nystagmus

Familial Acorea, Microphthalmia and Cataract Syndrome

Clinical Characteristics
Ocular Features: 

The pupil is obscured or absent secondary to fibrous overgrowth.  Microcornea and microphthalmia are present.  Iridocorneal adhesions are commonly seen on ultrasonic examination and anterior chamber angles may be narrow.  The corneas are clear but thickened centrally.  Nystagmus and esotropia have been reported.

The iris is rudimentary with a poorly developed stromal pattern and sometimes eccentrically located holes.  The ultrasound may reveal remnants of degenerative lens capsules.  Axial length in infants has been measured at about 14.7 mm but increases to 17 mm in children.  In adults the axial length is about 20 mm.  Refractive errors of +20-21 diopters have been measured.  Visual acuity is poor from birth but can be improved to some extent following pupiloplasty and lens extraction.  Intraocular pressure can be normal but one patient developed an increase in the 4th decade of life.  OCT and direct visualization of the fundus in several cases revealed normal retinal architecture and anatomy.

Systemic Features: 

None reported.  Specialty examinations failed to find any hearing loss or neurological deficits.

Genetics

The single 4 generation family tree reported is consistent with autosomal dominant inheritance.  Several likely loci on chromosomes 1, 5, 8, 11, and 17 have been reported but no candidate gene has been identified. 

Other conditions in which small pupils are found are Pierson syndrome (609049) and Warburg micro syndrome (600118) but these are associated with significant systemic abnormalities.  

Congenital microcoria (156600) is an autosomal dominant disorder with mild axial myopia and goniodysgenesis resulting from an unidentified mutation on chromosome 13.  Glaucoma is a common finding as is some iris hypoplasia.  Despite some clinical similarities, this is likely a unique disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Some improvement in visual acuity has been reported following lensectomy and reconstruction of the pupil.

References
Article Title: 

Trichomegaly Plus Syndrome

Clinical Characteristics
Ocular Features: 

Eyelashes are described as ‘long’, and the eyebrows are bushy.  The majority of individuals have poor vision secondary to severe receptor dysfunction.  Night blindness and severe photophobia are features in some cases.  Both retinal and choroidal atrophy have been diagnosed in the first 5 years of life and most patients have a progressive and extensive pigmentary retinopathy.

Systemic Features: 

Scalp alopecia and sparse body hair is common in spite of the trichomegaly of the eyebrows and eyelashes.  Frontal bossing has been noted in some patients.  Pituitary dysfunction is suggested by low growth hormone levels, features of hypogonadotropic hypogonadism, and possibly hypothyroidism.

Some deficit of cognitive function is usually present and a few patients have been described as mentally retarded.  There is evidence of progressive neurological damage both centrally and peripherally. Developmental milestones are often achieved late and some individuals have been observed to regress during the first decade of life.  The peripheral neuropathy includes both sensory and motor components.  Sensory nerve action potentials may be lost in the first decade while early motor functions may regress during the same period.  Several patients have had evidence of progressive cerebellar ataxia.

Genetics

Compund heterozygous mutations in PNPLA6 (19p13.2), coding for neuropathy target esterase, have been found in several patients presumed to have this condition.  Autosomal recessive inheritance has been proposed on the basis of a single family in which an affected brother and sister were born to first cousin parents.   

The relationship of this disorder to that found in two cousins, offspring of consanguineous matings, described as ‘cone-rod congenital amaurosis associated with congenital hypertrichosis: an autosomal recessive condition’ (204110 ) is unknown.  They were described as having visual impairment from birth and profound photophobia.  Fundus changes were minimal with a bull’s eye pattern of pigment changes in the macula described as indicative of a rod-cone congenital amaurosis.  ERG responses were unrecordable.  These individuals apparently did not have other somatic, psychomotor or neurologic deficits.

