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Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

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Hereditary Spastic Paraplegia Overview

Synonyms: Hereditary Spastic Paraparesis, Strumpell-Lorrain Syndrome


Author Information and Affiliations

Initial Posting: ; Last Revision: February 11, 2021.

Estimated reading time: 35 minutes


The purpose of this overview is to increase the awareness of clinicians regarding hereditary spastic paraplegia. The following are the goals of this overview.

Goal 1.

Describe the clinical characteristics of hereditary spastic paraplegia and recommended treatment.

Goal 2.

Review the causes of hereditary spastic paraplegia.

Goal 3.

Consider the differential diagnosis of hereditary spastic paraplegia.

Goal 4.

Provide an evaluation strategy to identify the genetic cause of hereditary spastic paraplegia in a proband.

Goal 5.

Inform genetic counseling of family members of a proband with hereditary spastic paraplegia.

1. Clinical Characteristics and Recommended Treatment: Hereditary Spastic Paraplegia

The predominant signs and symptoms of hereditary spastic paraplegia (HSP) are lower-extremity weakness and spasticity.

Neurologic examination. Individuals with HSP demonstrate the following:

  • Bilateral lower-extremity spasticity (maximal in hamstrings, quadriceps, adductors, and gastrocnemius-soleus muscles) and weakness (maximal in the iliopsoas, hamstring, and tibialis anterior muscles). Spasticity and weakness are variable. Some individuals have spasticity and no demonstrable weakness, whereas others have spasticity and weakness in approximately the same proportions.
  • Lower-extremity hyperreflexia and extensor plantar responses
  • Often, mildly impaired vibration sensation in the distal lower extremities

Symptom onset

  • Early onset. When symptoms begin in very early childhood, they may be non-progressive and resemble spastic diplegic cerebral palsy.
  • Later onset. When symptoms begin in later childhood or after they usually progress slowly and steadily. After a number of years, it is not usual for individuals with progressively worsening gait to experience a "functional plateau" (i.e., the rate of further worsening of gait impairment is similar to that attributable to age).

Classification. HSP is classified clinically as "uncomplicated" (nonsyndromic) or "complicated" (syndromic).

  • Uncomplicated (or "pure") HSP is characterized by neurologic impairment limited to progressive lower-extremity spastic weakness, hypertonic urinary bladder disturbance, and mild diminution of lower-extremity vibration sensation [Harding 1983]. Individuals with uncomplicated HSP experience the following:
    • Difficulty walking (may either be non-progressive or worsen insidiously)
    • Often, the need for canes, walkers, or wheelchairs
    • Possible urinary urgency and lower-extremity paresthesias
    • Typically, normal strength and dexterity of the upper extremities
    • No involvement of speech, chewing, or swallowing
    Though symptoms may be disabling, life span is not shortened.
  • Complicated HSP is characterized by the impairments present in uncomplicated HSP plus other system involvement or other neurologic findings including any of the following:*
    • Ataxia
    • Seizures
    • Intellectual disability
    • Dementia
    • Muscle atrophy
    • Extrapyramidal disturbance
    • Peripheral neuropathy
    * In the absence of other causes for these additional features

Treatment of Manifestations

At present, there is no specific treatment to prevent or reverse nerve degeneration in HSP. Treatments are directed at reducing symptoms and improving balance, strength, and agility. Individuals should be evaluated periodically (annually or as needed) by a neurologist and physiatrist to assess progression and develop treatment strategies to maximize walking ability and reduce symptoms.

Current recommendations:

  • Daily regimen of physical therapy directed toward improving cardiovascular fitness, maintaining and improving muscle strength and gait, and reducing spasticity
  • Occupational therapy, assistive walking devices, and ankle-foot orthotics as needed
  • Drugs to reduce muscle spasticity (e.g., Lioresal® [oral or intrathecal], tizanidine, dantrolene, botulinum A and B toxin injections [Botox®, Dysport, Xeomin, or Myoblock]) and urinary urgency (e.g., oxybutynin, solifenacin, mirabegron, or intrabladder injections with Botox®)

2. Causes of Hereditary Spastic Paraplegia

Genetic types of hereditary spastic paraplegia (HSP). To date, more than 80 genetic types of HSP have been defined by genetic linkage analysis and identification of HSP-related gene variants. In the past, genetic loci for HSP were designated SPG (for "spastic paraplegia") and numbered in order of their discovery. With the identification of the causative genes at those loci, reference by clinicians and clinical labs to a specific genetic type of HSP has moved to the name of the gene rather than the locus designation. Autosomal dominant, autosomal recessive, X-linked, and maternally inherited (mitochondrial) forms of HSP have been identified.

Autosomal dominant HSP is the most common type of HSP, found in 75%-80% of affected individuals.

  • SPG4, caused by a pathogenic variant in SPAST, is the most common type, accounting for approximately 40% of all autosomal dominant HSP.
  • SPG3A, caused by a pathogenic variant in ATL1, is the second most common type of autosomal dominant HSP, accounting for approximately 10%-15% of all autosomal dominant HSP. SPG3A is the main cause of autosomal dominant HSP with early onset (occurs in >75% of individuals in this category).
  • SPG30 (caused by a pathogenic variant in KIF1A) and SPG31 (caused by a pathogenic variant in REEP1) are both relatively common, each accounting for about 5% of all autosomal dominant HSP.
  • Other types of autosomal dominant HSP with a predominantly adult onset are relatively rare and most of them account for 1% or less of all autosomal dominant HSP.

Autosomal recessive HSP is very heterogeneous, with an ever-growing list of newly identified genes. Many new causes of autosomal recessive HSP are very rare and may be limited to a single family or even a single individual. The frequency is increased in populations with a higher degree of consanguinity. AR HSP is found in an estimated 25%-30% of all individuals with HSP.

Most common types of autosomal recessive HSP are encountered in the general population:

  • SPG5A, caused by pathogenic variants in CYP7B1, accounts for 7.3% of all autosomal recessive HSP and 3% of apparently sporadic pure spastic paraplegia.
  • SPG7, caused by pathogenic variants in SPG7, may account for approximately 5% of all autosomal recessive HSP.
  • SPG11, caused by pathogenic variants in SPG11, accounts for 3%-5% of all autosomal recessive HSP but is found in 75% of individuals with all types of HSP who have radiologic signs of thin or absent corpus callosum.

X-linked HSP and mitochondrial HSP are the rarest genetic forms of HSP, accounting for fewer than 1%-2% of all individuals affected with HSP.

Other. Several types of HSP (e.g., those associated with pathogenic variants in ATL1 [Khan et al 2014], SPG7 [McDermott et al 2001], and ALDH18A1 [Coutelier et al 2015]) may be inherited as either autosomal recessive or autosomal dominant disorders.

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


Genes are listed alphabetically.


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


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


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


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

Table 2.

