autosomal recessive

Retinitis Pigmentosa 38

Clinical Characteristics
Ocular Features: 

This is a rare clinically heterogeneous condition in which both rods and cones functions are variably affected.  It is a progressive disorder with children often being aware of night vision difficulties during the latter half of the first decade of life.  Reduced vision is often present at this time as well and progressively deteriorates.  Visual fields are constricted to 20-30 degrees.  Rod responses may be nondetectable in the first decade.

Central vision is subnormal as early as childhood and progressively worsens with age.  Dyschromatopsia to some degree is often present early as well and some patients have a maculopathy with a bull’s eye pattern and thinning of the photoreceptor layer seen on OCT.  Attenuated retinal vessels, pale optic discs, and variable fundus pigmentary changes (including pigmentary mottling and bone spicules) have been seen.  The degree and course of the photoreceptor damage is variable leading some to propose that RP38 is primarily a cone-rod dystrophy.

Systemic Features: 

None

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the MERTK gene (2q13).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported but young people especially could benefit from low vision aids and special education therapy.

References
Article Title: 

Myasthenic Syndromes, Congenital, Including AChR Deficiency

Clinical Characteristics
Ocular Features: 

The congenital myasthenic syndromes are genetically and clinically heterogeneous.  Ptosis is the outstanding ocular sign and virtually always present.  Strabismus and ophthalmoplegia are less common.  These signs are not helpful in the differential diagnosis of the many types of congenital myasthenia.

Some degree of ptosis is usually evident during the first 6 months of life.  By about 2 years of age strabismus and ophthalmoparesis are apparent but this sequence is highly variable.

Systemic Features: 

This is a group of nonprogressive disorders most often associated with acetylcholine receptor (AChR) defects at the neuromuscular junction.  An early sign may be decreased fetal movements.  Generalized weakness, a weak cry, and hypotonia are evident at birth.  Easy fatigability and limb weakness are noted in early childhood and affected children have difficulty running. Facial weakness, dysarthria, weakness of the tongue, and dysphagia are often present and many patients have respiratory difficulties. Motor development can be delayed.  Acute illnesses may exacerbate muscle weakness.

Genetics

This is the most common form of the congenital myasthenic syndromes. It is an autosomal recessive disorder of the postsynaptic type, so called because the mutations occur in genes that encode the subunits of acetylcholine receptors: CHRNE(17P13.2), and CHRNB1(17p13.1).  A similar phenotype results from mutations in MUSK (9p31.3) which is critical for synaptic differentiation.

Mutations in RAPSN(11p11.2), whose protein product is important for stabilization of the acetylcholine receptors at the endplate, may result in a similar phenotype but may also produce the fetal akinesia deformation sequence.  This lethal condition is often associated with severe respiratory disease and dysmorphism including limb contractures, micrognathia, and feeding difficulties.  Nothing is known about the ocular signs.

Another autosomal recessive congenital myasthenic syndrome (610542), CMSTA1, has a somewhat later onset (adolescence) and weakness in a limb girdle distribution but no ptosis or oculomotor problems.  Tubular aggregates of muscle fibers can be seen on biopsy.

Presynaptic autosomal recessive forms of congenital myasthenia such as CMS20 (617143) caused by mutations in SLC5A7 (2q12) and CMS21 (617239) secondary to mutations in SLC18A3 (10q11.23) with severe episodic apnea and ocular signs of ptosis and ophthalmoparesis have been reported.

Other postsynaptic forms of congenital myasthenia are the fast-channel type (FCCNS) (608930) and the slow channel type (SCCMS) (601462).  Ophthalmoparesis occurs early in both types.

The classification of congenital myasthenia syndromes is under construction.  In the case of many types only a single or very few families have been reported.   While the clinical manifestations involve alterations in the neuromuscular junnction, some result from heterozygous mutations while others are due to homozygous changes.  The defect may reside in presynaptic, synaptic, or postsynaptic mechanisms.  For a discussion and comprehensive listing of the various types see 601462.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cholinesterase inhibitor drugs can be highly beneficial in some forms of the disease but genotyping is necessary before attempting pharmacological therapy.  Frequent ventilation and enteric feeding may be helpful for selected individuals.  Individuals should be protected from acute illnesses, especially respiratory infections.

