pigmentary retinopathy

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: 

Myotonic Dystrophy 2

Clinical Characteristics
Ocular Features: 

Polychromatic lens opacities and posterior subcapsular sclerosis are found in 15-30% of patients. 

Ptosis, ophthalmoplegia and strabismus are not features of DM2.As many as 25% of patients with DM have a pigmentary retinopathy, usually in a butterfly pattern.

Systemic Features: 

Symptoms of myotonia usually appear in the third and fourth decades of life while evidence of limb girdle muscle weakness usually appears much later.  There is no infancy or childhood form of the disease and developmental delays do not occur.   In some patients the proximal muscles seem to be more affected than distal muscles and such cases are sometimes referred to as PROMM disease.  In these patients the neck and finger flexors may be the first to be affected.  However, there is considerable clinical variability.  Facial weakness is minimal.  Eventually both proximal and distal muscles weaken.  Myalgia of a burning, tearing nature can be debilitating.  Cardiac arrhythmias occur in a minority of patients.  Frontal balding is characteristic.  The long-term prognosis is better than in patients with myotonic dystrophy 1 (160900), and some but not all reports suggest fewer individuals experience age-related cognitive decline.  Insulin insensitivity and testicular failure occur in approximately half of patients.

PROMM disease and DM2 are now generally accepted as the same disease and the latter designation is preferred.

Genetics

Like classic myotonic dystrophy 1 (160900), this disorder also results from an abnormal number of repeats (in this case of CCTG).  Up to 30 tetranucleotide repeats in CNBP (3q21.3) is normal but patients with myotonic dystrophy 2 may have 11,000 or more and the number increases with age.  The repeat length may diminish with generational transmission.  Unlike DM 1, the repeat number does not seem to correlate with disease severity.  Both DM1 and DM2 are inherited in an autosomal dominant pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the muscle disease but many patients require analgesic medication for muscle pain.  Visually significant cataracts should be removed.  Some patients require supportive care.

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: 

Sjogren-Larsson Syndrome

Clinical Characteristics
Ocular Features: 

The retina often has glistening white intraretinal dots which may be concentrated in the macula.  They have been found in 1 to 2 year old infants.  The macula may have ‘punched out’ lesions.  A pigmentary retinopathy is present in about 50% of patients and fluorescein angiography reveals a mottled hyperfluorescence. The cornea often has grayish stromal opacities that become vascularized, most commonly in the lower half.  Most patients have punctate keratitis resulting in marked photophobia.  Visual acuities can range from about 20/40 to finger counting.  The retinal changes may be progressive but EOG and ERG studies do not reveal abnormalities of retinal function.  VEPs though are often abnormal.  Ichthyosis may involve the lids and periorbital areas.

Systemic Features: 

The skin changes are present at birth and consist of an ichthyosiform erythroderma.  Hyperkeratosis is also present at birth and full blown ichthyosis develops during infancy.  The skin changes are most marked about the neck, flexion creases, and lower abdomen.  Scales in these areas are often darker than the surrounding skin.  Mental retardation may be mild to severe and spastic diplegia or quadriplegia is common but there is little evidence of progression.  There does not seem to be any correlation of age with the severity of neurological disease.

Genetics

Mutations in the ALDH3A2 gene (17p11.2) are responsible for this autosomal recessive disorder resulting in a deficiency of fatty aldehyde dehydrogenase. This can lead to long-chain fatty alcohol accumulation as demonstrated in the brain with proton magnetic resonance spectroscopy.

A form of Sjogren-Larsson syndrome with more severe neurologic signs is caused by recessive mutations in ELOVL4 (6p14,1),  Mutations in the same gene have been identified in patients with autosomal dominant Stargardt disease 3 (600110).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder but moisturizing skin treatments can be beneficial.

References
Article Title: 

Peroxisome Biogenesis Disorder 1B (neonatal adrenoleukodystrophy)

Clinical Characteristics
Ocular Features: 

This peroxisomal disorder presents in the first year of life with both systemic and ocular features.  Night blindness is the major ocular feature and at least some have optic atrophy similar to the adult form.  Central acuity is reduced secondary to macular degeneration.  A pigmentary retinopathy is frequently present and often follows the appearance of whitish retinal flecks in the midperipheray.  Nystagmus and cataracts are common features.  Reduction or absence of ERG responses can be used in young children to document the retinopathy.  Blindness and deafness commonly occur in childhood.