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

Gene 1HSP DesignationType of HSPOnsetDistinguishing Clinical FeaturesOtherReferences
or OMIM Entry
  • Ataxia
  • Adult-onset dementia & parkinsonism
  • Polyneuropathy
  • Akinetic mutism seen in advanced cases
  • Rare, first described in Old Order Amish population (later identified in various ethnic groups)
  • Also known as Mast syndrome
OMIM 248900Cross & McKusick [1967a], Simpson et al [2003], Ishiura et al [2014]
ALDH18A1 SPG9BComplicatedAdolescence to adulthood (one subject w/infantile onset)
  • Cataracts
  • Gastroesophageal reflux
  • Motor neuronopathy
Variably present:
  • Dysarthria
  • Ataxia
  • Cognitive impairment
  • Rare
  • Allelic w/AD HSP (SPG9A)
OMIM 616586 Coutelier et al [2015]
ALDH3A2 Not assignedComplicatedChildhood
  • Congenital ichthyosis
  • Macular dystrophy
  • Leukodystrophy
  • Seizures in ~40% of patients
  • Rare
  • Most common in people of Swedish ancestry
  • Known as Sjögren-Larsson syndrome
Rizzo et al [1999], Gordon [2007]
AMPD2 2SPG63ComplicatedInfancy
  • Short stature
  • Thin corpus callosum
  • White matter changes
RareOMIM 615686Novarino et al [2014], Kortüm et al [2018]
AP4B1 SPG47ComplicatedInfancy
  • Severe ID
  • Facial dysmorphism
  • Seizures
  • Stereotypic laughter w/tongue protrusion
RareOMIM 614066Abou Jamra et al [2011], Bauer et al [2012]
AP4E1 SPG51ComplicatedInfancy
  • Severe ID
  • Facial dysmorphism
  • Seizures
  • Stereotypic laughter w/tongue protrusion
RareOMIM 613744Abou Jamra et al [2011], Moreno-De-Luca et al [2011]
AP4M1 SPG50ComplicatedInfancy
  • Severe ID
  • Facial dysmorphism
  • Seizures
  • Stereotypic laughter w/tongue protrusion
RareOMIM 612936 Verkerk et al [2009]
AP4S1 SPG52ComplicatedInfancy
  • Severe ID
  • Facial dysmorphism
  • Seizures
  • Stereotypic laughter w/tongue protrusion
RareOMIM 614067Abou Jamra et al [2011], Hardies et al [2015]
AP5Z1 SPG48UncomplicatedTypically adulthood; rarely infancy
  • Urinary incontinence
  • Parkinsonism
  • Dystonia
  • Thin corpus callosum
  • Leukodystrophy
  • Severe DD in infantile onset
Single familyOMIM 613647Słabicki et al [2010], Pensato et al [2014]
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
AR inheritance is very rare. Spastic Paraplegia 3A Khan et al [2014]
B4GALNT1 SPG26ComplicatedJuvenile
  • Amyotrophy
  • Dysarthria
  • Ataxia
  • DD
  • Dystonia
RareOMIM 609195Boukhris et al [2013], Harlalka et al [2013]
BICD2 Not assignedComplicatedChildhood
  • Amyotrophy
  • Contractures
Rare Oates et al [2013]
MTRFR (C12orf65)SPG55ComplicatedChildhood
  • DD
  • Visual loss
  • Polyneuropathy
  • Arthrogryposis
  • Signs of mitochondrial encephalomyopathy, some classified as Leigh's syndrome
RareOMIM 615035 Shimazaki et al [2012]
C19orf12 SPG43ComplicatedChildhood
  • Amyotrophy
  • Dysarthria
  • Multiple contractures
  • Neurodegeneration w/brain iron accumulation in some
RareOMIM 615043Landouré et al [2013], Schubert et al [2016]
CYP2U1 SPG56ComplicatedInfancy
  • Severe DD
  • Dystonia
  • Polyneuropathy
  • Calcification of basal ganglia
RareOMIM 615030 Tesson et al [2012]
CYP7B1 SPG5AUncomplicated or complicatedJuvenile to early adulthood
  • Ataxia
  • Polyneuropathy
  • Extrapyramidal signs
  • MRI signs of leukodystrophy
SPG5A was diagnosed in 9 of 172 families w/histories consistent w/AR inheritance of HSP. 3OMIM 270800Tsaousidou et al [2008], Goizet et al [2009]
DDHD1 SPG28UncomplicatedChildhoodScoliosisRareOMIM 609340 Tesson et al [2012]
DDHD2 SPG54ComplicatedInfancy
  • Severe DD
  • Optic atrophy
  • Thin corpus callosum
  • Leukodystrophy
RareOMIM 615033 Schuurs-Hoeijmakers et al [2012]
ENTPD1 SPG64ComplicatedInfancy
  • Mild cognitive disability
  • Behavioral disturbances
  • White matter changes
Rare ENTPD1-Related Neurodevelopmental Disorder Novarino et al [2014]
ERLIN1 SPG62ComplicatedChildhood
  • Amyotrophy
  • Ataxia
  • Phenotype consistent w/juvenile onset of ALS reported
RareOMIM 615681Novarino et al [2014], Tunca et al [2018]
ERLIN2 SPG18Complicated (rarely pure AR HSP reported)Childhood
  • DD
  • Seizures
  • Contractures
  • Juvenile primary lateral sclerosis phenotype reported
  • Allelic w/AD pure HSP
RareOMIM 611225Alazami et al [2011], Yıldırım et al [2011], Al-Saif et al [2012]
FA2H 4SPG35ComplicatedChildhood
  • Seizures
  • Dystonia
  • Parkinsonism w/iron accumulation in basal ganglia
RareOMIM 612319Edvardson et al [2008], Dick et al [2010], Pensato et al [2014]
GAD1 Not assignedComplicatedChildhood
  • Moderate to severe ID
  • Single reported family was described as having AR cerebral palsy
Rare (single family reported) Lynex et al [2004]
GBA2 SPG46ComplicatedChildhood
  • DD
  • Ataxia
  • Hearing loss
  • Polyneuropathy
RareOMIM 614409Hammer et al [2013], Coarelli et al [2018]
GJC2 5SPG44ComplicatedChildhood
  • Febrile seizures
  • Deafness
  • Episodic spasms
  • Variable degree of leukodystrophy
RareOMIM 613206Uhlenberg et al [2004], Orthmann-Murphy et al [2009]
GRID2 6Not assignedComplicatedChildhood
  • Amyotrophy
  • Ataxia
RareUtine et al [2013], Maier et al [2014]
IBA57 7SPG74ComplicatedChildhood
  • Optic atrophy
  • Peripheral neuropathy
RareOMIM 616451Lossos et al [2015], Torraco et al [2017]
KIF1A 8SPG30ComplicatedChildhood
  • Spastic ataxia
  • Polyneuropathy
RareOMIM 610357Hamdan et al [2011], Rivière et al [2011], Klebe et al [2012]
KIF1C SPG58ComplicatedChildhood
  • Spastic ataxia
  • Dystonia
RareCaballero Oteyza et al [2014], Dor et al [2014]
KLC2 Not assignedComplicatedChildhood
  • Optic atrophy
  • Neuropathy
  • Contractures in later stages
  • Cognition remains intact
  • Rare
  • Also known as spastic paraplegia optic atrophy, & neuropathy (SPOAN)
OMIM 609541 Melo et al [2015]
KLC4 Not assignedComplicatedChildhood
  • Ataxia
  • Multiple contractures
  • Variable degree of leukodystrophy
Rare Bayrakli et al [2015]
MARS1 9SPG70ComplicatedInfancy
  • Nephrotic syndrome, polyneuropathy
  • Mild ID
  • Late onset of CMT2 (axonal) type also reported
RareGonzalez et al [2013], Novarino et al [2014]
NT5C2 SPG45ComplicatedChildhood
  • Optic atrophy
  • Nystagmus
  • Strabismus
  • ID
  • Hypoplastic corpus callosum
RareOMIM 613162Novarino et al [2014], Elsaid et al [2017]
PGAP1 10SPG67ComplicatedInfancy
  • Severe DD
  • Tremor
  • Agenesis of corpus callosum
  • Hypomyelination
RareMurakami et al [2014], Novarino et al [2014]
PNPLA6 11SPG39ComplicatedChildhood
  • Amyotrophy
  • Endocrine abnormalities w/short stature or hypogonadotropic hypogonadism
  • Chorioretinal dystrophy
Rare PNPLA6-Related Disorders Rainier et al [2008], Synofzik et al [2014],
Hufnagel et al [2015]
REEP2 SPG72UncomplicatedEarly childhood
  • Musculoskeletal problems
  • Mild postural tremor
  • Rare
  • Inheritance can be dominant or recessive.
OMIM 615625 Esteves et al [2014]
SPART SPG20ComplicatedJuvenile
  • Distal amyotrophy
  • Short stature
  • Kyphoscoliosis
  • Multiple limb contractures
  • Rare
  • Mostly seen among Old Order Amish
Troyer Syndrome Cross & McKusick, [1967b], Patel et al [2002]
SPG7 SPG7Uncomplicated or complicatedJuvenile or adulthood
  • Dysarthria
  • Ataxia
  • Optic atrophy
  • Supranuclear palsy
  • Mitochondrial abnormalities on skeletal muscle biopsy
  • 5%-12% of AR HSP
  • AD inheritance suggested for some pathogenic variants; this remains controversial
Spastic Paraplegia 7 Casari et al [1998], McDermott et al [2001], Arnoldi et al [2008], Brugman et al [2008]
SPG11 SPG11ComplicatedChildhood or early adulthood
  • DD
  • Optic atrophy
  • Ataxia
  • Pseudobulbar signs
  • Polyneuropathy
  • Levodopa-responsive parkinsonism
  • Hypoplastic or absent corpus callosum
  • 5% of AR HSP
  • 75% of HSP w/DD & hypoplasia of corpus callosum
Spastic Paraplegia 11 Stevanin et al [2007], Paisan-Ruiz et al [2008], Riverol et al [2009], Guidubaldi et al [2011]
TECPR2 SPG49ComplicatedChildhood
  • Central apnea
  • Severe DD
  • Microcephaly
  • Dysmorphic features
Rare TECPR2-HSAN with ID Oz-Levi et al [2012]
TFG SPG57ComplicatedChildhood
  • Optic atrophy
  • Severe polyneuropathy
RareOMIM 615658 Beetz et al [2013]
USP8 SPG59UncomplicatedChildhoodNoneRare Novarino et al [2014]
WDR48 SPG60ComplicatedInfancy
  • Polyneuropathy
  • DD
Rare Novarino et al [2014]
ZFYVE26 SPG15ComplicatedChildhood or early adulthood
  • DD
  • Optic atrophy
  • Ataxia
  • Central retinal degeneration
  • Polyneuropathy
1%-2% of AR HSP Spastic Paraplegia 15 Hanein et al [2008], Pensato et al [2014]

AD = autosomal dominant; AR = autosomal recessive; ALS = amyotrophic lateral sclerosis; DD = developmental delay; HSP = hereditary spastic paraplegia; ID = intellectual disability; TECPR2-HSAN with ID = TECPR2-related hereditary sensory and autonomic neuropathy with intellectual disability


Genes are listed alphabetically.


Allelic with pontocerebellar hypoplasia type 9


Allelic with Pelizaeus-Merzbacher-like disease 1 and hereditary lymphedema type IC


Allelic with autosomal recessive spinocerebellar ataxia 18 (See Hereditary Ataxia Overview.)


