dysphagia

Leukodystrophy, Hypomyelinating, 15

Clinical Characteristics
Ocular Features: 

Severe optic atrophy with marked vision loss is commonly present.  Hypermetropia and nystagmus have also been reported.

Systemic Features: 

The clinical features of 4 unrelated patients are highly variable.  Onset of clinical signs is also variable and most are progressive.   Several patients have presented in the first month of life with microcephaly and delayed motor development.  Progressive cerebellar signs of ataxia with dystonia, dysphagia and motor signs from infancy has been seen.  Other patients with cognitive deterioration and progressive neurologic deficits may present late in the first decade of life at which time ataxia, dysarthria, spasticity, and pyramidal signs nay also be noted.  Dystonic and athetoid movements and intention tremor have been reported in some patients.

Brain MRIs in older individuals in the second decade of life reveal hypomyelinating leukodystrophy with thinning of the corpus callosum and cerebellar atrophy.

Genetics

Homozygous or compound heterozygous mutations in the EPRS (1q41) gene are responsible for this autosomal recessive disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

Brown-Vialetto-Van Laere Syndrome 2

Clinical Characteristics
Ocular Features: 

Decreased vision, optic atrophy, and nystagmus are frequently present.  Pupillary reflexes may be absent.

Systemic Features: 

Rapidly progressive muscle weakness and ataxia present in childhood.  Early development may be normal but the first symptoms usually appear by age 2 or 3 years of age.  Cognition is usually normal.  Exercise intolerance soon appears along with dysphonia, dyspnea, dysphagia, and weakness of shoulder, neck and axial muscles.  Wasting and weakness of hand muscles is often noticeable.  Kyphoscoliosis, tongue fasciculations, and areflexia are often seen.  Sensorineural hearing loss is a common feature.

Death from respiratory insufficiency often occurs within a few years after onset.

Genetics

Homozygous mutations in the SLC52A2 (8q24.3) gene have been identified in patients with this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Administration of riboflavin has been reported to be beneficial in lessening symptoms.

References
Article Title: 

SLC52A2 mutations cause SCABD2 phenotype: A second report

Babanejad M, Adeli OA, Nikzat N, Beheshtian M, Azarafra H, Sadeghnia F, Mohseni M, Najmabadi H, Kahrizi K. SLC52A2 mutations cause SCABD2 phenotype: A second report. Int J Pediatr Otorhinolaryngol. 2018 Jan;104:195-199.

PubMed ID: 
29287867

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2

Foley AR, Menezes MP, Pandraud A, Gonzalez MA, Al-Odaib A, Abrams AJ, Sugano K, Yonezawa A, Manzur AY, Burns J, Hughes I, McCullagh BG, Jungbluth H, Lim MJ, Lin JP, Megarbane A, Urtizberea JA, Shah AH, Antony J, Webster R, Broomfield A, Ng J, Mathew AA, O'Byrne JJ, Forman E, Scoto M, Prasad M, O'Brien K, Olpin S, Oppenheim M, Hargreaves I, Land JM, Wang MX, Carpenter K, Horvath R, Straub V, Lek M, Gold W, Farrell MO, Brandner S, Phadke R, Matsubara K, McGarvey ML, Scherer SS, Baxter PS, King MD, Clayton P, Rahman S, Reilly MM, Ouvrier RA, Christodoulou J, Zuchner S, Muntoni F, Houlden H. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain. 2014 Jan;137(Pt 1):44-56.

PubMed ID: 
24253200

Encephalopathy, Progressive, Early-Onset, wtih Brain Atrophy and Spasticity

Clinical Characteristics
Ocular Features: 

Optic atrophy or cortical visual impairment with lack of visual tracking have been described in all patients.

Systemic Features: 

Microcephaly is evident at birth with global developmental delay and hearing loss.  One patient of 3 reported in 2 unrelated families had brief flexion seizures at 5 months.  Developmental regression and stagnation may become evident within the first months of life.  The EEG showed a hypsarrhythmia pattern.  Truncal hypotonia, spasticity, dystonia and/or myoclonus, scoliosis, and dysphagia are also features.  Two of the three reported patients had seizures. 

