Table 2. [Hereditary Spastic Paraplegia: Genes and...]. - GeneReviews®

Table 2.

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

Gene ¹	HSP Designation	Type of HSP	Onset	Distinguishing Clinical Features	Other	References
Gene ¹	HSP Designation	Type of HSP	Onset	Distinguishing Clinical Features	Other	GeneReview or OMIM Entry	Citation
SPG21 (ACP33)	SPG21	Complicated	Childhood	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 248900	Cross & McKusick [1967a], Simpson et al [2003], Ishiura et al [2014]
ALDH18A1	SPG9B	Complicated	Adolescence 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 assigned	Complicated	Childhood	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 ²	SPG63	Complicated	Infancy	Short stature Thin corpus callosum White matter changes	Rare	OMIM 615686	Novarino et al [2014], Kortüm et al [2018]
AP4B1	SPG47	Complicated	Infancy	Severe ID Facial dysmorphism Seizures Stereotypic laughter w/tongue protrusion	Rare	OMIM 614066	Abou Jamra et al [2011], Bauer et al [2012]
AP4E1	SPG51	Complicated	Infancy	Severe ID Facial dysmorphism Seizures Stereotypic laughter w/tongue protrusion	Rare	OMIM 613744	Abou Jamra et al [2011], Moreno-De-Luca et al [2011]
AP4M1	SPG50	Complicated	Infancy	Severe ID Facial dysmorphism Seizures Stereotypic laughter w/tongue protrusion	Rare	OMIM 612936	Verkerk et al [2009]
AP4S1	SPG52	Complicated	Infancy	Severe ID Facial dysmorphism Seizures Stereotypic laughter w/tongue protrusion	Rare	OMIM 614067	Abou Jamra et al [2011], Hardies et al [2015]
AP5Z1	SPG48	Uncomplicated	Typically adulthood; rarely infancy	Urinary incontinence Parkinsonism Dystonia Thin corpus callosum Leukodystrophy Severe DD in infantile onset	Single family	OMIM 613647	Słabicki et al [2010], Pensato et al [2014]
ATL1	SPG3A	Uncomplicated	Infantile 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	SPG26	Complicated	Juvenile	Amyotrophy Dysarthria Ataxia DD Dystonia	Rare	OMIM 609195	Boukhris et al [2013], Harlalka et al [2013]
BICD2	Not assigned	Complicated	Childhood	Amyotrophy Contractures	Rare		Oates et al [2013]
MTRFR (C12orf65)	SPG55	Complicated	Childhood	DD Visual loss Polyneuropathy Arthrogryposis Signs of mitochondrial encephalomyopathy, some classified as Leigh's syndrome	Rare	OMIM 615035	Shimazaki et al [2012]
C19orf12	SPG43	Complicated	Childhood	Amyotrophy Dysarthria Multiple contractures Neurodegeneration w/brain iron accumulation in some	Rare	OMIM 615043	Landouré et al [2013], Schubert et al [2016]
CYP2U1	SPG56	Complicated	Infancy	Severe DD Dystonia Polyneuropathy Calcification of basal ganglia	Rare	OMIM 615030	Tesson et al [2012]
CYP7B1	SPG5A	Uncomplicated or complicated	Juvenile 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. ³	OMIM 270800	Tsaousidou et al [2008], Goizet et al [2009]
DDHD1	SPG28	Uncomplicated	Childhood	Scoliosis	Rare	OMIM 609340	Tesson et al [2012]
DDHD2	SPG54	Complicated	Infancy	Severe DD Optic atrophy Thin corpus callosum Leukodystrophy	Rare	OMIM 615033	Schuurs-Hoeijmakers et al [2012]
ENTPD1	SPG64	Complicated	Infancy	Mild cognitive disability Behavioral disturbances White matter changes	Rare	ENTPD1-Related Neurodevelopmental Disorder	Novarino et al [2014]
ERLIN1	SPG62	Complicated	Childhood	Amyotrophy Ataxia Phenotype consistent w/juvenile onset of ALS reported	Rare	OMIM 615681	Novarino et al [2014], Tunca et al [2018]
ERLIN2	SPG18	Complicated (rarely pure AR HSP reported)	Childhood	DD Seizures Contractures Juvenile primary lateral sclerosis phenotype reported Allelic w/AD pure HSP	Rare	OMIM 611225	Alazami et al [2011], Yıldırım et al [2011], Al-Saif et al [2012]
