dysarthria

Gillespie Syndrome

Clinical Characteristics
Ocular Features: 

Bilateral aniridia, partial or complete, is the ocular characteristic of Gillespie syndrome.  The iris may be relatively intact but immobile leading to the description in some patients of "dilated and fixed pupils", or congenital mydriasis.  The pupillary margin may be scalloped with iris strands to the lens.  The pupillary sphincter is sometimes absent and the mesodermal surface missing.  The fovea sometimes appears hypoplastic and some patients have decreased visual acuity.  Strabismus and ptosis are often present.  There may also be retinal hypopigmentation.  Cataract, glaucoma, and corneal opacities are not present. 

Systemic Features: 

Most patients have some degree of developmental delay ranging from difficulties with fine motor tasks to frank mental retardation.  Many have a hand tremor, some degree of hypotonia, and learning difficulties.  MRI imaging often shows cerebellar and sometimes cerebral hypoplasia. 

Genetics

This is an autosomal dominant disorder usually due to a heterozygous mutation in the PAX6 gene (11p13).  However, some patients with typical features do not have a mutation in this gene suggesting that there is genetic heterogeneity.  Some patients without point mutations nevertheless have defects in adjacent DNA suggesting a positional effect.  The possibility of autosomal recessive inheritance in some families with parental consanguinity cannot be ruled out.  The PAX6 gene plays an important role in iris development as it is also mutant in simple aniridia (106210) and in Peters anomaly (604229).

Mutations in the ITPR1 gene have also been identified in Gillespie syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Spinocerebellar Ataxia 7

Clinical Characteristics
Ocular Features: 

Pigmentary changes in the retina are somewhat variable but often begin with a granular appearance in the macula and spread into the periphery.  The macula often becomes atrophic and dyschromatopsia is common.   Retinal thinning is evident, especially in the macula.  Decreased visual acuity and loss of color vision are early symptoms and the ERG shows abnormalities of both rod and cone function.  External ophthalmoplegia without ptosis is a frequent sign.  Most adults and some children eventually are blind. 

Systemic Features: 

Symptoms of developmental delay and failure to thrive may appear in the first year of life followed by loss of motor milestones.  Dysarthria and ataxia are nearly universal features while pyramidal and extrapyramidal signs are more variable.  This can be a rapidly progressive disease and children who develop symptoms by 14 months are often deceased before two years of age.  However, adults with mild disease can survive into the 5th and 6th decades.  Peripheral neuropathy with sensory loss and motor deficits are usually present to some degree but the range of clinical disease is wide.  Cognitive decline and some degree of dementia occur sometimes. 

Genetics

Spinocerebellar ataxia 7 is caused by expanded trinucleotide repeats (CAG) in the ATXN7 gene (3p21.1-p12) and inherited in an autosomal dominant pattern.  The number of repeats is variable and correlated with severity of disease.  Most patients with 36 or more repeats have significant disease. This disorder is sometimes classified as a progressive cone-rod dystrophy.  It is sometimes referred to as olivopontocerebellar atrophy type III or OPCA3.

This disorder exhibits genetic anticipation especially with paternal transmission as succeeding generations often have earlier onset with more severe and more rapidly progressive disease. This is explained by the fact that younger generations tend to have a larger number of repeats and sometimes the diagnosis is made in children before the disease appears in parents or grandparents.

Spinocerebellar ataxia 1 (164400) is a similar autosomal dominant disorder with many of the same clinical and genetic features.  It is caused by excess CAG repeats on the ATXN1 gene on chromosome 6. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is known for the disease.  Low vision aids and mobility training may be useful in early stages. 

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: 

Optic Atrophy 2, X-Linked

Clinical Characteristics
Ocular Features: 

Visual symptoms can begin in early childhood (males only) and vision deteriorates slowly.  All affected individuals have optic atrophy with acuities ranging from 20/30 to 20/100.  ERGs are usually normal whereas VEPs show prolonged latencies.  Color vision is variably defective and central scotomas are present.

Systemic Features: 

Some but not all patients have additional neurological signs including absent ankle jerks, hyperactive knee jerks, extensor plantar reflexes, dysarthria and dysdiadochokinesia.  Symptoms are usually minor.  Obligatory female carriers do not have optic atrophy or neurologic signs.  Mental retardation has been reported in a few patients.

Genetics

This is an X-linked recessive disorder secondary to a mutation in OPA2 (Xp11.4-p11.21). Only males are affected and female carriers are clinically normal.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

No treatment is available for the optic atrophy.

References
Article Title: 

Oculopharyngeal Muscular Dystrophy

Clinical Characteristics
Ocular Features: 

Progressive ptosis is the cardinal ocular feature of this syndrome (present in at least 88% of patients).  External ophthalmoparesis of some degree is often present with weakness of upgaze most common.

Systemic Features: 

This is a late onset form of progressive muscular dystrophy with onset of symptoms during midlife (mean age of onset ~48 years).  Evidence of pharyngeal muscle weakness often occurs concomitantly with the ocular signs (43%).  Ptosis occurs first in 43% and dysphagia first in 14%.    Dysarthria and dysphagia are often associated with facial muscle weakness.  Swallowing times for ice cold water and dry food is usually prolonged.  Evidence of weakness and wasting of neck and limb muscles is usually noted later.  Life expectancy is normal in contrast to some other forms of muscular dystrophy.  Some patients have significant gait problems and generalized disability as a result of muscle weakness.

