mental retardation

Hurler and Scheie Syndromes (MPS IH, IS, IH/S)

Clinical Characteristics
Ocular Features: 

Progressive corneal clouding is a major feature and appears early in life.  Intracellular accumulations of heparan and dermatan sulfate are responsible for the ground glass appearance.  However, congenital glaucoma also occurs in MPS I and must be considered as a concomitant cause of a diffusely cloudy cornea.

Abnormal storage of mucopolysaccharides has been found in all ocular tissues and in the retina leads to a pigmentary retinopathy.  The ERG may be abolished by 5 or 6 years of age.  Papilledema is often followed by optic atrophy.  Photophobia is a common symptom.  Shallow orbits give the eyes a prominent appearance.

Systemic Features: 

This group of lysosomal deficiency diseases is probably the most common.  MPS I is clinically heterogeneous encompassing three clinical entities: Hurler, Hurler-Scheie, and Scheie.  In terms of clinical severity, Hurler is the most severe and Scheie is the mildest.  Infants generally appear normal at birth and develop the typical coarse facial features in the first few months of life.  Physical growth often stops at about 2 years of age.  Skeletal changes of dysostosis multiplex are often seen and kyphoscoliosis is common as vertebrae become flattened.  The head is large with frontal bossing and a depressed nasal bridge.  Cranial sutures, especially the metopic and sagittal sutures, often close prematurely.  The lips are prominent and an open mouth with an enlarged tongue is characteristic.  The neck is often short.  Odontoid hypoplasia increases the risk of vertebral subluxation and cord compression.  Joints are often stiff and arthropathy eventually affects all joints.  Claw deformities of the hands and carpal tunnel syndrome are common.  Most patients are short in stature and barrel-chested.

Cardiac valves often are thickened and endocardial fibroelastosis is frequently seen.  The coronary arteries are often narrowed.  Respiratory obstructions are common and respiratory infections can be serious problems.  Hearing loss is common.

Most patients reach a maximum functional age of 2 to 4 years and then regress.  Language is limited.  Untreated, many patients die before 10 years of age.

Genetics

The Hurler/Scheie phenotypes are all the result of mutations in the IDUA gene (4p16.3).  They are inherited in an autosomal recessive pattern.  A deficiency in alpha-L-iduronidase causes three phenotypes: Hurler (607014; MPS IH), Hurler-Scheie (607015; MPS IH/S), and Scheie (607016; MPS IS) syndromes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Various treatments have had some success.  Enzyme replacement using laronidase (Aldurazyme©) has been shown to reduce organomegaly and improve motor and respiratory functions.  It has been used alone and in combination with bone marrow transplantation but therapeutic effects are greater if given to younger patients.  It does not improve skeletal defects or corneal clouding.  MRI imaging has documented improvement in CNS signs.  Gene therapy has shown promise but remains experimental.  Regular lifelong monitoring is important using a multidisciplinary approach to identify potential problems.  Joint problems may be surgically correctable with special emphasis on the need for atlanto-occipital stabilization.  Corneal transplants may be helpful in the restoration of vision in selected patients.

References
Article Title: 

Sanfilippo Syndrome (MPS IIIA, B, C, D)

Clinical Characteristics
Ocular Features: 

This form of mucopolysaccharidosis causes little or no corneal clouding.  Abnormal retinal pigmentation can be seen.

Systemic Features: 

Sanfilippo syndrome differs from other forms of mucopolysaccharidoses in the severity of the neurologic degeneration compared to the amount of somatic disease.  Infants usually appear healthy but developmental delay becomes evident by 2 or 3 years of age and physical growth slows.  Deterioration in mental development is progressive and seizures occur in some.  Gait and speech are impaired and by age 10 years patients have severe disabilities.  Behavioral problems including hyperactivity and aggression are often severe.

