dysphagia

Cerebral Palsy, Spastic Quadriplegic, 3

Clinical Characteristics
Ocular Features: 

One family with 4 affected sibs has been reported but without detailed information on ophthalmological findings.  Strabismus reported as exotropia in one individual, and "convergent retraction nystagmus" in another was present.  Supranuclear gaze palsy was described in one individual. 

Systemic Features: 

Borderline microcephaly has been reported.  Evidence for global neurologic disease, primarily spasticity, may be present as early as 3 months of age.  Intellectual disability ranges from borderline to severe.  Progression is somewhat variable but by the second decade there may be sufficient spastic quadriparesis and cognitive impairment that full time assistive care is required.  Dysarthria and dysphagia are also features and gastrostomy feeding tubes may be required to maintain nutrition.  Seizures are uncommon.

The MRI does not show major structural abnormalities and an EEG in one patient revealed only bifrontal spike-waves.

Genetics

This condition is caused by homozygous mutations in the ADD3 gene (10q24).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Mutations in gamma adducin are associated with inherited cerebral palsy

Kruer MC, Jepperson T, Dutta S, Steiner RD, Cottenie E, Sanford L, Merkens M, Russman BS, Blasco PA, Fan G, Pollock J, Green S, Woltjer RL, Mooney C, Kretzschmar D, Paisan-Ruiz C, Houlden H. Mutations in gamma adducin are associated with inherited cerebral palsy. Ann Neurol. 2013 Dec;74(6):805-14.

PubMed ID: 
23836506

Spinocerebellar Ataxia 42

Clinical Characteristics
Ocular Features: 

 Saccadic eye movements with nystagmus and diplopia have been reported (7 of 10 reported patients).

Systemic Features: 

Cerebellar signs usually have their onset in midlife or later with slow progression.  Most patients are mildly to moderately disabled.  Dysarthria, dysphagia, and a spastic gait are experienced by the majority of individuals.  Hyperreflexia and a positive Babinski sign are commonly presently.  Mild cognitive impairment and depression have been seen in a minority of patients.

Brain MRIs show cerebellar hemispheric and vermian atrophy.  The cerebral cortex appeared histologically normal in one deceased patient.

Genetics

This disorder is caused by heterozygous mutations in the CACNA1G gene (17q21.33).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Spastic Paraplegia 11

Clinical Characteristics
Ocular Features: 

Gaze evoked nystagmus and pigmentation in the macula are components of this syndrome and adults have some degree of retinal degeneration with poor vision eventually.  Optic atrophy and ptosis have been reported but rarely.   

Systemic Features: 

his progressive condition nay have its onset in childhood or early adolescence although rarely it first appears in adulthood.  Obesity is a component in older individuals.  Loss of ambulation usually occurs within 10 years of the onset of gait difficulties.  Hyperreflexia and spasticity develop early while ataxia, urinary sphincter disturbances, extensor plantar responses, and dysarthria appear later.  Amyotrophy is frequently seen in the thenar and hypothenar muscles.  Children have learning difficulties while cognitive decline and frank mental retardation occur somewhat later.  

Peripheral nerve biopsy may reveal hypomyelination and loss of unmyelinated nerve fibers.  MRI imaging in some individuals shows a thin or absent corpus callosum and cortical atrophy. 

Genetics

Homozygous mutations in the gene SPG11 (15q21.1) encoding spatacsin are responsible for this disorder. 

See spastic paraplegia 15 (Kjellin syndrome) (270700) and spastic paraplegia 7 (607259) for other disorders with retinal degeneration, optic atrophy, and nystagmus.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None known.

References
Article Title: 

Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum

Stevanin G, Santorelli FM, Azzedine H, Coutinho P, Chomilier J, Denora PS, Martin E, Ouvrard-Hernandez AM, Tessa A, Bouslam N, Lossos A, Charles P, Loureiro JL, Elleuch N, Confavreux C, Cruz VT, Ruberg M, Leguern E, Grid D, Tazir M, Fontaine B, Filla A, Bertini E, Durr A, Brice A. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet. 2007 Mar;39(3):366-72.

PubMed ID: 
17322883

3-methylglutaconic Aciduria with Cataracts, Neurologic Involvement and Neurtropenia

Clinical Characteristics
Ocular Features: 

Descriptions of ocular findings have been limited.  Congenital nuclear cataracts have been described in one patient but lens opacities have been noted in others.

