Hereditary spastic paraparesis: not always HSP!

A 20-year-old patient with learning disability and growth impairment had limb spasticity of childhood onset principally affecting the lower limbs and of such severity that walking was not possible. He was the son of a consanguineous marriage (first cousin parents). Magnetic resonance (MR) brain imaging showed diffuse mild cerebral atrophy but striking cerebellar atrophy (Figure). Because of the suspicion of an autosomal recessive disorder, neurogenetic testing was undertaken, which included analysis of the ARG1 gene on chromosome 6q that showed a homozygous point mutation in exon 4 confirming the diagnosis of arginase deficiency. D e f i c i e n c y o f a r g i n a s e (OMIM#207800), which catalyses the hydrolysis of arginine in the final step of the urea cycle, is a rare disorder, typically presenting in childhood with developmental delay, intellectual disability, seizures, hyperargininaemia and spastic paraparesis.1 Neuroimaging typically shows mild cerebral and cerebellar atrophy2 but, as shown in this case, severe cerebellar atrophy may occur, more akin to that seen in the spinocerebellar ataxia (SCA) syndromes. Multiple mutations have been described in the ARG1 gene.3 Although arginase deficiency is an inherited disorder characterised by spastic paraparesis, it is not classified as one of the hereditary spastic paraplegias (HSP), a group of clinically and genetically heterogeneous disorders due to length-dependent damage to upper motor neurones.4 However, arginase deficiency does feature in the differential diagnosis of HSP and should be considered in any patient with childhood-onset complicated spastic paraparesis, since misdiagnosis as HSP has been reported.5 Cerebel lar atrophy on magnetic resonance imaging of the brain may point towards arginase deficiency, although this neuroimaging finding has been reported in some cases of childhood-onset HSP.6 The symptom complex of early onset physical and learning disability in this patient might initially have suggested the non-specific diagnostic category of ‘cerebral palsy’ but the neuroimaging and genetic characterisation allowed a more fine-grained diagnosis – arginase deficiency – hence opening up the opportunity for genetic counselling of the family.