There is some hepatosplenomegaly, mild coarseness of the facial features, claw hands and mild bony changes such as biconvexity of the vertebral bodies and thick calvaria.  Hirsutism and synophrys are common.  The hair is unusually coarse.  Joints are frequently stiff and more severely affected individuals may have hearing loss.  Diarrhea is frequently a problem and most patients have some airway obstruction and are susceptible to recurrent respiratory infections.  Some patients have cardiovascular problems.

Genetics

MPS III is a lysosomal storage disease and may be caused by mutations in 1 of 4 genes that result in defective enzymes unable to break down mucopolysaccharides (glycosaminoglycans).  MPS IIIA (252900)results from a defect in the heparan sulfate sulfatase gene SGSH (17q25.3), type IIIB (252920)from a defect in the N-acetyl-alpha-D-glucosaminidase gene NAGLU (17q21), type IIIC (252930) from a defect in the acetyl-CoA:alpha-glucosaminide acetyltransferase gene HGSNAT (8p11.1), and type IIID (252940) from a defect in the N-acetylglucosamine-6-sulfatase gene GNS (12q14).  Heparan sulfate is excreted in all types.  Because of their clinical similarities these are discussed as a group in this database.  All are inherited in autosomal recessive patterns.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the underlying disease.  Therapy is primarily supportive.  A multidisciplinary approach with neurologists, ophthalmologists, audiologists, cardiologists, gastroenterologists, and orthopedists is most likely to result in treatments that can improve quality of life.

References
Article Title: 

Pantothenate Kinase-Associated Neurodegeneration

Clinical Characteristics
Ocular Features: 

Clinically evident retinal degeneration is present in a significant number (25-50%) of individuals.  However, when combined with ERG evidence the proportion rises to 68%.  When present it occurs early and one series reported that it is unlikely to appear later if it was not present early in the course of the neurodegeneration.  Some patients have a fleck-like retinopathy.  Optic atrophy may be present in advanced cases.

Systemic Features: 

This is a disorder primarily of the basal ganglia resulting from progressive damage secondary to iron accumulation.  There is an early onset classic form with symptoms of extrapyramidal disease beginning in the first decade of life and rapid progression to loss of ambulation in about 15 years.  Others with atypical disease may not have symptoms until the second or third decades.  Clumsiness, gait disturbance, and difficulty with tasks requiring fine motor coordination are common presenting symptoms.  Motor tics are often seen.  Dysarthria, dystonia, rigidity and corticospinal signs are often present early as well.  Swallowing difficulties may be severe sometimes leading to malnutrition.  Cognitive decline and psychiatric disturbances such as obsessive-compulsive behavior and depression may follow.  Independent ambulation is lost in the majority of patients within one to two decades.    Brain MRIs show an ‘eye of the tiger’ sign with a specific T2- weighted pattern of hyperintensity within the medial globus pallidus and the substantia nigra pars reticulata.

Genetics

Iron accumulation in the basal ganglia resulting from homozygous mutations in the PANK2 gene (20p13-12.3) encoding a pantothenate kinase leads to the classic form of this autosomal recessive disorder. 

This is the most common of several diseases of neurodegeneration with iron accumulation in the brain known collectively as NBIAs.  The group is genetically heterogeneous with many overlapping features.  Mutations in PLA2G6 cause NBIA2A (256600) and NBIA2B (610217) while mutations in a FLT gene cause NBIA3 (606159). The latter does not have apparent eye signs.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Pharmacologic treatment is aimed at alleviation of specific symptoms such as dystonia and spasticity.  Some symptoms may improve with deep brain stimulation.

References
Article Title: 

Usher Syndrome Type I

Clinical Characteristics
Ocular Features: 

The fundus dystrophy of retinitis pigmentosa in Usher syndrome is indistinguishable from isolated retinitis pigmentosa.   Night blindness begins by about 10 years of age and the ERG by that time is often markedly diminished or absent.  Patches of hyperfluorescence are seen in younger individuals and these enlarge and coalesce with age.  Tunnel vision occurs early as the peripheral visual field is constricted to 5-10 degrees by midlife.  The retinal disease is progressive and blindness may be the final result.

