spastic ataxia

Spastic Ataxia 2

Clinical Characteristics
Ocular Features: 

Horizontal nystagmus is present in some patients.

Systemic Features: 

Cerebellar ataxia, dysarthria, and spasticity of the lower limbs appear in the first two decades of life.  The spasticity may involve all 4 limbs late in life.  Cognition is not impacted. Cervical dystonia has been noted. No consistent changes have been found on brain imaging.  The neurologic signs are slowly progressive although patients may remain ambulatory.

Tremor, clonus, and extrapyramidal chorea has been seen in several families with what has been called spastic paraplegia-58 which may be the same disorder as SPAX2 since mutations are found in the same gene (KIF1C).  Symptoms and prognosis are similar in these conditions except for the reported presence of developmental delay and mild mental retardation in some individuals diagnosed to have SPG58.

Genetics

This is an autosomal recessive condition as the result of homozygous mutations in the KIF1C gene (17p13.2).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment for this disease is available although speech and physical therapy may be helpful.

References
Article Title: 

Motor protein mutations cause a new form of hereditary spastic paraplegia

Caballero Oteyza A, Battaloglu E, Ocek L, Lindig T, Reichbauer J, Rebelo AP, Gonzalez MA, Zorlu Y, Ozes B, Timmann D, Bender B, Woehlke G, Zuchner S, Schols L, Schule R. Motor protein mutations cause a new form of hereditary spastic paraplegia. Neurology. 2014 May 7. [Epub ahead of print].

PubMed ID: 
24808017

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 Ataxia 6, Charlevoix-Saguenay Type

Clinical Characteristics
Ocular Features: 

Patches of myelinated axons from retinal neurons in the retina are not unusual in the general population but are especially prominent among families in Canada with SPAX6.  These typically appear as striated white or yellowish-white patches with 'fuzzy' borders in the nerve fiber layer of the retina and radiate from the disc.   These findings are usually of no functional significance but if sufficiently large and dense can be demonstrated on perimetry as small scotomas.   OCT studies in two Belgian families have revealed increased thickness of the peri-papillary retinal nerve fiber layer in both patients and carriers without clinical evidence of myelination.  In addition the retinal nerve fiber layer has been described as 'hypertrophied' outside the areas of myelination.   Horizontal gaze nystagmus and deficits in conjugate pursuit movements are often present.   

Systemic Features: 

This neurodegenerative disorder begins in early childhood (12-18 months) with signs of cerebellar ataxia, pyramidal signs, and peripheral neuropathy.  Slightly older children develop a mixed-sensorimotor peripheral neuropathy. Dysarthria, limb spasticity, distal muscle wasting, and mitral valve prolapse are often present.  Knee reflexes are exaggerated while ankle reflexes are often absent.  Extensor plantar responses are usually present.  The EMG can show signs of denervation with slowed conduction while brain neuroimaging demonstrates regional atrophy in the cerebellum, especially the superior vermis.  Most patients eventually become wheelchair-bound.  However, cognitive and daily living skills are preserved into adulthood.  Most patients live into the sixth decade.

Genetics

Homozygous or compound heterozygous mutations in the SACS gene (13q12.12) are responsible for this autosomal recessive disorder.

The largest number of cases is found in the Charlevoix-Saguenay region of Quebec, Canada among the descendents of a founder but families have also been found in Asia and Europe.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general disease is available but specific therapies for some functions such as urinary urgency are available.  Physical and speech therapy as well as special education assistance can be helpful for adaptation.

References
Article Title: 

Location score and haplotype analyses of the locus for autosomal recessive spastic ataxia of Charlevoix-Saguenay, in chromosome region 13q11

Richter A, Rioux JD, Bouchard JP, Mercier J, Mathieu J, Ge B, Poirier J, Julien D, Gyapay G, Weissenbach J, Hudson TJ, Melan?sson SB, Morgan K. Location score and haplotype analyses of the locus for autosomal recessive spastic ataxia of Charlevoix-Saguenay, in chromosome region 13q11. Am J Hum Genet. 1999 Mar;64(3):768-75. Erratum in: Am J Hum Genet 1999 Apr;64(4):1257.

PubMed ID: 
10053011

Spastic Ataxia 4, mtPAP Deficiency

Clinical Characteristics
Ocular Features: 

Ocular examinations in 4 adult individuals of a single family aged 18 to 27 years were reported to have optic atrophy.  One of these had a horizontal nystagmus and another was described as having a vertical nystagmus.  No ocular evaluations were available for 2 children, aged 2 and 6 years.  Visual acuity testing was not reported but all individuals participated appropriately in family and educational activities. 

Systemic Features: 

This is a congenital disorder with cerebral ataxia (limb and truncal), spastic paraparesis (increased lower limb tone with brisk knee jerks and extensor plantar responses), cerebellar and spastic dysarthria, learning difficulties and emotional lability as prominent features.  The onset of both speech and mobility are delayed.  Older individuals have slow and spastic tongue movements with brisk jaw jerks, and increased tone in the upper limbs.  Motor function progressively declines although even older individuals in the third decade of life remain mobile albeit with an increasingly spastic and ataxic gait, and require only minimal assistance with self-care.  Children in grade school require special education accommodations but there is no obvious deterioration in intellectual function as they mature.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the MTPAP gene (10p11.22).  The mutation leads to a defect of mitochondrial mRNA maturation in which the poly(A) tails are severely truncated.

Optic atrophy is also present in some patients who have autosomal dominant spastic ataxia with miosis (SPAX7) (108650) and in another form of autosomal recessive childhood-onset spastic ataxia and mental retardation (270500).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known but special education and physical and speech therapy may be helpful.

References
Article Title: 

Defective mitochondrial mRNA maturation is associated with spastic ataxia

Crosby AH, Patel H, Chioza BA, Proukakis C, Gurtz K, Patton MA, Sharifi R, Harlalka G, Simpson MA, Dick K, Reed JA, Al-Memar A, Chrzanowska-Lightowlers ZM, Cross HE, Lightowlers RN. Defective mitochondrial mRNA maturation is associated with spastic ataxia. Am J Hum Genet. 2010 Nov 12;87(5):655-60.

PubMed ID: 
20970105
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