Microscopic studies of muscle biopsies usually show evidence of myopathy with abnormal fibers and accumulations of sarcoplasmic matter.  Intranuclear inclusions consisting of tubular filaments and mitochondrial abnormalities have also been described.  Serum CK can be significantly elevated in severe cases.  

Genetics

This is an autosomal dominant disorder resulting from mutations in the PABPN1 gene located at 14q11.2-q13. Several patients with homozygous and compound heterozygous mutations have also been reported.  The PABPN1 gene product is normally a facilitator of polyadenylation of mRNA molecules and may also be active in regulating mRNA production.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Blepharoplasty may be helpful in cases with severe ptosis.  Cricopharyngeal myotomy for dysphagia and recurrent pneumonia can alleviate symptoms in severe cases although recurrence has been noted after many years.

References
Article Title: 

Niemann-Pick Disease, Types C1 (D)

Clinical Characteristics
Ocular Features: 

The predominant ocular sign in types C1 is difficulty in upgaze described as a supranuclear palsy.  Abnormal saccadic movements have been reported as well.  Retinal signs such as a cherry red spot are not common.

Systemic Features: 

Hepatosplenomegaly and cognitive decline are similar in nature to those found in Niemann-Pick disease types A and B.  Types C1 and C2 are clinically similar but discussed separately as they are caused by mutations in separate genes.  Type D is caused by the same mutation causing C1.  Onset of disease manifested by ataxia, seizures and spasticity is usually between 2 and 4 years.  Dystonia, intention tremor, dysarthria, and hepatosplenomegaly are other features but visceral involvement may be absent.  Ascites and jaundice are sometimes present.  Dementia and extrapyramidal signs are often seen later.  However, there is considerable variation in onset and progression of disease but the symptoms are generally milder than that in types A and B.

Genetics

Type C1 (and D) are caused by mutations in the NPC1 gene (18q11-q12), and type C2 (607625) by mutations in the NPC2 gene (14q24.3).  Mutations in C1 are far more common (95%) than C2 mutations.  The gene mutations reduce the efficiency of sphingosine efflux from lysosomes and late endosomes as a result of a defect in esterification of cholesterol.

Types A (257200) and B (607616) Niemann-Pick disease generally cause more severe clinical signs and are the result of a sphingomyelinase deficiency.  All types of Niemann-Pick disease follow autosomal recessive patterns of inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

It has recently been reported that intrathecal 2-hydroxypropyl-beta-cyclodextrin slows progression of clinical symptoms and prolonged lifespan.

References
Article Title: 

Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial

Ory DS, Ottinger EA, Farhat NY, King KA, Jiang X, Weissfeld L, Berry-Kravis E, Davidson CD, Bianconi S, Keener LA, Rao R, Soldatos A, Sidhu R, Walters KA, Xu X, Thurm A, Solomon B, Pavan WJ, Machielse BN, Kao M, Silber SA, McKew JC, Brewer CC, Vite CH, Walkley SU, Austin CP, Porter FD. Intrathecal 2-hydroxypropyl-v-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial. Lancet. 2017 Aug 10. pii: S0140-6736(17)31465-4. doi: 10.1016/S0140-6736(17)31465-4. [Epub ahead of print].

PubMed ID: 
28803710

Niemann-Pick disease type C

Vanier MT, Millat G. Niemann-Pick disease type C. Clin Genet. 2003 Oct;64(4):269-81. Review.

PubMed ID: 
12974729

Corneal Dystrophy, Lattice Type II

Clinical Characteristics
Ocular Features: 

This is a systemic amyloidosis disorder with significant corneal disease.  The corneal stroma contains linear deposits which are more discrete, more peripheral, more delicate, and more radial than those in lattice type I with which it is sometimes confused.  There is also less accumulation of amorphous amyloid material than in type I.  The onset is often later as well, and rarely seen in childhood.  Corneal sensitivity is reduced.  Vision is less affected than in type I lattice dystrophy and patients rarely require keratoplasty, and, if so, later in life.

Amyloid deposits are found in the cornea, sclera, choroid, lacrimal gland, ciliary nerves, and adnexal blood vessels.  Ptosis and extraocular muscle dysfunction is not significant.

Systemic Features: 

Amyloid deposits are found throughout the body including blood vessels, heart, kidney, skin and nerves.  A "mask-like" facies with a protruding lower lip, dry itchy skin, peripheral and cranial neuropathy, and renal failure are clinical features but often have their onset late in life.  Facial paralysis and bulbar palsy may be the result.

Genetics

While this is considered an autosomal dominant disorder, presumed homozygous cases have been reported in Finland where the first cases were described.  These cases seem to have more severe disease with an earlier onset than found among patients with heterozygous mutations.  Mutations in the GSN gene located at 9q34 are responsible.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Penetrating keratoplasty can be beneficial but is rarely needed for visual rehabilitation.  The amyloid deposits may recur in the donor tissue.  The reduced corneal sensitivity secondary to neural involvement increases the risk of post-operative neurotrophic epithelial defects.

References
Article Title: 

Hereditary gelsolin amyloidosis

Kiuru-Enari S, Haltia M. Hereditary gelsolin amyloidosis. Handb Clin Neurol. 2013;115:659-81. PubMed PMID: 23931809.

PubMed ID: 
23931809

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