Treatable genetic disorder misdiagnosed as HSP

Addition to HSP gene testing panels recommended

A rare genetic urea cycle disorder, Arginase 1 Deficiency, presents with progressive lower limb spasticity, much like HSP, making accurate diagnosis difficult and a sometimes lengthy process.

Disease progression can occur before a correct diagnosis is made, representing a significant negative impact of delayed treatment.

It is recommended that the ARG1-D gene be added to HSP gene panels and considered in HSP differential diagnosis.

Background: Arginase 1 Deficiency (ARG1-D) is a rare autosomal recessive urea cycle disorder (UCD) characterized by pathologic elevation of plasma arginine and debilitating manifestations. Based on clinical commonalities and low disease awareness, ARG1-D can be diagnosed as hereditary spastic paraplegia (HSP), leading to treatment delays.

Cases: A Hispanic woman with unremarkable medical history experienced progressive lower-limb spasticity in her 20s and received a diagnosis of HSP. She developed significant gait abnormalities and is unable to walk without assistance. More recently, two Hispanic brothers with childhood-onset manifestations including lower-limb spasticity, developmental delays, and seizures presented with suspected HSP. All three patients were ultimately diagnosed with ARG1-D based on plasma arginine several-fold above normal levels and loss-of-function ARG1 variants. Disease progression occurred before ARG1-D was correctly diagnosed.

Literature review: Retrospective analyses demonstrate that diagnostic delays in ARG1-D are common and can be lengthy. Because of clinical similarities between ARG1-D and HSP, such as insidious onset and progressive spasticity, accurate diagnosis of ARG1-D is challenging. Timely ARG1-D diagnosis is critical because this UCD is a treatable genetic cause of progressive lower-limb spasticity.

Conclusions: Arginase 1 Deficiency should be considered in HSP differential diagnosis until biochemically/genetically excluded, and should be routinely included in HSP gene panels.

SOURCE:  Mov Disord Clin Pract. 2022 Nov 22;10(1):109-114. doi: 10.1002/mdc3.13612. eCollection 2023 Jan. PMID: 36698992 © 2022 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Arginase 1 Deficiency in Patients Initially Diagnosed with Hereditary Spastic Paraplegia

Markey C McNutt  1 Nathan Foreman  2 Garrett Gotway  1

1. UT Southwestern Medical Center Dallas Texas USA.

2. RehabMetrics Colleyville Texas USA.

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