dysarthria

Ataxia and Polyneuropathy, Adult-Onset

Clinical Characteristics
Ocular Features: 

This condition has its onset in young adults.  Early ocular signs are gaze-evoked horizontal nystagmus and defective ocular pursuit movements with the full range of extraocular movements.  Some patients but not all have optic atrophy.  Ptosis is not present.

Systemic Features: 

Gait disturbances have their onset in the first or second decades of life.  The gait may be broad-based.  Intermittent hemiparesis with headache, nausea and vomiting has been reported in some individuals.  Absent ankle jerks and extensor plantar responses have been noted but general muscle tone and strength is usually normal.   An axonal sensorimotor neuropathy may be present in midlife as documented by nerve conduction studies.  MRIs of the brain may reveal cerebellar atrophy.

Mild cognitive problems have been reported in a few individuals.

Genetics

This is a mitochondrial disorder secondary to mutations in the mitochondrial MT-ATP6 gene.

Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy, Childhood-Onset

Clinical Characteristics
Ocular Features: 

Vertical gaze palsy has its onset between 7 and 15 years of age.   Nystagmus and oculomotor apraxia are often present.

Systemic Features: 

Onset of unsteadiness, gait ataxia, and cognitive decline are evident in the first or second decades of life.  Dysdiadokinesis, dysarthria, dysmetria, dystonia, athetotic movements, signs of Parkinsonism with tremor may also be present.  Some patients have a mild hearing loss.  Tissue from muscle biopsies are normal.  Brain imaging reveals cerebellar atrophy in some families and iron deposition in the basal ganglia in others.

Many patients are wheelchair-bound eventually.

Genetics

Homozygous mutations in the SQSTM1 gene (5q35.3) are responsible for this condition. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported but physical therapy, speech therapy, and special education may be of benefit.

References
Article Title: 

Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy

Haack TB, Ignatius E, Calvo-Garrido J, Iuso A, Isohanni P, Maffezzini C, Lonnqvist T, Suomalainen A, Gorza M, Kremer LS, Graf E, Hartig M, Berutti R, Paucar M, Svenningsson P, Stranneheim H, Brandberg G, Wedell A, Kurian MA, Hayflick SA, Venco P, Tiranti V, Strom TM, Dichgans M, Horvath R, Holinski-Feder E, Freyer C, Meitinger T, Prokisch H, Senderek J, Wredenberg A, Carroll CJ, Klopstock T. Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy. Am J Hum Genet. 2016 Sep 1;99(3):735-43.

PubMed ID: 
27545679

Cataracts, Congenital, Intellectual Disability, Abnormal Striatum, and ADHD

Clinical Characteristics
Ocular Features: 

Cataracts (not further described) were described as congenital although the diagnosis was usually made early in the first decade of life.  One patient was diagnosed at the age of 8 years with glaucoma and a cloudy cornea of the left eye.  Another patient had cataract surgery.  Visual acuities have not been reported.

Systemic Features: 

Four members of a consanguineous Saudi family have been reported with growth and mental retardation, microcephaly, dystonia, and spasticity.  IQs in the range of 77-89 were reported.  Linguistic delay is common.  Dysarthria and decreased cognitive function are present.  MRIs revealed thinning of the lentiform nucleus and swelling of the caudate heads.  

Genetics

Homozygous mutations in the KCNA4 (11p14.1) (176266) gene are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the general condition.  Cataract surgery may be considered.

References
Article Title: 

KCNA4 deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability

Kaya N, Alsagob M, D'Adamo MC, Al-Bakheet A, Hasan S, Muccioli M, Almutairi FB, Almass R, Aldosary M, Monies D, Mustafa OM, Alyounes B, Kenana R, Al-Zahrani J, Naim E, Binhumaid FS, Qari A, Almutairi F, Meyer B, Plageman TF, Pessia M, Colak D, Al-Owain M. KCNA4 deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability. J Med Genet. 2016 Aug 31. pii: jmedgenet-2015-103637. doi: 10.1136/jmedgenet-2015-103637. [Epub ahead of print].

PubMed ID: 
27582084

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: 

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

Spastic Paraplegia, Optic Atrophy, and Neuropathy

Clinical Characteristics
Ocular Features: 

Non-progressive optic atrophy with vision loss is described as congenital in onset.