Systemic Features: 

Type I Usher syndrome is characterized by profound hearing impairment beginning at birth, vestibular dysfunction, and unintelligible speech in addition to retinitis pigmentosa.  Vestibular areflexia is virtually complete and constitutes a defining feature.  Ataxic gait disturbances are common secondary to labyrinthine dysfunction and many children do not walk until 18-24 months of age.  Sitting alone may also be delayed.  Sperm motility is abnormal which is likely the basis for reduced fertility in male patients.  An abnormal exoneme morphology from ciliated progenitors is likely the common basis for these clinical findings.  MRI imaging has found a significant decrease in intracranial volume and brain size.  About 1 in 4 children have behavioral problems or psychosocial difficulties.

Genetics

Type I Usher syndrome is an autosomal recessive genetically heterogeneous disorder as mutations in at least 8 genes produce a similar disease.  These are: MYO7A (276900) at 11q13.5 causing USH1B (USH1A is now considered to be the same), USH1C at 11p15.1 causing USH1C (276904), CDH23 at 10q21-q22, causing USH1D (601067), PCDH15 at 10q21.1 causing USH1F (602083), and USH1G at 17q24-25 causing USH1G (606943).  Mutations in as yet unnamed genes in loci at 21q21 (USH1E; 602097), 10p11.21-q21.1 (USH1K), and 15q22-q23 (USH1H; 612632) may also cause this type I phenotype. They are discussed here as a single entity designated type I since the clinical features of each are indistinguishable.'

A varant of USH1C resulting from homozygous deletions in 11p15-p14, known as homozygous 11p15-p14 deletion syndrome, has the additional feature of severe hyperinsulinemia due to the involvement of ABCC8 and KCNJ11 genes (606528).

Clinical differences have led to the categorization of three types of Usher syndrome:  type I described here, type II (276901) caused by mutations in at least 4 genes, and type III (276902) caused by mutations in CLRN1.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

At-risk infants should have hearing evaluations as soon as possible after birth.  Assistive hearing devices are of little benefit.  Unless cochlear implants are placed in young children, speech may not develop.  Extra precautions during physical activities such as swimming, bicycling, and night-time driving are highly recommended. Speech therapy and low vision aids can be beneficial.

References
Article Title: 

Targeted exon sequencing in Usher syndrome type I

Bujakowska KM, Consugar MB, Place E, Harper S, Lena J, Taub DG, White J, Navarro-Gomez D, Weigel-DiFranco C, Farkas MH, Gai X, Berson EL, Pierce EA. Targeted exon sequencing in Usher syndrome type I. Invest Ophthalmol Vis Sci. 2014 Dec 2.  [Epub ahead of print].

PubMed ID: 
25468891

Heterogeneity in Phenotype of Usher-Congenital Hyperinsulinism Syndrome: Hearing Loss, Retinitis Pigmentosa, and Hyperinsulinemic Hypoglycemia Ranging from Severe to Mild with Conversion to Diabetes

Al Mutair AN, Brusgaard K, Bin-Abbas B, Hussain K, Felimban N, Al Shaikh A, Christesen HT. Heterogeneity in Phenotype of Usher-Congenital Hyperinsulinism Syndrome: Hearing Loss, Retinitis Pigmentosa, and Hyperinsulinemic Hypoglycemia Ranging from Severe to Mild with Conversion to Diabetes. Diabetes Care. 2012 Nov 12. [Epub ahead of print].

PubMed ID: 
23150283

Optic Atrophy 2, X-Linked

Clinical Characteristics
Ocular Features: 

Visual symptoms can begin in early childhood (males only) and vision deteriorates slowly.  All affected individuals have optic atrophy with acuities ranging from 20/30 to 20/100.  ERGs are usually normal whereas VEPs show prolonged latencies.  Color vision is variably defective and central scotomas are present.

