Leukoencephalopathy due to variants in GFPT1-associated congenital myasthenic syndrome

Guy Helman, Suvasini Sharma, Joanna Crawford, Bijoy Patra, Puneet Jain, Stephen J. Bent, J. Andoni Urtizberea, Ravindra K. Saran, Ryan J. Taft, Marjo S. van der Knaap, Cas Simons

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

OBJECTIVE: To determine the molecular etiology of disease in 4 individuals from 2 unrelated families who presented with proximal muscle weakness and features suggestive of mitochondrial disease. METHODS: Clinical information and neuroimaging were reviewed. Genome sequencing was performed on affected individuals and biological parents. RESULTS: All affected individuals presented with muscle weakness and difficulty walking. In one family, both children had neonatal respiratory distress while the other family had 2 children with episodic deteriorations. In each family, muscle biopsy demonstrated ragged red fibers. MRI was suggestive of a mitochondrial leukoencephalopathy, with extensive deep cerebral white matter T2 hyperintense signal and selective involvement of the middle blade of the corpus callosum. Through genome sequencing, homozygous GFPT1 missense variants were identified in the affected individuals of each family. The variants detected (p.Arg14Leu and p.Thr151Lys) are absent from population databases and predicted to be damaging by in silico prediction tools. Following the genetic diagnosis, nerve conduction studies were performed and demonstrated a decremental response to repetitive nerve stimulation, confirming the diagnosis of myasthenia. Treatment with pyridostigmine was started in one family with favorable response. CONCLUSIONS: GFPT1 encodes a widely expressed protein that controls the flux of glucose into the hexosamine-biosynthesis pathway that produces precursors for glycosylation of proteins. GFPT1 variants and defects in other enzymes of this pathway have previously been associated with congenital myasthenia. These findings identify leukoencephalopathy as a previously unrecognized phenotype in GFPT1-related disease and suggest that mitochondrial dysfunction could contribute to this disorder.

Original languageEnglish
Pages (from-to)e587-e593
Number of pages7
JournalNeurology
Volume92
Issue number6
Early online date11 Jan 2019
DOIs
Publication statusPublished - 5 Feb 2019

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Congenital Myasthenic Syndromes
Leukoencephalopathies
Mitochondrial Diseases
Muscle Weakness
Genome
Pyridostigmine Bromide
Mobility Limitation
Hexosamines
Protein Precursors
Corpus Callosum
Neural Conduction
Glycosylation
Neuroimaging
Computer Simulation
Parents
Databases
Phenotype
Biopsy
Glucose
Muscles

Cite this

Helman, G., Sharma, S., Crawford, J., Patra, B., Jain, P., Bent, S. J., ... Simons, C. (2019). Leukoencephalopathy due to variants in GFPT1-associated congenital myasthenic syndrome. Neurology, 92(6), e587-e593. https://doi.org/10.1212/WNL.0000000000006886
Helman, Guy ; Sharma, Suvasini ; Crawford, Joanna ; Patra, Bijoy ; Jain, Puneet ; Bent, Stephen J. ; Urtizberea, J. Andoni ; Saran, Ravindra K. ; Taft, Ryan J. ; van der Knaap, Marjo S. ; Simons, Cas. / Leukoencephalopathy due to variants in GFPT1-associated congenital myasthenic syndrome. In: Neurology. 2019 ; Vol. 92, No. 6. pp. e587-e593.
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abstract = "OBJECTIVE: To determine the molecular etiology of disease in 4 individuals from 2 unrelated families who presented with proximal muscle weakness and features suggestive of mitochondrial disease. METHODS: Clinical information and neuroimaging were reviewed. Genome sequencing was performed on affected individuals and biological parents. RESULTS: All affected individuals presented with muscle weakness and difficulty walking. In one family, both children had neonatal respiratory distress while the other family had 2 children with episodic deteriorations. In each family, muscle biopsy demonstrated ragged red fibers. MRI was suggestive of a mitochondrial leukoencephalopathy, with extensive deep cerebral white matter T2 hyperintense signal and selective involvement of the middle blade of the corpus callosum. Through genome sequencing, homozygous GFPT1 missense variants were identified in the affected individuals of each family. The variants detected (p.Arg14Leu and p.Thr151Lys) are absent from population databases and predicted to be damaging by in silico prediction tools. Following the genetic diagnosis, nerve conduction studies were performed and demonstrated a decremental response to repetitive nerve stimulation, confirming the diagnosis of myasthenia. Treatment with pyridostigmine was started in one family with favorable response. CONCLUSIONS: GFPT1 encodes a widely expressed protein that controls the flux of glucose into the hexosamine-biosynthesis pathway that produces precursors for glycosylation of proteins. GFPT1 variants and defects in other enzymes of this pathway have previously been associated with congenital myasthenia. These findings identify leukoencephalopathy as a previously unrecognized phenotype in GFPT1-related disease and suggest that mitochondrial dysfunction could contribute to this disorder.",
author = "Guy Helman and Suvasini Sharma and Joanna Crawford and Bijoy Patra and Puneet Jain and Bent, {Stephen J.} and Urtizberea, {J. Andoni} and Saran, {Ravindra K.} and Taft, {Ryan J.} and {van der Knaap}, {Marjo S.} and Cas Simons",
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Helman, G, Sharma, S, Crawford, J, Patra, B, Jain, P, Bent, SJ, Urtizberea, JA, Saran, RK, Taft, RJ, van der Knaap, MS & Simons, C 2019, 'Leukoencephalopathy due to variants in GFPT1-associated congenital myasthenic syndrome' Neurology, vol. 92, no. 6, pp. e587-e593. https://doi.org/10.1212/WNL.0000000000006886