Allelic with multiple mitochondrial dysfunctions syndrome 3


Allelic with hereditary sensory and autonomic neuropathy type 2C and AD intellectual disability type 9


Allelic with autosomal recessive intellectual disability type 42


Allelic with Boucher-Neuhauser syndrome, Gordon-Holmes syndrome, Oliver-McFarlane syndrome, and Laurence-Moon syndrome

Table 3.

Hereditary Spastic Paraplegia: Genes and Distinguishing Clinical Features – X-Linked Inheritance

Gene 1HSP DesignationType of HSPOnsetDistinguishing Clinical FeaturesOtherReferences
or OMIM Entry
L1CAM SPG1 2ComplicatedInfancy
  • ID
  • Adducted thumbs
  • Corpus callosum hypoplasia
  • Aphasia
  • Obstructive hydrocephalus
Rare L1 Syndrome Jouet et al [1994], Schrander-Stumpel et al [1995], Yamasaki et al [1995], Finckh et al [2000]
PLP1 3SPG2ComplicatedEarly-childhood to juvenile onset
(in manifesting female heterozygotes: onset in 4th-7th decade)
  • Pure HSP phenotype present in early stages; later, other signs emerge
  • Nystagmus
  • Optic atrophy
  • Dysarthria
  • ID
  • Variable degree of leukodystrophy on MRI
PLP1-Related Disorders Saugier-Veber et al [1994], Cambi et al [1996], Hodes et al [1999], Sivakumar et al [1999]
SLC16A2 SPG22ComplicatedEarly childhood
  • Severe ID
  • Infantile hypotonia
  • Progressive spasticity
  • Ataxia
  • Dystonia
  • ↑ T3 & normal to mildly ↑ TSH
  • ↓ T4 hypomyelination on neuroimaging
  • Rare
  • SPG22 is a proposed designation. 4
  • Also referred to as Allan-Herndon-Dudley syndrome 5
Allan-Herndon-Dudley Syndrome Dumitrescu et al [2004], Boccone et al [2010]

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; HSP = hereditary spastic paraplegia; ID = intellectual disability


Genes are listed alphabetically.


SPG1 is more commonly referred to as MASA syndrome (mental retardation [intellectual disability], aphasia [delayed speech], spastic paraplegia, adducted thumbs). Allelic disorders are X-linked hydrocephalus with stenosis of the aqueduct of Sylvius and X-linked complicated corpus callosum agenesis.


OMIM 300523


Because of the overlap between the clinical phenotype in individuals with SLC16A2 abnormalities and in those with a previously described syndrome, Allan-Herndon-Dudley syndrome (AHDS), Schwartz et al [2005] analyzed SLC16A2 in six families with AHDS. SLC16A2 pathogenic variants were identified in all six; therefore, AHDS is now synonymous with MCT8-specific thyroid hormone cell-membrane transporter deficiency due to pathogenic variants in SLC16A2 (see Allan-Herndon-Dudley Syndrome).

Table 4.

Hereditary Spastic Paraplegia: Gene and Distinguishing Clinical Features – Maternal (Mitochondrial) Inheritance

GeneHSP DesignationType of HSPOnsetDistinguishing Clinical Features
MT-ATP6 Not assignedComplicatedAdultCardiomyopathy, diabetes mellitus, sensory polyneuropathy

3. Differential Diagnosis of Hereditary Spastic Paraplegia

The differential diagnosis includes the following:

4. Evaluation Strategies to Identify the Genetic Cause of Hereditary Spastic Paraplegia in a Proband

Establishing a specific genetic cause of hereditary spastic paraplegia (HSP):

  • Can aid in discussions of prognosis (which are beyond the scope of this GeneReview) and genetic counseling;
  • Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.

Medical history and physical examination is directed at identifying neurologic features associated with HSP as well as any additional features that could indicate the presence of a complicated HSP (see Clinical Characteristics and Tables 1, 2, 3, and 4).

Family history includes a three-generation family history with attention to other relatives with possible HSP. Documentation of relevant findings in family members can be accomplished either through direct examination of those individuals or through review of their medical records including neuroimaging, neuropathology, neurologic examination, and results of molecular genetic testing. Autosomal dominant, autosomal recessive, and X-linked or maternal (mitochondrial) inheritance patterns have all been reported with HSP.

Exclusion of other disorders. See Differential Diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.

  • Concurrent or serial single-gene testing can be considered if clinical findings and/or family history indicate that involvement of a particular gene or small subset of genes is most likely (see Tables 1, 2, 3, and 4).
  • A multigene panel that includes some or all of the genes listed in Table 1 is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) may be considered. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

5. Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hereditary spastic paraplegia (HSP) can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner or by maternal (mitochondrial) inheritance, depending on the genetic subtype in a family.

Several types of HSP (e.g., those associated with pathogenic variants in ATL1, SPG7, ALDH18A1, and possibly SPG11) may be inherited either as autosomal recessive or autosomal dominant disorders (see Causes of Hereditary Spastic Paraplegia).

Risk to Family Members

Autosomal Dominant HSP

Parents of a proband

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents: if one of the proband's parents has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • The age of onset and degree of disability are highly variable among members of the same family, in different families with the same pathogenic variant, or between genetic types of HSP.
  • If the HSP-related pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant HSP is at a 50% risk of inheriting the HSP-related pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.

Autosomal Recessive HSP

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one HSP-related pathogenic variant).
  • Heterozygotes (carriers) are typically asymptomatic. The only known exception to this rule is SPG7, where an apparently dominant inheritance was suggested for otherwise autosomal recessive HSP [McDermott et al 2001].

Sibs of a proband

  • At conception, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes are typically asymptomatic if the pattern of inheritance is consistent with autosomal recessive mode and affected individuals harbor biallelic pathogenic variants.

Offspring of a proband. The offspring of an individual with autosomal recessive HSP are obligate heterozygotes (carriers) for an HSP-related pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an HSP-related pathogenic variant.

X-Linked HSP

Parents of a male proband

  • The father of an affected male will not have the disorder nor will he be hemizygous for the HSP-related pathogenic variant; therefore, he does not require further evaluation/testing.
  • In a family with more than one individual with X-linked HSP, the mother of an affected male is an obligate carrier of the HSP-related pathogenic variant. If a woman has more than one affected child and if the HSP-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism (maternal germline and somatic mosaicism in L1CAM-related HSP [SPG1] has been reported [Du et al 1998, Vits et al 1998]).
  • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a de novo HSP-related pathogenic variant, in which case the mother is not a heterozygote.

Parents of a female proband

  • A female proband may have inherited the HSP-related pathogenic variant from either her mother or her father, or the pathogenic variant may be de novo.
  • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant. Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can determine if the pathogenic variant was inherited.

Sibs of a male proband

  • The risk to sibs depends on the genetic status of the mother.
    • If the mother of the proband with X-linked HSP has an HSP-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygotes and may have a range of clinical manifestations (see Table 3).
    • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the HSP-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of maternal germline mosaicism.
  • The age of onset, penetrance, and degree of disability are not predictable in members of the same family, in different families with the same pathogenic variant, or between genetic types of HSP.

Sibs of a female proband

  • The risk to sibs depends on the genetic status of the parents.
    • If the mother of the proband has an HSP-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygotes and may have a range of clinical manifestations (see Table 3).
    • If the father of the proband has an HSP-related pathogenic variant, he will transmit it to all of his daughters and none of his sons.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the HSP-related pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.
  • The age of onset, penetrance, and degree of disability are not predictable in members of the same family, in different families with the same pathogenic variant, or between genetic types of HSP.

Offspring of a male proband. Affected males transmit the HSP-related pathogenic variant to:

  • All of their daughters, who will be heterozygotes and may have a range of clinical manifestations (see Table 3);
  • None of their sons.

Offspring of a female proband. Women with an HSP-related pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child:

  • Males who inherit the pathogenic variant will be affected.
  • Females who inherit the variant will be heterozygotes and may have a range of clinical manifestations (see Table 3). This is best documented for SPG2, where female heterozygotes may show a mild paraparesis with late onset of the disease [Sivakumar et al 1999].

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the HSP-related pathogenic variant, the parent's family members may be at risk.

Heterozygote (carrier) detection. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.


(1) Females who are heterozygous for X-linked HSP may have a range of clinical manifestations (see Table 3).

(2) Identification of female heterozygotes requires either (a) prior identification of the HSP-related pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.

Maternal (Mitochondrial) Inheritance

Parents of a proband

Sibs of a proband

  • The risk to the sibs depends on the genetic status of the mother.
  • If the mother has the MT-ATP6 pathogenic variant, all sibs of a proband will inherit the MT-ATP6 pathogenic variant and may or may not have symptoms.

Offspring of a proband

  • All offspring of females with a mtDNA pathogenic variant will inherit the pathogenic variant.
  • Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's mother. If the mother has an MT-ATP6 pathogenic variant, her sibs and mother are also at risk.

