blepharospasm

Spinocerebellar Ataxia 1

Clinical Characteristics
Ocular Features: 

Early manifestations include gaze-evoked nystagmus and saccadic hypermetria.  Ophthalmoplegia develops later in the disease process.  Some patients experience a decrease in acuity and dyschromatopsia.  The ERG shows evidence of generalized rod and cone photoreceptor dysfunction in some patients.  Optic atrophy, central scotomas, central RPE changes, retinal arteriolar attenuation, and blepharospasm have also been reported.

Time-domain OCT has revealed microscopic changes in the macula with thinning of the inner-outer segment junction and nuclear layer in areas with RPE hypopigmentation. 

Systemic Features: 

This is a progressive cerebellar syndrome characterized by systems of ataxia, dysarthria, and bulbar palsy.  Speech is often scanning and explosive.  DTRs can be exaggerated, and dysmetria is common.  The mean age of onset is about age 40.  Some cognitive decline may occur.  Muscle atrophy, and symptoms of peripheral neuropathy can be present.  MRI shows atrophy in the cerebellum, spinal cord, and brainstem.  There is considerable variation in clinical expression.  Individuals with adult onset of symptoms can survive for 10-30 years whereas those with a juvenile-onset often do not live beyond the age of 16 years.

Genetics

This disorder is caused by an expanded CAG repeat in the ataxin-1 gene (ATXN1) at 6p23.  It is an autosomal dominant disorder.  Alleles with 39-44 or more CAG repeats are likely to be associated with symptoms. 

A male bias and the phenomenon of anticipation have been demonstrated in this disorder as in spinocerebellar ataxia 7 (SCA7) (164500), in which affected offspring of males with SCA develop disease earlier and symptoms progress more rapidly than in offspring of females.  This is often explained by the fact that males generally transmit a larger number of CAG repeats.

SCA7 (164500), also inherited in an autosomal dominant pattern and caused by expanded CAG repeats on chromosome 3, has many similar ocular and neurologic features.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Supportive care is often required.          

References
Article Title: 

Neurodegeneration with Brain Iron Accumulation

Clinical Characteristics
Ocular Features: 

Optic atrophy is a major ocular feature and the primary cause of visual impairment.  A minority (25%) of patients also have a diffuse fleck retinopathy with a bull’s eye maculopathy.  Later the retinopathy may resemble retinitis pigmentosa with a bone spicule pattern. Nystagmus is often present.  These signs usually follow systemic signs such as difficulties in locomotion.  An apraxia of eyelid opening has been noted and some patients have blepharospasm. 

Systemic Features: 

This is a progressive disorder of the basal ganglia with prominent symptoms of extrapyramidal dysfunction.  Onset is in early childhood or in the neonatal period with delayed development and sometimes mental retardation.  Choreoathetoid writhing movements, stuttering, dysphagia, muscle rigidity, and intermittent dystonia are prominent features.  Seizures are uncommon.  Older individuals may exhibit dementia and ambulation is eventually impaired.  The MRI usually shows an area of hyperintensity in the medial globus pallidus that has been called the ‘eye of the tiger’ sign but this is not pathognomonic.  Axonal degeneration with accumulation of spheroidal inclusions can be seen histologically. 

Genetics

The title of this disorder ‘neurodegeneration with brain iron accumulation’ actually refers to a group of disorders with somewhat common characteristics.  Pentothenate kinase-associated neurodegeneration or NB1A1 (234200) is  the most common of these. 

Types  NBIA2A (256600) and NBIA2B (610217) are caused by mutations in the PLA2G6 gene (22q13.1).  The former can be seen neonatally but usually has its onset in the first two years of life and is sometimes called infantile neuroaxonal dystrophy or Seitelberger disease.  Death may occur before the age of 10 years.  Signs of motor neuron and cerebellar disease are more prominent than in NB1A1. 

NBIA2B has a later onset (4-5 years) and profound sensorimotor impairment but there are many overlapping features and the nosology is confusing.  Mutations in the FTL gene cause yet another form designated NBIA3 (606159) but ocular signs seem to be absent. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is evidence that treatment with deferiprone reduces the amount of iron accumulation in the globus pallidus with motor improvement in at least some patients.  Most patients require supportive care.

References
Article Title: 

Pantothenate Kinase-Associated Neurodegeneration

Clinical Characteristics
Ocular Features: 

Clinically evident retinal degeneration is present in a significant number (25-50%) of individuals.  However, when combined with ERG evidence the proportion rises to 68%.  When present it occurs early and one series reported that it is unlikely to appear later if it was not present early in the course of the neurodegeneration.  Some patients have a fleck-like retinopathy.  Optic atrophy may be present in advanced cases.

Systemic Features: 

This is a disorder primarily of the basal ganglia resulting from progressive damage secondary to iron accumulation.  There is an early onset classic form with symptoms of extrapyramidal disease beginning in the first decade of life and rapid progression to loss of ambulation in about 15 years.  Others with atypical disease may not have symptoms until the second or third decades.  Clumsiness, gait disturbance, and difficulty with tasks requiring fine motor coordination are common presenting symptoms.  Motor tics are often seen.  Dysarthria, dystonia, rigidity and corticospinal signs are often present early as well.  Swallowing difficulties may be severe sometimes leading to malnutrition.  Cognitive decline and psychiatric disturbances such as obsessive-compulsive behavior and depression may follow.  Independent ambulation is lost in the majority of patients within one to two decades.    Brain MRIs show an ‘eye of the tiger’ sign with a specific T2- weighted pattern of hyperintensity within the medial globus pallidus and the substantia nigra pars reticulata.

Genetics

Iron accumulation in the basal ganglia resulting from homozygous mutations in the PANK2 gene (20p13-12.3) encoding a pantothenate kinase leads to the classic form of this autosomal recessive disorder. 

This is the most common of several diseases of neurodegeneration with iron accumulation in the brain known collectively as NBIAs.  The group is genetically heterogeneous with many overlapping features.  Mutations in PLA2G6 cause NBIA2A (256600) and NBIA2B (610217) while mutations in a FLT gene cause NBIA3 (606159). The latter does not have apparent eye signs.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Pharmacologic treatment is aimed at alleviation of specific symptoms such as dystonia and spasticity.  Some symptoms may improve with deep brain stimulation.

References
Article Title: 
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