Brain MRI showed a pattern of pontine hypoplasia, partial agenesis of the corpus callosum, modified frontal gyri and diffuse cortical atrophy with enlarged ventricles have been described.  The cerebellum seems to be spared.

Genetics

Homozygous or compound heterozygous mutations in the TRAPPC12 gene (2p25.3) were found in 3 children in 2 unrelated families with this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Spinocerebellar Ataxia 37

Clinical Characteristics
Ocular Features: 

 Abnormal ocular movements are common, beginning with dysmetric vertical saccades and irregularities of vertical pursuit, with later development of irregular horizontal tracking movements.  Nystagmus is sometimes present. 

Two otherwise asymptomatic individuals with dysmetric vertical saccades and irregular vertical pursuit movements had normal horizontal pursuit movements at the ages of 32 and 40 years and were found to have the SCA37 haplotype.   

Systemic Features: 

The mean age of onset in is about 50 years with signs of dysarthria and a clumsy gait.  Other more variable findings include truncal ataxia, dysmetria, and sometimes dysphagia.  Slow progression of signs may lead to eventual wheelchair dependence within one or two decades of disease onset.  Brain imaging reveals cerebellar atrophy with sparing of the brainstem.

Genetics

Heterozygous mutations in the DAB1 gene (1p32.2) are responsible for this disorder.   This disorder of adult onset has been described in several families living on the Iberian peninsula.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia

Seixas AI, Loureiro JR, Costa C, Ordonez-Ugalde A, Marcelino H, Oliveira CL, Loureiro JL, Dhingra A, Brandao E, Cruz VT, Timoteo A, Quintans B, Rouleau GA, Rizzu P, Carracedo A, Bessa J, Heutink P, Sequeiros J, Sobrido MJ, Coutinho P, Silveira I. A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia. Am J Hum Genet. 2017 Jul 6;101(1):87-103.

PubMed ID: 
28686858

Carey-Fineman-Ziter Syndrome

Clinical Characteristics
Ocular Features: 

Abnormal eye movements with prominent external ophthalmoplegia are hallmarks of this disease.  An oculomotor nerve palsy with limited abduction and some degree of facial palsy are usually present.  The Moebius sequence is present in many patients.  Epicanthal folds, downslanting lid fissures, and ptosis are frequently seen.

Systemic Features: 

Clinical signs are highly variable.  Unusual facies with features of the Pierre Robin complex are characteristic.  Micrognathia and retrognathia are often present with glossoptosis.  Hypotonia and failure to thrive are commonly seen.  Dysphagia and even absent swallowing likely contribute to this.  Respiratory insufficiency can be present from birth, often with laryngostenosis, and some patients develop pulmonary hypertension and restrictive lung disease as adults.  Progressive scoliosis may contribute to this.  Many patients have club feet with joint contractures.  Skull formation consisting of microcephaly, or macrocephaly, or plagiocephaly is commonly seen.  Cardiac septal defects are common.

Intellectual disability is present in some but not all individuals.  Neuronal heterotopias, enlarged ventricles, reduced white matter, a small brainstem, microcalcifications, and enlarged ventricles have been observed.

Genetics

Homozygous or compound heterozygosity of the MYMK gene (9q34) is responsible for this condition.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general disorder has been reported.

References
Article Title: 

A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome

Di Gioia SA, Connors S, Matsunami N, Cannavino J, Rose MF, Gilette NM, Artoni P, de Macena Sobreira NL, Chan WM, Webb BD, Robson CD, Cheng L, Van Ryzin C, Ramirez-Martinez A, Mohassel P, Leppert M, Scholand MB, Grunseich C, Ferreira CR, Hartman T, Hayes IM, Morgan T, Markie DM, Fagiolini M, Swift A, Chines PS, Speck-Martins CE, Collins FS, Jabs EW, Bonnemann CG, Olson EN; Moebius Syndrome Research Consortium, Carey JC, Robertson SP, Manoli I, Engle EC. A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome. Nat Commun. 2017 Jul 6;8:16077. doi: 10.1038/ncomms16077.

