multiple

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

Meckel Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype is highly variable.  The globe is often malformed or may be clinically absent.  Cryptophthalmos, clinical anophthalmia, and microphthalmos with sclerocornea and microcornea have been reported.  Posterior staphylomas, retinal dysplasia, partial aniridia, cataracts, and hypoplasia or absence of the optic nerve are sometimes seen.  Some patients have incompletely formed eyes with shallow anterior chambers, angle anomalies, and a persistent tunica vasculosa with lens opacification.  Histopathology may reveal thinning of the nerve fiber layer and a paucity of retinal ganglion cells.  The retina has been described as dysplastic with foci of rosette-like structures and abundant glial cells.

Systemic Features: 

Meckel or Meckel-Gruber syndrome is a clinically and genetically heterogeneous group of disorders with severe multisystem manifestations.  The triad of cystic renal disease, polydactyly (and sometimes syndactyly), and a skull malformation (usually an encephalocele) is considered characteristic of MKS.  However, these signs are variable and only about 60% of patients have all three features.  Many patients have additional signs such as malformations of the biliary tree, cleft palate (and/or lip), sloping forehead, low-set ears, short neck, low-set ears, ambiguous genitalia, and short, bowed limb bones.  Pulmonary hypoplasia is common which, together with kidney and liver disease, is responsible for the poor prognosis of most infants. 

Many clinical abnormalities resemble those present in the Smith-Lemli-Opitz syndrome (270400) and in Joubert syndrome (213300).

Genetics

Most conditions in this group are inherited in an autosomal recessive pattern.  Mutations in 9 genes have been identified as responsible for some variant of MKS in which there is a considerable range of clinical expression.  There is significant clinical overlap with Joubert syndrome and it is not surprising that at least 5 of these mutations have been identified in both conditions.  Further nosological confusion is generated by those who consider patients with the severe, lethal phenotype to have Meckel syndrome while those with milder disease are labeled Joubert syndrome, regardless of genotype.

Rare heterozygotes have been reported with isolated features such as polydactyly.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this syndrome.  The prognosis for life beyond infancy is poor due to the advanced dysfunction of numerous organs such as the kidney, lungs, liver and the central nervous system.

References
Article Title: 

Clinical and genetic heterogeneity in Meckel syndrome

Paavola P, Salonen R, Baumer A, Schinzel A, Boyd PA, Gould S, Meusburger H, Tenconi R, Barnicoat A, Winter R, Peltonen L. Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet. 1997 Nov;101(1):88-92.

PubMed ID: 
9385376

Joubert Syndrome and Related Disorders

Clinical Characteristics
Ocular Features: 

Ocular findings like systemic features are highly variable both within and between families.  Vision can be normal but in other patients it is severely reduced to the range of 20/200.  The pupils may respond sluggishly or even paradoxically to light.  ERG recordings have been reported to be normal in some patients, but absent or reduced in others.  The fundus appearance is often normal but in other individuals the pigmentation is mottled, the retinal arterioles are attenuated, and the macula has a cellophane maculopathy.  Drusen and colobomas are sometimes seen in the optic nerve while occasional patients have typical chorioretinal colobomas.  The eyebrows are often highly arched.

The oculomotor system is frequently involved.  Apraxia to some degree is common with most patients having difficulty with smooth pursuit and saccadic movements.  Compensatory head thrusting is often observed.  A pendular nystagmus may be present while esophoria or esotropia is present in many patients.

Systemic Features: 

There is a great deal of clinical heterogeneity in this group of ciliary dyskinesias.  Developmental delays, cognitive impairment, truncal ataxia, breathing irregularities, and behavioral disorders are among the more common features.  Hyperactivity and aggressiveness combined with dependency require constant vigilance and care.  Postaxial polydactyly is a feature of some cases.  Hypotonia is evident at birth.  Liver failure and renal disease develop in many individuals.  Neuroimaging of the midbrain-hindbrain area reveals agenesis or some degree of dysgenesis of the vermis with the 'molar tooth sign' in the isthmus region considered to be a diagnostic sign.  The fourth ventricle is usually enlarged while the cerebellar hemispheres may be hypoplastic.

The facies features are said to be distinctive in older individuals.  The face appears long with frontal prominence due to bitemporal narrowing, the nasal bridge and tip are prominent, the jaw is prominent, the lower lip protrudes, and the corners of the mouth are turned down.

Genetics

This is a clinically and genetically heterogeneous group of disorders with many overlapping features.  Most disorders in this disease category, known as JSRD, are inherited in an autosomal recessive pattern.  Mutations in at least 34 genes have been identified.  One, OFD1 (300804), is located on the X chromosome (Xp22.2).

There are significant clinical similarities to Meckel syndrome (249000) and Smith-Lemli-Opitz syndrome (270400).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is mostly for specific symptoms such as respiratory distress, renal disease, speech and physical therapy, low vision, and hepatic failure.

