ataxia

Baker-Gordon Syndrome

Clinical Characteristics
Ocular Features: 

Poor visual acuity described as central in origin with poor eye contact.  Periorbital anomalies of low-set eyebrows and epicanthal folds are common.  The eyes have been described as "almond-shaped".  Strabismus and nystagmus are commonly present.

Systemic Features: 

The facial features ae described as "fine" with a short nose and a thin upper lip.  The forehead is unusually high. 

There is general developmental delay with impaired intellectual development, delayed or absent walking, and behavioral psychiatric manifestations such as stereotypic and unpredictable outbursts.   There are often involuntary and hyperkinetic movements with dystonia, dyskinesia, ataxia and choreoathetosis.  The EEG is often abnormal although seizures have not been reported.

Genetics

De novo heterozygous mutations in the SYT1 gene (12q21.2) have been associated with this condition.  

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

SYT1-associated neurodevelopmental disorder: a case series

Baker K, Gordon SL, Melland H, Bumbak F, Scott DJ, Jiang TJ, Owen D, Turner BJ, Boyd SG, Rossi M, Al-Raqad M, Elpeleg O, Peck D, Mancini GMS, Wilke M, Zollino M, Marangi G, Weigand H, Borggraefe I, Haack T, Stark Z, Sadedin S; Broad Center for Mendelian Genomics, Tan TY, Jiang Y, Gibbs RA, Ellingwood S, Amaral M, Kelley W, Kurian MA, Cousin MA, Raymond FL. SYT1-associated neurodevelopmental disorder: a case series. Brain. 2018 Sep 1;141(9):2576-2591.

PubMed ID: 
30107533

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

Myopathy, Mitochondrial Anomalies, and Ataxia

Clinical Characteristics
Ocular Features: 

Ocular findings are variable.  One of three individuals with compound heterozygous mutations had a pigmentary retinopathy with pallor of the optic nerve but no visual abnormalities.  Her sister had only optic nerve pallor.  The eyes are described as "small" and "close-set".

No ocular findings were reported for the family with autosomal dominant inheritance.

Systemic Features: 

Ataxia, short stature, and gait difficulties from an early age are consistent findings.  Some patients are never able to walk.  Motor development is generally delayed.  Truncal and limb ataxia is a feature.  Some degree of intellectual disability is generally present and speech is often delayed.  

The face is long with a myopathic appearance.  Both micrognathia and a prominent jaw may be seen.  The palate is highly arched.  Patients are described as hypotonic and there is generalized muscle weakness both proximal and distal.  Distal sensory impairment has been described in the family with presumed dominant inheritance and there may be psychiatric symptoms of anxiety, depression, and schizophrenia.  Dysmetria with dysdiadochokinesis is often present and a fine intention tremor has been observed.

Mitochondria in fibroblasts exhibit abnormal dynamics and occur in a fragmented network.  Muscle biopsies reveal changes consistent with myopathy.  Serum creatine kinase may be elevated.

Genetics

Compound heterozygous mutations in the MSTO1 gene (1q22) have been found in two families with 3 affected individuals suggesting autosomal recessive inheritance.  In a third family, heterozygous mutations in the same gene were found in a mother and 3 of her adult children, consistent with autosomal dominant transmission.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Neurodevelopmental Disorder, Mitochondrial, with Abnormal Movements and Lactic Acidosis

Clinical Characteristics
Ocular Features: 

Optic atrophy is sometimes present.  Nystagmus, and strabismus are seen in some patients.  A pigmentary retinopathy was found in one individual.

Systemic Features: 

This is a clinically heterogeneous disorder with extensive neurological deficits.  Patients have feeding and swallowing difficulties from the neonatal period.  There is intrauterine growth retardation and postnatally patients usually exhibit psychomotor delays and intellectual disabilities.  Some develop seizures and few achieve normal developmental milestones.  Axial hypotonia is present from early infancy and most patients have muscle weakness and atrophy.  However, there may be spastic quadriplegia which is often associated with dysmetria, tremor, and athetosis.  Ataxia eventually develops in most patients. 