Leukoencephalopathy due to variants in GFPT1-associated congenital myasthenic syndrome. / Helman, Guy; Sharma, Suvasini; Crawford, Joanna; Patra, Bijoy; Jain, Puneet; Bent, Stephen J.; Urtizberea, J. Andoni; Saran, Ravindra K.; Taft, Ryan J.; van der Knaap, Marjo S.; Simons, Cas.

In: Neurology, Vol. 92, No. 6, 05.02.2019, p. e587-e593.

Research output: Contribution to JournalArticleAcademicpeer-review

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T1 - Leukoencephalopathy due to variants in GFPT1-associated congenital myasthenic syndrome

AU - Helman, Guy

AU - Sharma, Suvasini

AU - Crawford, Joanna

AU - Patra, Bijoy

AU - Jain, Puneet

AU - Bent, Stephen J.

AU - Urtizberea, J. Andoni

AU - Saran, Ravindra K.

AU - Taft, Ryan J.

AU - van der Knaap, Marjo S.

AU - Simons, Cas

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N2 - OBJECTIVE: To determine the molecular etiology of disease in 4 individuals from 2 unrelated families who presented with proximal muscle weakness and features suggestive of mitochondrial disease. METHODS: Clinical information and neuroimaging were reviewed. Genome sequencing was performed on affected individuals and biological parents. RESULTS: All affected individuals presented with muscle weakness and difficulty walking. In one family, both children had neonatal respiratory distress while the other family had 2 children with episodic deteriorations. In each family, muscle biopsy demonstrated ragged red fibers. MRI was suggestive of a mitochondrial leukoencephalopathy, with extensive deep cerebral white matter T2 hyperintense signal and selective involvement of the middle blade of the corpus callosum. Through genome sequencing, homozygous GFPT1 missense variants were identified in the affected individuals of each family. The variants detected (p.Arg14Leu and p.Thr151Lys) are absent from population databases and predicted to be damaging by in silico prediction tools. Following the genetic diagnosis, nerve conduction studies were performed and demonstrated a decremental response to repetitive nerve stimulation, confirming the diagnosis of myasthenia. Treatment with pyridostigmine was started in one family with favorable response. CONCLUSIONS: GFPT1 encodes a widely expressed protein that controls the flux of glucose into the hexosamine-biosynthesis pathway that produces precursors for glycosylation of proteins. GFPT1 variants and defects in other enzymes of this pathway have previously been associated with congenital myasthenia. These findings identify leukoencephalopathy as a previously unrecognized phenotype in GFPT1-related disease and suggest that mitochondrial dysfunction could contribute to this disorder.

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Helman G, Sharma S, Crawford J, Patra B, Jain P, Bent SJ et al. Leukoencephalopathy due to variants in GFPT1-associated congenital myasthenic syndrome. Neurology. 2019 Feb 5;92(6):e587-e593. https://doi.org/10.1212/WNL.0000000000006886