Systemic Features: 

There is considerable heterogeneity in the phenotype with some patients having minimal signs and living to adulthood whereas others succumb to their disease in the first year of life.  The onset of progressive encephalopathy usually occurs in infancy as evidenced by various movement abnormalities and psychomotor delays.  Neonatal hypotonia sometimes progresses to spasticity.  However, other infants are neurologically normal.  Delayed psychomotor development, ataxia, seizures, and dystonia may be seen.  Brain imaging may reveal cerebellar and cerebral atrophy along with brain stem abnormalities.  Neuronal loss, diffuse gliosis, and microvacuolization have been seen on neuropathologic examination.  Dysphagia is common.  Severe neutropenia and recurrent infections may begin in infancy as well.

Increased amounts of 3-methylglutaconic acid are found in the urine while the bone marrow may contain evidence of arrested granulopoiesis. 

Genetics

This autosomal recessive disorder results from homozygous or compound heterozygous mutations in the CLPB gene (11q13.4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported for this condition.

References
Article Title: 

CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder

Wortmann SB, Zietkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, Strom TM, Meitinger T, Rubio-Gozalbo ME, Chrusciel E, Distelmaier F, Golzio C, Jansen JH, van Karnebeek C, Lillquist Y, Lucke T, Ounap K, Zordania R, Yaplito-Lee J, van Bokhoven H, Spelbrink JN, Vaz FM, Pras-Raves M, Ploski R, Pronicka E, Klein C, Willemsen MA, de Brouwer AP, Prokisch H, Katsanis N, Wevers RA. CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder. Am J Hum Genet. 2015 Feb 5;96(2):245-57.

PubMed ID: 
25597510

Cerebral Atrophy, Autosomal Recessive

Clinical Characteristics
Ocular Features: 

Severe visual impairment is noted before one year of age when infants cease following objects in their environment.  Cortical visual impairment has been diagnosed although 'atrophic optic fundi' and hypotrophic optic nerves and fovea have also been described.  Nystagmus has been observed as well.

Systemic Features: 

Microcephaly relative to age norms is evident usually by 2 months of age and there is little subsequent growth of the skull.  Regression of developmental milestones is noted by 4 months of age with signs of irritability, akathisia, spasticity, visual impairment, seizures, and increased startle responses.  Sucking responses and eye-to-eye contact are usually lost by 6 months of age.  Repetitive body stiffening and extension of arms in older individuals consistent with seizure activity has been confirmed by EEG in at least one infant.  Imaging consistently reveals cerebral atrophy with ventriculomegaly and general loss of brain volume. Progressive muscle weakness is evident after about 1 year of age and oral feeding is impaired. There is complete lack of responsive interaction beyond irritability and agitation while motor function is limited to involuntary responses.  Two individuals have lived into the second decade of life.

Genetics

This condition has been described in 4 individuals who were products of consanquineous Amish couples.  Homozygous mutations in the TMPRSS4 gene (11q23.3), whose product is a serine transmembrane protease, seems to be responsible.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Optic Atrophy, Areflexia, Ataxia, Hearing Loss

Clinical Characteristics
Ocular Features: 

Progressive optic atrophy is a consistent feature of all reported cases.  It may have its onset during the first year or two of life but always before the age of 10 years.  Nystagmus may be seen early during acute febrile episodes but eventually becomes permanent.

Systemic Features: 

Onset of neurological symptoms usually occurs in childhood during or following an acute febrile illness which may be recurrent.  This may consist of cerebellar ataxia, hypotonia, drowsiness, dysarthria, and lethargy.  There may be partial or full recovery following the febrile illness initially but some signs remain after subsequent episodes.  Areflexia and sensorineural deafness can be additional signs and pes cavus eventually appears.

The acute febrile episodes tend to decrease in time along with the progression of neurological signs.  Plantar responses remain normal while peripheral neuropathy and seizures are not consistent features.  MRI imaging of the brain is normal.  Cognitive function usually remains normal but some children have autism features and social adjustment problems have been noted.

Genetics

This is an autosomal dominant condition (which may be considered a form of ‘ataxia-plus’) secondary to heterozygous mutations in the ATP1A3 gene (19q13.31).  The protein product is a subunit of an ATPase enzyme primarily active in neural tissue.

Other mutations in the same gene have been found in dystonia-12 and alternating hemiplegia of childhood.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known for this condition but physical therapy and mobility-assistive devices may be helpful.  Low vision aids may be useful as well.