Mutations in PNPLA6 occur in other conditions including a form of Bardet-Biedl Syndrome (209900), and Boucher-Neuhauser Syndrome (215470) also known as Chorioretinopathy, Ataxia, Hypogonadism Syndrome in this database.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this condition although growth hormone and testosterone supplementation have been reported to have the appropriate selective effects.

References
Article Title: 

Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes

Hufnagel RB, Arno G, Hein ND, Hersheson J, Prasad M, Anderson Y, Krueger LA, Gregory LC, Stoetzel C, Jaworek TJ, Hull S, Li A, Plagnol V, Willen CM, Morgan TM, Prows CA, Hegde RS, Riazuddin S, Grabowski GA, Richardson RJ, Dieterich K, Huang T, Revesz T, Martinez-Barbera JP, Sisk RA, Jefferies C, Houlden H, Dattani MT, Fink JK, Dollfus H, Moore AT, Ahmed ZM. Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. J Med Genet. 2015 Feb;52(2):85-94.

PubMed ID: 
25480986

Retinal Nonattachment, Congenital

Clinical Characteristics
Ocular Features: 

The common denominator in this condition is, of course, congenital nonattachment of the retina.  Many eyes are small as well.  Some patients in addition have a vascularized hyperplastic vitreous and often present with blindness and a congenital leukocoria.  Many at some stage have lens opacification, as well as glaucoma and anterior chamber anomalies including anterior synechiae and some degree of corneal opacification.  These signs are often progressive beginning in childhood.  Pendular nystagmus and esotropia are common.  MRI studies reveal optic nerves and the chiasm that are either absent or abnormally small.

Systemic Features: 

This condition is nonsyndromic and has no systemic abnormalities.

Genetics

Congenital retinal nonattachment consists of a group of sometimes familial conditions for which no responsible gene has been identified.  In a genomic study of 21 consanguineous NCRNA Pakistani families 3 had mutations in ATOH7 and 10 had mutations in familial exudative vitreoretinopathy genes.  Genotyping did not reveal associated mutations in the remaining 38% of these families. It is likely that multiple entities are represented but until the molecular etiologies are identified, no more specific classification is possible.

Studies in mice document that the Atoh7 gene is important to retinal ganglion cell neurogenesis.  In humans, both autosomal recessive PHPV and congenital nonattachment of the retina are associated with microsatellite linkage and haplotype matching to a region at 10q21 adjacent to the ATOH7 gene but so far no causative mutation has been found in this region.  However, studies in large consanguineous kindreds in which a deleted DNA segment adjacent to ATOH7 segregated with the NCRNA phenotype suggest that a transcription regulator may be at fault in the timing and level of ATOH7 expression.

The disorder known as persistent hyperplastic primary vitreous is generally not considered hereditary since it usually occurs unilaterally and sporadically.  It is sometimes found in association with a number of syndromal conditions as well.  However, it has also been reported in familial patterns consistent with both autosomal recessive and autosomal dominant patterns.  DNA mapping of individuals with bilateral disease found in a consanguineous Pakistani kindred with presumed autosomal recessive disease suggests that a locus at 10q11-q21 may be responsible.

Evidence for autosomal dominant inheritance of persistent hyperplastic primary vitreous comes from rare families with an apparent vertical transmission of the condition.

Congenital nonattachment of the retina is also seen in the osteoporosis-pseudoglioma syndrome (250770).  However, this is a syndromal disorder with neurologic and joint disease in addition to porotic, thin, fragile bones (sometimes called the ocular form of osteogenesis imperfecta) resulting from mutations in LRP5 on chromosome 11.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

With rare exceptions, the retina cannot be reattached successfully and phthisis with blindness is the usual outcome.

References
Article Title: 

Spastic Paraplegia 2

Clinical Characteristics
Ocular Features: 

Nystagmus is common but variable in age of onset, and half of affected individuals have optic atrophy.

