Table 1.

Hereditary Spastic Paraplegia: Genes and Distinguishing Clinical Features – Autosomal Dominant Inheritance

Gene 1HSP DesignationType of HSPOnsetDistinguishing Clinical FeaturesOtherReferences
GeneReview or OMIM EntryCitation
ADAR Not assignedUncomplicatedEarly childhoodAbnormal pattern of interferon expression determined by reverse transcription PCR assayReported in a single Hispanic individual Crow et al [2014]
ALDH18A1 SPG9AComplicatedAdolescence to adulthood (1 subject w/infantile onset)
  • Cataracts
  • Gastroesophageal reflux
  • Motor neuronopathy
Variably present:
  • Dysarthria
  • Ataxia
  • Cognitive impairment
  • Rare
  • Allelic w/AR HSP (SPG9B)
OMIM 601162 Coutelier et al [2015]
ATAD3A Not assignedComplicatedEarly onset
  • Amyotrophy
  • Hyperkinetic movements
  • May be confused w/hyperkinetic cerebral palsy
Rare Cooper et al [2017]
ATL1 SPG3AUncomplicatedInfantile to childhood (rarely adult onset)
  • Progression may be minimal w/static course.
  • May present as spastic diplegic cerebral palsy
  • Complicated phenotype w/peripheral neuropathy or autonomic failure reported
  • 80% of early-onset AD HSP
  • 10%-15% of all AD HSP
 Spastic Paraplegia 3A Zhao et al [2001], Namekawa et al [2006], Rainier et al [2006], Ivanova et al [2007]
BICD2 Not assignedComplicatedChildhood or adult
  • Infantile onset assoc w/SMA w/variable upper motor signs & contractures
  • Adult onset assoc w/mild amyotrophy
Rare Oates et al [2013]
BSCL2 2SPG17ComplicatedAdulthood
  • Distal amyotrophy affecting hands & feet
  • Motor neuropathy
  • Can be indistinguishable from ALS
Rare BSCL2-Related Neurologic Disorders/ Seipinopathy Windpassinger et al [2004], Musacchio et al [2017]
CPT1C SPG73UncomplicatedEarly adulthoodFoot deformity may be present.Single familyOMIM 616282 Rinaldi et al [2015]
DNM2 3Not assignedComplicatedBefore age 20 yrs
  • Axonal polyneuropathy may be present.
  • Mild distal amyotrophy in feet
Single family Sambuughin et al [2015]
ERLIN2 SPG18 4UncomplicatedJuvenile to adulthoodNone
  • Single family
  • Most pathogenic variants assoc w/AR HSP (See Table 2.)
 Rydning et al [2018]
HSPD1 SPG13UncomplicatedAdulthoodMild distal amyotrophyRareOMIM 605280 Hansen et al [2002]
KIF1A SPG30Uncomplicated (for AD inheritance)Juvenile to adulthood
  • Some individuals have mild ID.
  • Optic nerve atrophy, epilepsy can be rarely seen in AD SPG30.
5%-6% of all AD HSPOMIM 610357Roda et al [2017], Pennings et al [2020]
KIF5A 4SPG10ComplicatedJuvenile or adulthood
  • Polyneuropathy
  • Pes cavus
  • 1%-2% of all AD HSP
  • 5%-8% of all complicated AD HSP
OMIM 604187Reid et al [2002], Blair et al [2006], Liu et al [2014]
NIPA1 SPG6UncomplicatedAdulthood (infantile onset rare)
  • Severe weakness & spasticity
  • Rapidly progressive
  • Rarely, complicated by epilepsy or variable peripheral neuropathy
Rare (~1% of AD HSP)OMIM 600363Rainier et al [2003], Du et al [2011], Svenstrup et al [2011], Hedera [2013]
ATP2B4 (PMCA4)Not assignedUncomplicatedAdulthoodNoneSingle family Li et al [2014]
REEP1 SPG31UncomplicatedVariable from 2nd to 7th decadesMild amyotrophy variably present.Common, 4%-6% of all AD HSPOMIM 610250Züchner et al [2006], Hewamadduma et al [2009]
REEP2 SPG72UncomplicatedVery early, average age 4 yrs
  • Musculoskeletal problems
  • Mild postural tremor
  • Rare
  • Inheritance can be dominant or recessive
OMIM 615625 Esteves et al [2014]
RTN2 SPG12UncomplicatedBefore age 20 yrsNone5% of early-onset AD HSP but overall rareOMIM 604805 Montenegro et al [2012]
SLC33A1 SPG42UncomplicatedEarly adulthood
  • Slowly progressive
  • Mild pes cavus
Single family knownOMIM 612539 Lin et al [2008]
SPAST SPG4UncomplicatedVariable from infancy to 7th decade
  • Cognitive decline & dementia common
  • Distal amyotrophy variably present
  • Complicated phenotype w/ataxia variably present
40% of AD HSP Spastic Paraplegia 4 Hazan et al [1999], Fonknechten et al [2000], Nielsen et al [2004], Murphy et al [2009]
SPG7 SPG7Uncomplicated or complicatedJuvenile or adulthood
  • Dysarthria
  • Ataxia
  • Optic atrophy
  • Supranuclear palsy
  • Mitochondrial abnormalities on skeletal muscle biopsy
AD inheritance suggested for some pathogenic variants, but overall this is rare Spastic Paraplegia 7 McDermott et al [2001]
WASHC5 SPG8UncomplicatedAdulthood (rare infantile onset reported)Severe motor deficit in some individualsRare (~1% of AD HSP) Spastic Paraplegia 8 Hedera et al [1999], Valdmanis et al [2007]
TUBB4A 5Not assignedComplicatedJuvenile
  • Cerebellar ataxia
  • MRI evidence of hypomyelination
Rare Kancheva et al [2015]
ZFYVE27 SPG33UncomplicatedAdulthoodMild pes cavusSingle family knownOMIM 610244 Mannan et al [2006]

AD = autosomal dominant; AR = autosomal recessive; ALS = amyotrophic lateral sclerosis; CMT = Charcot-Marie-Tooth neuropathy; DI-CMT = dominant intermediate Charcot-Marie-Tooth neuropathy; HMN = hereditary motor neuropathy; HSP = hereditary spastic paraplegia; ID = intelectual disability; SMA = spinal muscular atrophy

1.

Genes are listed alphabetically.

2.

Allelic with distal hereditary motor neuropathy type V (dHMN-V) and variants of Charcot-Marie-Tooth disease type 2

3.

Allelic with CMT2M; DI-CMTB, centronuclear myopathy; & lethal congenital contractures syndrome type 5

4.

Allelic with Charcot-Marie-Tooth disease axonal CMT2A and ALS25 (susceptibility to ALS)

5.

Allelic with hypomyelinating leukodystrophy type 6 and autosomal dominant dystonia type 4

From: Hereditary Spastic Paraplegia Overview

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