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, 14 (1), 208

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

Giorgia Olivieri et al. Orphanet J Rare Dis.


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.

Keywords: HHH syndrome; Hereditary spastic paraplegia; Ornithine; Urea cycle defects.

Conflict of interest statement

The authors declare that they have no competing interests.


Fig. 1
Fig. 1
Lower limbs motor evoked potential (MEPs) in eight patients with HHH syndrome. Mean central motor conduction time (CMCT) at rest and during muscle facilitation (tibialis anterior muscle) in HHH patients (grey bars) in comparison with healthy controls (white bars). Values are expressed as milliseconds (ms)
Fig. 2
Fig. 2
Brain MRI in patients with HHH syndrome. T2 weighted axial (upper panel), coronal (middle panel), and T1 weighted sagittal (lower panel) brain MRI. Atrophy of variable degree is detected in supra-tentorial region (moderate in patients #2, 3, 5 and 6; mild in patient # 4; absent in patients #8, and 9), corpus callosum (moderate in patients #3 and 5; mild in patients # 2, 4 and 6; absent in patients # 8 and 9) and cerebellum (mild in patients #2, 4, 5, 6 and 9, absent in patients # 3, and 8)
Fig. 3
Fig. 3
Spinal cord MRI in patients with HHH syndrome. T1 weighted spinal cord MRI showed atrophy of variable degree (severe in patients #3, moderate in patient #2, mild in patient #4, and absent in patients #5, 8 and 9)
Fig. 4
Fig. 4
Urea cycle and related pathways. The illustration shows the biochemical pathways connecting HHH syndrome, argininemia and pyrroline-5-carboxylate synthetase deficiency (gray boxes), the three disorders of aminoacid metabolism related to the distal part of the urea cycle sharing phenotypic similarities. AGAT, l-arginine:glycine amidinotransferase; ASL, argininosuccinate lyase; ASS, argininosuccinate synthetase; CPS, carbamyl-phosphate synthetase; GAA, guanidinoacetate; GAMT, guanidinoacetate N-methyltransferase; OAT, ornithine aminotransferase; ODC, ornithine decarboxylase; ORNT1, ornithine/citrulline antiporter; OTC, ornithine transcarbamylase; P5C, pyrroline-5-carboxylate; P5CR, pyrroline-5-carboxylate reductase; P5CS, pyrroline-5-carboxylate synthase

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