nystagmus

Chorioretinopathy with Microcephaly 2

Clinical Characteristics
Ocular Features: 

Microphthalmia and microcornea are seen in most individuals and one patient had unilateral clinical anophthalmia. Hyperopia and cataracts may be present. Nystagmus is common.  One patient had a corneal opacity.  The chorioretinopathy has not been described beyond evidence of the maculopathy, attenuated retinal vessels, and occasionally hyperpigmented zones.  The ERG is either not recordable or consistent with a severe rod-cone dystrophy.  Vitreous inclusions and a 'vitreoretinal dystrophy' with falciform retinal folds were noted in several patients.  A traction detachment was present in one and bilateral serous detachments were noted in another.

Systemic Features: 

Patients have mild to severe microcephaly (up to -15 SD) with psychomotor delays.  Profound intellectual disability is a consistent feature.  Physical growth is retarded and patients have shortness of stature.  Most patients are unable to sit, stand, or walk unassisted.  One patient died at 5.5 years of age while another was alive at 20 years of age.  Rare patients may have hearing loss and seizures.

Scoliosis, kyphosis, and lordosis may be seen while  other skeletal malformations seem to occur sporadically e.g., triphalangeal thumbs, brachydactyly, postaxial polydactyly, and restricted large joint motion.  

The forehead slopes markedly.  Neuroimaging shows a consistent reduction in cortex size with simple gyral folding while the cerebellum and the brain stem are also small.  Subarachnoid cysts have been noted in several patients and the corpus callosum may be short or otherwise malformed.

Genetics

Homozygous mutations in the PLK4 gene (4q28.2) segregate with this condition.  Its product localizes to centrioles and plays a central role in centriole duplication.

For a somewhat similar condition but without the sloping forhead see Chorioretinoapathy with Microcephaly 1 (251270) but resulting from homozygous mutations in TUBGCP6.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is know.

References
Article Title: 

Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy

Martin CA, Ahmad I, Klingseisen A, Hussain MS, Bicknell LS, Leitch A, Nurnberg G, Toliat MR, Murray JE, Hunt D, Khan F, Ali Z, Tinschert S, Ding J, Keith C, Harley ME, Heyn P, Muller R, Hoffmann I, Daire VC, Dollfus H, Dupuis L, Bashamboo A, McElreavey K, Kariminejad A, Mendoza-Londono R, Moore AT, Saggar A, Schlechter C, Weleber R, Thiele H, Altmuller J, Hohne W, Hurles ME, Noegel AA, Baig SM, Nurnberg P, Jackson AP. Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat Genet. 2014 Dec;46(12):1283-92.

PubMed ID: 
25344692

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: 

Galloway-Mowat Syndrome

Clinical Characteristics
Ocular Features: 

Microphthalmia, hypertelorism, epicanthal folds and ptosis are prominent ocular features.  Other manifestations include corneal opacities, cataracts, and optic atrophy.  Nystagmus of a roving nature is seen in all individuals and is usually present at birth.  There is evidence of visual impairment in more than 90% of individuals.  Features of an anterior chamber dysgenesis such as a hypoplastic iris are sometimes present.

The ocular features of this syndrome have not been fully described.

Systemic Features: 

Infants are born with low birth weight due to intrauterine growth retardation and there is often a history of oligohydramnios.  Newborns are often floppy and hypotonic although spasticity may develop later.  A small midface and microcephaly (80%) with a sloping forehead and a flat occiput are frequently evident.  The ears are large, floppy, and low-set while the hard palate is highly arched and the degree of micrognathia can be severe.  The fists are often clenched and the digits can appear narrow and arachnodactylous.  Hiatal hernias may be present.

Many patients develop features of the nephrotic syndrome in the first year of life with proteinuria and hypoalbuminemia due to glomerular kidney disease and renal system malformations.  Renal biopsies show focal segmental glomerulosclerosis in the majority of glomeruli.

Evidence of abnormal neuronal migration with brain deformities such as cystic changes, porencephaly, encephalomalacia, and spinal canal anomalies have been reported.  MRI imaging shows diffuse cortical and cerebellar atrophy atrophic optic nerves, and thinning of the corpus callosum.  The normal striated layers of the lateral geniculate nuclei are obliterated.  The cerebellum shows severe cellular disorganization with profound depletion of granule cells and excessive Bergmann gliosis.  The vermis is shortened. 