References
Article Title: 

A novel recurrent mutation in ATP1A3 causes CAPOS syndrome

Demos MK, van Karnebeek CD, Ross CJ, Adam S, Shen Y, Zhan SH, Shyr C, Horvath G, Suri M, Fryer A, Jones SJ, Friedman JM; FORGE Canada Consortium. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis. 2014 Jan 28;9:15.

PubMed ID: 
24468074

Myasthenic Syndromes, Congenital, Including AChR Deficiency

Clinical Characteristics
Ocular Features: 

The congenital myasthenic syndromes are genetically and clinically heterogeneous.  Ptosis is the outstanding ocular sign and virtually always present.  Strabismus and ophthalmoplegia are less common.  These signs are not helpful in the differential diagnosis of the many types of congenital myasthenia.

Some degree of ptosis is usually evident during the first 6 months of life.  By about 2 years of age strabismus and ophthalmoparesis are apparent but this sequence is highly variable.

Systemic Features: 

This is a group of nonprogressive disorders most often associated with acetylcholine receptor (AChR) defects at the neuromuscular junction.  An early sign may be decreased fetal movements.  Generalized weakness, a weak cry, and hypotonia are evident at birth.  Easy fatigability and limb weakness are noted in early childhood and affected children have difficulty running. Facial weakness, dysarthria, weakness of the tongue, and dysphagia are often present and many patients have respiratory difficulties. Motor development can be delayed.  Acute illnesses may exacerbate muscle weakness.

Genetics

This is the most common form of the congenital myasthenic syndromes. It is an autosomal recessive disorder of the postsynaptic type, so called because the mutations occur in genes that encode the subunits of acetylcholine receptors: CHRNE(17P13.2), and CHRNB1(17p13.1).  A similar phenotype results from mutations in MUSK (9p31.3) which is critical for synaptic differentiation.

Mutations in RAPSN(11p11.2), whose protein product is important for stabilization of the acetylcholine receptors at the endplate, may result in a similar phenotype but may also produce the fetal akinesia deformation sequence.  This lethal condition is often associated with severe respiratory disease and dysmorphism including limb contractures, micrognathia, and feeding difficulties.  Nothing is known about the ocular signs.

Another autosomal recessive congenital myasthenic syndrome (610542), CMSTA1, has a somewhat later onset (adolescence) and weakness in a limb girdle distribution but no ptosis or oculomotor problems.  Tubular aggregates of muscle fibers can be seen on biopsy.

Presynaptic autosomal recessive forms of congenital myasthenia such as CMS20 (617143) caused by mutations in SLC5A7 (2q12) and CMS21 (617239) secondary to mutations in SLC18A3 (10q11.23) with severe episodic apnea and ocular signs of ptosis and ophthalmoparesis have been reported.

Other postsynaptic forms of congenital myasthenia are the fast-channel type (FCCNS) (608930) and the slow channel type (SCCMS) (601462).  Ophthalmoparesis occurs early in both types.

The classification of congenital myasthenia syndromes is under construction.  In the case of many types only a single or very few families have been reported.   While the clinical manifestations involve alterations in the neuromuscular junnction, some result from heterozygous mutations while others are due to homozygous changes.  The defect may reside in presynaptic, synaptic, or postsynaptic mechanisms.  For a discussion and comprehensive listing of the various types see 601462.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cholinesterase inhibitor drugs can be highly beneficial in some forms of the disease but genotyping is necessary before attempting pharmacological therapy.  Frequent ventilation and enteric feeding may be helpful for selected individuals.  Individuals should be protected from acute illnesses, especially respiratory infections.

References
Article Title: 

Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea

Bauche S, O'Regan S, Azuma Y, Laffargue F, McMacken G, Sternberg D, Brochier G, Buon C, Bouzidi N, Topf A, Lacene E, Remerand G, Beaufrere AM, Pebrel-Richard C, Thevenon J, El Chehadeh-Djebbar S, Faivre L, Duffourd Y, Ricci F, Mongini T, Fiorillo C, Astrea G, Burloiu CM, Butoianu N, Sandu C, Servais L, Bonne G, Nelson I, Desguerre I, Nougues MC, Boeuf B, Romero N, Laporte J, Boland A, Lechner D, Deleuze JF, Fontaine B, Strochlic L, Lochmuller H, Eymard B, Mayer M, Nicole S. Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea. Am J Hum Genet. 2016 Sep 1;99(3):753-61.

PubMed ID: 
27569547

Congenital myasthenic syndromes

Hanta?O D, Richard P, Koenig J, Eymard B. Congenital myasthenic syndromes. Curr Opin Neurol. 2004 Oct;17(5):539-51. Review.