PubMed ID: 
28681861

Möbius sequence, Robin complex, and hypotonia: severe expression of brainstem disruption spectrum versus Carey-Fineman-Ziter syndrome

Verloes A, Bitoun P, Heuskin A, Amrom D, van de Broeck H, Nikkel SM, Chudley AE, Prasad AN, Rusu C, Covic M, Toutain A, Moraine C, Parisi MA, Patton M, Martin JJ, Van Thienen MN. Mobius sequence, Robin complex, and hypotonia: severe expression of brainstem disruption spectrum versus Carey-Fineman-Ziter syndrome. Am J Med Genet A. 2004 Jun 15;127A(3):277-87.

PubMed ID: 
15150779

Spinocerebellar Ataxia 3

Clinical Characteristics
Ocular Features: 

External ophthalmoplegia in some form is usually present and there may be a supranuclear component.  Smooth horizontal movements are impaired and saccades are dysmetric.  Gaze-evoked nystagmus is a common finding.  The eyes are often described as 'bulging' and this has been attributed to eyelid retraction.  With time the abnormal saccadic movements slow resulting in ophthalmoparesis with restriction of upgaze.

Systemic Features: 

This form of spinocerebellar ataxia is considered to be the most frequent.  It is a progressive disease in all aspects which accounts for some of the considerable clinical heterogeneity reported.  Onset is likewise highly variable depending upon the number of repeats but usually sometime between the second to fifth decades.  In a large cohort of Azorean individuals the mean age of onset was reported to be 37 years.

An unsteady gait, dysarthric speech, general clumsiness, and diplopia are among the early symptoms.  Nystagmus, spasticity, and various autonomic signs including reduced bladder control may also be noted.  Chronic pain, sleep disturbances, impaired mental functioning, and memory deficits are often present and some authors have labelled these as indicative of dementia.

Virtually all clinical signs progress with ambulation difficulties requiring the need for assistive devices about a decade after the onset of disease.  Eventually signs of brain stem involvement appear with facial atrophy, perioral twitching, tongue fasciculations and atrophy, and dysphagia. Some degree of peripheral polyneuropathy with muscle wasting and loss of sensation are often present.  Tremors and other signs of Parkinsonism may be present.  Dystonic movements are often seen.

Imagining of the brain has revealed pontocerebellar atrophy and enlargement of the 4th ventricle but this is variable.  Nerve conduction studies documents involvement of the sensory nerves.  Neuropathologic studies show widespread neuronal loss in the CNS and spinal cord.

Genetics

This is considered to be an autosomal dominant disorder caused by an excess of heterozygous trinucleotide repeats in the ataxin3 gene (14q32) encoding glutamine.  The number in normal individuals is up to 44 repeats whereas patients with SCA3 have 52-86 repeats.  However, clinical signs of SCA3 have been found in patients with as few as 45 glutamine repeats.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Physical and occupational therapy combined with regular exercise has been reported to slow the progression of symptoms.

References
Article Title: 

Machado-Joseph disease

Sudarsky L, Coutinho P. Machado-Joseph disease. Clin Neurosci. 1995;3(1):17-22. Review.

PubMed ID: 
7614089

Dystonia, Childhood Onset, With Optic Atrophy

Clinical Characteristics
Ocular Features: 

Optic atrophy is often observed during the first decade of life and has been noted as early as 15 months.  It may be congenital.  Nystagmus has been seen in some patients.

Systemic Features: 

Signs of motor dysfunction are seen in the first decade of life, and as early as 15 months of age.  Motor development may be mildly delayed.  Features are variable and include facial dystonia, myoclonus, dyskinesia, dysarthria, dysphagia, limb spasticity, and chorea-like movements all of which may progress.  Some patients lose independent ambulation but cognition is not affected.

Brain imaging reveals hyperintense T2-weighted signals in the basal ganglia.

Genetics

The transmission pattern in 5 reported families is consistent with autosomal recessive inheritance.  Biallelic mutations in the MECR gene (1p35) have been found in 7 affected individuals.

