GLRX5-associated [Fe-S] cluster biogenesis disorder: further characterisation of the neurological phenotype and long-term outcome

Abstract Background Identification and characterisation of monogenic causes of complex neurological phenotypes are important for genetic counselling and prognostication. Bi-allelic pathogenic variants in the gene encoding GLRX5, a protein involved in the early steps of Fe-S cluster biogenesis, are r...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Bindu Parayil Sankaran, Sachin Gupta, Michel Tchan, Beena Devanapalli, Yusof Rahman, Peter Procopis, Kaustuv Bhattacharya
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	GLRX5 Fe-S cluster biogenesis Non ketotic hyperglycinemia Spastic paraplegia SPON Lipoic acid Medicine R
Acceso en línea:	https://doaj.org/article/ae0e69e797854fe5a5b73d0e5e8ba192
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ae0e69e797854fe5a5b73d0e5e8ba192
record_format	dspace
spelling	oai:doaj.org-article:ae0e69e797854fe5a5b73d0e5e8ba1922021-11-08T10:57:06ZGLRX5-associated [Fe-S] cluster biogenesis disorder: further characterisation of the neurological phenotype and long-term outcome10.1186/s13023-021-02073-z1750-1172https://doaj.org/article/ae0e69e797854fe5a5b73d0e5e8ba1922021-11-01T00:00:00Zhttps://doi.org/10.1186/s13023-021-02073-zhttps://doaj.org/toc/1750-1172Abstract Background Identification and characterisation of monogenic causes of complex neurological phenotypes are important for genetic counselling and prognostication. Bi-allelic pathogenic variants in the gene encoding GLRX5, a protein involved in the early steps of Fe-S cluster biogenesis, are rare and cause two distinct phenotypes: isolated sideroblastic anemia and a neurological phenotype with variant non-ketotic hyperglycinemia. In this study, we analysed the evolution of clinical and MRI findings and long-term outcome of patients with GLRX5 mutations. Methods Four patients from three Australian families of Lebanese descent were identified. All patients presented in childhood and were followed up into adult life through multiple clinical assessments. All were prescribed sodium benzoate. Results All patients (all females, age range 18–56 years) showed a complex neurological phenotype characterised by varying combinations of spastic paraparesis, length-dependent motor/sensory-motor axonal polyneuropathy, and psychiatric disturbances with variable intellectual disability. All had non-ketotic hyperglycinemia and a homozygous pathogenic c.151_153delAAG (p.K51del) change in GLRX5. Motor disability gradually progressed reaching moderate disability during adolescence and moderately severe disability during adult life. The major MRI finding was the upper cervical spinal cord signal changes with contrast enhancement noted in all and additional leukoencephalopathy in one. On follow up MRI, the white matter lesions diminished on a subsequent scan and then remained static over time. The spinal cord showed gliotic changes. Two patients have previously demonstrated low pyruvate dehydrogenase complex deficiency but none had plasma lactate elevation, nor biochemical evidence of branch-chain keto-dehydrogenase deficiency. Glycine levels reduced in patients that tolerated sodium benzoate, possibly stabilising clinical manifestations. Conclusions This report demonstrates that the p.K51del GLRX5 variant causes a distinct and predictable neurological phenotype. The clinical assessments spanning from childhood to adult life enable physicians to infer the natural history of GLRX5 related neurological disorder. There may be widespread metabolic consequences, and optimal management is unknown.Bindu Parayil SankaranSachin GuptaMichel TchanBeena DevanapalliYusof RahmanPeter ProcopisKaustuv BhattacharyaBMCarticleGLRX5Fe-S cluster biogenesisNon ketotic hyperglycinemiaSpastic paraplegiaSPONLipoic acidMedicineRENOrphanet Journal of Rare Diseases, Vol 16, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	GLRX5 Fe-S cluster biogenesis Non ketotic hyperglycinemia Spastic paraplegia SPON Lipoic acid Medicine R
spellingShingle	GLRX5 Fe-S cluster biogenesis Non ketotic hyperglycinemia Spastic paraplegia SPON Lipoic acid Medicine R Bindu Parayil Sankaran Sachin Gupta Michel Tchan Beena Devanapalli Yusof Rahman Peter Procopis Kaustuv Bhattacharya GLRX5-associated [Fe-S] cluster biogenesis disorder: further characterisation of the neurological phenotype and long-term outcome
