Wilson’s disease

DEFINITION/OVERVIEW AND ETIOLOGY

Although Kayser and Fleischer first described

the corneal ring associated with Wilson’s disease in 1902 and 1903,40,41 Wilson

published what is considered to be the landmark clinical description of the disease in 1912.42 Wilson’s disease is now known to be a disorder of copper transport caused by mutations in the P-type ATPase transporter that is specific to the liver.43 This copper transporter functions in the liver and regulates copper excretion into the bile. If its function is impaired, copper cannot be incorporated into ceruloplasmin and thus accumulates in the liver, cornea, and brain.

Clinically, affected individuals have a highly variable presentation44 with an asymptomatic period. During this time, hepatic copper deposition is occurring. Children can present with hepatic disease, even though presentation can be either hepatic or neurologic. Although it can also present as an acute hemolytic crisis in infants and young children, it more typically presents between the ages of 8 and 16 years with hepatic dysfunction. Neurologic presentation can be dystonia with rigidity, tremors, and contractures, pseudosclerotic with tremors, or psychiatric with intellectual deterioration and behavioral changes.45

Diagnosis relies on demonstration of copper levels in liver biopsy samples, elevated serum nonceruloplasmin-bound copper levels, and decreased serum ceruloplasmin levels. Measurement of 24-hour urinary copper can also be helpful.46 Wilson’s disease is inherited in an AR fashion and results from a defect in biliary copper excretion related to mutations in the ATP7B gene. Molecular genetic testing is available. Treatment revolves around removing excess copper from the system,46 using penicillamine, trientine and zinc. Fulminant liver failure is treated by transplantation; however, chelation therapy must be continued afterwards in order to avoid liver failure of the transplanted liver. Because prognosis is good if treatment is initiated early, there is a current push for the inclusion of this disorder on all expanded newborn screening panels.

CLINICAL PRESENTATION

The Kayser–Fleischer ring, found in 95% of patients, is the most important ophthalmic feature of Wilson’s disease (246). It is a deposition of copper and sulfur-rich granules in the Descemet’s membrane of the peripheral cornea that appear as gold or gray-brown opacities. It appears first in the superior peripheral cornea and spreads horizontally, eventually spreading inferiorly. The width and density increase as the disease progresses and the severity of the disease correlates with the density of the ring. There are no visual aberrations produced from its presence. It is not pathognomonic of the disease, and it can be seen with intraocular copper foreign bodies and also in liver diseases such as hepatitis and cirrhosis.

A sunflower cataract can develop. This cataract develops in the anterior capsule of the lens and is likened to a sunflower with a spherical center and satellite extensions. Oculomotor problems with saccadic pursuit movements and losses of accommodation and near responses have been described.22

MANAGEMENT/TREATMENT

No treatment is needed for the corneal deposits; however, these tend to fade with chelation therapy. Successful liver transplantation has also resulted in the fading and disappearance of the Kayser–Fleischer ring. Cataract surgery is rarely needed for the sunflower cataract.

246

246 Wilson’s disease.Kayser-Fleischer ring in a child.(From Strobel S et al.Paediatrics and Child Health – The Great Ormond Street Colour Handbook,Manson Publishing.)

Fabry disease

DEFINITION/OVERVIEW AND ETIOLOGY

Fabry disease is an inborn error of metabolism that results from a deficiency of ceramide trihexosidase (α-galactosidase A) and leads to an accumulation of glycosphingolipids. The disease was first described independently by two dermatologists: Anderson in England and Fabry in Germany.47,48 Nonocular cardinal features of this disorder are episodic pain (particularly of the extremities), angiokeratomas of the skin, hypohydrosis, postprandial pain, and diarrhea. Due to the enzymatic defect, renal disease, along with coronary and cerebral vascular disease, typically develops over time. Intermittent and burning pain, often beginning in the first decade, is the primary complaint. Pain crises tend to be self-limited, although they can last from days to weeks. Recurrent fevers may also be present. Dark red punctate skin lesions, which microscopically are found to be angiokeratomas, appear at puberty and are commonly seen in a ‘swim trunk’ distribution, especially on the scrotum and buttocks. The disease is inherited in an X-linked fashion, but due to random X inactivation, carrier females may also be symptomatic. In one study, up to 70% of carrier females described pain episodes.49 Enzyme replacement therapy with α-galactosidase is available and has helped to reverse storage of glycosphingolipids in lysosomes and alleviate some of the symptoms.50 Renal failure is a long-term consequence of the disease. Transplantation cures the kidney disease, but does not affect accumulation of glycosphingolipids in other tissues. Molecular analyses of the GLA gene are clinically available to confirm the diagnosis after deficient enzyme activity is identified. Since heterozygous females may have normal levels of enzyme activity, this is the most reliable method of determining carrier status in females.

CLINICAL PRESENTATION AND MANAGEMENT/TREATMENT

Eye findings related to Fabry disease are subtle and rarely affect the vision. The most well known are cornea verticulatta, which are bilateral whirl-like opacities that are located in the inferior cornea. Their colors range from white to golden brown and they do not affect the vision. Although these deposits have been identified at as early as 3 years of age, there is no correlation with the progression of the disease, the deterioration of renal function, or the increase in cardiac size.51 They bear some resemblance to the lesions produced by the systemic administration of chloroquines, indomethacin, and amiodarone.22 This ocular finding may be seen in isolation and, therefore, is a reliable marker of the disease.

