# Argininemia: Pathophysiology and Novel Methods for Evaluation of the Disease
## 2 Clinical Manifestations and Physical History  
ARG1-D manifests with a combination of both neurological and extra-neurological symptoms along with an elevated risk of premature mortality [10]. Despite considerable variability in disease severity and progression rates among affected individuals, there is a strikingly consistent pattern of clinical manifestations over time [3]. Various cases have been described, for instance, the case of a 46-year-old female patient who had a history of frequent falls, and delayed development of speech ability at the age of 1 with subsequent progressive lower limbs spasticity, and dependency on a wheelchair by the age of 14. In contrast, there are cases such as that of a 16-year-old girl who also had a history of frequent falls, spastic gait, repetitive vomiting, and global developmental delay at the age of 1, followed by epileptic seizures at the age of 5, but after treatment with sodium benzoate, and a low-protein diet demonstrated no further clinical deterioration [11]. Neurological symptoms associated with this syndrome encompass motor signs such as progressive spastic diplegia/paraparesis--which constitutes the hallmark of the disease and typically begins in the first decade of life [11; 12]. Motor symptoms can also present between 1 to 5 years as hyperreflexia, clonus, toe walking, and other gait abnormalities, with 80% of the patients showing upper motor neuron involvement. Less frequently, ataxia, dystonia, and athetoid movements may be observed [8; 13]. Progressive lower limb spasticity can lead to loss of ambulation and functional mobility -including fine motor skills decline, particularly in adult patients [10; 13]. The rate of neurologic deterioration is not associated with the age of the symptoms' onset [14]. Cognitive deficits present as stagnation or regression of cognitive development over time. Additional cognitive and psychiatric symptoms that can be detected in arginine individuals involve intellectual disability, attention-deficit/hyperactivity disorder (ADHD), aggressive behavior, pervasive developmental disorder, and impaired memory recollection, especially in adult patients [10; 15]. Seizures, experienced by approximately 60-75% of the patients, most commonly present as tonic-clonic episodes, and their onset ranges from 4 months to 30 years [16; 17; 18]. Catabolic states, including infections, increased protein intake, and certain medications like valpro, can induce intermittent episodic hyperammonemia, which can be of variable severity and even result in hyperammonemic encephalopathy or death [10; 19; 20]. Extra-neurological symptoms, though relatively rare, primarily affect the liver and skeletal system. Hepatic dysfunction can range from mild to severe, encompassing neonatal jaundice, hepatomegaly, acute liver failure, liver fibrosis/cirrhosis, and hepatocellular carcinoma [2; 21; 22]. Due to increased chronic spasticity, scoliosis, kyphosis and lordosis may also be present [23]. In early infancy, ARG1-D is typically asymptomatic. Infants may display intermittent episodes of irritability, feeding difficulties, protein aversion, anorexia, vomiting, and decreased alertness when introduced to cow's milk [24]. The disease's first manifestations become evident in late infancy or early childhood (between 1-3 years) and progress in severity over time [1]. Adult-onset cases have also been reported [25; 26]. During early childhood (3 months-4 years), patients may be of short stature and exhibit clumsiness, psychomotor impairment, loss of developmental milestones, global developmental delay, and regression after initial normal neurodevelopment [27; 28]. Loss of bowel and bladder control can also occur [29]. Hearing and visual impairments have not been documented [13]. Imaging studies in individuals with ARG1-D have revealed the following: cerebral and cerebellar atrophy, cerebral edema, a thin corpus callosum, dysmyelination, and corticospinal tract degeneration [8; 30; 31; 32].