Brain imaging shows cerebral and cerebellar atrophy, enlarged ventricles, white matter defects, and delayed myelination. 

Incomplete metabolic studies suggest there may be abnormalities in mitochondrial oxidative phosphorylation activity in at least some tissues.  Most patients have an elevated serum lactate.

Death in childhood is common.

Genetics

Homozygous and compound heterozygous mutations in the WARS2 gene have been found in several families with this condition.  The considerable variation in the phenotype may at least partially be explained by the fact that an additional variant in the W13G gene is sometimes present which impairs normal localization of the WARS2 gene product within mitochondria.

The transmission pattern in several families is consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for the general condition.

References
Article Title: 

Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy

Wortmann SB, Timal S, Venselaar H, Wintjes LT, Kopajtich R, Feichtinger RG, Onnekink C, Muhlmeister M, Brandt U, Smeitink JA, Veltman JA, Sperl W, Lefeber D, Pruijn G, Stojanovic V, Freisinger P, V Spronsen F, Derks TG, Veenstra-Knol HE, Mayr JA, Rotig A, Tarnopolsky M, Prokisch H, Rodenburg RJ. Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy. Hum Mutat. 2017 Dec;38(12):1786-1795.

PubMed ID: 
28905505

Pontocerebellar Hypoplasia 11

Clinical Characteristics
Ocular Features: 

Some patients are reported to have poor eye contact, hyperopia, and strabismus.  Three individuals had colobomas.  Strabismus, poor eye contact, and hyperopia have been noted in some individuals.   

Systemic Features: 

Microcephaly and large ears may be noted at birth.  Some patients have general hypotonia while others have spastic hypertonia.  Neurological features include markedly delayed psychomotor development, truncal and appendicular ataxia, and cognitive delays.  Developmental milestones such as walking, sitting, and speech are delayed.  Some patients have seizures.  A variety of behavior abnormalities have been reported including stereotypical movements, autistic behavior, repetitive motor movements, and poor communication.  Dysarthria and dysphagia are sometimes present.  There seems to be little progression of the neurological manifestations.

Brain MRIs reveal cerebellar hypoplasia and hypoplasia or agenesis of the corpus callosum in most patients.

Genetics

Homozygous mutations in the TBC1D23 gene (3q12.1q12.2) cause this disorder

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development

Ivanova EL, Mau-Them FT, Riazuddin S, Kahrizi K, Laugel V, Schaefer E, de Saint Martin A, Runge K, Iqbal Z, Spitz MA, Laura M, Drouot N, Gerard B, Deleuze JF, de Brouwer APM, Razzaq A, Dollfus H, Assir MZ, Nitchke P, Hinckelmann MV, Ropers H, Riazuddin S, Najmabadi H, van Bokhoven H, Chelly J. Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development. Am J Hum Genet. 2017 Sep 7;101(3):428-440.

PubMed ID: 
28823707

Birk-Landau-Perez Syndrome

Clinical Characteristics
Ocular Features: 

Patients have oculomotor apraxia, saccadic pursuits, lack of fixation, and ptosis.  No pigmentary changes were seen in the fundi but the optic nerves have not been described.

Systemic Features: 

This is a progressive disorder in which psychomotor regression and loss of speech develop by 1 to 2 years of age, often appearing as the first sign of abnormalities.  Cognitive impairment can progress to profound intellectual disability.  Older patients have limb and truncal ataxia and experience frequent falls.  Muscle tone in the limbs is increased and children often exhibit dyskinesia, dystonia, and axial hypotonia.  General muscle weakness is often present.  No abnormalities have been seen on brain imaging.

Some patients develop a nephropathy with renal insufficiency, hypertension, and hyperechogenic kidneys though deterioration of the renal disease is slow.  Renal biopsy in one patient revealed tubulointerstitial nephritis but no individuals have reached end-stage renal failure.

Genetics

Homozygous mutations in the SLC30A9 gene (4p13) are responsible for this disorder.  A single multigenerational consanguineous Bedouin family of 6 affected individuals has been reported with a transmission pattern consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general disorder has been reported.  Electrolytes should be monitored and metabolic issues resulting from kidney malfunction may need to be addressed.

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

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: 

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