Related Genetic Counseling Issues

Caution must be exercised when counseling an individual who has all the signs and symptoms of HSP but no similarly affected relatives. Such individuals may be diagnosed as having primary lateral sclerosis (PLS). While such individuals with no known family history of HSP may have autosomal recessive HSP (and thus low risk of transmitting the disorder to offspring), it is also possible that they have X-linked HSP, autosomal dominant HSP with reduced penetrance, a de novo pathogenic variant, a mtDNA pathogenic variant, mistaken paternity, or an environmentally acquired disorder.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including general discussion of potential risks to offspring and reproductive options) to young adults who are affected, carriers, or at risk of being affected or a carrier; however, it is not possible to make specific predictions about the potential severity of disease in offspring.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for hereditary spastic paraplegia are possible.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Chapter Notes

Author History

John K Fink, MD; University of Michigan (2000-2018)
Peter Hedera, MD, PhD, FACMG (2018-present)

Revision History

  • 11 February 2021 (aa/ha/ph) Revision: added AD SPG30 and associated references; updated SPG1/MASA syndrome terminology information
  • 27 September 2018 (ha) Comprehensive update posted live
  • 6 February 2014 (me) Comprehensive update posted live
  • 3 February 2009 (cd) Revision: sequence analysis for SPG5A available clinically
  • 21 May 2008 (cd) Revision: pathogenic variants in ZFYVE26 identified as causative of SPG15
  • 4 March 2008 (cd) Revision: sequence analysis of entire coding region available for SPG8 and SPG33
  • 4 October 2007 (cd) Revision: sequence analysis for SPG10 available on a clinical basis
  • 11 July 2007 (me) Comprehensive update posted live
  • 21 October 2004 (cd) Revision: arginase deficiency added
  • 26 February 2004 (cd) Revision: testing for SPG6 clinically available
  • 15 October 2003 (cd) Revision: test availability
  • 22 September 2003 (me) Comprehensive update posted live
  • 15 August 2000 (me) Overview posted live
  • 21 March 2000 (jf) Original submission