Systemic Features: 

This is a complex form of spastic paraplegia in which primarily lower limb spasticity is associated with dysarthria, sensory disturbances, cognitive deficits, muscle wasting and mild ataxia.  There is, however, considerable variability in age of onset and rate of symptom progression.  The first motor symptoms are often evident when children start walking, which is often delayed and clumsy.  However, evidence of spasticity may be present in children under 1 year of age.   Some patients have normal mental functions while others are considered mentally retarded.  The MRI reveals patchy leukodystrophy and degeneration of both corticospinal and spinocerebellar tracks was found in an autopsied individual.  Progression is relentless with many individuals requiring assistive devices such as crutches or walkers by early adult life.

Genetics

This is an X-linked disorder secondary to a mutation in the PLP1 gene at Xq22.2which codes for 2 major proteins found in myelin.  SPG2 is allelic to the more severe Pelizaeus-Merzbacher disease (312080).

Treatment
Treatment Options: 

Mobility devices and physical therapy can be helpful, especially in younger individuals.

References
Article Title: 

Spinocerebellar Ataxia, Autosomal Recessive 7

Clinical Characteristics
Ocular Features: 

Nystagmus and saccadic pursuit eye movements are common signs.  Some patients complain of diplopia.  No other ocular abnormalities are present.

Systemic Features: 

Symptoms have their onset in late childhood and are slowly progressive.  Walking and balancing are difficult.  Dysarthria, postural tremor, and limb ataxia are evident in adults.  Fine motor movements are difficult and there is often a tremor in the hands.  Deep tendon reflexes are abnormally brisk and extensor plantar responses are seen in some individuals.  Vibration sense may be diminished.  These signs are variable as is the rate of progression.  Usually patients remain mobile and productive through the fourth decade of life.  They may become wheelchair-bound by the fifth or sixth decade.  There is no cognitive impairment.

Genetics

This is an autosomal recessive condition secondary to homozygous mutations in TPP1(11p15).

The same gene is mutated in neuronal ceroid lipofuscinosis 2 (CLN2, 204500), a far more serious condition with epilepsy, optic atrophy, retinal degeneration, and a rapidly progressive course leading to early death in many individuals. It has been suggested that mutations resulting in the more severe CLN2 phenotype completely or nearly completely abolish TPP1 enzyme activity whereas those that cause SCAR7 simply result in diminished activity.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known for the neurological symptoms but physical therapy and mobility devices could be helpful in maintaining ambulation.  Speech therapy could be useful for dysarthria.

References
Article Title: 

Autosomal Recessive Spinocerebellar Ataxia 7 (SCAR7) is Caused by Variants in TPP1, the Gene Involved in Classic Late-Infantile Neuronal Ceroid Lipofuscinosis 2 Disease (CLN2 Disease)

Sun Y, Almomani R, Breedveld GJ, Santen GW, Aten E, Lefeber DJ, Hoff JI, Brusse E, Verheijen FW, Verdijk RM, Kriek M, Oostra B, Breuning MH, Losekoot M, den Dunnen JT, van de Warrenburg BP, Maat-Kievit AJ. Autosomal Recessive Spinocerebellar Ataxia 7 (SCAR7) is Caused by Variants in TPP1, the Gene Involved in Classic Late-Infantile Neuronal Ceroid Lipofuscinosis 2 Disease (CLN2 Disease). Hum Mutat. 2013 Feb 15. [Epub ahead of print].

PubMed ID: 
23418007

Mannosidosis, Alpha B

Clinical Characteristics
Ocular Features: 

Many (probably most) patients have lens opacities and some have corneal opacities as well.  Nystagmus and strabismus have been described.  Pigmentary changes of a mottled nature can be present in the posterior pole and may be associated with retinal vessel attenuation and diminished ERG responses.  Retinal thinning can be demonstrated.  A mixture of hypo- and hyperautofluorescence is often visible.  Mild optic atrophy has been seen.  There is evidence for progressive visual loss, even late in life.  Eyebrows appear thick.    