Multifocal seizures are sometimes (40%) seen in infancy and early childhood and the EEG generally shows slowed and disorganized backgound and sometimes a high-voltage hypsarrhythmia.  The degree of psychomotor delay and intellectual disability is often severe.   Most patients are unable to sit independently (90%), ambulate (90%), or make purposeful hand movements (77%).  The majority (87%) of children have extrapyramidal movements and a combination of axial dystonia and limb chorea.  Mean age of death is about 11 years (2.7 to 28 years in one series) and most die from renal failure.

Genetics

Gallaway-Mowat syndrome is likely a spectrum of disease.  Homozygous mutations in the WDR73 gene (15q25) are responsible for one form of this syndrome.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for GAMOS.

References
Article Title: 

Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73

Jinks RN, Puffenberger EG, Baple E, Harding B, Crino P, Fogo AB, Wenger O, Xin B, Koehler AE, McGlincy MH, Provencher MM, Smith JD, Tran L, Al Turki S, Chioza BA, Cross H, Harlalka GV, Hurles ME, Maroofian R, Heaps AD, Morton MC, Stempak L, Hildebrandt F, Sadowski CE, Zaritsky J, Campellone K, Morton DH, Wang H, Crosby A, Strauss KA. Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73. Brain. 2015 Aug;138(Pt 8):2173-90.  PubMed PMID: 26070982.

PubMed ID: 
26070982

Loss-of-Function Mutations in WDR73 Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: Galloway-Mowat Syndrome

Colin E, Huynh Cong E, Mollet G, Guichet A, Gribouval O, Arrondel C, Boyer O, Daniel L, Gubler MC, Ekinci Z, Tsimaratos M, Chabrol B, Boddaert N, Verloes A, Chevrollier A, Gueguen N, Desquiret-Dumas V, Ferre M, Procaccio V, Richard L, Funalot B, Moncla A, Bonneau D, Antignac C. Loss-of-Function Mutations in WDR73 Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: Galloway-Mowat Syndrome. Am J Hum Genet. 2014 Dec 4;95(6):637-48..

PubMed ID: 
25466283

Familial Exudative Vitreoretinopathy, EVR5

Clinical Characteristics
Ocular Features: 

The clinical picture is highly heterogeneous.  Abnormal peripheral vascularization of the retina is generally evident and most individuals have retinal exudates.  The amount of exudation is dependent to some extent upon age.  Fluorescein angiography may demonstrate incomplete vascularization of the peripheral retina.  The ocular phenotype can resemble retinal dysplasia.  Occasional infants can have severe retinal disease and may be considered blind but many individuals have minimal disease and retain good vision into adulthood.  Unfortunately, traction retinal detachments may develop at any time and are responsible for blindness in some patients. 

Cataracts are sometimes present. Ectopic pupils, lack of well-defined pupillary collarettes, remnants of the fetal vascular stalk, and shallowing of the anterior chamber have been noted in several patients.  Microphthalmia and corneal opacities may also be present.  Horizontal nystagmus can be seen in severely affected babies before one month of age.

Systemic Features: 

No systemic features have been reported.

Genetics

This disorder can be inherited in an autosomal dominant pattern as the result of heterozygous mutations in the TSPAN12 gene (7q31.31).  However, individuals with more severe disease may have homozygous mutations in this gene. 

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

This disorder can be inherited in an autosomal dominant pattern as the result of heterozygous mutations in the TSPAN12 gene (7q31.31).  However, individuals with more severe disease may have homozygous or compound heterozygous mutations in this gene. 

References
Article Title: 

Cataracts, Growth Hormone Deficiency, and Skeletal Dysplasia

Clinical Characteristics
Ocular Features: 

Lens opacities can be seen in infancy or childhood and may be congenital in onset.  Nystagmus has been noted in one patient. 

Systemic Features: 

There is considerable clinical heterogeneity in the phenotype.  Motor milestones may be slightly delayed.  Dysmorphic features in at least some individuals include bushy eyebrows, a prominent forehead, and a small mouth.  Thoracic scoliosis and genu valgum may be present.  Physical growth is reduced during infancy and childhood resulting in a short stature in adulthood.  Growth hormone and cortisol deficiency have been documented. Episodic hypoglycemia has been documented. The pituitary adenohypophysis appears atrophied on MRI.

