autosomal dominant

External Ophthalmoplegia, Facial Weakness, and Malignant Hyperthermia

Clinical Characteristics
Ocular Features: 

A subset of patients with malignant hyperthermia susceptibility (MHS) secondary to mutations in RYR1 has congenital ophthalmoplegia and ptosis.   Magnetic resonance imaging may reveal hypoplasia of extraocular muscles and intraorbital cranial nerves.

Systemic Features: 

The weakness in extraocular and levator muscles is sometimes associated with more generalized myopathy of a variable degree.  The myopathy may be progressive and individuals with extensive skeletal muscle weakness may have respiratory insufficiency and scoliosis. The clinical spectrum is broad and there is no consistent pattern in the degree of skeletal muscle weakness associated with ocular muscle involvement.  This may be explained in part by the variety of myopathies found among patients with mutations in RYR1 such as:  central core disease, multiminicore disease, congenital fiber type disproportion, centronuclear myopathy, and nemaline myopathy.

Malignant hyperthermia due to mutations in RYR1 is most commonly inherited as an autosomal dominant trait precipitated by exposure to certain volatile anesthetic agents such as halothane, isoflurane, and enflurane used in association with succinylcholine during general anesthesia.  Patients may experience acidosis, muscle rigidity, rhabdomyolysis and tachycardia with arrhythmias.  Myoglobinuria may lead to renal failure.

Exercise-induced heat stress rarely precipitates malignant hyperthermia.

Genetics

Ptosis, ophthalmoplegia, and susceptibility to malignant hyperthermia can occur as separate heritable conditions and it is uncommon for them to coexist as in the MHS1 syndrome described here.  Due to the heterogeneous signs of muscle disease reported among and between families, it is likely that MHS1 consists of more than one disorder.  Mutations in RYR1 are commonly associated with susceptibility to malignant hyperthermia while the co-occurrence of skeletal muscle disease is inconsistent and involvement of extraocular muscles is even rarer.

There is good evidence that at least 6 types of MHS exist.  A large number of responsible mutations in 2 genes, RYR1 (19q13.2) and CACNA1S (1q32.1), have been identified and there is good evidence that at least 4 additional loci exist.  Mutations in RYR1 are responsible for MHS1 and account for approximately 70% of susceptible individuals.  Families with both autosomal dominant and autosomal recessive inheritance patterns have been reported.  

It is not understood why some families with MHS1 have ocular and skeletal muscle abnormalities while others do not.  External ophthalmoplegia is most often secondary to mutations in mitochondrial DNA but the importance of presurgical recognition of the risk of malignant hyperthermia suggests that pre-surgery gene screening for RYR1 in such patients is warranted.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

The best treatment is prevention by using alternate anesthetic agents if the risk is recognized preoperatively.  Temperature should be monitored in all patients undergoing general anesthesia since prompt recognition of hyperthermia is essential.  Inhalation agents and succinylcholine must be discontinued and dantrolene sodium should be given promptly.  Metabolic abnormalities must be corrected and both external and internal body cooling should be initiated immediately.  Intravascular coagulation is an additional risk and coagulation profiles should be obtained.

A positive family history of MHS requires pre-anesthesia gene testing but failure to detect a mutation in known genes does not rule out susceptibility.

Ptosis surgery may be helpful in selected patients.

References
Article Title: 

Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization

Bevilacqua JA, Monnier N, Bitoun M, Eymard B, Ferreiro A, Monges S, Lubieniecki F, Taratuto AL, Laquerriere A, Claeys KG, Marty I, Fardeau M, Guicheney P, Lunardi J, Romero NB. Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization. Neuropathol Appl Neurobiol. 2011 Apr;37(3):271-84.

PubMed ID: 
21062345

Nystagmus 7, Congenital, AD

Clinical Characteristics
Ocular Features: 

A pendular nystagmus is usually diagnosed in infancy.  The eye is otherwise anatomically and functionally normal.  No photophobia, hypopigmentation, night blindness have been noted in the two Chinese families reported.  The ERG and foveal appearance are normal.  Visual acuity has not been reported.

Systemic Features: 

No systemic abnormalities have been found.

Genetics

The two reported multigenerational pedigrees show a pattern consistent with autosomal dominant inheritance. No causative mutation has been identified but mapping suggests a locus at 1q31-q32.2 that segregates with the condition.

Nystagmus 2 (164100), nystagmus 3 (608345), and nystagmus 4 (614826) are other autosomal dominant forms of simple nystagmus but they are unique disorders as they map to other chromosomal locations.

Several forms of X-linked recessive inheritance are contained in this database: NYS1, NYS5, and NYS6.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported. 