Systemic Features: 

Some but not all patients have additional neurological signs including absent ankle jerks, hyperactive knee jerks, extensor plantar reflexes, dysarthria and dysdiadochokinesia.  Symptoms are usually minor.  Obligatory female carriers do not have optic atrophy or neurologic signs.  Mental retardation has been reported in a few patients.

Genetics

This is an X-linked recessive disorder secondary to a mutation in OPA2 (Xp11.4-p11.21). Only males are affected and female carriers are clinically normal.

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

No treatment is available for the optic atrophy.

References
Article Title: 

Myotonic Dystrophy 1

Clinical Characteristics
Ocular Features: 

Posterior subcapsular cataracts may be seen at any age, often with striking iridescent opacities in the overlying cortex as well.  These polychromatic lens changes can be diagnostic but are present in only 50% of young adults with myotonic dystrophy.  When present, they are almost always bilateral.  Proximal muscle involvement leads to ptosis, strabismus, weakness of the orbicularis oculi, and sometimes ophthalmoplegia.  Such muscle weakness may lead to exposure keratitis. 

As many as 25% of patients with DM have a pigmentary retinopathy, usually in a butterfly pattern.

A low IOP and even hypotony is sometimes seen.  The mean IOP in a series of 51 patients has been reported as 10.9 compared with 15.4 in controls.  Using ultrasound biomicroscopy, ciliary body detachments were found in at least one quadrant of all eyes.

Systemic Features: 

In the congenital form, hypotonia, generalized weakness, mental retardation and respiratory insufficiency are often present.  There is a great deal of clinical heterogeneity among patients.  Those with mild disease may have only cataracts and mild myotonia with a normal life expectancy.  Those with more severe disease (classical myotonic dystrophy) have these signs plus marked muscle weakness and wasting.  Cardiac conduction defects with secondary arryhthmias are a significant cause of mortality. Such patients tend to become disabled in adulthood.  Symptoms become evident in the second decade or later.  Deep muscle pain is common and can be severe.  Distal muscle weakness usually begins before facial muscle weakness is apparent.  Myotonia often involves the tongue while proximal muscle weakness can cause dysphagia and dysarthria.  Such patients may also suffer respiratory distress. Reproductive fitness is reduced in males who can have gonadal atrophy.  Frontal balding is common.  Some age-related cognitive decline occurs.

Over 60% of patients have a hearing impairment and more than half of these have auditory brainstem response abnormalities.  Vestibular hypesthesia is present in 37.5%.

Genetics

Myotonic dystrophy 1 is an autosomal dominant disorder caused by a trinucleotide (CTG) repeat expansion in a region of the DMPK gene (19q13.2-q13.3).  The number of repeats varies widely and is roughly correlated with severity of disease.  Infants with congenital myotonia usually have the highest number of repeats and have the most severe cognitive deficits.  The number can expand during gametogenesis each generation (resulting in the phenomenon of anticipation) and females generally transmit larger numbers.  Most infants with congenital myotonia are offspring of affected mothers.  Reduced fetal movement and hydramnios are often noted during such pregnancies.

Affected males have few offspring secondary to gonadal atrophy.  Affected heterozygous females, however, do not have the expected ratio of affected offspring because of the dynamic nature of the number of repeats.  The risk of an affected offspring for a nulliparous afflicted female is only 3-9% and she has a 20-40% risk of recurrence after the birth of an affected child.

In a study of sibships with myotonic dystrophy, 58% of offspring were affected when the transmitting parent was male and 63% when the transmitting parent was female.

At least some of the variable transmission risks and clinical heterogeneity may be explained by somatic instability of the CTG repeat numbers.  The degree of instability, moreover, may also be heritable.  Age of onset, for example, is modified by the level of somatic instability.  Further, patients in whom the repeat expands more rapidly develop symptoms earlier. 