References
Article Title: 

Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center

Brooks BP, Zein WM, Thompson AH, Mokhtarzadeh M, Doherty DA, Parisi M, Glass IA, Malicdan MC, Vilboux T, Vemulapalli M, Mullikin JC, Gahl WA, Gunay-Aygun M. Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center. Ophthalmology. 2018 Jul 25. pii: S0161-6420(18)30686-9. doi: 10.1016/j.ophtha.2018.05.026. [Epub ahead of print].

PubMed ID: 
30055837

Ophthalmological findings in Joubert syndrome

Sturm V, Leiba H, Menke MN, Valente EM, Poretti A, Landau K, Boltshauser E. Ophthalmological findings in Joubert syndrome. Eye (Lond). 2010 Feb;24(2):222-5.

PubMed ID: 
19461662

MELAS Syndrome

Clinical Characteristics
Ocular Features: 

This progressive mitochondrial disorder primarily affects muscles and the CNS, including the visual system.  The pattern of ocular deficits is not consistent and those that are present are not specific, requiring the clinician to take the entire neurological picture into consideration.  Hemianopsia, cortical blindness and ophthalmoplegia may be present.  The ERG can show reduced b-wave amplitudes and VEPs may be absent.  The optic nerve head has been described as normal without the atrophy often seen with other mitochondrial disorders.  A pigmentary retinopathy may be present.

Systemic Features: 

The clinical picture is highly variable.  Most commonly patients have myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.  The onset of symptoms is usually in the first two decades of life, most commonly consisting of headaches of sudden onset accompanied by vomiting and seizures.  The headaches may simulate migraines.  Weakness, lethargy, and apathy may be present early.  However, infants and young children may present with failure to thrive, developmental delay, and learning disabilities.  Neurosensory deafness is often seen and peripheral neuropathy is usually evident.  MRIs may show cerebellar hypoplasia and infarctions in the cerebral hemispheres.  Some patients have calcifications in the basal ganglia.  Patients may develop lactic acidosis.  Muscle biopsies often show ragged, red fibers.  The heart is commonly involved with both structural and rhythm defects.  Depending upon the degree and location of brain damage, patients may have hemiparesis, lethargy, ataxia, myoclonic jerks, cognitive decline, and dementia.  Morbidity and mortality are high.

Genetics

MELAS syndrome is a group of disorders caused by mutations in mitochondrial genes (at least 9 have been identified) that alter transfer RNA molecules resulting in disruption of intramitochondrial synthesis of proteins involved in oxidative phosphorylation pathways.  It is both clinically and genetically heterogeneous.  One can expect that any familial occurrence would result from maternal transmission but the occurrence of heteroplasmy results in considerable variability in the severity of clinical disease.

Treatment
Treatment Options: 

There is no effective treatment that prevents development of disease or that slows its progress.

References
Article Title: 

Retinitis Pigmentosa, AR

Clinical Characteristics
Ocular Features: 

The term retinitis pigmentosa is applied to a large group of disorders with great clinical and genetic heterogeneity.  The ocular disease is characterized by night blindness, field constriction, and pigmentary changes in the retina.  The latter is sometimes described as having a ‘bone corpuscle’ appearance with a perivascular distribution.  A ring scotoma is usually evident.  Age of onset and rate of progression is highly variable, even within families.  The rods are impacted early but cone deterioration with loss of central vision usually follows.  Some patients complain of dyschromatopsia and photophobia.  The ERG generally documents this progression but the mfERG shows wide variations in central cone functioning.  Legal blindness is common by the 5thdecade of life or later.  The course of clinical and ERG changes is more aggressive in the X-linked form than in the autosomal dominant disease.  The final common denominator for all types is first rod and then cone photoreceptor loss through apoptosis.

As many as 50% of patients develop posterior subcapsular cataracts.  The vitreous often contains cells and particulate debris.   Retinal arterioles are often attenuated and the optic nerve may have a waxy pallor, especially late in the disease.  Occasional patients have cysts in the macula.  Some patients experience continuous photopsia. 

Systemic Features: 

The ‘simple’ or nonsyndromal type of RP described here has no systemic features.  However, the retinopathy is seen in a number of syndromes and, of course, in some infectious diseases as well.  It is more accurate to label the fundus finding as 'pigmentary retinopathy' in such cases.

Genetics

A significant proportion of RP cases occur sporadically, i.e., without a family history.  Mutations in more than 30 genes cause autosomal recessive RP disorders and these account for more than half of all cases of retinitis pigmentosa.  More than 100 mutations have been identified in the RHO gene (3q21-q24) alone.  Mutations in some genes cause RP in both autosomal recessive and autosomal dominant inheritance patterns.  Compound heterozygosity is relatively common in autosomal recessive disease.  See OMIM 268000 for a complete listing of mutations.

Many genes associated with retinitis pigmentosa have also been implicated in other pigmentary retinopathies.  In addition, numerous phenocopies occur, caused by a variety of drugs, trauma, infections and numerous neurological disorders.  To make diagnosis even more difficult, the fundus findings and ERG responses in nonsyndromic RP in most patients are too nonspecific to be useful for classification. Extensive systemic and ocular evaluations are important and should be combined with genotyping in both familial and nonfamilial cases to determine the diagnosis and prognosis. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Photoreceptor transplantation has been tried in without improvement in central vision or interruption in the rate of vision loss.  Longer term results are needed.  Resensitizing photoreceptors with halorhodopsin using archaebacterial vectors shows promise in mice.  High doses of vitamin A palmitate slow the rate of vision loss but plasma levels and liver function need to be checked at least annually.  Oral acetazolamide can be helpful in reducing macular edema.

