A p.Arg499His mutation in SPAST is associated with infantile-onset complicated spastic paraplegia: a case report and review of the literature

Abstract

Background Spastic paraplegia type 4 (SPG4) is caused by mutations in the SPAST gene, is the most common form of autosomal-dominant pure hereditary spastic paraplegias (HSP), and is rarely associated with a complicated form that includes ataxia, epilepsy, and cognitive decline. To date, the genotype-phenotype correlation has not been substantially established for SPAST mutations. Case presentation We present a Japanese patient with infantile-onset HSP and a complex form with coexisting ataxia and epilepsy. The sequencing of SPAST revealed a de novo c.1496G > A (p.R499H) mutation. A review of the literature revealed 16 additional patients with p.R499H mutations in SPAST associated with an early-onset complicated form of HSP. We found that the complicated phenotype of patients with p.Arg499His mutations could be mainly divided into three subgroups: (1) infantile-onset ascending hereditary spastic paralysis, (2) HSP with severe dystonia, and (3) HSP with cognitive impairment. Moreover, the c.1496G > A mutation in SPAST may occur as a de novo variant at noticeably high rates. Conclusion We reviewed the clinical features of the patients reported in the literature with the p.Arg499His mutation in SPAST and described the case of a Japanese patient with this mutation presenting a new complicated form. Accumulating evidence suggests a possible association between infantile-onset complicated HSP and the p.Arg499His mutation in SPAST. The findings of this study may expand the clinical spectrum of the p.Arg499His mutation in SPAST and provide an opportunity to further study the genotype-phenotype correlation of SPG4.

Early‐Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST

“…Notably, of 40 individuals in our cohort, all but 1 carry missense variants, with 19 harboring the recurrent Arg499His variant. Prior studies have linked missense variants, including p.Arg499His, to an earlier age of onset, 11,27,28 but these studies did not specify de novo cases versus familial cases. Our study raised the possibility that a subset of severely affected individuals with p.Arg499His and other missense mutations in prior studies could potentially have been de novo cases.…”

Early‐Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST

“…Interestingly, despite a severe phenotype, normal imaging has usually been described. 1,3,4 In our patient, magnetic resonance imaging initially suggested a metabolic disorder and, later, brain iron accumulation, posing an additional challenge. The WESbased multigene panel was crucial for diagnosis, after three decades of investigation.…”

“…Joana Dam asio, MD, 1,2,3 * Clara Barbot, MD, PhD, 2 Rui Felgueiras, MD, 1 Ana Filipa Brand ão, MSc, 3 José Barros, MD, PhD, 1,4 Jorge Oliveira, MSc, PhD, 2,3 and Jorge Sequeiros, MD, PhD…”

Movement disorders in hereditary spastic paraplegias

“…SPG4, related to SPAST gene mutation, is the most common SPG and may rarely present with cerebellar atrophy. 63 Other AD SPG may also present with ataxia, including SPG6, SPG10, SPG27, SPG30 and SPG31. 61 Moreover, another AD neurologic disorder that manifests either as isolated spastic paraplegia or the combination of ataxia, spastic paraplegia, and mental retardation, was described in 2002 and named as spastic paraplegia, ataxia and mental retardation (SPAR).…”