Systemic Features: 

Mannosidosis is a highly variable multisystem disorder.  Onset may be in infancy but in other patients symptoms appear later in the first decade.  Progression of disease is more rapid in individuals with early onset (type 3) with rapid mental, motor deterioration and early death.  The characteristic coarse facial features usually are evident later in milder cases (types 1 and 2) that have mild or moderate intellectual disabilities.  Regardless, mannosidosis is relentlessly progressive with mental deterioration and motor disabilities.  Ataxia is a common feature.  Dental anomalies (diastema), large ears, macroglossia, joint stiffness,, hepatosplenomegaly, enlarged head circumference, hearing loss (sensorineural), increased susceptibility to infections, dysarthria, and spondylolysis may be present.

Genetics

Alpha-mannosidoosis is an autosomal recessive lysosomal storage disorder resulting from mutations in the MAN2B1 gene (19p13.2).  There is another form of mannosidosis known as beta A  (248510) caused by mutations in MANBA but ocular features have not been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Prompt treatment for infections is required and prophylactic vaccinations are indicated.  All individuals should be seen annually and assistive devices such as wheel chairs and hearing aids prescribed when needed.

References
Article Title: 

Retinal and optic nerve degeneration in α-mannosidosis

Matlach J, Zindel T, Amraoui Y, Arash-Kaps L, Hennermann JB, Pitz S. Retinal and optic nerve degeneration in a-mannosidosis. Orphanet J Rare Dis. 2018 Jun 1;13(1):88. doi: 10.1186/s13023-018-0829-z.

PubMed ID: 
29859105

Ocular findings in mannosidosis

Arbisser AI, Murphree AL, Garcia CA, Howell RR. Ocular findings in mannosidosis. Am J Ophthalmol. 1976 Sep;82(3):465-71. PubMed PMID: 961797.

PubMed ID: 
961797

Spastic Paraplegia 7

Clinical Characteristics
Ocular Features: 

Many but not all individuals have significant visual loss due to optic atrophy.  Other ocular signs include supranuclear palsy, ptosis, and nystagmus.  Older individuals with advanced disease may have progressive external ophthalmoplegia.

Systemic Features: 

There is a great deal of clinical heterogeneity between families and not all individuals have severe neurological disease.  Progressive neurological signs (primarily abnormal gait) are often present in late childhood or early adolescence but may occur late in life.  Clinical features include muscle atrophy and weakness with spasticity (more pronounced in the lower limbs), ataxia, pyramidal signs, dysphagia, and cerebellar dysarthria.  Hyperreflexia and extensor plantar responses are often present.  Cognitive deficits are manifest as deficits in attention and higher levels of reasoning.  Some patients have a mild peripheral neuropathy with decreased vibratory sense.  Many patients have significant dysfunction of the bladder sphincter.  Adults may lose their mobility and are confined to a wheelchair.

Some patients develop scoliosis and pes cavus.  The MRI often shows cerebellar and mild frontal cortical atrophy.

Genetics

This type of spastic paraplegia results from mutations in the paraplegin gene, SPG7 (16q24.3).  It is usually transmitted in an autosomal recessive pattern although heterozygous patients with symptoms have been reported. Evidence suggests that the symptoms arise from a defect in mitochondrial respiration.

Patients with spastic paraplegia 15 (270700) have a similar neurological phenotype plus a flecked retina.  Congenital cataracts are part of the phenotype of spastic paraplegia 46 (614409).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is symptomatic.  Physical, speech, and occupational therapy may be helpful in selected patients.  Low vision aids may be of benefit in some individuals, at least early in the disease.

