spastic paraparesis

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 74

Clinical Characteristics
Ocular Features: 

Onset of visual impairment occurs at ages of 10-14 years with optic pallor evident on fundoscopy. MRI imaging reveals physical atrophy of the optic nerve.  Visual acuity ranges from 0.5 to finger counting.  Visual field defects include central scotomas and peripheral concentric constriction.

Systemic Features: 

Symptoms consisting of a spastic gait and distal sensory impairment usually appear in the first decade and are slowly progressive.  Increased deep tendon reflexes and extensor plantar responses may be present at that time but later distal leg muscle atrophy and pes cavus appear.  The ankle reflexes later disappear.  Cognitive function is normal and adults are able to lead an independent life.

Nerve conduction studies in 4 individuals showed reduced muscle action potentials and velocity while sensory conduction was normal.  Cerebellar atrophy along with an attenuated corpus callosum and cervical spinal cord atrophy was noted on MRI imaging in one of 3 studied patients.

Genetics

A homozygous splice site mutation in IBA57 (1q42) has been found to segregate with this condition in a large consanquineous Arab family.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known for the basic disease but physical therapy and low vision aids are likely beneficial.

References
Article Title: 

Fe S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia

Lossos A, Stumpfig 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 Feb 17;84(7):659-67.

PubMed ID: 
25609768

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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