References
Article Title: 

Optic Atrophy, Ophthalmoplegia, Myopathy, and Neuropathy

Clinical Characteristics
Ocular Features: 

Visual symptoms have an insidious onset in childhood with vision loss and progressive external ophthalmoplegia.  Ptosis may be evident later.  The optic atrophy is progressive.   ERG abnormalities have been reported but no pigmentary retinopathy has been seen.  Myopia is sometimes present.

Systemic Features: 

The extraocular signs and symptoms are variable and generally have a later onset.  Some patients have an early onset of sensorineural hearing loss.  Muscle cramps and hyperreflexia may occur with clonus and a spastic gait.  Ataxia seems to be common.  The neurological phenotype has been likened to muscular sclerosis, Kearns-Sayre syndrome, and spastic paraplegia.  Muscle biopsies show variable-sized and atrophic fibers.

Genetics

This is generally considered an autosomal dominant disorder secondary to mutations in the OPA1 gene.  It is allelic to optic atrophy 1 (165500) but may also be the same condition since the p.Arg247His mutation has been found in patients with both disorders.  This syndromic form of optic atrophy may also result from biallelic mutations in OPA1 in which the clinical disease is more severe and earlier in onset. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the neurological disease but low vision aids should be considered to selected patients especially during childhood educational activities.

References
Article Title: 

Multi-system neurological disease is common in patients with OPA1 mutations

Yu-Wai-Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M, Toscano A, Musumeci O, Valentino ML, Caporali L, Lamperti C, Tallaksen CM, Duffey P, Miller J, Whittaker RG, Baker MR, Jackson MJ, Clarke MP, Dhillon B, Czermin B, Stewart JD, Hudson G, Reynier P, Bonneau D, Marques W Jr, Lenaers G, McFarland R, Taylor RW, Turnbull DM, Votruba M, Zeviani M, Carelli V, Bindoff LA, Horvath R, Amati-Bonneau P, Chinnery PF. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 2010 Mar;133(Pt 3):771-86.

PubMed ID: 
20157015

Nystagmus 3, Congenital, AD

Clinical Characteristics
Ocular Features: 

The nystagmus is horizontal in type and accentuated by fixation and decreased by convergence.  It also increases during smooth pursuit and by lateral gaze.  There may be components of jerk, circular, and pendular nystagmus.  The nystagmus may be present at birth.

Systemic Features: 

No systemic disease is present.   

Genetics

No specific mutation has been found but 3 individuals in one family shared a haplotype suggesting a locus at 7p11.2.  The pedigree pattern suggests autosomal dominant inheritance.  A four generation family with male to male transmission and a balanced 7;15 translocation has been reported with a similar phenotype.

Other forms of congenital nystagmus transmitted in a similar autosomal pattern are: NYS2, NYS4, and NYS7.

X-linked recessive transmission patterns have also been identified for congenital nystagmus: NYS1, NYS5, and NYS6.

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no effective cure for congenital nystagmus but some patients can benefit from extraocular muscle surgery, correction of refractive errors, and low vision aids.

References
Article Title: 

Nystagmus 2, Congenital, AD

Clinical Characteristics
Ocular Features: 

Pendular and sometimes jerk nystagmus are often present at birth.  Other patients are diagnosed between 3 and 6 months.  Vision is usually stable in the range of 20/30 to 20/100 with most patients having 20/50.  Between 35% and 50% of individuals have strabismus as well.

Systemic Features: 

None have been reported.

Genetics

Familial cases have an autosomal dominant transmission pattern.  No specific mutation has been found but strong linkage with a region at 6p12 has been reported.

Several additional autosomal dominant forms of congenital nystagmus have been linked to chromosomal regions 7p11 (NYS3, 608345), 13q (NYS4, 193003), 1q31.3-q32.1, and NYS7 (614826).  Autosomal recessive inheritance has been proposed for several pedigrees but adequate documentation is lacking (see 257400).

This database also contains 3 types of congenital nystagmus inherited in X-linked recessive patterns: NYS1, NYS5, and NYS6.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Nystagmus cannot be cured.  However, there are several treatments that can help.  Glasses and contact lenses, and, occasionally, extraocular muscle surgery may be helpful.  The latter should be considered especially when patients adopt a consistent head position for best vision.  This avoids long-term secondary changes in neck muscles and many individuals experience an improvement of two or more lines in visual acuity.  Low vision aids should be offered.