A similar disorder, myotonic dystrophy 2 (602668), is caused by a tetranucleotide repeat expansion in the CNBP gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

A variety of pharmaceutical agents have been tried for pain management without consistent results.  No treatment improves the muscle weakness.  Cholesterol lowering drugs such as statins should be avoided.  Physical therapy may be helpful.

Cardiac conduction and structural defects are a significant threat even in asymtomatic patients and require constant monitoring for the development of arrythmias.

References
Article Title: 

Inner ear dysfunction in myotonic dystrophy type 1

Balatsouras DG, Felekis D, Panas M, Xenellis J, Koutsis G, Kladi A, Korres SG. Inner ear dysfunction in myotonic dystrophy type 1. Acta Neurol Scand. 2012 Nov 5. doi: 10.1111/ane.12020. [Epub ahead of print].

PubMed ID: 
23121018

Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity

les F, Couto JM, Higham CF, Hogg G, Cuenca P, Braida C, Wilson RH, Adam B, Del Valle G, Brian R, Sittenfeld M, Ashizawa T, Wilcox A, Wilcox DE, Monckton DG. Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity. Hum Mol Genet. 2012 May 16. [Epub ahead of print].

PubMed ID: 
22595968

Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1

Wahbi K, Babuty D, Probst V, Wissocque L, Labombarda F, Porcher R, Becane HM, Lazarus A, Behin A, Laforet P, Stojkovic T, Clementy N, Dussauge AP, Gourraud JB, Pereon Y, Lacour A, Chapon F, Milliez P, Klug D, Eymard B, Duboc D. Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1. Eur Heart J. 2016 Dec 9. pii: ehw569. [Epub ahead of print] PubMed.

PubMed ID: 
27941019

Lowe Oculocerebrorenal Syndrome

Clinical Characteristics
Ocular Features: 

Lens development is abnormal from the beginning secondary to abnormal migration of lens epithelium which has been described in fetuses by 20-24 weeks of gestation.  This leads to some degree of opacification in 100% of affected males.  The lens opacities may be polar or nuclear in location but complete opacification also occurs.   Leukocoria, miosis, microphthalmos and a shallow anterior chamber has been noted in neonates.  The cataractous lenses may be small and abnormally formed.  Glaucoma is present in more than half of affected males with onset by the age of 6 years and may be difficult to control.  Conjunctival and corneal keloids are found in about one-fourth of patients.

Adult female carriers characteristically have peripheral cortical opacities, appearing in a radial configuration.  These 'snowflake' opacities seldom cause visual symptoms.   It has been proposed that slit lamp examinations for such opacities can accurately determine the carrier status of females.

Systemic Features: 

Mental retardation, hypotonia, short stature, and developmental delays are common.  Seizures and behavior problems are seen in older children.  The renal defect secondary to defective phosphatidylinositol 4, 5-biphosphate 5- phosphatase results in a Fanconi-type aminoaciduria beginning late in the first year of life.  The phosphaturia leads to hypophosphatemia and eventually renal rickets.  Proteinuria, polyuria, as well as bicarbonate, sodium and potassium wasting with tubular acidosis are all part of the urinary profile.  Some patients have dental cysts and/or defective dentin.

Genetics

The mutation causing this X-linked disorder is in the OCRL gene located at Xq26.1.  New mutations have been found among nearly one-third of affected males.  

Another X-linked disorder with similar but less severe kidney disease, Dent disease 2 (300555), has been found to have mutations in the same gene.  However, none of the ocular features are present.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts need to be removed before sensory nystagmus and amblyopia develop.  Fluid and electrolyte balance must be maintained.  Growth hormone can be used in selected patients.  Supportive systemic care is necessary in most cases.  Lifelong kidney and ocular monitoring is recommended.