References
Article Title: 

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance

Pfeffer G, Gorman GS, Griffin H, Kurzawa-Akanbi M, Blakely EL, Wilson I, Sitarz K, Moore D, Murphy JL, Alston CL, Pyle A, Coxhead J, Payne B, Gorrie GH, Longman C, Hadjivassiliou M, McConville J, Dick D, Imam I, Hilton D, Norwood F, Baker MR, Jaiser SR, Yu-Wai-Man P, Farrell M, McCarthy A, Lynch T, McFarland R, Schaefer AM, Turnbull DM, Horvath R, Taylor RW, Chinnery PF. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance. Brain. 2014 Apr 10. [Epub ahead of print].

PubMed ID: 
24727571

A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia

Arnoldi A, Tonelli A, Crippa F, Villani G, Pacelli C, Sironi M, Pozzoli U, D'Angelo MG, Meola G, Martinuzzi A, Crimella C, Redaelli F, Panzeri C, Renieri A, Comi GP, Turconi AC, Bresolin N, Bassi MT. A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia. Hum Mutat. 2008 Apr;29(4):522-31.

PubMed ID: 
18200586

Congenital Disorder of Glycosylation, Type Ia

Clinical Characteristics
Ocular Features: 

Strabismus, roving eye movements (and nystagmus), and visual inattention are found in nearly all patients. Esotropia with defective abduction seems to be the most common oculomotor finding and may be present at birth.  Cataracts, ocular colobomas, oculomotor apraxia, disc pallor, and glaucoma have also been reported.  Vision is always subnormal. Reports of ocular disease before modern genotyping are not specific to the subtypes of CDG I now recognized.

This is a congenital, progressive disorder of photoreceptor degeneration with a later onset of progressive pigmentary retinopathy.  It is described in some cases as a typical retinitis pigmentosa.  The ERG is abnormal in all patients even if the pigmentary pattern is atypical for RP.  Rod responses are usually absent while the cone b-wave implicit time is delayed.  The degree of photoreceptor damage is variable, however.  Extended retinal function among younger patients suggest that the ‘on-pathway’ evolving synapses in the outer plexiform layer among photoreceptors, bipolar cells, and horizontal cells is severely dysfunctional.

Systemic Features: 

This is a multisystem disorder, often diagnosed in the neonatal period by the presence of severe encephalopathy with hypotonia, hyporeflexia, and poor feeding.  Failure to thrive, marked psychomotor retardation, delayed development, growth retardation, and ataxia become evident later in those who survive.  Cerebellar and brainstem atrophy with a peripheral neuropathy can be demonstrated during late childhood.  Some older patients have a milder disease, often with muscle atrophy and skeletal deformities such as kyphoscoliosis and a fusiform appearance of the digits.  Maldistribution of subcutaneous tissue is often seen resulting in some dysmorphism, especially of the face.  Hypogonadism and enlargement of the labia majora are commonly present.  Some patients have evidence of hepatic and cardiac dysfunction which together with severe infections are responsible for a 20% mortality rate in the first year of life.

Genetics

This is one of a group of genetically (and clinically) heterogeneous autosomal recessive conditions caused by gene mutations that result in enzymatic defects in the synthesis and processing of oligosaccharides onto glycoproteins. This type (Ia) is the most common.   The mutation lies in the PMM2 gene (16p13.2).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Most children require tube feeding with nutritional supplements.  The risk of systemic infections is high.  Those patients who survive into the second decade and beyond may require orthopedic procedures and are confined to wheelchairs.  Physical, occupational, and speech therapy along with parental support are important.

References
Article Title: 

Congenital Disorder of Glycosylation, Type Iq

Clinical Characteristics
Ocular Features: 

Colobomas (iris, choroid, and sometimes optic nerve), optic nerve hypoplasia and nystagmus have been reported.  Visual acuity is variable depending upon the degree of nerve hypoplasia. The eyebrows may be highly arched, while downward slanting lid fissures, and hypertelorism may also be present.

Congenital cataracts, glaucoma and microphthalmia have been reported in several individuals.

