cerebellar atrophy

Ataxia with Oculomotor Apraxia 2

Clinical Characteristics
Ocular Features: 

Patients with this disorder have difficulty initiating voluntary ocular movements upon command or following targets (oculomotor apraxia).  This feature is not as prominent or frequent in AOA2 (56%) as it is in ataxia with oculomotor apraxia 1 (208920).  Gaze changes are often initiated first by head thrusting, followed by saccadic eye movements. One may test for this by holding the head whereupon the patient is unable to move the eyes.  Strabismus and nystagmus are present in a significant proportion of patients.  Optokinetic nystagmus is impaired.

Systemic Features: 

Initial development proceeds normally but cerebellar ataxia with significant gait problems appear toward the end of the first decade of life and sometimes not until the third decade (mean age of onset 15 years).   Distal muscle weakness and atrophy are often seen.  Mental decline has been observed in a few individuals but does not occur until midlife.  Sensorimotor deficits are present in many patients.  Tremors, dystonia, and choreiform movements are sometimes seen.  Many patients become wheelchair-bound by the 4th decade of life.

Cerebellar atrophy is revealed by MRI.  Serum alpha-fetoprotein concentrations are usually elevated while serum creatine kinase is increased in some patients.  Circulating cholesterol may also be above normal.  Mild serum changes in these components may be seen in heterozygotes.  Hypoalbuminemia is not present in AOA2.

Genetics

Homozygous mutations in SETX (9q34.13) are responsible for this disorder.  Ataxia with oculomotor apraxia 2 is distinguished from ataxia-telangiectasia (208900) by the lack of telangiectases and immunological deficiencies. It differs from ataxia with oculomotor apraxia 1 (208920) in having a somewhat later onset, somewhat slower course, and milder oculopraxic manifestations. Cogan-type oculomotor apraxia (257550) lacks other neurologic signs. Oculomotor apraxia may be the presenting sign in Gaucher disease (230800, 230900, 231000).

See also Ataxia with Oculomotor Apraxia 3 (615217), and Ataxia with Oculomotor Apraxia 4 (616267).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no beneficial treatment for the neurological disease but physical therapy, speech therapy, and sometimes special education can be helpful.

References
Article Title: 

Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management

Anheim M, Fleury M, Monga B, Laugel V, Chaigne D, Rodier G, Ginglinger E, Boulay C, Courtois S, Drouot N, Fritsch M, Delaunoy JP, Stoppa-Lyonnet D, Tranchant C, Koenig M. Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management. Neurogenetics. 2010 Feb;11(1):1-12.

PubMed ID: 
19440741

Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study

Criscuolo C, Chessa L, Di Giandomenico S, Mancini P, Sacc?+ F, Grieco GS, Piane M, Barbieri F, De Michele G, Banfi S, Pierelli F, Rizzuto N, Santorelli FM, Gallosti L, Filla A, Casali C. Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study. Neurology. 2006 Apr 25;66(8):1207-10.

PubMed ID: 
16636238

Sandhoff Disease

Clinical Characteristics
Ocular Features: 

Retinal ganglion cells are rendered dysfunctional from the toxic accumulation of intra-lysosomal GM2 ganglioside molecules causing early visual symptoms.  These cells in high density around the fovea centralis create a grayish-white appearance.  Since ganglion cells are absent in the foveolar region, this area retains the normal reddish appearance, producing the cherry-red spot.  Axonal decay and loss of the ganglion cells leads to optic atrophy and blindness. 

Systemic Features: 

Sandhoff disease may be clinically indistinguishable from Tay-Sachs disease even though the same enzyme is defective (albeit in separate subunits A and B that together comprise the functional enzymes).  The presence of hepatosplenomegaly in Sandoff disease may be distinguishing. The infantile form of this lysosomal storage disease seems to be the most severe.  Infants appear to be normal until about 3-6 months of age when neurological development slows and muscles become weak.  Seizures, loss of interest, and progressive paralysis begin after this together with loss of vision and hearing.  An exaggerated startle response is considered an early and helpful sign in the diagnosis.  Among infants with early onset disease, death usually occurs by 3 or 4 years of age.   

Ataxia with spinocerebellar degeneration, motor neuron disease, dementia, and progressive dystonia are more common in individuals with later onset of neurodegeneration.  The juvenile and adult-onset forms of the disease also progress more slowly.  

Genetics

Sandhoff disease results from mutations in the beta subunit of the hexosaminidase A and B enzymes.  It is an autosomal recessive disorder caused by mutations in HEXB (5q13). 

Tay-Sachs disease (272800) can be clinically indistinguishable from Sandoff disease and they are allelic disorders.  However, the mutation in Tay-Sachs (272800) is in HEXA resulting in dysfunction of the alpha subunit of hexosaminidase A enzyme. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available beyond general support with proper nutrition and maintainence of airways.  Anticonvulsants may be helpful in some stages.  Gene therapy in fibroblast cultures has achieved some restoration of  hexosaminidase A activity in Tay-Sachs disease and may have potential in Sandhoff disease as well. 

References
Article Title: 

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