Table 2.

Spastic paraparesis and their corresponding cell biology mechanisms and metabolic impairment (cellular neurometabolism approach)

Predominant neurological syndrome	Gene	Disease, other symptoms	Biological role/location	Metabolic involvement	Reference
Spastic paraparesis Clinical signs: lower extremity spastic weakness that produces difficulty walking Symptoms may begin at any age. In infancy HSP may manifest as “toe walking” and mimic spastic diplegic cerebral palsy. HSP can be isolated or complex (with other symptoms). SPG (spastic gait) locus and the number refers to the OMIMno.	KIF5a	SPG10. Pure SP starting in childhood or at young adulthood. Sometimes distal sensory impairment	Axonal transport	Energy impairment, endosome/lysosome trafficking	Reid et al. 2002
	KIF1A	SPG30. Slowly progressive SP characterised by onset in the first or second decades.	Axonal transport	Energy impairment	Erlich et al. 2011
	Spastin	SPG4. Uncomplicated SP starting from childhood to adulthood	Defective mitochondria and vesicle transport, Endosomal tubule fission, trafficking	Energy impairment, complex molecule def, lysosome ultrastructural morphology	Starling et al. 2002
	SPG7 (Paraplegin)	SPG7. SP may associated cortical, cerebellar and optic nerve atrohpy	Quality control defect, ATP-dependent protease (mitochondrial inner membrane) that degrades misfolded proteins	Energy impairment, respiratory chain defects in mucle, UPR	Koppen et al. 2007
	REEP1	SPG31, distal motor neuropathy	Trafficking morphogenesis of the ER, mitochondrial function	Energy impairment, complex molecule def,	Beetz et al. 2008
	ATL1	SPG3A, early onset HSP, Hereditary Sensory Neuropathy Type 1D	Trafficking morphogenesis of the ER	Complex molecule defect	Abel et al. 2004
	KIAA0196, NIPA1, Spartin	SPG 8 (with ataxia), 6, 20 (early childhood, cerebellar signs)	Trafficking endosome morphogenesis and signalling	Complex molecule defect	De Matteis and Luini 2011
	KIAA 1840 Spactasin	SPG11. Most common AR HSP. Also related with juvenile ALS and CMT	Autophagy impairment, lysosome reformation	Complex molecule defect	Bauer et al. 2009
	ZFYVE26	SPG15. Second most common AR HSP. Complex, can associate epilepsy and dementia	Autophagy impairment, autophagosome maturation, lysosome reformation	Complex molecule defect	Hanein et al. 2008
	TECPR2	SPG49. Complicated, developmental delay, dysmorphic features, neurodegenerative disease	Autophagy impairment, autophagosome formation	Complex molecule defect	Oz-Levi et al. 2012
	IEM with predominant spastic paraparesis	-Complex lipid defects: such as DDHD1, DDHD2, CYP2U1, NTE, FAH2, GBA2, B4GALNT1, PLA2G6 -Other complex molecule defects and in particular those leading to leukodystrophy (ADL, lysosomal…) -Small molecule diseases: arginase deficiency, HHH, Homocysteine remethylation defects, neurotransmitter defects
	Spastic paraparesis General comments	We have included in this table only a small selection of genes. Metabolic abnormalities in both, neurogenetic and classic IEM include: -Complex molecule defects including trafficking, autophagy, quality control processes (UPR), complex lipid metabolism and remodelling are the most frequent mechanisms in HSP. -Energy defect including defects of ATP production and mitochondrial transport. -Interestingly some IEM of small molecules (mainly intoxication diseases) are also a cause of HSP. Further studies on the pathophysiology of these particular IEM would probably lead to defects related to trafficking and quality control mechanisms.

This table contains diseases that are representative of well-defined cell biology mechanisms which can be “easily” linked to pathophysiological categories described in IEM. This is not an exhaustive list of genes related to spastic paraparesis and does not describe in detail the clinical features of every disease

Abbreviations: ADL, adrenoleukodystrophy; ALS, amiotrophic lateral sclerosis (progressive muscle weakness and paralysis by motor neuron degeneration); CMT, Charcot-Marie-Tooth; ER, endoplasmic reticulum; HSP, hereditary spastic paraparesis; SP, spastic paraparesis; UPR, unfolded protein response