Literature Cited

  • Abou Jamra R, Philippe O, Raas-Rothschild A, Eck SH, Graf E, Buchert R, Borck G, Ekici A, Brockschmidt FF, Nöthen MM, Munnich A, Strom TM, Reis A, Colleaux L. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am J Hum Genet. 2011;88:788–95. [PMC free article: PMC3113253] [PubMed: 21620353]
  • Alazami AM, Adly N, Al Dhalaan H, Alkuraya FS. A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18). Neurogenetics. 2011;12:333–6. [PMC free article: PMC3215864] [PubMed: 21796390]
  • Al-Saif A, Bohlega S, Al-Mohanna F. Loss of ERLIN2 function leads to juvenile primary lateral sclerosis. Ann Neurol. 2012;72:510–6. [PubMed: 23109145]
  • Arnoldi A, Tonelli A, Crippa F, Villani G, Pacelli C, Sironi M, Pozzoli U, D'Angelo MG, Meola G, Martinuzzi A, Crimella C, Redaelli F, Panzeri C, Renieri A, Comi GP, Turconi AC, Bresolin N, Bassi MT. A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia. Hum Mutat. 2008;29:522–31. [PubMed: 18200586]
  • Aulitzky A, Friedrich K, Gläser D, Gastl R, Kubisch C, Ludolph AC, Volk AE. A complex form of hereditary spastic paraplegia in three siblings due to somatic mosaicism for a novel SPAST mutation in the mother. J Neurol Sci. 2014;347:352–5. [PubMed: 25315759]
  • Bauer P, Leshinsky-Silver E, Blumkin L, Schlipf N, Schröder C, Schicks J, Lev D, Riess O, Lerman-Sagie T, Schöls L. Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47). Neurogenetics. 2012;13:73–6. [PubMed: 22290197]
  • Bayrakli F, Poyrazoglu HG, Yuksel S, Yakicier C, Erguner B, Sagiroglu MS, Yuceturk B, Ozer B, Doganay S, Tanrikulu B, Seker A, Akbulut F, Ozen A, Per H, Kumandas S, Altuner Torun Y, Bayri Y, Sakar M, Dagcinar A, Ziyal I. Hereditary spastic paraplegia with recessive trait caused by mutation in KLC4 gene. J Hum Genet. 2015;60:763–8. [PubMed: 26423925]
  • Beetz C, Johnson A, Schuh AL, Thakur S, Varga RE, Fothergill T, Hertel N, Bomba-Warczak E, Thiele H, Nürnberg G, Altmüller J, Saxena R, Chapman ER, Dent EW, Nürnberg P, Audhya A. Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmicreticulum structure. Proc Natl Acad Sci U S A. 2013;110:5091–6. [PMC free article: PMC3612678] [PubMed: 23479643]
  • Blair MA, Ma S, Hedera P. Mutation in KIF5A can also cause adult-onset hereditary spastic paraplegia. Neurogenetics. 2006;7:47–50. [PubMed: 16489470]
  • Boccone L, Mariotti S, Dessì V, Pruna D, Meloni A, Loudianos G. Allan-Herndon-Dudley syndrome (AHDS) caused by a novel SLC16A2 gene mutation showing severe neurologic features and unexpectedly low TRH-stimulated serum TSH. Eur J Med Genet. 2010;53:392–5. [PubMed: 20713192]
  • Boukhris A, Schule R, Loureiro JL, Lourenço CM, Mundwiller E, Gonzalez MA, Charles P, Gauthier J, Rekik I, Acosta Lebrigio RF, Gaussen M, Speziani F, Ferbert A, Feki I, Caballero-Oteyza A, Dionne-Laporte A, Amri M, Noreau A, Forlani S, Cruz VT, Mochel F, Coutinho P, Dion P, Mhiri C, Schols L, Pouget J, Darios F, Rouleau GA, Marques W Jr, Brice A, Durr A, Zuchner S, Stevanin G. Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. Am J Hum Genet. 2013;93:118–23. [PMC free article: PMC3710753] [PubMed: 23746551]
  • Brugman F, Scheffer H, Wokke JH, Nillesen WM, de Visser M, Aronica E, Veldink JH, van den Berg LH. Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes. Neurology. 2008;71:1500–5. [PubMed: 18799786]
  • Caballero Oteyza A, Battaloğlu E, Ocek L, Lindig T, Reichbauer J, Rebelo AP, Gonzalez MA, Zorlu Y, Ozes B, Timmann D, Bender B, Woehlke G, Züchner S, Schöls L, Schüle R. Motor protein mutations cause a new form of hereditary spastic paraplegia. Neurology. 2014;82:2007–16. [PMC free article: PMC4105256] [PubMed: 24808017]
  • Cambi F, Tang XM, Cordray P, Fain PR, Keppen LD, Barker DF. Refined genetic mapping and proteolipid protein mutation analysis in X-linked pure hereditary spastic paraplegia. Neurology. 1996;46:1112–7. [PubMed: 8780101]
  • Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, De Michele G, Filla A, Cocozza S, Marconi R, Dürr A, Fontaine B, Ballabio A. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell. 1998;93:973–83. [PubMed: 9635427]
  • Coarelli G, Romano S, Travaglini L, Ferraldeschi M, Nicita F, Spadaro M, Fornasiero A, Frontali M, Salvetti M, Bertini E, Ristori G. Novel homozygous GBA2 mutation in a patient with complicated spastic paraplegia. Clin Neurol Neurosurg. 2018;168:60–3. [PubMed: 29524657]
  • Cooper HM, Yang Y, Ylikallio E, Khairullin R, Woldegebriel R, Lin KL, Euro L, Palin E, Wolf A, Trokovic R, Isohanni P, Kaakkola S, Auranen M, Lönnqvist T, Wanrooij S, Tyynismaa H. ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia. Hum Mol Genet. 2017;26:1432–43. [PMC free article: PMC5393146] [PubMed: 28158749]
  • Coutelier M, Goizet C, Durr A, Habarou F, Morais S, Dionne-Laporte A, Tao F, Konop J, Stoll M, Charles P, Jacoupy M, Matusiak R, Alonso I, Tallaksen C, Mairey M, Kennerson M, Gaussen M, Schule R, Janin M, Morice-Picard F, Durand CM, Depienne C, Calvas P, Coutinho P, Saudubray JM, Rouleau G, Brice A, Nicholson G, Darios F, Loureiro JL, Zuchner S, Ottolenghi C, Mochel F, Stevanin G. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain. 2015;138:2191–205. [PMC free article: PMC4553756] [PubMed: 26026163]
  • Cross HE, McKusick VA. The mast syndrome. A recessively inherited form of presenile dementia with motor disturbances. Arch Neurol. 1967a;16:1–13. [PubMed: 6024251]
  • Cross HE, McKusick VA. The Troyer syndrome: a recessive form of spastic paraplegia with distal muscle wasting. Arch Neurol. 1967b;16:473–85. [PubMed: 6022528]
  • Crow YJ, Zaki MS, Abdel-Hamid MS, Abdel-Salam G, Boespflug-Tanguy O, Cordeiro NJ, Gleeson JG, Gowrinathan NR, Laugel V, Renaldo F, Rodriguez D, Livingston JH, Rice GI. Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia. Neuropediatrics. 2014;45:386–93. [PubMed: 25243380]
  • Dick KJ, Eckhardt M, Paisán-Ruiz C, Alshehhi AA, Proukakis C, Sibtain NA, Maier H, Sharifi R, Patton MA, Bashir W, Koul R, Raeburn S, Gieselmann V, Houlden H, Crosby AH. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Hum Mutat. 2010;31:E1251–60. [PubMed: 20104589]
  • Dor T, Cinnamon Y, Raymond L, Shaag A, Bouslam N, Bouhouche A, Gaussen M, Meyer V, Durr A, Brice A, Benomar A, Stevanin G, Schuelke M, Edvardson S. KIF1C mutations in two families with hereditary spastic paraparesis and cerebellar dysfunction. J Med Genet. 2014;51:137–42. [PubMed: 24319291]
  • Du JS, Bason L, Woffendin H, Zackai E, Kenwrick S. Somatic and germ line mosaicism and mutation origin for a mutation in the L1 gene in a family with X-linked hydrocephalus. Am J Med Genet. 1998;75:200–2. [PubMed: 9450886]
  • Du J, Hu YC, Tang BS, Chen C, Luo YY, Zhan ZX, Zhao GH, Jiang H, Xia K, Shen L. Expansion of the phenotypic spectrum of SPG6 caused by mutation in NIPA1. Clin Neurol Neurosurg. 2011;113:480–2. [PubMed: 21419568]
  • Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet. 2004;74:168–75. [PMC free article: PMC1181904] [PubMed: 14661163]
  • Edvardson S, Hama H, Shaag A, Gomori JM, Berger I, Soffer D, Korman SH, Taustein I, Saada A, Elpeleg O. Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. Am J Hum Genet. 2008;83:643–8. [PMC free article: PMC2668027] [PubMed: 19068277]
  • Elsaid MF, Ibrahim K, Chalhoub N, Elsotouhy A, El Mudehki N, Abdel Aleem A. NT5C2 novel splicing variant expands the phenotypic spectrum of spastic paraplegia (SPG45): case report of a new member of thin corpus callosum SPG-Subgroup. BMC Med Genet. 2017;18:33. [PMC free article: PMC5359868] [PubMed: 28327087]
  • Esteves T, Durr A, Mundwiller E, Loureiro JL, Boutry M, Gonzalez MA, Gauthier J, El-Hachimi KH, Depienne C, Muriel MP, Acosta Lebrigio RF, Gaussen M, Noreau A, Speziani F, Dionne-Laporte A, Deleuze JF, Dion P, Coutinho P, Rouleau GA, Zuchner S, Brice A, Stevanin G, Darios F. Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia. Am J Hum Genet. 2014;94:268–77. [PMC free article: PMC3928657] [PubMed: 24388663]
  • Finckh U, Schroder J, Ressler B, Veske A, Gal A. Spectrum and detection rate of L1CAM mutations in isolated and familial cases with clinically suspected L1-disease. Am J Med Genet. 2000;92:40–6. [PubMed: 10797421]
  • Fonknechten N, Mavel D, Byrne P, Davoine CS, Cruaud C, Bönsch D, Samson D, Coutinho P, Hutchinson M, McMonagle P, Burgunder JM, Tartaglione A, Heinzlef O, Feki I, Deufel T, Parfrey N, Brice A, Fontaine B, Prud'homme JF, Weissenbach J, Dürr A, Hazan J. Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Hum Mol Genet. 2000;9:637–44. [PubMed: 10699187]
  • Goizet C, Boukhris A, Durr A, Beetz C, Truchetto J, Tesson C, Tsaousidou M, Forlani S, Guyant-Maréchal L, Fontaine B, Guimarães J, Isidor B, Chazouillères O, Wendum D, Grid D, Chevy F, Chinnery PF, Coutinho P, Azulay JP, Feki I, Mochel F, Wolf C, Mhiri C, Crosby A, Brice A, Stevanin G. CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. Brain. 2009;132:1589–600. [PubMed: 19439420]
