autosomal recessive

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.  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.

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: 

Microphthalmia and Anophthalmia, ALDH1A3 Associated

Clinical Characteristics
Ocular Features: 

Patients have a variety of ocular malformations including microphthalmia and clinical anophthalmia.  Some have orbital cysts. Imaging may reveal hypoplastic optic nerves and chiasms.

Systemic Features: 

Both cardiac (pulmonary stenosis and septal defects) and neurological deficits (autism spectrum disorders and 'intellectual disability') have been reported.  Birth weight and head circumference are often low.  However, brain imaging has revealed no consistent malformations.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the gene ALDH1A3 (15q26.3) which encodes the enzyme retinaldehyde dehydrogenase.  Mutations in ALDH1A3 impair the enzymatic oxidation of retinaldehyde important to the synthesis of retinoic acid, a key signaling molecule in eye development. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the ocular problems is available.

References
Article Title: 

ALDH1A3 Mutations Cause Recessive Anophthalmia and Microphthalmia

Fares-Taie L, Gerber S, Chassaing N, Clayton-Smith J, Hanein S, Silva E, Serey M, Serre V, G?(c)rard X, Baumann C, Plessis G, Demeer B, Br?(c)tillon L, Bole C, Nitschke P, Munnich A, Lyonnet S, Calvas P, Kaplan J, Ragge N, Rozet JM. ALDH1A3 Mutations Cause Recessive Anophthalmia and Microphthalmia. Am J Hum Genet. 2013 Feb 7;92(2):265-70.

PubMed ID: 
23312594

Cataracts, CRYAA Mutations

Clinical Characteristics
Ocular Features: 

This seems to be a clinically heterogeneous group of lens opacities all due to mutations in the crystallin gene CRYAA.  Some patients also have colobomas and may have microcornea and corneal opacities.  The lens opacities are usually bilateral but there is considerable asymmetry in their morphology.  Opacities may be nuclear, polar, cortical, sutural, embryonal, and anterior subcapsular in location.  The cataracts are often present at birth.

Systemic Features: 

Systemic disease is absent.

Genetics

A variety of mutations in the CRYAA (21q22.3) have been reported in a several ethnic groups.  Most pedigrees are consistent with autosomal dominant inheritance but autosomal recessive inheritance has been suggested in other families.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Lens extraction may be necessary.

References
Article Title: 

Cataracts, Congenital, with Brain Hemorrhage and Subependymal Calcification

Clinical Characteristics
Ocular Features: 

Bilateral neonatal leukocoria secondary to dense congenital cataracts (not further characterized) is evident at birth. Microphthalmia and pale optic discs have each been reported in a single patient.

Systemic Features: 

Newborns have catastrophic intracranial hemorrhages with massive cystic destruction of white matter and basal ganglia.  Subependymal calcification can be seen on CT scans.  Most individuals do not live beyond the neonatal period or early infancy.  Hyperreflexia, seizures, and spasticity are frequent clinical features.  Some patients have hepatomegaly and mild renal anomalies in size and location.  The forehead may be prominent and sloping.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the JAM3 (junctional adhesion molecule 3) gene (11q25).  The gene product is one of a family of proteins that contributes to intercellular tight junctions between epithelial cells, among others, and is postulated to be important to vascular permeability as well as lens development.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Delineation of the Clinical, Molecular and Cellular Aspects of Novel JAM3 Mutations Underlying the Autosomal Recessive Hemorrhagic Destruction of the Brain, Subependymal Calcification and Congenital Cataracts

Akawi NA, Canpolat FE, White SM, Quilis-Esquerra J, Sanchez MM, Gamundi MJ, Mochida GH, Walsh CA, Ali BR, Al-Gazali L. Delineation of the Clinical, Molecular and Cellular Aspects of Novel JAM3 Mutations Underlying the Autosomal Recessive Hemorrhagic Destruction of the Brain, Subependymal Calcification and Congenital Cataracts. Hum Mutat. 2012 Dec 15.[Epub ahead of print]

PubMed ID: 
23255084

A homozygous mutation in the tight-junction protein JAM3 causes hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts

Mochida GH, Ganesh VS, Felie JM, Gleason D, Hill RS, Clapham KR, Rakiec D, Tan WH, Akawi N, Al-Saffar M, Partlow JN, Tinschert S, Barkovich AJ, Ali B, Al-Gazali L, Walsh CA. A homozygous mutation in the tight-junction protein JAM3 causes hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Am J Hum Genet. 2010 Dec 10;87(6):882-9.

PubMed ID: 
21109224

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