References
Article Title: 

Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea

Bauche S, O'Regan S, Azuma Y, Laffargue F, McMacken G, Sternberg D, Brochier G, Buon C, Bouzidi N, Topf A, Lacene E, Remerand G, Beaufrere AM, Pebrel-Richard C, Thevenon J, El Chehadeh-Djebbar S, Faivre L, Duffourd Y, Ricci F, Mongini T, Fiorillo C, Astrea G, Burloiu CM, Butoianu N, Sandu C, Servais L, Bonne G, Nelson I, Desguerre I, Nougues MC, Boeuf B, Romero N, Laporte J, Boland A, Lechner D, Deleuze JF, Fontaine B, Strochlic L, Lochmuller H, Eymard B, Mayer M, Nicole S. Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea. Am J Hum Genet. 2016 Sep 1;99(3):753-61.

PubMed ID: 
27569547

Congenital myasthenic syndromes

Hanta?O D, Richard P, Koenig J, Eymard B. Congenital myasthenic syndromes. Curr Opin Neurol. 2004 Oct;17(5):539-51. Review.

PubMed ID: 
15367858

Retinal Cone Dystrophy 3B

Clinical Characteristics
Ocular Features: 

This is a degenerative disorder in which patients have a progressive deterioration of visual acuity and color vision.  Most patients have significant myopia.  Visual difficulties begin in early childhood with acuity of 20/100 or worse by the second decade of life.  Color vision deficits can be detected in the second decade but nyctalopia occurs later in young adults.  Photophobia is a prominent symptom.  The ERG shows reduced and delayed cone responses.  Rod responses to low intensity flashes are undetectable but increased stimulus intensity leads to an abrupt increase in amplitude, often exceeding the upper limits of normal.

The fundus appears normal in some patients but foveal or parafoveal atrophy, a macular bull’s eye, hyperfluorescence anomalies, and a generalized fine pigmentary retinopathy have been reported.  There may be some temporal pallor in the optic nerves.  Nystagmus and strabismus may be present.

Systemic Features: 

No systemic disease has been reported.

Genetics

This is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in the KCNV2 gene (9p24.2).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available for this dystrophy.  Low vision aids and tinted lenses may be helpful.

References
Article Title: 

Charcot-Marie-Tooth Disease(s)

Clinical Characteristics
Ocular Features: 

Optic atrophy is present in some patients, particularly in X-linked recessive (CMTX5; 311070), X-linked dominant (CMTX5; 302800), and autosomal recessive (CMT2A2B; 617087) disease.  Congenital and juvenile-onset open-angle glaucoma has been reported among members of 2 consanguineous families with type 4B2, or CMT4B2; (604563).  The mean age of onset was 8 years.

Systemic Features: 

Charcot-Marie-Tooth disease is a large group of clinically and genetically heterogeneous disorders characterized by progressive motor and sensory polyneuropathy.  These can be separated (with overlap) into two large groups on the basis of electrophysiologic criteria: type 1 is the demyelinating form, and type 2 the axonal form.  Patients with primarily distal motor neuropathy are sometimes considered to comprise a third type.

 Symptoms such as weakness in the extremities and digits have a variable age of onset but usually become evident in late childhood or early adulthood.  Small muscles of the hands and feet are often atrophied to some degree.  Some patients develop hearing loss of the neurosensory type.  Foot deformities such as pes cavus are common.  Nerve conduction velocity (reduction) and electromyography can be helpful diagnostically.  It may be helpful to look for characteristic changes such as loss of myelinated fibers and focal myelin sheath folding in sural nerve biopsies.  Intellectual impairment and dementia are usually not features of Charcot-Marie-Tooth disease.

Hemizygous individuals with X-linked types of CMT such as CMTX2-5 seem to be more likely to have intellectual disabilities, hearing loss, spasticity, and optic neuropathy.

Genetics

Charcot-Marie-Tooth disease can also be classified on the basis of their hereditary patterns including autosomal dominant, autosomal recessive, X-linked recessive, and X-linked dominant.  Each of these contains yet more distinct subtypes as defined by mutations in at least 40 genes.

The wide range of disease severity and the overlapping of many signs can make pedigree construction and the determination of recurrence risks and prognosis challenging.  The only recourse may be genotyping.

See Charcot-Marie-Tooth Disease with Glaucoma (604563) for a form of this disease in which glaucoma occurs early.