  • Gonzalez M, McLaughlin H, Houlden H, Guo M, Yo-Tsen L, Hadjivassilious M, Speziani F, Yang XL, Antonellis A, Reilly MM, Züchner S., Inherited Neuropathy Consortium. Exome sequencing identifies a significant variant in methionyl-tRNA synthetase (MARS) in a family with late-onset CMT2. J Neurol Neurosurg Psychiatry. 2013;84:1247–9. [PMC free article: PMC3796032] [PubMed: 23729695]
  • Gordon N. Sjögren-Larsson syndrome. Dev Med Child Neurol. 2007;49:152–4. [PubMed: 17254005]
  • Guidubaldi A, Piano C, Santorelli FM, Silvestri G, Petracca M, Tessa A, Bentivoglio AR. Novel mutations in SPG11 cause hereditary spastic paraplegia associated with early-onset levodopa-responsive Parkinsonism. Mov Disord. 2011;26:553–6. [PubMed: 21381113]
  • Hamdan FF, Gauthier J, Araki Y, Lin DT, Yoshizawa Y, Higashi K, Park AR, Spiegelman D, Dobrzeniecka S, Piton A, Tomitori H, Daoud H, Massicotte C, Henrion E, Diallo O. S2D Group, Shekarabi M, Marineau C, Shevell M, Maranda B, Mitchell G, Nadeau A, D'Anjou G, Vanasse M, Srour M, Lafrenière RG, Drapeau P, Lacaille JC, Kim E, Lee JR, Igarashi K, Huganir RL, Rouleau GA, Michaud JL. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet. 2011;88:306–16. [PMC free article: PMC3059427] [PubMed: 21376300]
  • Hammer MB, Eleuch-Fayache G, Schottlaender LV, Nehdi H, Gibbs JR, Arepalli SK, Chong SB, Hernandez DG, Sailer A, Liu G, Mistry PK, Cai H, Shrader G, Sassi C, Bouhlal Y, Houlden H, Hentati F, Amouri R, Singleton AB. Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am J Hum Genet. 2013;92:245–51. [PMC free article: PMC3567281] [PubMed: 23332917]
  • Hanein S, Martin E, Boukhris A, Byrne P, Goizet C, Hamri A, Benomar A, Lossos A, Denora P, Fernandez J, Elleuch N, Forlani S, Durr A, Feki I, Hutchinson M, Santorelli FM, Mhiri C, Brice A, Stevanin G. Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. Am J Hum Genet. 2008;82:992–1002. [PMC free article: PMC2427184] [PubMed: 18394578]
  • Hansen JJ, Dürr A, Cournu-Rebeix I, Georgopoulos C, Ang D, Nielsen MN, Davoine CS, Brice A, Fontaine B, Gregersen N, Bross P. Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. Am J Hum Genet. 2002;70:1328–32. [PMC free article: PMC447607] [PubMed: 11898127]
  • Hardies K, May P, Djémié T, Tarta-Arsene O, Deconinck T, Craiu D. AR working group of the EuroEPINOMICS RES Consortium, Helbig I, Suls A, Balling R, Weckhuysen S, De Jonghe P, Hirst J. Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly. Hum Mol Genet. 2015;24:2218–27. [PMC free article: PMC4380070] [PubMed: 25552650]
  • Harding AE. Classification of the hereditary ataxias and paraplegias. Lancet. 1983;1:1151–5. [PubMed: 6133167]
  • Harlalka GV, Lehman A, Chioza B, Baple EL, Maroofian R, Cross H, Sreekantan-Nair A, Priestman DA, Al-Turki S, McEntagart ME, Proukakis C, Royle L, Kozak RP, Bastaki L, Patton M, Wagner K, Coblentz R, Price J, Mezei M, Schlade-Bartusiak K, Platt FM, Hurles ME, Crosby AH. Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis. Brain. 2013;136:3618–24. [PMC free article: PMC3859217] [PubMed: 24103911]
  • Hazan J, Fonknechten N, Mavel D, Paternotte C, Samson D, Artiguenave F, Davoine CS, Cruaud C, Dürr A, Wincker P, Brottier P, Cattolico L, Barbe V, Burgunder JM, Prud'homme JF, Brice A, Fontaine B, Heilig B, Weissenbach J. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet. 1999;23:296–303. [PubMed: 10610178]
  • Hedera P. Hereditary and metabolic myelopathies. Handb Clin Neurol. 2016;136:769–85. [PubMed: 27430441]
  • Hedera P. Recurrent de novo c.316G>A mutation in NIPA1 hotspot. J Neurol Sci. 2013;335:231–2. [PubMed: 24075313]
  • Hedera P, DiMauro S, Bonilla E, Wald J, Eldevik OP, Fink JK. Phenotypic analysis of autosomal dominant hereditary spastic paraplegia linked to chromosome 8q. Neurology. 1999;53:44–50. [PubMed: 10408535]
  • Hewamadduma C, McDermott C, Kirby J, Grierson A, Panayi M, Dalton A, Rajabally Y, Shaw P. New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP). Neurogenetics. 2009;10:105–10. [PubMed: 19034539]
  • Hodes ME, Zimmerman AW, Aydanian A, Naidu S, Miller NR, Garcia Oller JL, Barker B, Aleck KA, Hurley TD, Dlouhy SR. Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2). Am J Med Genet. 1999;82:132–9. [PubMed: 9934976]
  • Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
  • Hufnagel RB, Arno G, Hein ND, Hersheson J, Prasad M, Anderson Y, Krueger LA, Gregory LC, Stoetzel C, Jaworek TJ, Hull S, Li A, Plagnol V, Willen CM, Morgan TM, Prows CA, Hegde RS, Riazuddin S, Grabowski GA, Richardson RJ, Dieterich K, Huang T, Revesz T, Martinez-Barbera JP, Sisk RA, Jefferies C, Houlden H, Dattani MT, Fink JK, Dollfus H, Moore AT, Ahmed ZM. Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. J Med Genet. 2015;52:85–94. [PMC free article: PMC8108008] [PubMed: 25480986]
  • Ishiura H, Takahashi Y, Hayashi T, Saito K, Furuya H, Watanabe M, Murata M, Suzuki M, Sugiura A, Sawai S, Shibuya K, Ueda N, Ichikawa Y, Kanazawa I, Goto J, Tsuji S. Molecular epidemiology and clinical spectrum of hereditary spastic paraplegia in the Japanese population based on comprehensive mutational analyses. J Hum Genet. 2014;59:163–72. [PubMed: 24451228]
  • Ivanova N, Claeys KG, Deconinck T, Litvinenko I, Jordanova A, Auer-Grumbach M, Haberlova J, Löfgren A, Smeyers G, Nelis E, Mercelis R, Plecko B, Priller J, Zámecník J, Ceulemans B, Erichsen AK, Björck E, Nicholson G, Sereda MW, Seeman P, Kremensky I, Mitev V, De Jonghe P. Hereditary spastic paraplegia 3A associated with axonal neuropathy. Arch Neurol. 2007;64:706–13. [PubMed: 17502470]
  • Jouet M, Rosenthal A, Armstrong G, MacFarlane J, Stevenson R, Paterson J, Metzenberg A, Ionasescu V, Temple K, Kenwrick S. X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet. 1994;7:402–7. [PubMed: 7920659]
  • Kancheva D, Chamova T, Guergueltcheva V, Mitev V, Azmanov DN, Kalaydjieva L, Tournev I, Jordanova A. Mosaic dominant TUBB4A mutation in an inbred family with complicated hereditary spastic paraplegia. Mov Disord. 2015;30:854–8. [PubMed: 25772097]
  • Khan TN, Klar J, Tariq M, Anjum Baig S, Malik NA, Yousaf R, Baig SM, Dahl N. Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation. Eur J Hum Genet. 2014;22:1180–4. [PMC free article: PMC4169543] [PubMed: 24473461]
  • Klebe S, Lossos A, Azzedine H, Mundwiller E, Sheffer R, Gaussen M, Marelli C, Nawara M, Carpentier W, Meyer V, Rastetter A, Martin E, Bouteiller D, Orlando L, Gyapay G, El-Hachimi KH, Zimmerman B, Gamliel M, Misk A, Lerer I, Brice A, Durr A, Stevanin G. KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations. Eur J Hum Genet. 2012;20:645–9. [PMC free article: PMC3355258] [PubMed: 22258533]
  • Kortüm F, Jamra RA, Alawi M, Berry SA, Borck G, Helbig KL, Tang S, Huhle D, Korenke GC, Hebbar M, Shukla A, Girisha KM, Steinlin M, Waldmeier-Wilhelm S, Montomoli M, Guerrini R, Lemke JR, Kutsche K. Clinical and genetic spectrum of AMPD2-related pontocerebellar hypoplasia type 9. Eur J Hum Genet. 2018;26:695–708. [PMC free article: PMC5945775] [PubMed: 29463858]
  • Landouré G, Zhu PP, Lourenço CM, Johnson JO, Toro C, Bricceno KV, Rinaldi C, Meilleur KG, Sangaré M, Diallo O, Pierson TM, Ishiura H, Tsuji S, Hein N, Fink JK, Stoll M, Nicholson G, Gonzalez MA, Speziani F, Dürr A, Stevanin G, Biesecker LG, Accardi J, Landis DM, Gahl WA, Traynor BJ, Marques W Jr, Züchner S, Blackstone C, Fischbeck KH, Burnett BG, et al. Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12. Hum Mutat. 2013;34:1357–60. [PMC free article: PMC3819934] [PubMed: 23857908]
  • Li M, Ho PW, Pang SY, Tse ZH, Kung MH, Sham PC, Ho SL. PMCA4 (ATP2B4) mutation in familial spastic paraplegia. PLoS One. 2014;9:e104790. [PMC free article: PMC4132067] [PubMed: 25119969]
  • Lin P, Li J, Liu Q, Mao F, Li J, Qiu R, Hu H, Song Y, Yang Y, Gao G, Yan C, Yang W, Shao C, Gong Y. A missense mutation in SLC33A1, which encodes the acetyl-CoA transporter, causes autosomal-dominant spastic paraplegia (SPG42). Am J Hum Genet. 2008;83:752–9. [PMC free article: PMC2668077] [PubMed: 19061983]
  • Liu YT, Laurá M, Hersheson J, Horga A, Jaunmuktane Z, Brandner S, Pittman A, Hughes D, Polke JM, Sweeney MG, Proukakis C, Janssen JC, Auer-Grumbach M, Zuchner S, Shields KG, Reilly MM, Houlden H. Extended phenotypic spectrum of KIF5A mutations: from spastic paraplegia to axonal neuropathy. Neurology. 2014;83:612–9. [PMC free article: PMC4141994] [PubMed: 25008398]
  • Lossos A, Stümpfig C, Stevanin G, Gaussen M, Zimmerman BE, Mundwiller E, Asulin M, Chamma L, Sheffer R, Misk A, Dotan S, Gomori JM, Ponger P, Brice A, Lerer I, Meiner V, Lill R. Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia. Neurology. 2015;84:659–67. [PubMed: 25609768]
