Argininemia: A Treatable Genetic Cause of Progressive Spastic Diplegia Simulating Cerebral Palsy: Case Reports and Literature Review

Abstract

Argininemia, a rare autosomal recessive urea cycle disorder, is caused by a deficiency of arginase, with resulting elevated plasma arginine and ammonia levels. Reports to date have focused little on the neurology of this disorder or the efficacy of treatments. A MEDLINE search revealed 25 previously reported cases, to which we have added two brothers who presented with late onset progressive spastic diplegia. Though their degree of enzyme deficiency was comparable, the severity of their phenotypic abnormalities differed substantially. With dietary therapy, both showed improved cognitive and motor function. Late metabolic crises occurred in both, resulting in death of the less severely affected brother. Based on analysis of our clinical database, we report on the full spectrum of neurologic abnormalities seen in argininemia with particular focus on the accompanying progressive spastic diplegia and its response to treatment; progressive decline in head growth; distinctive neuroradiologic findings; and life-threatening later complications. Current and potential future therapies and long-term outcome are summarized.

Rescue of the Functional Alterations of Motor Cortical Circuits in Arginase Deficiency by Neonatal Gene Therapy

“…Ammonia is freely diffusible across the blood-brain barrier, and, although astroglial cells can provide short-term buffering, osmotically active glutamine leads to edema in addition to alteration of neurotransmitter systems and signal transduction pathways, energy metabolism, and oxidative stress (Butterworth et al, 1987;Braissant et al, 2013;Helman et al, 2014). Ammonia also compromises potassium buffering of astrocytic membranes and causes clinical neurological abnormalities by impairing cortical inhibition (Rangroo Thrane et al, 2013).…”

“…It usually presents later in life beginning in late infancy to the second year with microcephaly, spasticity, seizures, loss of ambulation, progressive mental impairment, growth retardation, periodic episodes of hyperammonemia, and failure to thrive (Prasad et al, 1997). Spastic diplegia, a unique feature of arginase deficiency, is not typical of any other urea cycle disorder (Prasad et al, 1997). Although the etiology of this neurologic phenotype is unknown, it appears that the origin is in upper motor neuron function affecting the motor cortex, the basal ganglia, and the corticospinal tract.…”

Spastic diplegia with nonperinatal asphyxia in pediatric population

“…4,16 Other metabolic disorders exhibiting spastic diplegia are disorders of purine and pyrimidine metabolism such as deficiency of hypoxanthine phosphoribosyl transferees, which is essential in the purine salvage pathway 17 and urea cycle disorders such as argininemia. 18 SjogrenLarsson syndrome, one of the IEMs due to mutations in the ALDH3A2 gene coding fatty aldehyde dehydrogenase, causes ichthyosis, developmental delay and spastic diplegia. 19 Furthermore, cretinism due to maternal iodine deficiency has been reported to cause spastic diplegia in children.…”

Anesthetic Management Of A Pediatric Patient With Arginase Deficiency

“…Paucity of relevant information in the literature poses several challenges in the anesthetic management of these patients. Few cases of arginase-deficiency have been described in the literature, one of which was related to anesthetic management (3,5). In this report, we presented the anesthetic management of a pediatric patient with arginase deficiency.…”

“…Arginase deficiency causes a neurological syndrome characterized by progressive spastic quadriparesis, psychomotor growth retardation and epileptic seizures (2). Peak ammonia levels are typically lower than those of other urea cycle disorders, but may occasionally be excessive in the presence of accelerated endogenous catabolism (1,3). In a healthy individual, amino acids that are not utilized for protein synthesis are eliminated through several biochemical pathways and excess nitrogen is converted to urea.…”