Pedigree: 
Autosomal dominant
Autosomal recessive
X-linked dominant, father affected
X-linked dominant, mother affected
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

The widespread and debilitating polyneuropathy requires a multidisciplinary management approach with neurologists, physical and occupational therapists, audiologists, pain specialists, and orthopedists.  Pharmaceuticals such as gabapentin may be used for neuropathic pain.  Surgery for pes cavus and joint dysplasias can be helpful.

References
Article Title: 

Charcot-Marie-Tooth disease

Carter GT, Weiss MD, Han JJ, Chance PF, England JD. Charcot-Marie-Tooth disease. Curr Treat Options Neurol. 2008 Mar;10(2):94-102.

PubMed ID: 
18334132

Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma

Azzedine H, Bolino A, Taieb T, Birouk N, Di Duca M, Bouhouche A, Benamou S, Mrabet A, Hammadouche T, Chkili T, Gouider R, Ravazzolo R, Brice A, Laporte J, LeGuern E. Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma. Am J Hum Genet. 2003 May;72(5):1141-53.

PubMed ID: 
12687498

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: 

Spinocerebellar Ataxia, Infantile-Onset

Clinical Characteristics
Ocular Features: 

Ocular problems begin by about age 7 years when various degrees of ophthalmoplegia appear.  By the second decade damage to the optic nerves is evident (optic atrophy) leading to severe vision loss.

Systemic Features: 

This mitochondrial DNA depletion syndrome allows normal development in the first year of life.  By 10-18 months of age, muscle weakness and coordination become evident.  Deep tendon reflexes are diminished or absent.  The muscle deficits are relentlessly progressive and by teenage years most individuals are wheelchair-bound.  Generalized seizures are common.  Facial and limb dyskinesia of an athetoid nature is evident to a variable degree.  A sensory polyneuropathy develops in many patients.  Cerebellar atrophy is evident on neuroimaging.

Neurosensory hearing loss may become evident late in the first decade of life.  The amount of hearing loss is progressive, leading eventually to profound deafness.  Some patients experience a complete loss of vestibular caloric responses. 

Most individuals live to adulthood but a severe form of this disease in which liver damage and encephalopathy occur limits the lifespan to about 5 years.

Genetics

This infantile-onset form of spinocerebellar atrophy results from homozygous or compound heterozygous mutations in the C10ORF2 gene (10q24) which encodes the so-called Twinkle and Twinky mitochondrial proteins. Since the Twinkle protein is involved in the production and maintenance of mitochondrial DNA, its malfunction leads to reduced quantities of mtDNA in the liver and CNS but not in skeletal muscle.

Mutations in the C10ORF2 gene affecting the Twinkle protein may be responsible for an autosomal dominant progressive ophthalmoplegia (609286) in which ptosis and cataracts are often found but the more extensive muscle and sensory deficits are often missing.  This is one of the better examples of seemingly unique, allelic phenotypes resulting from different mutations in the same gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported but physical therapy, assistive hearing devices, and low vision aids might be helpful in selected patients.

References
Article Title: 

Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease

Pierce SB, Gulsuner S, Stapleton GA, Walsh T, Lee MK, Mandell JB, Morales A, Klevit RE, King MC, Rogers RC. Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease. Cold Spring Harb Mol Case Stud. 2016 Jul;2(4):a001107. doi: 10.1101/mcs.a001107.

PubMed ID: 
27551684

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

Spastic Paraplegia 46

Clinical Characteristics
Ocular Features: 

Congenital cataracts (not further described) have been reported in several individuals with this type of complicated spastic paraplegia.  Optic atrophy and nystagmus have not been reported.

Systemic Features: 

Stiffness and weakness of the lower limbs begins between 2 and 20 years of age.  This is slowly progressive although most individuals are still mobile with mild to moderate handicaps into the 4th decade.  The gait is spastic with weakness, hyperreflexia, and extensor plantar responses in the lower limbs.  The upper limbs are variably involved and movements are dysmetric.  Dysarthria and bladder dysfunction are often present.  Cerebellar ataxia is common and some patients first present with this as a prominent sign in the first and second decades.  Early cognitive development is normal but mild cognitive decline appears eventually.  Pes cavus and scoliosis may occur.

Brain imaging can show thinning of the corpus callosum, with mild cerebellar and cerebral atrophy.

