HACE1, GLRX5, and ELP2 gene variant cause spastic paraplegies

Sağer, Güneş; Türkyılmaz, Ayberk; Ateş, Esra Arslan; Kutlubay, Büşra

doi:10.1007/s13760-021-01649-7

Cited by 6 publications

(4 citation statements)

References 31 publications

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“…Two patients with neurological phenotypes have been reported since then and one patient with sideroblastic anemia reported in association with missense mutations in GLRX5. (11)(12)(13) This report aims to characterise the neurological phenotype of GLRX5 over the course of childhood into adult life in four patients emphasising the long term follow up, management and neurological outcome.…”

Section: Introductionmentioning

confidence: 99%

GLRX5-associated [Fe-S] Cluster Biogenesis Disorder: Further Characterisation of the Neurological Phenotype and Long-term Outcome.

Sankaran

Gupta

Tchan

et al. 2021

Preprint

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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.Conclusion: 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.

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Section: Introductionmentioning

confidence: 99%

GLRX5-associated [Fe-S] Cluster Biogenesis Disorder: Further Characterisation of the Neurological Phenotype and Long-term Outcome.

Sankaran

Gupta

Tchan

et al. 2021

Preprint

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“…Functional analyses of the variant in that study confirmed its deleterious impact on Fe-S cluster biogenesis and subsequent failure of lipoate synthesis with associated deficiency in pyruvate dehydrogenase complex. Two patients with neurological phenotypes have been reported since then and one patient with sideroblastic anemia reported in association with missense mutations in GLRX5 [ 11 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

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

Sankaran

Gupta

Tchan

et al. 2021

Orphanet J Rare Dis

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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.

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“…In the following years, other studies identified additional HACE1 patients and at present, according to a recent bibliographic search in Pubmed, the number of reported individuals has increased up to 20. 4 , 5 , 6 , 7 , 8 The affected individuals presented in infancy or in the first months of life with a variety of symptoms that included intellectual disability, psychomotor retardation, hypotonia, dystonia, spasticity, epilepsy, and ataxia. Brain imaging revealed variable hypoplasia of the corpus callosum, brain atrophy, delayed myelinization, and white matter abnormalities.…”

mentioning

confidence: 99%

“…In this study, the authors identified six individuals, from four unrelated families, carrying HACE1 loss of function mutations and postulate, for the first time, that HACE1 deficiency could be associated with an inherited genetic condition. In the following years, other studies identified additional HACE1 patients and at present, according to a recent bibliographic search in Pubmed, the number of reported individuals has increased up to 20 4–8 . The affected individuals presented in infancy or in the first months of life with a variety of symptoms that included intellectual disability, psychomotor retardation, hypotonia, dystonia, spasticity, epilepsy, and ataxia.…”

mentioning

confidence: 99%

HACE1 builds molecular crosstalks between rare diseases and (more) common disorders

Tort

2022

Clinical & Translational Med

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HACE1, GLRX5, and ELP2 gene variant cause spastic paraplegies

Cited by 6 publications

References 31 publications

GLRX5-associated [Fe-S] Cluster Biogenesis Disorder: Further Characterisation of the Neurological Phenotype and Long-term Outcome.

GLRX5-associated [Fe-S] Cluster Biogenesis Disorder: Further Characterisation of the Neurological Phenotype and Long-term Outcome.

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

HACE1 builds molecular crosstalks between rare diseases and (more) common disorders

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