dysphagia

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: 

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: 

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: 

Myotonic Dystrophy 1

Clinical Characteristics
Ocular Features: 

Posterior subcapsular cataracts may be seen at any age, often with striking iridescent opacities in the overlying cortex as well.  These polychromatic lens changes can be diagnostic but are present in only 50% of young adults with myotonic dystrophy.  When present, they are almost always bilateral.  Proximal muscle involvement leads to ptosis, strabismus, weakness of the orbicularis oculi, and sometimes ophthalmoplegia.  Such muscle weakness may lead to exposure keratitis. 

As many as 25% of patients with DM have a pigmentary retinopathy, usually in a butterfly pattern.

A low IOP and even hypotony is sometimes seen.  The mean IOP in a series of 51 patients has been reported as 10.9 compared with 15.4 in controls.  Using ultrasound biomicroscopy, ciliary body detachments were found in at least one quadrant of all eyes.

Systemic Features: 

In the congenital form, hypotonia, generalized weakness, mental retardation and respiratory insufficiency are often present.  There is a great deal of clinical heterogeneity among patients.  Those with mild disease may have only cataracts and mild myotonia with a normal life expectancy.  Those with more severe disease (classical myotonic dystrophy) have these signs plus marked muscle weakness and wasting.  Cardiac conduction defects with secondary arryhthmias are a significant cause of mortality. Such patients tend to become disabled in adulthood.  Symptoms become evident in the second decade or later.  Deep muscle pain is common and can be severe.  Distal muscle weakness usually begins before facial muscle weakness is apparent.  Myotonia often involves the tongue while proximal muscle weakness can cause dysphagia and dysarthria.  Such patients may also suffer respiratory distress. Reproductive fitness is reduced in males who can have gonadal atrophy.  Frontal balding is common.  Some age-related cognitive decline occurs.

Over 60% of patients have a hearing impairment and more than half of these have auditory brainstem response abnormalities.  Vestibular hypesthesia is present in 37.5%.

Genetics

Myotonic dystrophy 1 is an autosomal dominant disorder caused by a trinucleotide (CTG) repeat expansion in a region of the DMPK gene (19q13.2-q13.3).  The number of repeats varies widely and is roughly correlated with severity of disease.  Infants with congenital myotonia usually have the highest number of repeats and have the most severe cognitive deficits.  The number can expand during gametogenesis each generation (resulting in the phenomenon of anticipation) and females generally transmit larger numbers.  Most infants with congenital myotonia are offspring of affected mothers.  Reduced fetal movement and hydramnios are often noted during such pregnancies.

Affected males have few offspring secondary to gonadal atrophy.  Affected heterozygous females, however, do not have the expected ratio of affected offspring because of the dynamic nature of the number of repeats.  The risk of an affected offspring for a nulliparous afflicted female is only 3-9% and she has a 20-40% risk of recurrence after the birth of an affected child.

In a study of sibships with myotonic dystrophy, 58% of offspring were affected when the transmitting parent was male and 63% when the transmitting parent was female.

At least some of the variable transmission risks and clinical heterogeneity may be explained by somatic instability of the CTG repeat numbers.  The degree of instability, moreover, may also be heritable.  Age of onset, for example, is modified by the level of somatic instability.  Further, patients in whom the repeat expands more rapidly develop symptoms earlier. 

A similar disorder, myotonic dystrophy 2 (602668), is caused by a tetranucleotide repeat expansion in the CNBP gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

A variety of pharmaceutical agents have been tried for pain management without consistent results.  No treatment improves the muscle weakness.  Cholesterol lowering drugs such as statins should be avoided.  Physical therapy may be helpful.

Cardiac conduction and structural defects are a significant threat even in asymtomatic patients and require constant monitoring for the development of arrythmias.

References
Article Title: 

Inner ear dysfunction in myotonic dystrophy type 1

Balatsouras DG, Felekis D, Panas M, Xenellis J, Koutsis G, Kladi A, Korres SG. Inner ear dysfunction in myotonic dystrophy type 1. Acta Neurol Scand. 2012 Nov 5. doi: 10.1111/ane.12020. [Epub ahead of print].