FA2H ⁴	SPG35	Complicated	Childhood	Seizures Dystonia Parkinsonism w/iron accumulation in basal ganglia	Rare	OMIM 612319	Edvardson et al [2008], Dick et al [2010], Pensato et al [2014]
GAD1	Not assigned	Complicated	Childhood	Moderate to severe ID Single reported family was described as having AR cerebral palsy	Rare (single family reported)		Lynex et al [2004]
GBA2	SPG46	Complicated	Childhood	DD Ataxia Hearing loss Polyneuropathy	Rare	OMIM 614409	Hammer et al [2013], Coarelli et al [2018]
GJC2 ⁵	SPG44	Complicated	Childhood	Febrile seizures Deafness Episodic spasms Variable degree of leukodystrophy	Rare	OMIM 613206	Uhlenberg et al [2004], Orthmann-Murphy et al [2009]
GRID2 ⁶	Not assigned	Complicated	Childhood	Amyotrophy Ataxia	Rare		Utine et al [2013], Maier et al [2014]
IBA57 ⁷	SPG74	Complicated	Childhood	Optic atrophy Peripheral neuropathy	Rare	OMIM 616451	Lossos et al [2015], Torraco et al [2017]
KIF1A ⁸	SPG30	Complicated	Childhood	Spastic ataxia Polyneuropathy	Rare	OMIM 610357	Hamdan et al [2011], Rivière et al [2011], Klebe et al [2012]
KIF1C	SPG58	Complicated	Childhood	Spastic ataxia Dystonia	Rare		Caballero Oteyza et al [2014], Dor et al [2014]
KLC2	Not assigned	Complicated	Childhood	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 assigned	Complicated	Childhood	Ataxia Multiple contractures Variable degree of leukodystrophy	Rare		Bayrakli et al [2015]
MARS1 ⁹	SPG70	Complicated	Infancy	Nephrotic syndrome, polyneuropathy Mild ID Late onset of CMT2 (axonal) type also reported	Rare		Gonzalez et al [2013], Novarino et al [2014]
NT5C2	SPG45	Complicated	Childhood	Optic atrophy Nystagmus Strabismus ID Hypoplastic corpus callosum	Rare	OMIM 613162	Novarino et al [2014], Elsaid et al [2017]
PGAP1 ¹⁰	SPG67	Complicated	Infancy	Severe DD Tremor Agenesis of corpus callosum Hypomyelination	Rare		Murakami et al [2014], Novarino et al [2014]
PNPLA6 ¹¹	SPG39	Complicated	Childhood	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	SPG72	Uncomplicated	Early childhood	Musculoskeletal problems Mild postural tremor	Rare Inheritance can be dominant or recessive.	OMIM 615625	Esteves et al [2014]
SPART	SPG20	Complicated	Juvenile	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	SPG7	Uncomplicated or complicated	Juvenile 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	SPG11	Complicated	Childhood 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	SPG49	Complicated	Childhood	Central apnea Severe DD Microcephaly Dysmorphic features	Rare	TECPR2-HSAN with ID	Oz-Levi et al [2012]
TFG	SPG57	Complicated	Childhood	Optic atrophy Severe polyneuropathy	Rare	OMIM 615658	Beetz et al [2013]
USP8	SPG59	Uncomplicated	Childhood	None	Rare		Novarino et al [2014]
WDR48	SPG60	Complicated	Infancy	Polyneuropathy DD	Rare		Novarino et al [2014]
ZFYVE26	SPG15	Complicated	Childhood 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
1.: Genes are listed alphabetically.
2.: Allelic with pontocerebellar hypoplasia type 9
3.: Goizet et al [2009]
4.: Allelic with fatty acid hydroxylase-associated neurodegeneration and leukodystrophy
5.: Allelic with Pelizaeus-Merzbacher-like disease 1 and hereditary lymphedema type IC
6.: Allelic with autosomal recessive spinocerebellar ataxia 18 (See Hereditary Ataxia Overview.)
7.: Allelic with multiple mitochondrial dysfunctions syndrome 3
8.: Allelic with hereditary sensory and autonomic neuropathy type 2C and AD intellectual disability type 9
9.: Allelic with Charcot-Marie-Tooth neuropathy type 2U
10.: Allelic with autosomal recessive intellectual disability type 42
11.: Allelic with Boucher-Neuhauser syndrome, Gordon-Holmes syndrome, Oliver-McFarlane syndrome, and Laurence-Moon syndrome

From: Hereditary Spastic Paraplegia Overview

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