Systemic Features: 

This disorder is classified as a leukodystrophy, or disease of white matter of the brain, associated with the breakdown of phytanic acid.  Ataxia and features of motor neuron disease are evident early.  Hepatomegaly and jaundice may also be early diagnostic features as bile acid metabolism is defective.  Infant hypotonia is often seen.  Nonspecific facial dysmorphism has been reported.  The ears are low-set and epicanthal folds are present.  The teeth are abnormally large and often have yellowish discoloration.  Postural unsteadiness is evident when patients begin walking.  Diagnosis can be suspected from elevated serum phytanic and pipecolic acid (in 20% of patients) or by demonstration of decreased phytanic acid oxidation in cultured fibroblasts.  Other biochemical abnormalities such as hypocholesterolemia, and elevated very long chain fatty acids and trihydroxycholestanoic acid are usually present.  Anosmia, developmental delays, and mental retardation are nearly universal features.  Early mortality in infancy or childhood is common.

Genetics

This is a genetically heterogeneous disorder of peroxisome biogenesis caused by mutations in at least three genes, PEX1 (7q21-q22), PEX2 (8q21.1), and PEX6 (22q11-21).  Each is inherited in an autosomal recessive pattern.  The mechanism of disease is different from the classic or adult Refsum disorder (266500) and some have debated whether the term ‘infantile Refsum disease’ is appropriate.

This disorder shares some clinical features with other peroxisomal disorders such as Zellweger syndrome (214100) and rhizomelic chondrodysplasia punctata (215100).  Zellweger syndrome (214100), neonatal adrenoleukodystrophy and infantile Refsum disease (601539) are now considered to be peroxisomal biogenesis or Zellweger spectrum disorders.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Refsum Disease, Adult

Clinical Characteristics
Ocular Features: 

A retinitis pigmentosa-like retinopathy is the major ocular manifestation of this disease.  There is typical night blindness and visual field constriction.   Rod ERG responses are usually subnormal.  However, central acuity is also reduced due to a degenerative maculopathy.   Cataracts and optic atrophy are common.  The macula may undergo progressive degeneration and optic atrophy is not uncommon.  Some patients have defective pupillary responses.

Systemic Features: 

Onset of symptoms is usually late in the first decade and sometimes into the third decade.  There is usually a polyneuropathy with impaired motor reflexes and paresis in the limbs.  A progressive sensorineural hearing loss occurs in many patients.  Sensory deficits also occur.  Some have ataxia and skin changes of ichthyosis.  Anosmia is a near universal feature.  Heart failure may occur and cardiac abnormalities such as conduction defects can occur.  A variety of skeletal abnormalities such as pes cavus, short fourth metatarsals, and evidence of epiphyseal dysplasia have been reported.  There is considerable clinical heterogeneity even within families.

Phytanic acid oxidase activity as measured in fibroblasts is often low while serum phytanic acid is increased.  The cerebrospinal fluid contains increased protein but no increase in cells.

Genetics

This disorder results from mutations in the PHYH (PAHX) gene (10pter-p11.2) encoding phytanoyl-CoA hydroxylase, or, more rarely in PEX7 (6q22-q24) encoding peroxin-7 resulting in an uncommon condition (10% of cases) sometimes called adult Refsum disease-2. 

Mutations in the latter gene also cause rhizomelic chondrodysplasia punctata type 1 (215100) which does not have all of the neurological features or the retinopathy.

There is also so-called infantile form of Refsum disease (266510).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

A diet low in phytanic acid can lead to improvement in the neurologic symptoms such as the ataxia and polyneuropathy but must be instituted in early stages of the disease.  This approach may not be as beneficial for the visual or auditory symptoms.

References
Article Title: 

Senior-Loken Syndromes

Clinical Characteristics
Ocular Features: 

The retinal disease associated with juvenile nephronophthisis has been variably diagnosed as retinitis pigmentosa, sector retinitis pigmentosa, Leber congenital amaurosis, and tapeto-retinal degeneration.  The retinal picture varies among members of the same pedigree and the various disorders.  Areas of bone-corpuscle pigment clumping may be seen sectorially in the periphery or throughout the fundus, and is associated with arteriolar narrowing.  The ERG usually suggests widespread receptor disease with decreased responses but often normal photopic and scotopic implicit times in some patients.  In other cases, blindness is evident in the first year of life and the fundus picture resembles Leber congenital amaurosis with a nonrecordable ERG and clinical nystagmus.  Retinal pigment changes in these cases may be absent or minimal although arteriolar narrowing is usually seen.  Visual fields are often severely constricted and vision can be limited to light perception.