Neurosensory hearing loss has been diagnosed in the first two years of life.  A distal sensory neuropathy with loss of pain, temperature and touch sensation may be present late in the first decade of life.  There are no cognitive deficits and patients can live independently.

Genetics

This is likely an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in the IARS2 gene (1q41).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Appropriate hormonal replacement therapy can be beneficial.  Individual skeletal surgery for scoliosis and hip dislocation should be considered.  Visually significant lens opacities may require surgery.

References
Article Title: 

Mutation in The Nuclear-Encoded Mitochondrial Isoleucyl-tRNA Synthetase IARS2 in Patients with Cataracts, Growth Hormone Deficiency with Short Stature, Partial Sensorineural Deafness, and Peripheral Neuropathy or with Leigh Syndrome

Schwartzentruber J, Buhas D, Majewski J, Sasarman F, Papillon-Cavanagh S, Thiffaut I, Sheldon KM, Massicotte C, Patry L, Simon M, Zare AS, McKernan KJ; FORGE Canada Consortium, Michaud J, Boles RG, Deal CL, Desilets V, Shoubridge EA, Samuels ME. Mutation in The Nuclear-Encoded Mitochondrial Isoleucyl-tRNA Synthetase IARS2 in Patients with Cataracts, Growth Hormone Deficiency with Short Stature, Partial Sensorineural Deafness, and Peripheral Neuropathy or with Leigh Syndrome. Hum Mutat. 2014 Nov;35(11):1285-9.

PubMed ID: 
25130867

Spinocerebellar Ataxia 38

Clinical Characteristics
Ocular Features: 

Gaze-evoked nystagmus is present with the onset of ataxia.  Some patients report diplopia.  Saccadic movements are described as slow.  Visual acuities and the appearance of the retina and optic nerve have not been reported.

Systemic Features: 

Truncal and gait ataxia are generally evident by age 40 years and progressively worsen.  Mobility requires assistance usually by age 50.  Mild sensory complaints are present in the majority of individuals.  Dysarthria is often a feature.

MRI reveals cerebellar atrophy with no evidence of brainstem involvement.

Genetics

Heterozygous mutations in the ELOVL5 gene (6p12.1) are responsible for this autosomal dominant disorder.  The gene is a member of family that encodes elongases that synthesize long chain fatty acids in the endoplasmic reticulum.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

None known.

References
Article Title: 

ELOVL5 mutations cause spinocerebellar ataxia 38

Di Gregorio E, Borroni B, Giorgio E, Lacerenza D, Ferrero M, Lo Buono N, Ragusa N, Mancini C, Gaussen M, Calcia A, Mitro N, Hoxha E, Mura I, Coviello DA, Moon YA, Tesson C, Vaula G, Couarch P, Orsi L, Duregon E, Papotti MG, Deleuze JF, Imbert J, Costanzi C, Padovani A, Giunti P, Maillet-Vioud M, Durr A, Brice A, Tempia F, Funaro A, Boccone L, Caruso D, Stevanin G, Brusco A. ELOVL5 mutations cause spinocerebellar ataxia 38. Am J Hum Genet. 2014 Aug 7;95(2):209-17.

PubMed ID: 
25065913

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

Spastic Ataxia 2

Clinical Characteristics
Ocular Features: 

Horizontal nystagmus is present in some patients.

Systemic Features: 

Cerebellar ataxia, dysarthria, and spasticity of the lower limbs appear in the first two decades of life.  The spasticity may involve all 4 limbs late in life.  Cognition is not impacted. Cervical dystonia has been noted. No consistent changes have been found on brain imaging.  The neurologic signs are slowly progressive although patients may remain ambulatory.

Tremor, clonus, and extrapyramidal chorea has been seen in several families with what has been called spastic paraplegia-58 which may be the same disorder as SPAX2 since mutations are found in the same gene (KIF1C).  Symptoms and prognosis are similar in these conditions except for the reported presence of developmental delay and mild mental retardation in some individuals diagnosed to have SPG58.

Genetics

This is an autosomal recessive condition as the result of homozygous mutations in the KIF1C gene (17p13.2).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment for this disease is available although speech and physical therapy may be helpful.