Tortuosity with aneurysmal dilatations of the conjunctival vessels, as well as retinovascular tortuosity, is also seen in Fabry disease. This tortuosity does have positive predictive value for the severity of the systemic disease. It usually does not occur in isolation, and therefore by itself is not diagnostic of Fabry. Cataracts were shown to be present in 9.8% of females and 23.1% of males in the European database for Fabry disease.51 They are typically diagnosed before 10 years of age and have two distinct forms. One has a whirl-like appearance in the subcapsular level of the lens, while the other presents as multiple minute dots along the nuclear suture lines.22 Both forms usually do not impair vision; slit-lamp examination is needed for visualization.

Treatment is not needed for the corneal, lenticular, conjunctival or retinal disease.

Osteogenesis imperfecta

DEFINITION/OVERVIEW AND ETIOLOGY

Osteogenesis imperfecta (OI) is a disorder of collagen synthesis.52 The descriptive term ‘osteogenesis imperfecta’ was introduced in 1849 by Vrolik in his Handbook of Pathological Anatomy.52 Because there are no specific diagnostic criteria for OI as are available for other connective tissue disorders, such as Marfan’s syndrome or Ehlers–Danlos syndrome, a classification scheme of type I–IV was introduced in 1979.53 This scheme, along with the identification of different bony disorders with similar clinical findings, has been widely accepted and modified. The diagnosis is dependent upon clinical presentations which include: fractures with minimal or no trauma, short stature often associated with bony deformities, blue to gray tinged sclerae, progressive hearing loss (usually after puberty), ligamentous laxity, and dentinogenesis imperfecta (which can also be seen as an independent entity not associated with OI). There can be phenotypic variability within and between families.

Types I–IV are all related to mutations in either the COL1A1 or COL1A2 genes which code for type 1 collagen. The less severe forms tend to result from mutations that result in premature chain termination or decreased chain production. This causes normal, albeit fewer, collagen fibers to be formed. The moderate and severe types are more likely to be caused by structural defects in the type I collagen, resulting in abnormal collagen molecules. The genes involved in types V and VI have not yet been identified. Type VII is caused by a mutation in the cartilage-associated protein gene, the function of which is required for prolyl 3-hydroxylation of collagens I and II. Type VIII is caused by a mutation in the leprecan protein, which is another collagen prolyl hydroxylase that is required for proper collagen biosynthesis folding and assembly.

After the diagnosis is suspected, confirmation can be done by either molecular analysis or collagen studies in fibroblasts. Mutation analysis can be quite sensitive if the diagnosis is highly suspected. Collagen studies in fibroblasts remain the gold standard of diagnosis. If no

biosynthesis abnormalities or mutations are identified, then urinary collagen N-telopeptide excretion can be helpful, especially in the diagnosis of OI V.

Treatment of OI tends to be supportive. The ultimate goal is to minimize fractures and maximize function using a combination of physical therapy and orthopedic interventions. Dental surveillance is also important. Conductive hearing loss is usually related to fracture of the bones in the middle ear. With age, sensorineural hearing loss becomes apparent and is not amenable to surgery. Cochlear implantation has been performed in a limited number of patients.54 The introduction of bisphosphonates has been heralded as a promising therapy. Some symptomatic improvements have been reported with the use of IV pamidronate, although there is a paucity of randomized, placebo-controlled clinical trials. More recently, oral alendronate has shown promising results and is quickly becoming the gold standard of care.55 Growth hormone has been used to improve linear growth and bone formation.

CLINICAL PRESENTATION

Blue sclera is a well known clinical finding of OI (247). Chan et al. (1982) found the thickness of collagen fibers to be reduced by 25% in the cornea and 50% in the sclera.56 They also demonstrated a lack of the typical cross striations found in these fibers. These abnormalities make the sclera near translucent and allow the underlying uveal pigment to become more clinically visible, resulting in a blue/gray appearance of the sclera. The region of sclera adjacent to the cornea often maintains a whiter appearance and is commonly referred to as a ‘Saturn’s ring’. Individuals affected with OI type I maintain this blue intensity throughout life, but those with types III and IV show a marked fading, typically resulting in a normal appearing sclera by adolescence and adult life.57 This scleral abnormality does not impact on the vision; however, it does lower ocular rigidity and therefore renders the eye more susceptible to minor trauma.

Corneal thickness is reduced, which also increases the risk of injury with minor trauma. The thickness of the cornea negatively correlates with the blueness of the sclera.58 This corneal thickness can artificially lower the IOP. Retinal

hemorrhages and subdural hematomas secondary to minor trauma were found during routine work-ups for shaken baby syndrome.59 Additional ocular findings include myopia, glaucoma, and kerataconus.

MANAGEMENT/TREATMENT

The most important role of the ophthalmologist in caring for children with OI is that of prevention. The decreased ocular rigidity and decreased corneal thickness make these children

more susceptible to major eye injuries from minor trauma. Protective eyewear should be prescribed for all children that are not bedbound. Once an injury has occurred, the ophthalmologist must be aware that repair by conventional means is not always possible; corneal grafting and scleral patching may be necessary. Pirouzian et al. (2007) reported a case of scleral perforation secondary to chronic rubbing that required a scleral patch.60