Systemic Features: 

Renal disease may begin with symptoms of polydipsia and polyuria often in the first decade of life.  The kidneys are cystic and renal function becomes progressively impaired.  The polycystic disease is referred to as nephronophthisis for the kidneys often fail completely.  A few patients have had sensorineural deafness.  Liver dysfunction has been reported in some patients but it is uncertain if this is coincidental or a part of the SLNS disorder.

Genetics

This renal-retinal phenotype seems to have an autosomal recessive pattern of inheritance but is genetically and clinically heterogeneous.  Together these account for the majority of hereditary causes of end-stage renal disease in children and young adults.  At least 5 renal-retinal disorders have been identified with a great deal of phenotypic overlap requiring genotyping for distinction.  The common causative mechanism may be defects in the cilia of photoreceptors and renal epithelial cells.

SLNS1 (266900) is caused by mutations in the NPHP1 gene (2q12-13) encoding nephrocystin.  Some form of pigmentary retinopathy is frequently present although its age of presentation is highly variable.

(There is a NPHP2 disorder [602088] but no SLSN disease is associated with the NPHP2 gene [now called INVS] at 9q22-31 and encoding inversin).

SLSN3 (606995) has been mapped to 3q21-22, overlapping the NPHP3 locus.  This is a later onset, adolescent disease often presenting with anemia and renal failure occurring at a mean age of 19 years.  'Tapetoretinal degeneration' is part of the clinical picture.

SLSN4 (606996) is caused by mutations in the NPHP4 gene (encoding nephrocystin-3) and located at 1p36.  The onset of retinal disease may be later in onset than in other conditions.

SLSN5 (IQCB1)(606254) is caused by mutations in the NPHP5 gene (encoding nephrocystin-5) and located at 3q13.33-21.2.  Multiple mutations in this gene have been found and all patients have a pigmentary retinopathy.

SLSN6 (610189) results from mutations in the NPHP6 (CEP290) gene at 12q21.  Some patients have had a 'tapetoretinal degeneration'.

SLSN7 (613615) is caused by mutations in the SDCCAG8 gene at 1q44.  Some patients have retinal degeneration leading to blindness.

SLSN8 (616307) is caused by mutations in the WDR19 gene at 4p14.  Patients have severe reduction in vision and visual fields are severely restricted.  Bone spicule pigmentation can be seen in the periphery, the retinal vessels are attenuated, the ERG is undetectable, and there may be temporal pallor of the optic discs.

Hereditary disorders with isolated pigmentary retinopathy and cystic kidney disease also occur separately.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond renal transplantation is available.  Low vison aids can be helpful in some patients.

References
Article Title: 

Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin

Otto EA, Loeys B, Khanna H, Hellemans J, Sudbrak R, Fan S, Muerb U, O'Toole JF, Helou J, Attanasio M, Utsch B, Sayer JA, Lillo C, Jimeno D, Coucke P, De Paepe A, Reinhardt R, Klages S, Tsuda M, Kawakami I, Kusakabe T, Omran H, Imm A, Tippens M, Raymond PA, Hill J, Beales P, He S, Kispert A, Margolis B, Williams DS, Swaroop A, Hildebrandt F. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet. 2005 Mar;37(3):282-8.

PubMed ID: 
15723066

Senior-Loken syndrome: revisited

Warady BA, Cibis G, Alon U, Blowey D, Hellerstein S. Senior-Loken syndrome: revisited. Pediatrics. 1994 Jul;94(1):111-2.

PubMed ID: 
8008515

Fleck Retina of Kandori

Clinical Characteristics
Ocular Features: 

This disorder is usually included in listings of flecked retina syndrome but few reports exist.  Irregular flecks of variable size are distributed in the equator and posteriorly up to but excluding the macula.  Some disturbances of the RPE are seen and some degree of night blindness is usually present.  It seems to be a stable disorder.

Systemic Features: 

No systemic disease is associated.

Genetics

The genetic basis, if any, is unknown.

Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Flecked retina disorders

De Laey JJ. Flecked retina disorders. Bull Soc Belge Ophtalmol. 1993;249:11-22. Review.

PubMed ID: 
7952338

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