dysarthria

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

Spastic Ataxia 8, Autosomal Recessive, with Hypomyelinating Leukodystrophy

Clinical Characteristics
Ocular Features: 

Reported ocular signs are limited to abnormal eye movements.  In other forms of spastic ataxia, nystagmus is evident in association with optic atrophy but no fundus examinations are reported in the 3 families with SPAX8.  Hypometric saccades and limited upgaze have also been found in these families.

Systemic Features: 

First signs and symptoms occur sometime in the first 5 years of life and often in the first year.   In 6 of 7 reported patients the presenting sign was nystagmus but one individual with reported onset of disease at age 5 years presented with ataxia.  Cerebellar signs, both truncal and limb, are usually present and the majority of individuals have evidence of dystonia.  Likewise, pyramidal signs are nearly always present.  Cerebellar dysarthria and titubation are often present with dystonic posturing and torticollis. 

Brain MRIs usually reveal cerebellar atrophy and widespread hypomyelination.  Two individuals in a single family had severe global psychomotor delays as well.  No sensory deficits were reported.  This disorder is progressive and patients in adulthood may require the use of a wheelchair.

Genetics

Homozygous mutations in the NKX6-2 (NKX6-2) gene (10q26.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for the general condition.

References
Article Title: 

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination

Chelban V, Patel N, Vandrovcova J, Zanetti MN, Lynch DS, Ryten M, Botia JA, Bello O, Tribollet E, Efthymiou S, Davagnanam I; SYNAPSE Study Group, Bashiri FA, Wood NW, Rothman JE, Alkuraya FS, Houlden H. Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination. Am J Hum Genet. 2017 Jun 1;100(6):969-977.

PubMed ID: 
28575651

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

Ataxia with Oculomotor Apraxia 3

Clinical Characteristics
Ocular Features: 

Ocular movement abnormalities are noted at the same time as other peripheral motor difficulties.  Slow saccadic eye movements, and head-eye lag are evident.  Pursuit movements are normal.

Systemic Features: 

Onset of gait instability occurs in the second decade of life with dysmetria and frequent falls. The eye movement abnormalities, dysarthria, and axial dysmetria with distal muscle atrophy and weakness are present at the same time.  Distal sensory deficits with lack of sensory nerve action potentials are also present in the lower limbs.  The upper limbs are involved somewhat later but with less pronounced movement impairment.  Hyporeflexia or areflexia is common.  The disorder is progressive with loss of independent mobility by the third decade.

Brain and spinal cord MRI imaging reveals cerebellar atrophy of the folia and vermis.  Persistently elevated alpha-fetoprotein levels have been found but no hypoalbuminemia.

Genetics

Homozygous missense mutations in the PIK3R5 gene (17p12-p13) have been associated with this clinical picture in one family of 4 affected sibs born of consanguineous parents.

See also Ataxia with Oculomotor Apraxia 1 (208920) with hypoalbuminemia, Ataxia with Oculomotor Apraxia 2 (606002) (also known as Spinocerebellar Ataxia, Autosomal Recessive 1 or SCAR1), and Ataxia with Oculomotor Apraxia 4 (616267).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Kufor-Rakeb Syndrome

Clinical Characteristics
Ocular Features: 

Most patients have a supranuclear gaze paresis.  Patients later may have dystonic oculogyric spasms.

Systemic Features: 

This is a rapidly progressive neurodegenerative disorder with juvenile onset.  First signs of Parkinisonism are evident between the ages of 12 and 16 years of age.  Within a year of onset severe motor handicaps develop along with some degree of dementia with aggression and visual hallucinations.  Cognitive decline is often a feature.  Fine tremors in the chin may be seen along with other extrapyramidal signs but these are not prominent in the limbs.  Instead there is often rigidity and bradykinesia.  Dysphagia, dysarthria, and ataxia are features in many patients.  Peripheral sensory neuropathy and anosmia are present in some individuals. 

Brain imaging often reveals generalized atrophy of the cerebellum, cerebral cortex, and brainstem.

Genetics

This condition results from homozygous or compound heterozygous mutations in the ATP13A2 gene (1p36.13).  

Biallelic mutations in the same gene are also responsible for spastic paraplegia 78 (617225) with somewhat similar clinical features except for the general absence of Parkinsonism.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There may be an initial therapeutic response to L-DOPA but this is often not maintained

References
Article Title: 

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

Estrada-Cuzcano A, Martin S, Chamova T, Synofzik M, Timmann D, Holemans T, Andreeva A, Reichbauer J, De Rycke R, Chang DI, van Veen S, Samuel J, Schols L, Poppel T, Mollerup Sorensen D, Asselbergh B, Klein C, Zuchner S, Jordanova A, Vangheluwe P, Tournev I, Schule R. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain. 2017 Feb;140(Pt 2):287-305.