Systemic Features: 

Onset of symptoms commonly begins in infancy with severe hypotonia while developmental delays soon become evident as most children do not achieve normal milestones.  The amount of cognitive impairment is variable.  Congenital cardiac defects, ichthyosis, and hypertrichosis may be present.  The skin over the dorsum of the hands and feet often appears dark.  Ataxia is sometimes present and MRIs may reveal vermal and cerebellar hypoplasia.

Facial dysmorphism is common.  Low-set malformed ears, low hairline, depressed nasal bridge, redundant facial skin, decreased subcutaneous tissue, large mouth, thin lips, and long face have been noted.

There is considerable variation in clinical manifestations and longevity varies from infancy to adulthood.

Genetics

This glycosylation disorder is one of a number of rare hepatic/intestinal disorders caused by a deficiency in N-oligosaccharide synthesis.  It is inherited in an autosomal recessive pattern as a result of mutations in SRD5A3 (4q12).  Both homozygous and compound heterozygous genotypes have been reported.  It is allelic to Kahrizi syndrome (612713) with a number of overlapping features including ocular colobomas and cognitive deficiencies.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The administration of caloric supplements through tube feeding may be required to maintain adequate nutrition.Orthopedic deformities can sometimes be corrected surgically.

References
Article Title: 

A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism

Morava E, Wevers RA, Cantagrel V, Hoefsloot LH, Al-Gazali L, Schoots J, van Rooij A, Huijben K, van Ravenswaaij-Arts CM, Jongmans MC, Sykut-Cegielska J, Hoffmann GF, Bluemel P, Adamowicz M, van Reeuwijk J, Ng BG, Bergman JE, van Bokhoven H, Korner C, Babovic-Vuksanovic D, Willemsen MA, Gleeson JG, Lehle L, de Brouwer AP, Lefeber DJ. A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. Brain. 2010 Nov;133(11):3210-20.

PubMed ID: 
20852264

SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder

Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, De Brouwer AP, Bl?omel P, Sykut-Cegielska J, Houliston S, Swistun D, Ali BR, Dobyns WB, Babovic-Vuksanovic D, van Bokhoven H, Wevers RA, Raetz CR, Freeze HH, Morava E, Al-Gazali L, Gleeson JG. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell. 2010 Jul 23;142(2):203-17.

PubMed ID: 
20637498

Nystagmus-Split Hand Syndrome

Clinical Characteristics
Ocular Features: 

The only consistent ocular finding is pendular nystagmus beginning at birth.  There is some evidence that the eye movements decrease with age.  Acuity in a 46 year old female was recorded to be 20/40 in each eye whereas one of her children had 20/70.  Two patients (father and daughter) have been described as having cataracts and “fundus changes”, not further defined.  Other patients have been described with normal fundi.  The ERG has been normal in several patients.  Some authors have noted hypertelorism.

The ocular phenotype requires further definition.  For example, in a single published photograph of a young child the medial portion of the eye brows is sparsely populated and all eyelashes in the medial one-third of the upper lid appear to be absent.  This has not been commented on in publications, however.

Systemic Features: 

The hand and foot malformation is severe, described as split-hand/split foot deformity.  It may involve all four extremities or just the upper extremity with monodactyly.  When the hand is involved, it may be called a lobster-claw deformity, or ectrodactyly.  The middle digit is characteristicly missing but other fingers and toes are sometimes absent.

The teeth erupt late, some may be missing and others are often poorly formed. Frontal bossing, sunken cheeks, and thick and everted lips may be part of the facial phenotype.

Genetics

The genetics of Karsch-Neugebauer is obscure although the majority of evidence is consistent with autosomal dominant inheritance.  Parent-child transmission and male-to-male transmission have been observed.  In other families the parents are normal but reduced penetrance has not been ruled out.  Further, there are several types of split-hand deformities but this is the only one associated with nystagmus.  No locus or mutation has been found for this condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical reconstruction can sometimes improve hand function.

References
Article Title: 

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