PubMed ID: 
23121018

Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity

les F, Couto JM, Higham CF, Hogg G, Cuenca P, Braida C, Wilson RH, Adam B, Del Valle G, Brian R, Sittenfeld M, Ashizawa T, Wilcox A, Wilcox DE, Monckton DG. Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity. Hum Mol Genet. 2012 May 16. [Epub ahead of print].

PubMed ID: 
22595968

Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1

Wahbi K, Babuty D, Probst V, Wissocque L, Labombarda F, Porcher R, Becane HM, Lazarus A, Behin A, Laforet P, Stojkovic T, Clementy N, Dussauge AP, Gourraud JB, Pereon Y, Lacour A, Chapon F, Milliez P, Klug D, Eymard B, Duboc D. Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1. Eur Heart J. 2016 Dec 9. pii: ehw569. [Epub ahead of print] PubMed.

PubMed ID: 
27941019

Cystinosis

Clinical Characteristics
Ocular Features: 

Cystinosis is a clinically heterogeneous disorder that has been divided into three allelic forms based on the age of onset and the amount of kidney disease.  Since the three types are caused by mutations in the same CTNS gene they are discussed here as a single entity with emphasis on the similarities and differences.  All three cause significant corneal disease secondary to crystalline cystine deposits.

The early onset and most common form of cystinosis (219800) causes severe photophobia and even corneal erosions from accumulation of refractile cystine crystals which can be seen in the first years of life.  Accumulation of cystine in the retina leads to peripheral pigmentary changes that progress centrally and is present to some degree in all patients by age 7 years.  Mottling of the retinal pigment epithelium is the most common finding but there are often alternating areas of hyperpigmentation and depigmentation as well.  Visual fields may be markedly constricted.  Photoreceptor damage eventually leads to decreased rod and cone responses as recorded by ERG.  Visual acuity ranges from near normal to NLP.

The late-onset juvenile nephropathic (219900) form has a similar corneal profile but the pigmentary retinopathy occurs later than in the infantile disease.

The adult nonnephropathic form (219750) likewise has visible cystine crystals in the cornea.  This disorder should be considered in all healthy adults with a crystalline dystrophy of the cornea.  The pigmentary retinopathy does not occur.

Systemic Features: 

In the more common infantile form of cystinosis, accumulation of cystine leads to dysfunction in many organs.  Nephropathy, hypothyroidism, and growth retardation in the infantile type are major complications.  The kidney disease leads to a Fanconi syndrome type pattern of kidney failure.  Pancreatic insufficiency, ovarian failure, myopathy, and central nervous system signs are often seen.  Patients require renal transplantation, often in the first decade of life.  Slow eating and dysphagia are common.  Heterozygotes may have elevated levels of free cystine in leukocytes.

The later onset juvenile form of cystinosis presents with kidney failure secondary to glomerular damage instead of tubular dysfunction.  The age of diagnosis varies widely, however, anywhere from 2-26 years of age, with end-stage kidney failure occurring generally in the third decade.  Aminoaciduria is usually not present and growth is normal.

The adult-onset or benign type is also uncommon.  Patients with this non-nephropathic type (219750), of course, do not develop kidney disease but have demonstrable cystine deposits in the cornea, buffy coat, and bone marrow.  No proteinuria or amino aciduria is detectable.

Genetics

Cystinosis is an autosomal recessive disease that is found in individuals homozygous for mutations in the CTNS gene (17p13) that encodes cystinosin.  The most common mutation among Caucasians of European descent is a 57-kb deletion which sometimes includes contiguous and regulatory genes.  Other sequence variants have also been found.  High cystine levels can be demonstrated in leucocytes of heterozygotes, at least in the infantile form.   A large number of mutations, both homozygous and compound heterozygous, have been found .  The accumulation of cystine seems to result from impaired cystine transport across the lysosomal membrane and it has been suggested that the severity of disease depends on the amount of functional cystinosin produced by various mutations in the CTNS gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Topical cysteamine eye drops can dramatically reduce the number of cornea crystals and improve symptoms such as photophobia and visual acuity.  Oral administration of the same drug can be beneficial for systemic disease as well, especially if initiated before the age of two years.  It can also reduce the frequency and severity of posterior segment disease with the most benefit occurring in those who begin the drug early in life.  Improved kidney function and quality of life may be dramatic.

The chronic nature and multisystem involvement require lifelong monitoring of ocular and systemic disease.

References
Article Title: 

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