PubMed ID: 
28137957

Spastic Paraplegia 78

Clinical Characteristics
Ocular Features: 

Reduced upgaze with nystagmus and strabismus have been reported.  

Systemic Features: 

This progressive neurodegenerative disorder usually has its onset in young adults but the signs and symptoms are highly variable.  Ambulation and gait difficulties combined with spasticity and lower limb weakness are common signs.  Ataxia and dysarthria are also important signs.  Some individuals have dementia while others have only mild cognitive impairment.  Some individuals have mild signs of Parkinsonism.

Brain imaging may show cerebellar and cortical atrophy with a thin corpus callosum. 

Genetics

This condition results from homozygous or compound heterozygous mutations in the ATP13A2 gene (1p36.13).

The same gene is also mutated in the Kufor-Rakeb syndrome (606693), an early-onset form of Parkinsonism.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

Estrada-Cuzcano A, Martin S, Chamova T, Synofzik M, Timmann D, Holemans T, Andreeva A, Reichbauer J, De Rycke R, Chang DI, van Veen S, Samuel J, Schols L, Poppel T, Mollerup Sorensen D, Asselbergh B, Klein C, Zuchner S, Jordanova A, Vangheluwe P, Tournev I, Schule R. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain. 2017 Feb;140(Pt 2):287-305.

PubMed ID: 
28137957

Genetic and phenotypic characterization of complex hereditary spastic paraplegia

Kara E, Tucci A, Manzoni C, Lynch DS, Elpidorou M, Bettencourt C, Chelban V, Manole A, Hamed SA, Haridy NA, Federoff M, Preza E, Hughes D, Pittman A, Jaunmuktane Z, Brandner S, Xiromerisiou G, Wiethoff S, Schottlaender L, Proukakis C, Morris H, Warner T, Bhatia KP, Korlipara LV, Singleton AB, Hardy J, Wood NW, Lewis PA, Houlden H. Genetic and phenotypic characterization of complex hereditary spastic paraplegia. Brain. 2016 Jul;139(Pt 7):1904-18.

PubMed ID: 
27217339

Encephalopathy, Progressive, with Amyotrophy and Optic Atrophy

Clinical Characteristics
Ocular Features: 

Optic atrophy is present.

Systemic Features: 

This is a progressive neurodegenerative condition in which hypotonia and delayed development are evident between birth and 14 months of age.  Developmental milestones, if attained, soon regress accompanied by distal amyotrophy, cognitive impairment that may be severe, ataxia, spastic tetraplegia, dysarthria, and scoliosis.  Seizures often occur.

Brain imaging reveals cerebellar and cerebral atrophy.  Iron accumulation may be seen in the pallidum and substantia nigra.  The corpus callosum appears abnormally thin.  Muscle biopsy shows evidence of denervation atrophy.

Genetics

Homozygous or compound heterozygous mutations in the TBCE gene (1q42.3) can cause this disorder.  

Biallelic mutations in the same gene also cause Kenny-Caffey syndrome type 1 (244460) and a hypoparathyroidism dysmorphism syndrome (241410).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy

Sferra A, Baillat G, Rizza T, Barresi S, Flex E, Tasca G, D'Amico A, Bellacchio E, Ciolfi A, Caputo V, Cecchetti S, Torella A, Zanni G, Diodato D, Piermarini E, Niceta M, Coppola A, Tedeschi E, Martinelli D, Dionisi-Vici C, Nigro V, Dallapiccola B, Compagnucci C, Tartaglia M, Haase G, Bertini E. TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy. Am J Hum Genet. 2016 Oct 6;99(4):974-983.

PubMed ID: 
27666369

Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy

Flex E, Niceta M, Cecchetti S, Thiffault I, Au MG, Capuano A, Piermarini E, Ivanova AA, Francis JW, Chillemi G, Chandramouli B, Carpentieri G, Haaxma CA, Ciolfi A, Pizzi S, Douglas GV, Levine K, Sferra A, Dentici ML, Pfundt RR, Le Pichon JB, Farrow E, Baas F, Piemonte F, Dallapiccola B, Graham JM Jr, Saunders CJ, Bertini E, Kahn RA, Koolen DA, Tartaglia M. Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):962-973.

PubMed ID: 
27666370

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.

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

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

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