Childhood-onset spasticity with hyperglycinemia is an autosomal recessive disorder characterized by onset of slowly progressive spasticity that results in impair...
Childhood-onset spasticity with hyperglycinemia is an autosomal recessive disorder characterized by onset of slowly progressive spasticity that results in impaired gait in the first decade of life. Imaging of the central nervous system shows leukodystrophy and/or lesions in the upper spinal cord. More variable features include visual defects and mild learning disabilities. Serum glycine is increased, but CSF glycine is only mildly increased or normal; serum lactate is normal. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including SPAHGC, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014).
▼ Clinical Features
Wei et al. (2011) reported a 7-year-old boy, born of unrelated Chinese parents, who developed visual disabilities at age 10 months and was diagnosed with optic atrophy and strabismus at age 1.5 years. At age 2.5 years, he developed gait disturbances associated with spasticity. Neurologic examination showed rotational nystagmus, hyperreflexia, and extensor plantar responses. Brain imaging showed marked bilateral leukodystrophy in the central and subcortical frontal white matter and in the genu of the corpus callosum and thin corpus callosum. His gait disturbance progressed over the next few years, and was associated with lesions in the brainstem and spinal cord. The disease course showed slow deterioration thereafter. Laboratory studies showed hyperglycinemia and mildly increased CSF glycine; blood lactate was normal.
Baker et al. (2014) reported 2 unrelated girls, both of Lebanese descent, with early-onset spasticity associated with increased serum glycine. The girl in the first family was more severely affected: she presented with spasticity affecting the upper and lower limbs at age 2.5 years. Other features included borderline cognitive ability, difficulties at school, pyramidal signs, and dysarthria. At age 11, she had mild learning difficulties and static spastic diplegia, which necessitated her walking with crutches. Brain imaging showed signal abnormalities in the frontal and parietal white matter, which progressed to involve the deep white matter, periaqueductal gray matter, and the central canal in the cervical spine. The proband in the second family, which was consanguineous, presented at age 7 years with spasticity. She was gifted cognitively and had no regression, hypotonia, or seizures. She had lower extremity spasticity and ataxia, but was able to walk and run after botulinum treatment. MRI showed lesions in the cervical spinal cord. Blood lactate and mitochondrial respiratory chain enzymes in both patients were normal. However, there was decreased activity of the pyruvate dehydrogenase complex (PDH), consistent with a defect in lipoic acid. Treatment with alpha-lipoic acid did not provide added improvement. Both patients, as well as the patient reported by Wei et al. (2011), had decreased glycine cleavage enzyme activity.
The transmission pattern of SPAHGC in the families reported by Baker et al. (2014) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
In 3 unrelated patients with SPAHGC, including the patient reported by Wei et al. (2011), Baker et al. (2014) identified biallelic mutations in the GLRX5 gene (K51del, 609588.0004 and an 8-bp insertion, 609588.0005). The mutations were found by analysis of candidate genes involved in lipoate synthesis or iron-sulfur cluster biogenesis. Patient cells showed reduced to absent levels of lipoate on the E2 subunits of the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase (alpha-KGDH) complexes compared to controls. Lipoate levels normalized after transfection with wildtype GLRX5.
In in vitro cellular transfection and functional expression assays, Liu et al. (2016) found that cells expressing the K51del mutation had decreased PDH and alpha-KGDH complex activities.