References
Article Title: 

Motor protein mutations cause a new form of hereditary spastic paraplegia

Caballero Oteyza A, Battaloglu E, Ocek L, Lindig T, Reichbauer J, Rebelo AP, Gonzalez MA, Zorlu Y, Ozes B, Timmann D, Bender B, Woehlke G, Zuchner S, Schols L, Schule R. Motor protein mutations cause a new form of hereditary spastic paraplegia. Neurology. 2014 May 7. [Epub ahead of print].

PubMed ID: 
24808017

Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders

Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GM, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, Mahmoud IG, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L,Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu PS, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa MY, Schroth J, Spencer EG, Rosti RO, Akizu N, Vaux KK, Johansen A, Koh AA, Megahed H, Durr A, Brice A, Stevanin G, Gabriel SB, Ideker T, Gleeson JG. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-11.

PubMed ID: 
24482476

Orofaciodigital Syndrome, Type VI

Clinical Characteristics
Ocular Features: 

Hypertelorism and epicanthal folds have been described.  Some patients have nystagmus and strabismus. Ocular apraxia and difficulties in smooth visual pursuit may be present.   

Systemic Features: 

Polydactyly of the hands is a common feature.  The central metacarpal is often Y-shaped leading to ‘central polydactyly’.  The large toes may be bifid.  Cognitive deficits are common and some patients have been considered mentally retarded.  The ears are low-set and rotated posteriorly.  Some patients have a conductive hearing loss.  Oral anomalies may include a lobed tongue, lingual and sublingual hemartomas, micrognathia, clefting, and multiple buccoalveolar frenula.  Congenital heart anomalies, micropenis, and cryptorchidism have been reported.  Tachypnea and tachycardia have been noted.  Some patients have some degree of skeletal dysplasia and many individuals are short in stature.

The presence of cerebellar abnormalities such as hypoplasia (including absence) of the vermis may help to distinguish type VI from other forms of OFDS.  Hypothalamic dysfunction may be responsible for poor temperature regulation (hyperthermia). The ‘molar tooth sign’ seen on brain MRIs in Joubert syndrome (213300) is also present in OFDS VI. 

Genetics

This is a rare condition with limited family information.  Parents in one family were consanguineous, and multiple affected sibs in other families suggest this may be an autosomal recessive condition.  Homozygous mutations in TMEM216 have been found. Other patients have mutations in C5orf42.

Many of the clinical features in OFDS VI are also found among individuals with Joubert (213300) and Meckel (249000) syndromes that also sometimes have mutations in the TMEM216 and C5orf42 genes.  Some consider all of these conditions to be members of a group of overlapping disorders called ciliopathies or ciliary dyskinesias.   

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available for this syndrome but individual signs and symptoms may need treatment.

References
Article Title: 

C5orf42 is the major gene responsible for OFD syndrome type VI

Lopez E, Thauvin-Robinet C, Reversade B, Khartoufi NE, Devisme L, Holder M, Ansart-Franquet H, Avila M, Lacombe D, Kleinfinger P, Kaori I, Takanashi JI, Le Merrer M, Martinovic J, No?'l C, Shboul M, Ho L, G?oven Y, Razavi F, Burglen L, Gigot N, Darmency-Stamboul V, Thevenon J, Aral B, Kayserili H, Huet F, Lyonnet S, Le Caignec C, Franco B, Rivi?(r)re JB, Faivre L, Atti?(c)-Bitach T. C5orf42 is the major gene responsible for OFD syndrome type VI. Hum Genet. 2013 Nov 1. [Epub ahead of print].

PubMed ID: 
24178751

Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes

Valente EM, Logan CV, Mougou-Zerelli S, Lee JH, Silhavy JL, Brancati F, Iannicelli M, Travaglini L, Romani S, Illi B, Adams M, Szymanska K, Mazzotta A, Lee JE, Tolentino JC, Swistun D, Salpietro CD, Fede C, Gabriel S, Russ C, Cibulskis K, Sougnez C, Hildebrandt F, Otto EA, Held S, Diplas BH, Davis EE, Mikula M, Strom CM, Ben-Zeev B, Lev D, Sagie TL, Michelson M, Yaron Y, Krause A, Boltshauser E, Elkhartoufi N, Roume J, Shalev S, Munnich A, Saunier S, Inglehearn C, Saad A, Alkindy A, Thomas S, Vekemans M, Dallapiccola B, Katsanis N, Johnson CA, Atti?(c)-Bitach T, Gleeson JG. Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet. 2010 Jul;42(7):619-25.

PubMed ID: 
20512146

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