Decreased ceramide underlies mitochondrial dysfunction in Charcot-Marie-Tooth 2F. FASEB J 2018;32:1716–1728.
      1. Takamiya K, Yamamoto A, Furukawa K, Yamashiro S, Shin M, Okada M, et al. Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides but exhibit only subtle defects in their nervous system. Proc Natl Acad Sci U S A 1996;93:10662–10667.
      1. Yao D, McGonigal R, Barrie JA, Cappell J, Cunningham ME, Meehan GR, et al. Neuronal expression of GalNAc transferase is sufficient to prevent the age-related neurodegenerative phenotype of complex ganglioside-deficient mice. J Neurosci 2014;34:880–891.
      1. Dad R, Malik U, Javed A, Minassian BA, Hassan MJ. Structural annotation of beta-1,4-N-acetyl galactosaminyltransferase 1 (B4GALNT1) causing hereditary spastic paraplegia 26. Gene 2017;626:258–263.
      1. Bhuiyan RH, Ohmi Y, Ohkawa Y, Zhang P, Takano M, Hashimoto N, et al. Loss of enzyme activity in mutated B4GALNT1 gene products in patients with hereditary spastic paraplegia results in relatively mild neurological disorders: similarity with phenotypes of B4galnt1 knockout mice. Neuroscience 2019;397:94–106.
      1. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–424.
    Cited by
    Crossref 5
    Google Scholar 
    PubMed Central 4
    Scopus 4
    Web of Science 2
    MeSH Terms
    Axons*
    Cell Line
    Charcot-Marie-Tooth Disease*
    Cognitive Dysfunction
    Compensation and Redress
    Humans
    Male
    Middle Aged
    Motor Neurons
    Muscle Spasticity
    Peripheral Nervous System Diseases
    Polyneuropathies
    Spastic Paraplegia, Hereditary
    Metrics
    Share
    Links to
    Figures
    slide
    slide

    1 / 2

    Tables
    slide
    slide

    1 / 2

    ORCID IDs
    Funding Information
    PERMALINK