References
Article Title: 

Microphthalmia, Syndromic 6

Clinical Characteristics
Ocular Features: 

Ultrasound evaluation reveals globe size to vary widely from extremely small (6 mm) to normal axial length. Clinical anophthalmia is often diagnosed.  Both anophthalmia and microphthalmia may exist in the same individual. True anophthalmia has been confirmed in some patients in which no ocular tissue was detectable with ultrasound examination.  In such cases the optic nerves and chiasm are often missing as well.  Iris colobomas are common and these may extend posteriorly.  Myopia is sometimes present.

The ERG reveals generalized rod and cone dysfunction in some eyes, but may be normal in others. In many eyes the ERG is nonrecordable. Cataracts are frequently present.

Systemic Features: 

Digital and hand anomalies are common.  The hands are often described as broad and the thumbs may be low-placed.  The nails can appear dysplastic and postaxial polydactyly is often present.  Mild webbing of the fingers has been reported as well.  Microcephaly and the cranium can be misshapen. A high arched palate is often present and clefting has also been noted.  Micrognathia may be present. Some evidence of physical growth retardation is often evident.

Pituitary hypoplasia is not uncommon and may be associated with hypothyroidism and cryptorchidism with hypospadias, and a small or bifid scrotum.

The brain anomalies vary considerably.  Many patients have mild to moderate developmental delays with some learning difficulties. Sensorineural hearing loss is often present. Hypoplasia of the vermis, thinning of the corpus callosum, widening of the lateral ventricles, and occasional generalized cortical atrophy, at least in older individuals, have been described.

Genetics

This is an autosomal dominant condition caused by a point mutation in BMP4 (bone morphogenetic protein-4) (14q22-q23).  A number of chromosomal deletions involving this gene have also been identified in individuals who have this syndrome but since contiguous genes such as OTX2 and SIX6 may also be involved, the phenotype is more likely to be associated with other anomalies including genital hypoplasia, pituitary hypoplasia, absence of the optic nerves and/or chiasm, developmental delay, digital malformations, and cerebellar dysplasia.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataracts can be removed in selected individuals with potential visual function.  Socket prostheses should be considered in anophthalmia and extreme microphthalmia.  Low vision devices, Braille, and mobility training should be initiated early when appropriate.  Hearing evaluations should be done as soon as practical.

Learning specialists and special education facilities should be available for selected patients.  Polydactyly, syndactyly, skull, and cleft palate repairs may be indicated.

References
Article Title: 

Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways

Bakrania P, Efthymiou M, Klein JC, Salt A, Bunyan DJ, Wyatt A, Ponting CP, Martin A, Williams S, Lindley V, Gilmore J, Restori M, Robson AG, Neveu MM, Holder GE, Collin JR, Robinson DO, Farndon P, Johansen-Berg H, Gerrelli D, Ragge NK. Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways. Am J Hum Genet. 2008 Feb;82(2):304-19.

PubMed ID: 
18252212

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: 

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: 

Feingold Syndrome 1

Clinical Characteristics
Ocular Features: 

Short, narrow palpebral fissures have been reported (73%).  The fissures may be up slanting and epicanthal folds have been noted.   

Systemic Features: 

The face can appear asymmetrical and triangular and the head is small in 89% of individuals.  Micrognathia is usually present and the lips appear full.  The nasal bridge is broad and the nostrils are anteverted.  The ears are often low-set and rotated posteriorly.  Syndactyly of the toes is common (97%) and the fingers are often anomalous (particularly 5th finger clinodactyly and brachydactyly) with hypoplastic thumbs.  Shortening of the 2nd and 5th middle phalanx of the fingers is especially common.  True short stature is uncommon but 60% are below the 10th centile.  Rare individuals have a sensorineural hearing loss.

Tracheoesophageal fistulas are often present, together with atresia of the duodenum and sometimes the esophagus as well.  Cardiac, renal, and vertebral malformations are seen in a minority of patients.

Intelligence may be normal but more often is below average and learning difficulties are often present.

Genetics

This is an autosomal dominant disorder secondary to mutations in the MYCN gene (2p24.3).

MYCN is up regulated in some patients with retinoblastoma (180200).

Feingold syndrome 2 (614326) is caused by hemizygous deletions of the MIR17HG gene but no ocular signs have been reported.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment for the syndrome but surgery can be important for some of the external and internal malformations. Special education and treatment of hearing loss are important.

References
Article Title: 

Genotype-phenotype correlations in MYCN-related Feingold syndrome

Marcelis CL, Hol FA, Graham GE, Rieu PN, Kellermayer R, Meijer RP, Lugtenberg D, Scheffer H, van Bokhoven H, Brunner HG, de Brouwer AP. Genotype-phenotype correlations in MYCN-related Feingold syndrome. Hum Mutat. 2008 Sep;29(9):1125-32.

PubMed ID: 
18470948

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