References
Article Title: 

Hunter Syndrome (MPS II)

Clinical Characteristics
Ocular Features: 

Corneal clouding may be noted as early as 6 months of age but is usually absent. When present it is milder than in some other forms of mucopolysaccharidosis.  A pigmentary retinopathy with variable severity is often present.  The disc may be elevated and appears swollen.  Secondary optic atrophy may be seen in long standing cases.

Systemic Features: 

Mild to severe developmental delays are common and mental retardation has been reported in some cases.  There is often 'pebbling' of the skin over the neck and chest.  Joint stiffness, short stature, and skeletal deformities are common.   Many have short necks, a protuberant abdomen, a broad chest, and facial coarseness.  Hepatosplenomegaly, hearing loss, hernias, and carpal tunnel syndrome are often present.  The skull is large with a J-shaped sella, the vertebral bodies are hypoplastic anteriorly, the pelvis and femoral heads are hypoplastic and the diaphyses are expanded.

A severe form, type A, has its onset in the first two to four years of life, with more rapid progression and death commonly by adolescence.  Many patients have obstructive pulmonary disease and heart failure.  The IDS deficiency is similar to that of type B which is less severe and compatible with life into the 7th decade.  Intelligence is often normal in type B.

Genetics

Hunter syndrome, or MPS II, is one of seven lysosomal enzyme deficiencies responsible for the degradation of mucopolysaccharides, and the only one known to be X-linked (Xq28).  The mutation in IDS leads to a deficiency of iduronate sulfatase resulting in accumulation of dermatan and heparin sulfate.  Rare affected females may have chromosomal deletions instead of a simple mutation in IDS.

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

Various therapies are under development including enzyme replacement, gene transfers, and bone marrow transplantation.  Human iduronate-2-sulfatase (Idursulfase) has been used with encouraging signs but it is too early to determine the long term effectiveness.

References
Article Title: 

Tuberous Sclerosis 2

Clinical Characteristics
Ocular Features: 

The primary clinical characteristic of tuberous sclerosis of both types 1 and 2 are the occurrence of hamartomas at multiple anatomic sites.  Ocular lesions include those of the eyelids which often appear in early childhood along with other facial angiofibromas (formerly called adenoma sebaceum).  Of greater clinical significance are lesions of the optic nerve and retina reported in about 75% of patients.  The latter (astrocytic hamartomas) may appear as mulberry-like growths typically located in the peripapillary area or as flat translucent lesions located more peripherally.  These are usually static but aggressive growth with retinal detachment and neovascular glaucoma requiring enucleation has been reported in several patients.  Calcification of these lesions may occur in utero or early in life.  They are seldom of clinical significance although optic atrophy has been reported.  The ocular phenotype is similar in types 1 and 2.

Systemic Features: 

Hamartomas develop throughout the body in many organs such as the skin, brain, eye, kidney, and heart.  Ninety per cent of patients have skin lesions, including hypomelanotic patches called 'ashleaf' spots that can best be visualized under a Woods lamp.  Symptoms vary widely depending upon the location and size of the growths.  These appear as rhabdomyomas in the heart, angiomyolipomas in the kidneys, bone cysts, and oral fibromas.  Other intracranial growths such as subependymal astrocytomas and cortical tubers are evidence of CNS involvement that can interfere with brain function leading to seizures (in 80% of patients) and subnormal intellectual abilities (60-70% patients) as manifested by learning difficulties, subnormal IQs, as well as social and communication difficulties.   Hypoplasia of dental enamel with pitting in permanent teeth is seen in the majority of patients.  Some progression of tumor size and symptoms may occur.  Most hamartomas are benign but renal carcinoma has been reported in some patients.

There is some evidence that the clinical disease is more severe in this type (TSC2) than in type 1 (191100).  TSC2 has more hypomelanotic patches and brain tubers.  Cognitive defects are more severe.  Those with TSC2 mutations also have an earlier onset of seizures and a higher incidence of infantile spasms.