Genetics

Linkage analysis identified a locus at 9p13.3 and sequencing confirmed homozygous or compound heterozygous mutations in GBA2.  The presence of parental consanguinity in some families supports autosomal recessive inheritance.

This database contains two other types of autosomal spastic paraplegia with ocular signs: spastic paraplegia 15 (270700) with a “flecked retina”, and spastic paraplegia 7 (607259) with optic atrophy and nystagmus.  Cataracts have not been reported in these two conditions.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known for the neurological deficits but cataract surgery may be beneficial for visually significant cataracts.

References
Article Title: 

Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity

Hammer MB, Eleuch-Fayache G, Schottlaender LV, Nehdi H, Gibbs JR, Arepalli SK, Chong SB, Hernandez DG, Sailer A, Liu G, Mistry PK, Cai H, Shrader G, Sassi C, Bouhlal Y, Houlden H, Hentati F, Amouri R, Singleton AB. Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am J Hum Genet. 2013 Feb 7;92(2):245-51. PubMed PMID: 23332917.

PubMed ID: 
23332917

Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia

Martin E, Sch?ole R, Smets K, Rastetter A, Boukhris A, Loureiro JL, Gonzalez MA, Mundwiller E, Deconinck T, Wessner M, Jornea L, Oteyza AC, Durr A, Martin JJ, Schols L, Mhiri C, Lamari F, Z?ochner S, De Jonghe P, Kabashi E, Brice A, Stevanin G. Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am J Hum Genet. 2013 Feb 7;92(2):238-44. PubMed PMID: 23332916.

PubMed ID: 
23332916

A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum

Boukhris A, Feki I, Elleuch N, Miladi MI, Boland-Aug?(c) A, Truchetto J, Mundwiller E, Jezequel N, Zelenika D, Mhiri C, Brice A, Stevanin G. A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum. Neurogenetics. 2010 Oct;11(4):441-8.

PubMed ID: 
20593214

Retinitis Pigmentosa 25

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity with a wide range in age of onset and progression.  Night blindness, sometimes with photophobia, has its onset in the second or third decade of life and central acuity can be impacted by age 30 years.  Other patients have no symptoms until the fifth decade.  Some patients lose the ability to perceive light by the sixth decade.  The visual fields are usually constricted although one patient had a central scotoma.  The ERG is usually nonrecordable but other patients may have a variable rod-cone pattern of attenuation.  The retinal vessels are also attenuated and some patients have mild optic atrophy.  The pigmentary retinopathy is also variable with sometimes central lesions and in other patients more peripheral.  One patient had posterior subcapsular cataracts.

Systemic Features: 

No systemic disease has been reported.

Genetics

This is an autosomal recessive form of retinitis pigmentosa resulting from homozygosity or compound heterozygosity in the EYS gene (6q12).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Knobloch Syndrome 3

Clinical Characteristics
Ocular Features: 

High myopia and marked nystagmus are cardinal ocular findings.  Night blindness leads to symptoms between 2 and 4 years of age.  Vision loss leads to complete blindness by age 15 to 18.  Visual acuity in young adults is often 20/400 to NLP.  Cataracts with subluxated lenses, glaucoma, and chorioretinal atrophy are often present.  Scattered pigment clumping, attenuation of the retinal vasculature, and prominent choroidal vessels can often be seen.  Marked optic atrophy is usually present.  Phthisis and band keratopathy may be seen in older individuals although no retinal detachments have been reported.  The vitreous is described as degenerated in several patients and a vitreal hemorrhage was seen in one patient.

Systemic Features: 

This variant was identified in a four-generation consanguineous Pakistani family in which detailed information was obtained in 5 members. A hairless, purplish-red patch is usually present in the occipital-parietal region during infancy but becomes smaller as children grow.  No encephalocele is present.  Hearing loss and heart defects have not been reported.  Intelligence is normal.

Genetics

This is an autosomal recessive condition resulting from a presumed homozygous mutation on chromosome 17 (17q11.2).

Other variants of Knobloch syndrome are Knobloch 1 (267750) caused by homozygous mutations in COL18A1 (21q22.3) and Knobloch 2 (608454) secondary to homozygous mutations in ADAMTS18 at 16q23.1.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts and dislocated lenses may be removed.

References
Article Title: 

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