“Cerebral Palsy” in a Patient With Arginase Deficiency

Jichlinski, Amanda; Clarke, Lindsay; Whitehead, Matthew T.; Gropman, Andrea

doi:10.1016/j.spen.2017.03.016

Cited by 20 publications

(16 citation statements)

References 11 publications

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“…Clinical, neurophysiological and neuroradiological findings in HHH syndrome resemble those observed in argininemia and pyrroline-5-carboxylate synthetase (P5CS) deficiency [33–36], two other disorders of aminoacid metabolism connected to the distal part of the urea cycle (Fig. 4).…”

Section: Discussionmentioning

confidence: 84%

Corticospinal tract damage in HHH syndrome: a metabolic cause of hereditary spastic paraplegia

Olivieri

Pro

Diodato

et al. 2019

Orphanet J Rare Dis

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Background Hyperornithinemia–hyperammonemia–homocitrullinuria (HHH) syndrome is a rare disorder of urea cycle characterized by progressive pyramidal and cerebellar dysfunction, whose pathophysiology is not yet fully understood. Here we describe the spectrum of the long fibers involvement in HHH syndrome, attempting a correlation between clinical, electrophysiological and neuro-radiological data. Methods Nine HHH patients were longitudinally evaluated by clinical examination, neurophysiological assessment including motor (MEPs), somato-sensory evoked potentials (PESS) and nerve conduction velocity (NCV), brain and spinal cord MRI Results All patients had pyramidal dysfunction and 3/9 an overt spastic paraplegia. Mild to moderate cerebellar signs were found in 7/9, intellectual disability in 8/9. At lower limbs, MEPs resulted abnormal in 7/8 patients and PESS in 2/8; peripheral sensory-motor neuropathy was found in 1/9. MRI documented atrophic changes in supra-tentorial brain regions in 6/9 patients, cerebellum in 6/9, spinal cord in 3/7. Conclusions A predominant corticospinal dysfunction is evident in HHH syndrome, along with milder cerebellar signs, intellectual disability of variable degree and rare peripheral neuropathy. Phenotypical similarities with other disorders affecting the urea cycle (argininemia and pyrroline-5-carboxylate synthetase deficiency) suggest possible common mechanisms contributing in the maintenance of the corticospinal tract integrity. HHH syndrome phenotype largely overlaps with complex Hereditary Spastic Paraplegias (HSPs), in the list of which it should be included, emphasizing the importance to screen all the unsolved cases of HSPs for metabolic biomarkers.

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Section: Discussionmentioning

confidence: 84%

Corticospinal tract damage in HHH syndrome: a metabolic cause of hereditary spastic paraplegia

Olivieri

Pro

Diodato

et al. 2019

Orphanet J Rare Dis

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“…These findings support the following conclusions: arginase deficiency is a leukodystrophy affecting the brain and spinal cord while sparing the peripheral nervous system, and neonatal AAV hepatic gene therapy can rescue the defects associated with myelinated axons, strongly implicating the functional recovery of oligodendrocytes after restoration of hepatic arginase activity. palsy in some patients (5). Later findings include microcephaly, seizures, loss of ambulation, growth retardation, intellectual disabilities, and progressive neurological decline (4,6,7).…”

Section: Introductionmentioning

confidence: 99%

Hepatic arginase deficiency fosters dysmyelination during postnatal CNS development

Liu¹,

Haney²,

Cantero³

et al. 2019

JCI Insight

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“…The extent of white matter abnormality also correlated with cognitive deficits, as we demonstrated key areas of difference underlie pathways important in executive function. The location of the frontal white matter deficits correlates with networks related to attention, executive function, and working memory that show deficiencies in this patient population ( 63 ). Specific details of imaging deserve mention.…”

Section: Current Imaging Modalities In Ucdmentioning

confidence: 99%

“…Mild striatal lesions may be present ( 63 , 77 ). These changes may reflect arginase induced, NOS-mediated oxidative damage ( 63 ). Furthermore, putaminal T1 shortening can occur ( 77 ).…”

Section: Neuroimaging Clinical Studies In Ucdmentioning

confidence: 99%

“…In the later onset forms, MRS may be normal or show mild changes including arginase elevation at 3.8 ppm, elevated glutamine, and decreased myoinositol. Rarely, arginase deficiency ( 63 , 80 ) can present earlier with hyperammonemic induced encephalopathy; in those cases, MRI findings are similar to those of proximal UCD including cerebral swelling/edema which may spare the thalami ( 80 ). Reduced diffusion may occur in the sub-insular and other subcortical white matter and capsules during active injury ( 80 ).…”

Section: Neuroimaging Clinical Studies In Ucdmentioning

confidence: 99%

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Review of Multi-Modal Imaging in Urea Cycle Disorders: The Old, the New, the Borrowed, and the Blue

Sen

Anderson²,

Whitehead

et al. 2021

Front. Neurol.

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The urea cycle disorders (UCD) are rare genetic disorder due to a deficiency of one of six enzymes or two transport proteins that act to remove waste nitrogen in form of ammonia from the body. In this review, we focus on neuroimaging studies in OTCD and Arginase deficiency, two of the UCD we have extensively studied. Ornithine transcarbamylase deficiency (OTCD) is the most common of these, and X-linked. Hyperammonemia (HA) in OTCD is due to deficient protein handling. Cognitive impairments and neurobehavioral disorders have emerged as the major sequelae in Arginase deficiency and OTCD, especially in relation to executive function and working memory, impacting pre-frontal cortex (PFC). Clinical management focuses on neuroprotection from HA, as well as neurotoxicity from other known and yet unclassified metabolites. Prevention and mitigation of neurological injury is a major challenge and research focus. Given the impact of HA on neurocognitive function of UCD, neuroimaging modalities, especially multi-modality imaging platforms, can bring a wealth of information to understand the neurocognitive function and biomarkers. Such information can further improve clinical decision making, and result in better therapeutic interventions. In vivo investigations of the affected brain using multimodal neuroimaging combined with clinical and behavioral phenotyping hold promise. MR Spectroscopy has already proven as a tool to study biochemical aberrations such as elevated glutamine surrounding HA as well as to diagnose partial UCD. Functional Near Infrared Spectroscopy (fNIRS), which assesses local changes in cerebral hemodynamic levels of cortical regions, is emerging as a non-invasive technique and will serve as a surrogate to fMRI with better portability. Here we review two decades of our research using non-invasive imaging and how it has contributed to an understanding of the cognitive effects of this group of genetic conditions.

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“Cerebral Palsy” in a Patient With Arginase Deficiency

Cited by 20 publications

References 11 publications

Corticospinal tract damage in HHH syndrome: a metabolic cause of hereditary spastic paraplegia

Corticospinal tract damage in HHH syndrome: a metabolic cause of hereditary spastic paraplegia

Hepatic arginase deficiency fosters dysmyelination during postnatal CNS development

Review of Multi-Modal Imaging in Urea Cycle Disorders: The Old, the New, the Borrowed, and the Blue

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