  • Lynex CN, Carr IM, Leek JP, Achuthan R, Mitchell S, Maher ER, Woods CG, Bonthon DT, Markham AF. Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with stiff-person syndrome and other movement disorders. BMC Neurol. 2004;4:20. [PMC free article: PMC544830] [PubMed: 15571623]
  • Maier A, Klopocki E, Horn D, Tzschach A, Holm T, Meyer R, Meyer T. De novo partial deletion in GRID2 presenting with complicated spastic paraplegia. Muscle Nerve. 2014;49:289–92. [PubMed: 24122788]
  • Mannan AU, Krawen P, Sauter SM, Boehm J, Chronowska A, Paulus W, Neesen J, Engel W. ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia. Am J Hum Genet. 2006;79:351–7. [PMC free article: PMC1559503] [PubMed: 16826525]
  • McDermott CJ, Dayaratne RK, Tomkins J, Lusher ME, Lindsey JC, Johnson MA, Casari G, Turnbull DM, Bushby K, Shaw PJ. Paraplegin gene analysis in hereditary spastic paraparesis (HSP) pedigrees in northeast England. Neurology. 2001;56:467–71. [PubMed: 11222789]
  • Melo US, Macedo-Souza LI, Figueiredo T, Muotri AR, Gleeson JG, Coux G, Armas P, Calcaterra NB, Kitajima JP, Amorim S, Olávio TR, Griesi-Oliveira K, Coatti GC, Rocha CR, Martins-Pinheiro M, Menck CF, Zaki MS, Kok F, Zatz M, Santos S. Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome. Hum Mol Genet. 2015;24:6877–85. [PMC free article: PMC6296331] [PubMed: 26385635]
  • Montenegro G, Rebelo AP, Connell J, Allison R, Babalini C, D'Aloia M, Montieri P, Schüle R, Ishiura H, Price J, Strickland A, Gonzalez MA, Baumbach-Reardon L, Deconinck T, Huang J, Bernardi G, Vance JM, Rogers MT, Tsuji S, De Jonghe P, Pericak-Vance MA, Schöls L, Orlacchio A, Reid E, Züchner S. Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. J Clin Invest. 2012;122:538–44. [PMC free article: PMC3266795] [PubMed: 22232211]
  • Moreno-De-Luca A, Helmers SL, Mao H, Burns TG, Melton AM, Schmidt KR, Fernhoff PM, Ledbetter DH, Martin CL. J Med Genet. 2011;48:141–4. [PMC free article: PMC3150730] [PubMed: 20972249]
  • Murakami Y, Tawamie H, Maeda Y, Büttner C, Buchert R, Radwan F, Schaffer S, Sticht H, Aigner M, Reis A, Kinoshita T, Jamra RA. Null mutation in PGAP1 impairing Gpi-anchor maturation in patients with intellectual disability and encephalopathy. PLoS Genet. 2014;10:e1004320. [PMC free article: PMC4006728] [PubMed: 24784135]
  • Murphy S, Gorman G, Beetz C, Byrne P, Dytko M, McMonagle P, Kinsella K, Farrell M, Hutchinson M. Dementia in SPG4 hereditary spastic paraplegia: clinical, genetic, and neuropathologic evidence. Neurology. 2009;73:378–84. [PubMed: 19652142]
  • Musacchio T, Zaum AK, Üçeyler N, Sommer C, Pfeifroth N, Reiners K, Kunstmann E, Volkmann J, Rost S, Klebe S. ALS and MMN mimics in patients with BSCL2 mutations: the expanding clinical spectrum of SPG17 hereditary spastic paraplegia. J Neurol. 2017;264:11–20. [PubMed: 27738760]
  • Namekawa M, Ribai P, Nelson I, Forlani S, Fellmann F, Goizet C, Depienne C, Stevanin G, Ruberg M, Dürr A, Brice A. SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years. Neurology. 2006;66:112–14. [PubMed: 16401858]
  • Nielsen JE, Johnsen B, Koefoed P, Scheuer KH, Grønbech-Jensen M, Law I, Krabbe K, Nørremølle A, Eiberg H, Søndergård H, Dam M, Rehfeld JF, Krarup C, Paulson OB, Hasholt L, Sørensen SA. Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation. Eur J Neurol. 2004;11:817–24. [PubMed: 15667412]
  • Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GMH, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, El Din Mahmoud IG, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L, Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu PS, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa MY, Schroth J, Spencer EG, Rosti RO, Akizu N, Vaux KK, Johansen A, Koh AA, Megahed H, Durr A, Brice A, Stevanin G, Gabriel SB, Ideker T, Gleeson JG. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014;343:506–11. [PMC free article: PMC4157572] [PubMed: 24482476]
  • Oates EC, Rossor AM, Hafezparast M, Gonzalez M, Speziani F, MacArthur DG, Lek M, Cottenie E, Scoto M, Foley AR, Hurles M, Houlden H, Greensmith L, Auer-Grumbach M, Pieber TR, Strom TM, Schule R, Herrmann DN, Sowden JE, Acsadi G, Menezes MP, Clarke NF, Züchner S. UK10K, Muntoni F, North KN, Reilly MM. Mutations in BICD2 cause dominant congenital spinal muscular atrophy and hereditary spastic paraplegia. Am J Hum Genet. 2013;92:965–73. [PMC free article: PMC3675232] [PubMed: 23664120]
  • Orthmann-Murphy JL, Salsano E, Abrams CK, Bizzi A, Uziel G, Freidin MM, Lamantea E, Zeviani M, Scherer SS, Pareyson D. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain. 2009;132:426–38. [PMC free article: PMC2640216] [PubMed: 19056803]
  • Oz-Levi D, Ben-Zeev B, Ruzzo EK, Hitomi Y, Gelman A, Pelak K, Anikster Y, Reznik-Wolf H, Bar-Joseph I, Olender T, Alkelai A, Weiss M, Ben-Asher E, Ge D, Shianna KV, Elazar Z, Goldstein DB, Pras E, Lancet D. Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis. Am J Hum Genet. 2012;91:1065–72. [PMC free article: PMC3516605] [PubMed: 23176824]
  • Paisan-Ruiz C, Dogu O, Yilmaz A, Houlden H, Singleton A. SPG11 mutations are common in familial cases of complicated hereditary spastic paraplegia. Neurology. 2008;70:1384–9. [PMC free article: PMC2730021] [PubMed: 18337587]
  • Patel H, Cross H, Proukakis C, Hershberger R, Bork P, Ciccarelli FD, Patton MA, McKusick VA, Crosby AH. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat Genet. 2002;31:347–8. [PubMed: 12134148]
  • Pennings M, Schouten MI, van Gaalen J, Meijer RPP, de Bot ST, Kriek M, Saris CGJ, van den Berg LH, van Es MA, Zuidgeest DMH, Elting MW, van de Kamp JM, van Spaendonck-Zwarts KY, Die-Smulders C, Brilstra EH, Verschuuren CC, de Vries BBA, Bruijn J, Sofou K, Duijkers FA, Jaeger B, Schieving JH, van de Warrenburg BP, Kamsteeg EJ. KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia. Eur J Hum Genet. 2020;28:40–9. [PMC free article: PMC6906463] [PubMed: 31488895]
  • Pensato V, Castellotti B, Gellera C, Pareyson D, Ciano C, Nanetti L, Salsano E, Piscosquito G, Sarto E, Eoli M, Moroni I, Soliveri P, Lamperti E, Chiapparini L, Di Bella D, Taroni F, Mariotti C. Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48. Brain. 2014;137:1907–20. [PubMed: 24833714]
  • Rainier S, Bui M, Mark E, Thomas D, Tokarz D, Ming L, Delaney C, Richardson RJ, Albers JW, Matsunami N, Stevens J, Coon H, Leppert M, Fink JK. Neuropathy target esterase gene mutations cause motor neuron disease. Am J Hum Genet. 2008;82:780–5. [PMC free article: PMC2427280] [PubMed: 18313024]
  • Rainier S, Chai JH, Tokarz D, Nicholls RD, Fink JK. NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am J Hum Genet. 2003;73:967–71. [PMC free article: PMC1180617] [PubMed: 14508710]
  • Rainier S, Sher C, Reish O, Thomas D, Fink JK. De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy. Arch Neurol. 2006;63:445–7. [PubMed: 16533974]
  • Reid E, Kloos M, Ashley-Koch A, Hughes L, Bevan S, Svenson IK, Graham FL, Gaskell PC, Dearlove A, Pericak-Vance MA, Rubinsztein DC, Marchuk DA. A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am J Hum Genet. 2002;71:1189–94. [PMC free article: PMC385095] [PubMed: 12355402]
  • Rinaldi C, Schmidt T, Situ AJ, Johnson JO, Lee PR, Chen KL, Bott LC, Fadó R, Harmison GH, Parodi S, Grunseich C, Renvoisé B, Biesecker LG, De Michele G, Santorelli FM, Filla A, Stevanin G, Dürr A, Brice A, Casals N, Traynor BJ, Blackstone C, Ulmer TS, Fischbeck KH. Mutation in CPT1C associated with pure autosomal dominant spastic paraplegia. JAMA Neurol. 2015;72:561–70. [PMC free article: PMC5612424] [PubMed: 25751282]
  • Riverol M, Samaranch L, Pascual B, Pastor P, Irigoyen J, Pastor MA, de Castro P, Masdeu JC. Forceps minor region signal abnormality "ears of the lynx": an early MRI finding in spastic paraparesis with thin corpus callosum and mutations in the spatascin gene (SPG11) on chromosome 15. J Neuroimaging. 2009;19:52–60. [PubMed: 19040626]
  • Rivière JB, Ramalingam S, Lavastre V, Shekarabi M, Holbert S, Lafontaine J, Srour M, Merner N, Rochefort D, Hince P, Gaudet R, Mes-Masson AM, Baets J, Houlden H, Brais B, Nicholson GA, Van Esch H, Nafissi S, De Jonghe P, Reilly MM, Timmerman V, Dion PA, Rouleau GA. KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2. Am J Hum Genet. 2011;89:219–30. [PMC free article: PMC3155159] [PubMed: 21820098]
  • Rizzo WB, Carney G, Lin Z. The molecular basis of Sjögren-Larsson syndrome: mutation analysis of the fatty aldehyde dehydrogenase gene. Am J Hum Genet. 1999;65:1547–60. [PMC free article: PMC1288365] [PubMed: 10577908]
  • Roda RH, Schindler AB, Blackstone C. Multigeneration family with dominant SPG30 hereditary spastic paraplegia. Ann Clin Transl Neurol. 2017;4:821–4. [PMC free article: PMC5682118] [PubMed: 29159194]
  • Rydning SL, Dudesek A, Rimmele F, Funke C, Krüger S, Biskup S, Vigeland MD, Hjorthaug HS, Sejersted Y, Tallaksen C, Selmer KK, Kamm C. A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia. Eur J Neurol. 2018;25:943–e71. [PubMed: 29528531]
