Department of Biochemical Genetics and Genetic Metabolic Disorders Service, The Children's Hospital at Westmead, Westmead, NSW, Australia.
The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
Orphanet J Rare Dis. 2021 Nov 3;16(1):465. doi: 10.1186/s13023-021-02073-z.
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.
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.
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.
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.
鉴定和描述复杂神经表型的单基因病因对于遗传咨询和预后具有重要意义。编码 GLRX5 的基因的双等位致病性变异，该基因参与铁硫簇生物发生的早期步骤，较为罕见，导致两种不同的表型：孤立性铁粒幼细胞性贫血和具有变异非酮性高甘氨酸血症的神经表型。在这项研究中，我们分析了 GLRX5 突变患者的临床和 MRI 表现的演变以及长期结局。
从三个黎巴嫩裔澳大利亚家族中鉴定出了 4 名患者。所有患者均在儿童期发病，并通过多次临床评估随访至成年。所有患者均接受苯甲酸钠治疗。
所有患者（均为女性，年龄 18-56 岁）均表现出复杂的神经表型，特征为痉挛性截瘫、长短依赖性运动/感觉运动轴索性多发性神经病的不同组合，以及伴有不同程度智力障碍的精神障碍。所有患者均存在非酮性高甘氨酸血症和 GLRX5 基因的纯合致病性 c.151_153delAAG(p.K51del)改变。运动功能障碍逐渐进展，青春期达到中度残疾，成年后达到中度严重残疾。主要 MRI 发现是所有患者均存在上颈段脊髓信号改变伴强化，其中 1 例存在额外的脑白质病变。在后续 MRI 随访中，白质病变在后续扫描中减轻，然后随着时间的推移保持稳定。脊髓显示出胶质改变。有 2 名患者之前表现出低丙酮酸脱氢酶复合物缺乏症，但没有患者出现血浆乳酸升高，也没有生化证据表明支链酮酸脱氢酶缺乏症。在耐受苯甲酸钠的患者中，甘氨酸水平降低，可能稳定了临床表现。
本报告表明，p.K51del GLRX5 变异导致了一种独特且可预测的神经表型。从儿童期到成年期的临床评估使医生能够推断出 GLRX5 相关神经障碍的自然病史。可能存在广泛的代谢后果，最佳治疗方法尚不清楚。