Systemic Features: 

Progressive spasticity has its onset in infancy with loss of independent mobility usually in the second decade of life.  An exaggerated startle response occurs in some individuals.  All patients are confined to wheelchairs after 15 years of age due to progressive motor neuropathy.  No intellectual disability has been reported.  Joint contractures occur.  Dysarthria is notable in the third decade of life.  Eventually joint contractures and spine deformities occur.

Genetics

Homozygous mutations in the KLC2 gene (11q13.2) have been found in this disorder.  A homozygous 216-bp deletion in a non-coding region upstream of the gene results in overexpression of the gene not found in heterozygotes.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been described.

References
Article Title: 

Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome

Melo US, Macedo-Souza LI, Figueiredo T, Muotri AR, Gleeson JG, Coux G, Armas P, Calcaterra NB, Kitajima JP, Amorim S, Olavio TR, Griesi-Oliveira K, Coatti GC, Rocha CR, Martins-Pinheiro M, Menck CF, Zaki MS, Kok F, Zatz M, Santos S. Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome. Hum Mol Genet. 2015 Dec 15;24(24):6877-85.

PubMed ID: 
26385635

Spastic Paraplegia with Psychomotor Retardation and Seizures

Clinical Characteristics
Ocular Features: 

The eyes are usually deeply set.  Nothing is known regarding visual acuity.  Strabismus is a common feature.  Retinal dystrophy (not further described) has been reported in 4 of 8 patients described.  The ERG in one individual was read as consistent with cone-rod dystrophy.

Systemic Features: 

Newborns are hypotonic and severe psychomotor retardation is evident a few months later.  Truncal ataxia and progressive lower limb spasticity are seen later.  Mobility is significantly impaired and many individuals are confined to bed or a wheelchair and never walk.  Dysarthria is frequently present and some individuals have a neurosensory hearing loss.  Myoclonic seizures may be evident.  Kyphoscoliosis, macrocephaly, and various foot deformities have been described.

CT scans of the brain may show generalized cerebral atrophy and a hypoplastic corpus callosum.  The ventricles may be enlarged and the EEG confirms the occurrence of myoclonic as well as tonic-clonic and focal epilepsy.

Genetics

This is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the HACE1 gene (6q16).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for this condition but physical therapy and assistive devices such as hearing and visual aids may be helpful.

References
Article Title: 

DDD study. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families

Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M, Brady AF, Clayton S, Cole T, Deshpande C, Fitzgerald TW, Foulds N, Francis R, Gabriel G, Gerety SS, Goodship J, Hobson E, Jones WD, Joss S, King D, Klena N, Kumar A, Lees M, Lelliott C, Lord J, McMullan D, O'Regan M, Osio D, Piombo V, Prigmore E, Rajan D, Rosser E, Sifrim A, Smith A, Swaminathan GJ, Turnpenny P, Whitworth J, Wright CF, Firth HV, Barrett JC, Lo CW, FitzPatrick DR, Hurles ME; DDD study. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nat Genet. 2015 Nov;47(11):1363-9.

PubMed ID: 
26437029

HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome

Hollstein R, Parry DA, Nalbach L, Logan CV, Strom TM, Hartill VL, Carr IM, Korenke GC, Uppal S, Ahmed M, Wieland T, Markham AF, Bennett CP, Gillessen-Kaesbach G, Sheridan EG, Kaiser FJ, Bonthron DT. HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome. J Med Genet. 2015 Dec;52(12):797-803.

PubMed ID: 
26424145

Spinocerebellar Ataxia 18

Clinical Characteristics
Ocular Features: 

Ocular signs in SCAR18 include nystagmus, oculomotor apraxia, and optic atrophy.  The nystagmus may be rotatory or horizontal and can be gaze-evoked.  Some patients have intermittent and tonic upgaze.  Visual acuity has not been reported.

Systemic Features: 

Patients are developmentally delayed and have intellectual disability.  These features do not seem to be progressive.  Ataxia, both truncal and cerebellar, is present.  Mobility is impaired from early childhood and eventually requires assistance.   Joint contractures sometimes develop and patients can be wheelchair-bound by the second decade.  Dysarthric speech is common.  No dysmorphic facial features are present.

Brain imaging shows progressive cerebellar and sometimes cerebral atrophy.

Genetics

This autosomal recessive disorder results from homozygous deletions in the GRID2 gene (4q22).  This gene codes for a subunit of the glutamate receptor channel and is thought to be selectively expressed in the Purkinje cells of the cerebellum.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.  However, physical therapy, assistive devices for mobility, and low vision aids may be helpful.

References
Article Title: 

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