This nuclear gene plays a role in mitochondrial fatty acid synthesis.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder

Heimer G, Keratar JM, Riley LG, Balasubramaniam S, Eyal E, Pietikainen LP, Hiltunen JK, Marek-Yagel D, Hamada J, Gregory A, Rogers C, Hogarth P, Nance MA, Shalva N, Veber A, Tzadok M, Nissenkorn A, Tonduti D, Renaldo F; University of Washington Center for Mendelian Genomics., Kraoua I, Panteghini C, Valletta L, Garavaglia B, Cowley MJ, Gayevskiy V, Roscioli T, Silberstein JM, Hoffmann C, Raas-Rothschild A, Tiranti V, Anikster Y, Christodoulou J, Kastaniotis AJ, Ben-Zeev B, Hayflick SJ. MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder. Am J Hum Genet. 2016 Dec 1;99(6):1229-1244.

PubMed ID: 
27817865

Encephalopathy Due To Defective Mitochondrial And Peroxisomal Fission 2

Clinical Characteristics
Ocular Features: 

Visual impairment and optic atrophy are usually present.  Visual-evoked potentials may be negative or slowed severely.  Some degree of ophthalmoparesis is often present while frank external ophthalmoplegia can develop in the second year of life.  In one patient aged 7 years, MRI showed increased T2 signals in the optic radiation.

Systemic Features: 

Microcephaly becomes evident in the first year of life and seizures can appear in this period as well.  General developmental delays are present.  There may be evidence of Leigh-like basal ganglia disease.  Dysphagia may require the placement of a gastroscopy tube.  Truncal hypotonia can be so severe that sitting and head control are not possible.  However, there is often spasticity and hyperreflexia in the limbs.  EEG recordings show hypsarrhythmia.

Brain MRI may show increased T2 signaling in the global pallidus, thalamus, and the subthalamic nucleus.

Patients may never be able to sit or walk and usually do not develop speech.  

Genetics

Homozygous or compound heterozygous truncating mutations in the MFF gene (mitochondrial fission factor) (2q36.3) is responsible for this condition.  Patients with EMPF2 may have abnormally elongated and tubular mitochondria and peroxisomes in fibroblasts.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the general disorder.  Gastrostomy tubes may be required to maintain adequate nutrition.  Airway hygiene is important.  Respiratory complications can be a factor in the early demise of children.

References
Article Title: 

External Ophthalmoplegia, Progressive, with mtDNA Deletions, AR 4

Clinical Characteristics
Ocular Features: 

Patients have adult onset (6th to 7th decade of life) and progressive ptosis and external ophthalmoplegia of variable severity.

Systemic Features: 

There is a great deal of clinical heterogeneity in this condition.  Some patients have adult onset proximal and limb girdle progressive muscle weakness.  Other individuals complain of exercise-induced muscle pain and increased weakness.  Dysphagia and dysphagia may be present.  More widespread signs such as peripheral neuropathy, hearing impairment, cortical atrophy, and liver disease are variably present.  

Genetics

Compound heterozygous mutations in the DGUOK (deoxyguanosine kinase) gene (2p13) have been identified in this disorder.  Multiple deletions in the mitochondrial DNA of skeletal muscle have been found as well.    

Biallelic mutations in the DGUOK gene also cause more widespread disease as evidenced in the mitochondrial DNA depletion syndrome MTDPS3 (251880). 

A similar condition, External Ophthalmoplegia, Progressive, with mtDNA Deletions, AR 3, (617069) is caused by mutations in the TK2 gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Ptosis surgery may be of benefit.

References
Article Title: 

External Ophthalmoplegia, Progressive, with mtDNA Deletions, AR 3

Clinical Characteristics
Ocular Features: 

The ophthalmoplegia is adult in onset (approx. age 40 years) and progressive.  Severe blepharoptosis is an associated sign.

Systemic Features: 

Proximal muscle weakness and atrophy in the shoulder girdle and legs were features in the two reported patients.  Rising from a squatting position and walking up stairs may be particularly difficult.  Dysarthria and dysphagia are associated findings.

Muscle biopsy showed mitochondrial myopathy.  Multiple mtDNA deletions occur in skeletal muscles.  

Genetics

One family with two sisters has been reported with this condition.  Both had compound heterozygous mutations in the thymidine kinase gene (TK2) (16q21) and multiple deletions in mitochondrial DNA.

A similar condition, External Ophthalmoplegia, Progressive, with mtDNA Deletions, AR 4, (617070) is caused by mutations in the DGUOK gene. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the generalized condition but blepharoplasty may be required.

References
Article Title: 

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