  • Sambuughin N, Goldfarb LG, Sivtseva TM, Davydova TK, Vladimirtsev VA, Osakovskiy VL, Danilova AP, Nikitina RS, Ylakhova AN, Diachkovskaya MP, Sundborger AC, Renwick NM, Platonov FA, Hinshaw JE, Toro C. Adult-onset autosomal dominant spastic paraplegia linked to a GTPase-effector domain mutation of dynamin 2. BMC Neurol. 2015;15:223. [PMC free article: PMC4628244] [PubMed: 26517984]
  • Saugier-Veber P, Munnich A, Bonneau D, Rozet JM, Le Merrer M, Gil R, Boespflug-Tanguy O. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet. 1994;6:257–62. [PubMed: 8012387]
  • Schrander-Stumpel C, Höweler C, Jones M, Sommer A, Stevens C, Tinschert S, Israel J, Fryns JP. Spectrum of X-linked hydrocephalus (HSAS), MASA syndrome, and complicated spastic paraplegia (SPG1): clinical review with six additional families. Am J Med Genet. 1995;57:107–16. [PubMed: 7645588]
  • Schubert SF, Hoffjan S, Dekomien G. Mutational analysis of the CYP7B1, PNPLA6 and C19orf12 genes in autosomal recessive hereditary spastic paraplegia. Mol Cell Probes. 2016;30:53–5. [PubMed: 26714052]
  • Schuurs-Hoeijmakers JH, Geraghty MT, Kamsteeg EJ, Ben-Salem S, de Bot ST, Nijhof B, van de Vondervoort II, van der Graaf M, Nobau AC, Otte-Höller I, Vermeer S, Smith AC, Humphreys P, Schwartzentruber J., FORGE Canada Consortium. Ali BR, Al-Yahyaee SA, Tariq S, Pramathan T, Bayoumi R, Kremer HP, van de Warrenburg BP, van den Akker WM, Gilissen C, Veltman JA, Janssen IM, Vulto-van Silfhout AT, van der Velde-Visser S, Lefeber DJ, Diekstra A, Erasmus CE, Willemsen MA, Vissers LE, Lammens M, van Bokhoven H, Brunner HG, Wevers RA, Schenck A, Al-Gazali L, de Vries BB, de Brouwer AP. Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia. Am J Hum Genet. 2012;91:1073–81. [PMC free article: PMC3516595] [PubMed: 23176823]
  • Schwartz CE, May MM, Carpenter NJ, Rogers RC, Martin J, Bialer MG, Ward J, Sanabria J, Marsa S, Lewis JA, Echeverri R, Lubs HA, Voeller K, Simensen RJ, Stevenson RE. Allan-Herndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8) gene. Am J Hum Genet. 2005;77:41–53. [PMC free article: PMC1226193] [PubMed: 15889350]
  • Shimazaki H, Takiyama Y, Ishiura H, Sakai C, Matsushima Y, Hatakeyama H, Honda J, Sakoe K, Naoi T, Namekawa M, Fukuda Y, Takahashi Y, Goto J, Tsuji S, Goto Y, Nakano I., Japan Spastic Paraplegia Research Consortium (JASPAC). A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55). J Med Genet. 2012;49:777–84. [PubMed: 23188110]
  • Simpson MA, Cross H, Proukakis C, Pryde A, Hershberger R, Chatonnet A, Patton MA, Crosby AH. Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am J Hum Genet. 2003;73:1147–56. [PMC free article: PMC1180493] [PubMed: 14564668]
  • Sivakumar K, Sambuughin N, Selenge B, Nagle JW, Baasanjav D, Hudson LD, Goldfarb LG. Novel exon 3B proteolipid protein gene mutation causing late-onset spastic paraplegia type 2 with variable penetrance in female family members. Ann Neurol. 1999;45:680–3. [PubMed: 10319897]
  • Słabicki M, Theis M, Krastev DB, Samsonov S, Mundwiller E, Junqueira M, Paszkowski-Rogacz M, Teyra J, Heninger AK, Poser I, Prieur F, Truchetto J, Confavreux C, Marelli C, Durr A, Camdessanche JP, Brice A, Shevchenko A, Pisabarro MT, Stevanin G, Buchholz F. A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia. PLoS Biol. 2010;8:e1000408. [PMC free article: PMC2893954] [PubMed: 20613862]
  • Stevanin G, Santorelli FM, Azzedine H, Coutinho P, Chomilier J, Denora PS, Martin E, Ouvrard-Hernandez AM, Tessa A, Bouslam N, Lossos A, Charles P, Loureiro JL, Elleuch N, Confavreux C, Cruz VT, Ruberg M, Leguern E, Grid D, Tazir M, Fontaine B, Filla A, Bertini E, Durr A, Brice A. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet. 2007;39:366–72. [PubMed: 17322883]
  • Svenstrup K, Møller RS, Christensen J, Budtz-Jørgensen E, Gilling M, Nielsen JE. NIPA1 mutation in complex hereditary spastic paraplegia with epilepsy. Eur J Neurol. 2011;18:1197–9. [PubMed: 21599812]
  • Synofzik M, Gonzalez MA, Lourenco CM, Coutelier M, Haack TB, Rebelo A, Hannequin D, Strom TM, Prokisch H, Kernstock C, Durr A, Schols L, Lima-Martinez MM, Farooq A, Schule R, Stevanin G, Marques W Jr, Zuchner S. PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain. 2014;137:69–77. [PMC free article: PMC3891450] [PubMed: 24355708]
  • Tesson C, Nawara M, Salih MA, Rossignol R, Zaki MS, Al Balwi M, Schule R, Mignot C, Obre E, Bouhouche A, Santorelli FM, Durand CM, Oteyza AC, El-Hachimi KH, Al Drees A, Bouslam N, Lamari F, Elmalik SA, Kabiraj MM, Seidahmed MZ, Esteves T, Gaussen M, Monin ML, Gyapay G, Lechner D, Gonzalez M, Depienne C, Mochel F, Lavie J, Schols L, Lacombe D, Yahyaoui M, Al Abdulkareem I, Zuchner S, Yamashita A, Benomar A, Goizet C, Durr A, Gleeson JG, Darios F, Brice A, Stevanin G. Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am J Hum Genet. 2012;91:1051–64. [PMC free article: PMC3516610] [PubMed: 23176821]
  • Torraco A, Ardissone A, Invernizzi F, Rizza T, Fiermonte G, Niceta M, Zanetti N, Martinelli D, Vozza A, Verrigni D, Di Nottia M, Lamantea E, Diodato D, Tartaglia M, Dionisi-Vici C, Moroni I, Farina L, Bertini E, Ghezzi D, Carrozzo R. Novel mutations in IBA57 are associated with leukodystrophy and variable clinical phenotypes. J Neurol. 2017;264:102–11. [PubMed: 27785568]
  • Tsaousidou MK, Ouahchi K, Warner TT, Yang Y, Simpson MA, Laing NG, Wilkinson PA, Madrid RE, Patel H, Hentati F, Patton MA, Hentati A, Lamont PJ, Siddique T, Crosby AH. Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am J Hum Genet. 2008;82:510–5. [PMC free article: PMC2426914] [PubMed: 18252231]
  • Tunca C, Akçimen F, Coşkun C, Gündoğdu-Eken A, Kocoglu C, Çevik B, Bekircan-Kurt CE, Tan E, Başak AN. ERLIN1 mutations cause teenage-onset slowly progressive ALS in a large Turkish pedigree. Eur J Hum Genet. 2018;26:745–8. [PMC free article: PMC5945623] [PubMed: 29453415]
  • Uhlenberg B, Schuelke M, Rüschendorf F, Ruf N, Kaindl AM, Henneke M, Thiele H, Stoltenburg-Didinger G, Aksu F, Topaloğlu H, Nürnberg P, Hübner C, Weschke B, Gärtner J. Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am J Hum Genet. 2004;75:251–60. [PMC free article: PMC1216059] [PubMed: 15192806]
  • Utine GE, Haliloğlu G, Salanci B, Çetinkaya A, Kiper PÖ, Alanay Y, Aktas D, Boduroğlu K, Alikaşifoğlu M. A homozygous deletion in GRID2 causes a human phenotype with cerebellar ataxia and atrophy. J Child Neurol. 2013;28:926–32. [PubMed: 23611888]
  • Valdmanis PN, Meijer IA, Reynolds A, Lei A, MacLeod P, Schlesinger D, Zatz M, Reid E, Dion PA, Drapeau P, Rouleau GA. Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. Am J Hum Genet. 2007;80:152–61. [PMC free article: PMC1785307] [PubMed: 17160902]
  • Verkerk AJ, Schot R, Dumee B, Schellekens K, Swagemakers S, Bertoli-Avella AM, Lequin MH, Dudink J, Govaert P, van Zwol AL, Hirst J, Wessels MW, Catsman-Berrevoets C, Verheijen FW, de Graaff E, de Coo IF, Kros JM, Willemsen R, Willems PJ, van der Spek PJ, Mancini GM. Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. Am J Hum Genet. 2009;85:40–52. [PMC free article: PMC2706965] [PubMed: 19559397]
  • Verny C, Guegen N, Desquiret V, Chevrollier A, Prundean A, Dubas F, Cassereau J, Ferre M, Amati-Bonneau P, Bonneau D, Reynier P, Procaccio V. Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation. Mitochondrion. 2011;11:70–5. [PubMed: 20656066]
  • Vits L, Chitayat D, Van Camp G, Holden JJ, Fransen E, Willems PJ. Evidence for somatic and germline mosaicism in CRASH syndrome. Hum Mutat. 1998 Suppl 1:S284–7. [PubMed: 9452110]
  • Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Hörl G, Malli R, Reed JA, Dierick I, Verpoorten N, Warner TT, Proukakis C, Van den Bergh P, Verellen C, Van Maldergem L, Merlini L, De Jonghe P, Timmerman V, Crosby AH, Wagner K. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet. 2004;36:271–6. [PubMed: 14981520]
  • Yamasaki M, Arita N, Hiraga S, Izumoto S, Morimoto K, Nakatani S, Fujitani K, Sato N, Hayakawa T. A clinical and neuroradiological study of X-linked hydrocephalus in Japan. J Neurosurg. 1995;83:50–5. [PubMed: 7782849]
  • Yıldırım Y, Orhan EK, Iseri SA, Serdaroglu-Oflazer P, Kara B, Solakoğlu S, Tolun A. A frameshift mutation of ERLIN2 in recessive intellectual disability, motor dysfunction and multiple joint contractures. Hum Mol Genet. 2011;20:1886–92. [PubMed: 21330303]
  • Zhao X, Alvarado D, Rainier S, Lemons R, Hedera P, Weber CH, Tukel T, Apak M, Heiman-Patterson T, Ming L, Bui M, Fink JK. Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat Genet. 2001;29:326–31. [PubMed: 11685207]
  • Züchner S, Wang G, Tran-Viet KN, Nance MA, Gaskell PC, Vance JM, Ashley-Koch AE, Pericak-Vance MA. Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet. 2006;79:365–9. [PMC free article: PMC1559498] [PubMed: 16826527]
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