spastic paraplegia

Spastic Paraplegia, Intellectual Disability, Nystagmus, and Obesity

Clinical Characteristics
Ocular Features: 

Patients have deep-set eyes with nystagmus, reduced vision, and often an esotropia perhaps secondary to hypermetropia.  In one of 3 reported patients the optic discs were described pale.

Systemic Features: 

Prominent foreheads are present at birth along with full cheeks and a prominent forehead.  Children grow rapidly in the first year eventually reaching the 90th percentiles in weight, height, and head circumference although neurologically they are developmentally delayed.  Speech and walking may be delayed as well.  While limbs have increased tone together with hyperreflexia, the trunk exhibits hypotonia.

Brain imaging reveals delayed myelination, dilated lateral ventricles, reduced while matter, and cerebral atrophy.

Genetics

Heterozygous mutations in the KIDINS220 gene (2p25.1) have been identified in 3 unrelated patients.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Heterozygous KIDINS220/ARMS nonsense variants cause spastic paraplegia, intellectual disability, nystagmus, and obesity

Josifova DJ, Monroe GR, Tessadori F, de Graaff E, van der Zwaag B, Mehta SG; DDD Study., Harakalova M, Duran KJ, Savelberg SM, Nijman IJ, Jungbluth H, Hoogenraad CC, Bakkers J, Knoers NV, Firth HV, Beales PL, van Haaften G, van Haelst MM. Heterozygous KIDINS220/ARMS nonsense variants cause spastic paraplegia, intellectual disability, nystagmus, and obesity. Hum Mol Genet. 2016 Jun 1;25(11):2158-2167.

PubMed ID: 
27005418

Kufor-Rakeb Syndrome

Clinical Characteristics
Ocular Features: 

Most patients have a supranuclear gaze paresis.  Patients later may have dystonic oculogyric spasms.

Systemic Features: 

This is a rapidly progressive neurodegenerative disorder with juvenile onset.  First signs of Parkinisonism are evident between the ages of 12 and 16 years of age.  Within a year of onset severe motor handicaps develop along with some degree of dementia with aggression and visual hallucinations.  Cognitive decline is often a feature.  Fine tremors in the chin may be seen along with other extrapyramidal signs but these are not prominent in the limbs.  Instead there is often rigidity and bradykinesia.  Dysphagia, dysarthria, and ataxia are features in many patients.  Peripheral sensory neuropathy and anosmia are present in some individuals. 

Brain imaging often reveals generalized atrophy of the cerebellum, cerebral cortex, and brainstem.

Genetics

This condition results from homozygous or compound heterozygous mutations in the ATP13A2 gene (1p36.13).  

Biallelic mutations in the same gene are also responsible for spastic paraplegia 78 (617225) with somewhat similar clinical features except for the general absence of Parkinsonism.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There may be an initial therapeutic response to L-DOPA but this is often not maintained

References
Article Title: 

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

Estrada-Cuzcano A, Martin S, Chamova T, Synofzik M, Timmann D, Holemans T, Andreeva A, Reichbauer J, De Rycke R, Chang DI, van Veen S, Samuel J, Schols L, Poppel T, Mollerup Sorensen D, Asselbergh B, Klein C, Zuchner S, Jordanova A, Vangheluwe P, Tournev I, Schule R. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain. 2017 Feb;140(Pt 2):287-305.

PubMed ID: 
28137957

Spastic Paraplegia, Optic Atrophy, and Neuropathy

Clinical Characteristics
Ocular Features: 

Non-progressive optic atrophy with vision loss is described as congenital in onset.

Systemic Features: 

Progressive spasticity has its onset in infancy with loss of independent mobility usually in the second decade of life.  An exaggerated startle response occurs in some individuals.  All patients are confined to wheelchairs after 15 years of age due to progressive motor neuropathy.  No intellectual disability has been reported.  Joint contractures occur.  Dysarthria is notable in the third decade of life.  Eventually joint contractures and spine deformities occur.

Genetics

Homozygous mutations in the KLC2 gene (11q13.2) have been found in this disorder.  A homozygous 216-bp deletion in a non-coding region upstream of the gene results in overexpression of the gene not found in heterozygotes.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been described.

References
Article Title: 

Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome

Melo US, Macedo-Souza LI, Figueiredo T, Muotri AR, Gleeson JG, Coux G, Armas P, Calcaterra NB, Kitajima JP, Amorim S, Olavio 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 Dec 15;24(24):6877-85.

PubMed ID: 
26385635

Spastic Paraplegia 75

Clinical Characteristics
Ocular Features: 

Nystagmus with optic atrophy is usually present and one individual had glaucoma. 

Systemic Features: 

This is an early-onset and progressive neurodegenerative disorder.  Hypotonia may be present at birth.  A spastic gait and difficulty walking is noted in early childhood and most individuals never walk unassisted. Yong adults have spastic paresis with extensor plantar responses and clonus has been reported.  Distal muscle atrophy in the lower extremities has been noted.  Speech is dysarthric.  Brain imaging has been normal in some patients whereas others have mild atrophy of the cerebellum and the corpus callosum.  Cognitive impairment is variable with some individuals showing poor school performance while others are described as mentally retarded.