PubMed ID: 
15367858

CHARGE Syndrome

Clinical Characteristics
Ocular Features: 

Both ocular and systemic abnormalities are highly variable, even within families.  Among the most common ocular features are unilateral or bilateral ocular colobomas (80%).  These involve the iris most frequently but they may extend into the posterior chamber and rarely involve the optic nerve.  A significant number of patients with uveal colobomas have an associated microphthalmia.  The lid fissures often slant downward.  A few patients have congenital cataracts, optic nerve hypoplasia, persistent hyperplastic vitreous, and strabismus.

Systemic Features: 

A wide variety of systemic anomalies have been reported.  Congenital heart defects (primarily septal) and CNS malformations are among the most common features, reported in 85% and 55% respectively.  Tetralogy of Fallot is considered by some to be the most common heart malformation.  Growth and mental retardation are found in nearly 100%.  The pinnae are often set low and hearing loss is common.  Ear anomalies, both internal and external, have been described in 91%, and some degree of conduction and/or sensorineural deafness is present in 62%.  Choanal atresia is found in at least 57% of patients.  This along with cleft palate and sometimes esophageal atresia or reflux often contributes to feeding difficulties which are common in all age groups.  Cranial nerve deficits are seen in 92% of patients and more than one nerve is involved in nearly 3 of 4 patients.  The most common cranial nerve defects involve numbers IX, X, VIII, and V.  Facial palsies are an especially important feature. Hypogonadotropic hypogonadism and underdevelopment of the external genitalia are often seen, especially in males.  One-third of patients have limb anomalies and many have short digits.  The facies is considered by some as characteristic with a square configuration, broad forehead, flat midface, and a broad nasal bridge.

Infant and childhood morbidity is high with feeding difficulties a major cause of death.

Genetics

Many cases occur sporadically but family patterns consistent with autosomal dominant inheritance are common as well.  Advanced paternal age may be a factor in de novo cases.  Sequence variants of multiple types have been reported in the CHD7 gene (8q12.1-q12.2) in more than 90% of familial patients.  The gene product is a DNA –binding protein that impacts transcription regulation via chromatin remodeling.

Kallmann syndrome (hypogonadotropic hypogonadism and anosmia) has been considered to be allelic to CHARGE syndrome but may be the same disorder since mutations in CHD7 are responsible and many patients have other features characteristic of the syndrome described here.

Several patients with classical features of the CHARGE syndrome and de novo mutations in the SEMA3E gene (7q21.11) have also been described.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is lesion dependent but focused on airway, feeding, and cardiac defects at least initially.  Regular ophthalmologic and audiologic evaluations are recommended beginning in infancy.  Evidence for hypogonadism should be evaluated if puberty is delayed.  Nutrition must be monitored especially in those with serious feeding problems.  Hearing devices, with speech, occupational, and education therapy may be required.

References
Article Title: 

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: 

Oculopharyngodistal Myopathy

Clinical Characteristics
Ocular Features: 

Progressive ptosis, which may be asymmetric, is an early sign.  Extraocular palsy occurs as well. 

Systemic Features: 

The mean age of onset of this progressive disease is 22 years.  Pharyngeal and distal limb muscles seem to be primarily involved.  Weakness in masseter, facial, and bulbar muscles have been observed but no muscle group seems to be spared.  Atrophy of facial muscles is common and may be pronounced.  There is considerable variability in expression, particularly in the degree of limb weakness which often appears by the fifth decade.  Swallowing difficulties can be severe.  Respiratory weakness may be evident relatively early, even while patients are still ambulatory.  Loss of ambulation most commonly occurs by the third or fourth decade after the onset of first symptoms.  Serum creatine kinase levels are mildly elevated and histologic changes show chronic myopathic changes with rimmed vacuole formation.  No changes have been found in the central or peripheral nervous system. 

Genetics

The causative mutation has not been identified but mutations causing other forms of hereditary myopathy have been ruled out.  Most families are consistent with autosomal dominant inheritance but the pattern in at least one family has suggested a recessive pattern indicating genetic heterogeneity. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Supportive treatment such as physical and respiratory therapies may be helpful but no specific treatment is available for the muscle disease.

References
Article Title: 

Oculopharyngodistal myopathy

Satoyoshi E, Kinoshita M. Oculopharyngodistal myopathy. Arch Neurol. 1977 Feb;34(2):89-92.

PubMed ID: 
836191

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