description	Abstract Background Identification and characterisation of monogenic causes of complex neurological phenotypes are important for genetic counselling and prognostication. Bi-allelic pathogenic variants in the gene encoding GLRX5, a protein involved in the early steps of Fe-S cluster biogenesis, are rare and cause two distinct phenotypes: isolated sideroblastic anemia and a neurological phenotype with variant non-ketotic hyperglycinemia. In this study, we analysed the evolution of clinical and MRI findings and long-term outcome of patients with GLRX5 mutations. Methods Four patients from three Australian families of Lebanese descent were identified. All patients presented in childhood and were followed up into adult life through multiple clinical assessments. All were prescribed sodium benzoate. Results All patients (all females, age range 18–56 years) showed a complex neurological phenotype characterised by varying combinations of spastic paraparesis, length-dependent motor/sensory-motor axonal polyneuropathy, and psychiatric disturbances with variable intellectual disability. All had non-ketotic hyperglycinemia and a homozygous pathogenic c.151_153delAAG (p.K51del) change in GLRX5. Motor disability gradually progressed reaching moderate disability during adolescence and moderately severe disability during adult life. The major MRI finding was the upper cervical spinal cord signal changes with contrast enhancement noted in all and additional leukoencephalopathy in one. On follow up MRI, the white matter lesions diminished on a subsequent scan and then remained static over time. The spinal cord showed gliotic changes. Two patients have previously demonstrated low pyruvate dehydrogenase complex deficiency but none had plasma lactate elevation, nor biochemical evidence of branch-chain keto-dehydrogenase deficiency. Glycine levels reduced in patients that tolerated sodium benzoate, possibly stabilising clinical manifestations. Conclusions This report demonstrates that the p.K51del GLRX5 variant causes a distinct and predictable neurological phenotype. The clinical assessments spanning from childhood to adult life enable physicians to infer the natural history of GLRX5 related neurological disorder. There may be widespread metabolic consequences, and optimal management is unknown.
format	article
author	Bindu Parayil Sankaran Sachin Gupta Michel Tchan Beena Devanapalli Yusof Rahman Peter Procopis Kaustuv Bhattacharya
author_facet	Bindu Parayil Sankaran Sachin Gupta Michel Tchan Beena Devanapalli Yusof Rahman Peter Procopis Kaustuv Bhattacharya
author_sort	Bindu Parayil Sankaran
title	GLRX5-associated [Fe-S] cluster biogenesis disorder: further characterisation of the neurological phenotype and long-term outcome
title_short	GLRX5-associated [Fe-S] cluster biogenesis disorder: further characterisation of the neurological phenotype and long-term outcome
title_full	GLRX5-associated [Fe-S] cluster biogenesis disorder: further characterisation of the neurological phenotype and long-term outcome
title_fullStr	GLRX5-associated [Fe-S] cluster biogenesis disorder: further characterisation of the neurological phenotype and long-term outcome
title_full_unstemmed	GLRX5-associated [Fe-S] cluster biogenesis disorder: further characterisation of the neurological phenotype and long-term outcome
title_sort	glrx5-associated [fe-s] cluster biogenesis disorder: further characterisation of the neurological phenotype and long-term outcome
publisher	BMC
publishDate	2021
url	https://doaj.org/article/ae0e69e797854fe5a5b73d0e5e8ba192
work_keys_str_mv	AT binduparayilsankaran glrx5associatedfesclusterbiogenesisdisorderfurthercharacterisationoftheneurologicalphenotypeandlongtermoutcome AT sachingupta glrx5associatedfesclusterbiogenesisdisorderfurthercharacterisationoftheneurologicalphenotypeandlongtermoutcome AT micheltchan glrx5associatedfesclusterbiogenesisdisorderfurthercharacterisationoftheneurologicalphenotypeandlongtermoutcome AT beenadevanapalli glrx5associatedfesclusterbiogenesisdisorderfurthercharacterisationoftheneurologicalphenotypeandlongtermoutcome AT yusofrahman glrx5associatedfesclusterbiogenesisdisorderfurthercharacterisationoftheneurologicalphenotypeandlongtermoutcome AT peterprocopis glrx5associatedfesclusterbiogenesisdisorderfurthercharacterisationoftheneurologicalphenotypeandlongtermoutcome AT kaustuvbhattacharya glrx5associatedfesclusterbiogenesisdisorderfurthercharacterisationoftheneurologicalphenotypeandlongtermoutcome
_version_	1718442457824231424

GLRX5-associated [Fe-S] cluster biogenesis disorder: further characterisation of the neurological phenotype and long-term outcome

Ejemplares similares