Genetics

Homozygous mutations in the MAG gene (19q13.12) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported although physical therapy may be helpful. Special education, speech and physical therapy, and low vision devices might also be of benefit.

References
Article Title: 

Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder

Lossos A, Elazar N, Lerer I, Schueler-Furman O, Fellig Y, Glick B, Zimmerman BE, Azulay H, Dotan S, Goldberg S, Gomori JM, Ponger P, Newman JP, Marreed H, Steck AJ, Schaeren-Wiemers N, Mor N, Harel M, Geiger T, Eshed-Eisenbach Y, Meiner V, Peles E. Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder. Brain. 2015 Sep;138(Pt 9):2521-36.

PubMed ID: 
26179919

Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders

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 GM, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, 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 Jan 31;343(6170):506-11.

PubMed ID: 
24482476

Spastic Paraplegia 46

Clinical Characteristics
Ocular Features: 

Congenital cataracts (not further described) have been reported in several individuals with this type of complicated spastic paraplegia.  Optic atrophy and nystagmus have not been reported.

Systemic Features: 

Stiffness and weakness of the lower limbs begins between 2 and 20 years of age.  This is slowly progressive although most individuals are still mobile with mild to moderate handicaps into the 4th decade.  The gait is spastic with weakness, hyperreflexia, and extensor plantar responses in the lower limbs.  The upper limbs are variably involved and movements are dysmetric.  Dysarthria and bladder dysfunction are often present.  Cerebellar ataxia is common and some patients first present with this as a prominent sign in the first and second decades.  Early cognitive development is normal but mild cognitive decline appears eventually.  Pes cavus and scoliosis may occur.

Brain imaging can show thinning of the corpus callosum, with mild cerebellar and cerebral atrophy.

Genetics

Linkage analysis identified a locus at 9p13.3 and sequencing confirmed homozygous or compound heterozygous mutations in GBA2.  The presence of parental consanguinity in some families supports autosomal recessive inheritance.

This database contains two other types of autosomal spastic paraplegia with ocular signs: spastic paraplegia 15 (270700) with a "flecked retina", and spastic paraplegia 7 (607259) with optic atrophy and nystagmus.  Cataracts have not been reported in these two conditions.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known for the neurological deficits but cataract surgery may be beneficial for visually significant cataracts.

References
Article Title: 

Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity

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 Feb 7;92(2):245-51. PubMed PMID: 23332917.

PubMed ID: 
23332917

Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia

Martin E, Sch?ole R, Smets K, Rastetter A, Boukhris A, Loureiro JL, Gonzalez MA, Mundwiller E, Deconinck T, Wessner M, Jornea L, Oteyza AC, Durr A, Martin JJ, Schols L, Mhiri C, Lamari F, Z?ochner S, De Jonghe P, Kabashi E, Brice A, Stevanin G. Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am J Hum Genet. 2013 Feb 7;92(2):238-44. PubMed PMID: 23332916.

PubMed ID: 
23332916

A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum

Boukhris A, Feki I, Elleuch N, Miladi MI, Boland-Aug?(c) A, Truchetto J, Mundwiller E, Jezequel N, Zelenika D, Mhiri C, Brice A, Stevanin G. A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum. Neurogenetics. 2010 Oct;11(4):441-8.

PubMed ID: 
20593214

Spastic Paraplegia 15

Clinical Characteristics
Ocular Features: 

Yellowish flecks resembling those seen in fundus flavimaculatus are present, primarily in the macular area.   These can be present in large numbers in homozygotes with the full neurological syndrome.  Background retinal pigmentation appears clinically normal but fluorescein angiography shows a strikingly mottled picture with areas of hyper- and hypofluorescence.  Retinal flecks have also been reported in heterozygous parents.

The central macula exhibits autofluorescence.  Standard EOG and ERG recordings are normal but multifocal electroretinography shows subnormal responses in the macular area.  Visual acuity is minimally impacted.

Systemic Features: 

This is a form of spastic paraplegia with progressive spasticity primarily affecting the lower limbs.  Mental retardation (or at least cognitive impairment), dysarthria, a thin corpus callosum, and distal amyotrophy are often present.  Hearing deficits have also been described.  Some but not all patients have tremors, cerebellar ataxia, epilepsy and behavioral disturbances. Onset is between 10 and 19 years of age.  Little is known about the rate of symptom progression.

Genetics

This is an autosomal recessive disorder resulting from mutations in the ZFYVE26 gene (14q24.1).

Spastic paraplegia 7 (607259) has similar neurological features but with ptosis, optic atrophy, and nystagmus.  Congenital cataracts occur in addition to the neurological signs in spastic paraplegia 46 (614409) .

Other disorders with retinal flecks are described in Flecked Retina Syndromes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Fleck retina in Kjellin's syndrome

Farmer SG, Longstreth WT Jr, Kalina RE, Todorov AB. Fleck retina in Kjellin's syndrome. Am J Ophthalmol. 1985 Jan 15;99(1):45-50.

PubMed ID: 
3966518
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