Low vision aids and mobility training can be facilitating for many patients.  Cataract surgery may restore several lines of vision, at least temporarily.

Several pharmaceuticals should be avoided, including isotretinoin, sildenafil, and vitamin E. 

References
Article Title: 

Bardet-Biedl Syndromes

Clinical Characteristics
Ocular Features: 

The term Bardet-Biedl is applied to a clinically and genetically diverse group of disorders, of which at least 21 entities (BBS1-BBS21) are recognized.  This discussion is generically relevant to all of the phenotypes since the retinal dystrophy is common to all.

A progressive rod-cone dystrophy is a cardinal feature of all forms of Bardet-Biedl syndrome.  However, a subset of patients have primary cone degeneration.  In at least some forms of this syndrome, the cause seems to be a defect in the cilia that impairs the intraciliary protein transport between the inner and outer segments of the photoreceptors.  Vision loss has an early onset and usually progresses rapidly with severe loss of central and peripheral vision by the second or third decade of life.  Night blindness may be evident by 7 or 8 years of age.  The ERG is not recordable even in early childhood.  Pigmentary changes in the retina are often labeled retinitis pigmentosa but they are atypical for the usual disease.  Early changes are more characteristic of atrophy with a paucity of pigment but later the bone spicule pattern of hyperpigmentation appears.  The macula can appear atrophic and sometimes has a bull's eye pattern.  Optic atrophy and retinal arteriole narrowing may be seen.  Bardet-Biedl syndrome is clinically similar to Biemond syndrome (210350) except for iris colobomas that occur in the latter disorder.

Systemic Features: 

Obesity, mental retardation, renal disease, and hepatic fibrosis with syndactyly, brachydactyly, and post-axial polydactyly are characteristic.  The degree of mental handicap varies widely.  Diabetes mellitus is present in about one-third of patients.  Structural deformities of genitalia as well as hypogonadism and menstrual irregularities often occur as in some other disorders but the association of severe vision loss and characteristic retinal changes are diagnostically helpful.  Kidney failure secondary to cystic nephronophthisis or other renal malformations is common. Hypercholesterolemia is found in many patients.  Many patients have motor difficulties, appearing clumsy and unsteady.  Emotional lability and inappropriate outbursts can be part of these syndromes as well.

Genetics

The syndromes of Bardet-Biedl are inherited in an autosomal recessive pattern.  At least 21 mutations have been identified.  Not all cases are caused by homozygosity of the same mutation since compound heterozygosity at two loci may also cause similar phenotypes.

Laurence-Moon syndrome (245800) is considered part of the Bardet-Biedl group of diseases in this database. 

Mutations in PNPLA6 have been found in some individuals with a form of Bardet-Biedl syndrome as well as in Boucher-Neuhauser Syndrome (215470) also known as Chorioretinopathy, Ataxia, Hypogonadism Syndrome, and Trichomegaly Plus Syndrome (275400), in this database.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment exists for these syndromes but organ specific therapy may be helpful.

Studies in a mice model suggest that the neural retina may at least partially recover in type 1 following subretinal injection of viral vectors containing the wild-type bbs1 gene.

 

References
Article Title: 

Bardet-Biedl Syndrome

Suspitsin EN, Imyanitov EN. Bardet-Biedl Syndrome. Mol Syndromol. 2016 May;7(2):62-71.

PubMed ID: 
27385362

Predominantly cone-system dysfunction as rare form of retinal degeneration in patients with molecularly confirmed Bardet-Biedl Syndrome

Scheidecker S, Hull S, Perdomo Y, Studer F, Pelletier V, Muller J, Stoetzel C, Schaefer E, Defoort-Dhellemmes S, Drumare I, Holder Graham E, Hamel Christian P, Webster Andrew R, Moore Anthony T, Puech B, Dollfus Helene J. Predominantly cone-system dysfunction as rare form of retinal degeneration in patients with molecularly confirmed Bardet-Biedl Syndrome. Am J Ophthalmol. 2015 May 14. [Epub ahead of print]. 

PubMed ID: 
25982971

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

Mutations in IFT172 Cause Isolated Retinal Degeneration and Bardet-Biedl Syndrome

Bujakowska KM, Zhang Q, Siemiatkowska AM, Liu Q, Place E, Falk MJ, Consugar M, Lancelot ME, Antonio A, Lonjou C, Carpentier W, Mohand-Sayid S, den Hollander AI, Cremers FP, Leroy BP, Gai X, Sahel JA, van den Born LI, Collin RW, Zeitz C, Audo I, Pierce EA. Mutations in IFT172 Cause Isolated Retinal Degeneration and Bardet-Biedl Syndrome. Hum Mol Genet. 2014 Aug 28.  [Epub ahead of print].

PubMed ID: 
25168386
Subscribe to RSS - multiple