Genetics

This is the more severe and more common of the two tuberous sclerosis complex phenotypes.  It is caused by mutations in the TSC2 gene encoding tuberin on chromosome 16p13.3.  Genotyping is necessary to determine which mutation is responsible for the TS complex in each case as the phenotypic differences are inadequate to distinguish between types 1 and 2.

Many cases (two-thirds) occur sporadically but numerous reported pedigrees are consistent with autosomal dominant inheritance.  Type 1 TSC (191100) is caused by mutations in the TSC1 gene (9p34) encoding hamartin and is responsible for the disorder in about 25% of patients.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective preventative treatment exists but individual lesions can be surgically removed when indicated.

References
Article Title: 

Tuberous Sclerosis 1

Clinical Characteristics
Ocular Features: 

The primary clinical characteristic of tuberous sclerosis of both types 1 and 2 are the occurrence of hamartomas at multiple anatomic sites.  Ocular lesions include those of the eyelids which often appear in early childhood along with other facial angiofibromas (formerly called adenoma sebaceum).  Of greater clinical significance are lesions of the optic nerve and retina reported in about 75% of patients.  The latter (astrocytic hamartomas) may appear as mulberry-like growths typically located in the peripapillary area or as flat translucent lesions located more peripherally.  These are usually static but aggressive growth with retinal detachment and neovascular glaucoma requiring enucleation has been reported in several patients.  Calcification of these lesions may occur in utero or early in life.  These are seldom of clinical significance although optic atrophy has been reported. The iris may have hypopigmented areas.

Systemic Features: 

Hamartomas develop throughout the body in many organs such as the skin, brain, eye, kidney, and heart.  Ninety per cent of patients have skin lesions, including hypomelanotic patches called 'ashleaf' spots that can best be visualized under a Woods lamp.  Symptoms vary widely depending upon the location and size of the growths.  These appear as rhabdomyomas in the heart, angiomyolipomas in the kidneys, bone cysts, and oral fibromas.  Other intracranial growths such as subependymal astrocytomas and cortical tubers are evidence of CNS involvement that can interfere with brain function leading to seizures (in 80% of patients) and subnormal intellectual abilities (60-70% patients) as manifested by learning difficulties, subnormal IQs, as well as social and communication difficulties.   Hypoplasia of dental enamel with pitting in permanent teeth is seen in the majority of patients.  Some progression of tumor size and symptoms may occur.  Most hamartomas are benign but renal carcinoma has been reported in some patients.

Genetics

Many cases (two-thirds) occur sporadically but numerous reported pedigrees are consistent with autosomal dominant inheritance.  Type 1 TSC is caused by mutations in the TSC1 gene (9p34) encoding hamartin and is responsible for the disorder in about 25% of patients.

A more severe phenotype, tuberous sclerosis 2 (613254), is caused by mutations in the TSC2 gene on chromosome 16p13.3 and accounts for the majority of cases of tuberous sclerosis complex.  Genotyping is necessary to determine which mutation is responsible for the TS complex in each case as the phenotypic differences are inadequate to distinguish clinically between types 1 and 2.

New mutations are responsible for 50-70% of cases.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective preventative treatment exists but individual lesions can be surgically removed when indicated.

References
Article Title: 

Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34

van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, Lindhout D, van den Ouweland A, Halley D, Young J, Burley M, Jeremiah S, Woodward K, Nahmias J, Fox M, Ekong R, Osborne J, Wolfe J, Povey S, Snell RG, Cheadle JP, Jones AC, Tachataki M, Ravine D, Sampson JR, Reeve MP, Richardson P, Wilmer F, Munro C, Hawkins TL, Sepp T, Ali JB, Ward S, Green AJ, Yates JR, Kwiatkowska J, Henske EP, Short MP, Haines JH, Jozwiak S, Kwiatkowski DJ. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997 Aug 8;277(5327):805-8.

PubMed ID: 
9242607

Tuberous sclerosis

Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008 Aug 23;372(9639):657-68. Review.

PubMed ID: 
18722871

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