Anamika Dwivedi, P. C. Dwivedi, Charudatt Chalisgaonkar and Deepak Dwivedi
The lysosomal lipid storage diseases are diverse disorders, each
due to an inherited deficiency of lysosomal hydrolase leading to intralysosomal accumulation of enzyme specific substrate. 1They are rare metabolic disordersthat can involve any organ of body. Though ocular involvement inthese disorders is rarer as compared to systemic involvement, easy accessibility of eye gives an opportunity to aid in accurate and final diagnosis of these disorders.
There is an understanding of many inborn errors of metabolism at biochemical and molecular level, but exact pathogenesis remains to be established. With the exception of a few, lipid substrates share a common structure having a ceramide (2-N-acylsphingosine) backbone from which various sphingolipids are derived. Because sphingolipids are essential component of all cell membranes, the inability to degrade these substances and their subsequent accumulation results in physiologic and morphologic alterations and characteristic clinical manifestations of lipid storage diseases.
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The storage of a substrate in a specific tissue is dependent on its normal distribution in the body. Progressive lysosomal accumulation of glycosphingolipid in
CNS leads to neurodegenerationand in visceral cells it leads to organomegaly, skeletal abnormalities, pulmonary infiltration and other manifestations. As in other organ systems, possible mechanism for ocular defects is direct toxic action, errors of synthetic pathways or deficient energy metabolism.
Lysosomal lipid storage disorders are classified
2 as follows:
- Gangliosidoses: GM1 Gangliosidosis, GM2 Gangliosidosis(Tay
–Sachs disease,Sandhoff disease)
- Leukodystrophy: Krabbe
- Disorder of neutral lipid: Farber disease
Inheritance of lipid disorders is autosomal recessive except for X-
Diagnosis of affected individual is made through clinical examination, biopsy, genetic testing, molecular analysis of cell or tissue to identify inherited metabolic disease and enzyme assays. 2 Enzyme assays are done by measurement of specific enzyme activity in isolated leukocytes or cultured fibroblasts or lymphoblasts. 1 Genetic testing is helpful in identifying disease carriers in individuals with family history of lipid storage diseases. It can also determine diseased or carrier fetus. Prenatal testing is done by chorionic villus sampling and cultured amniocytes. 2
Gaucherdisease is the most frequently encountered lipid storage disorder, characterized by hematologic abnormalities, organomegaly and skeletal involvement. The disease follows an autosomal recessive inheritance pattern and is more common in Jews (4.5%). The gene of the enzyme glucocerebrosidase is located on the short arm of chromosome 1. The deficiency of the enzyme glucocerebrosidase(acid β-glucosidase) that is normally present in macrophage lysosome
, leads to accumulation of glucosylceramide in scavenger macrophages and subsequent deposition in the organs of reticuloendothelial system (liver, spleen and bone marrow).
There are three clinical subtypes of Gaucher disease depending on the absence or presence and progression of neurologic manifestations
- Type 1: Adult, non-neuronopathic form, accounts for 99% of cases
- Type 2: Infantile or acute neuronopathic form
- Type 3: Juvenile or
The three forms cannot be distinguished from one another biochemically. Gaucher cells are found in the bone marrow of all three variants.
Majority of patients with Gaucher disease develop features in childhood.The progressive deposition oflipid results in infiltration of the bone marrow with resultant pancytopenia, progressive hepatosplenomegaly and skeletal complications manifesting as bone pain, pathologic fractures and skeletal deformities. 2 Pulmonary involvement is not common but it can lead to interstitial lung disease and pulmonary hypertension.
Classically described ocular and neurologic
al associations of this disease include conjunctivalpterygia, strabismus and trismus with retroflexion of the neck. 3 Ocular motor defect in Gaucher types 2 and 3 is a progressive deficient horizontal gaze, especially for voluntary saccades , that simulates those of congenital ocular motor apraxia. 4,5Horizontal supranuclear gaze palsy is often one of the first neurologic al signs of neuronopathicGaucher disease. 6
Vitreous opacities are seen in this disorder
7,8 An incidence of 3% vitreous opacities has been reported in one series. 9Only those who have undergone splenectomy have the tendency to form vitreous aggregates because is available. Shrier et al reported retinal vascular tortuosity along with very severe vitreous opacities need ing vitrectomy ’ 3 and the Gaucher cells in the vitreous cavity, while the vitreous gel contain ed large amounts of glucosylceramide. 10
Pathologic hallmarks of Gaucher disease are the largeglucosylceramide-laden histiocytes
“Gauchercells ”inreticuloendothelial system, particularly bone marrow. Presence of intracytoplasmic inclusion gives characteristic “wrinkled paper appearance ” toGaucher cells. The presence ofGaucher cells in marrow aspirate and tissue biopsy is highly suggestive of the disease. Diagnosis is confirmed by determination of glucocerebrosidase activity in isolated leukocytes or cultured fibroblasts. 1
Symptomatic management of blood cytopenias, joint replacement surgeries and bisphosphonates for bone mineralization are important supportive
therapy. 2 Enzyme replacement therapy with glucocerebrosidase(Imiglucerase) is the current treatment of choice. Enzyme replacement therapy is effective in type –1 ( non neuronopathic) form of disease , however in type-2 and type-3 disease the outcomes are disappointing as systemically administered glucocerebrosidase is unable to pass through blood
Niemann – Pick disease is an inborn error of metabolism that results from impaired metabolism of sphingomyelin. 11Hepatosplenomegaly and foam cells in the bone marrow are constant features in all variants.
Niemann – Pick disease type A and type B occur due to deficient activity of acid sphingomyelinase (ASM) and pathologically characterized by lipid laden foam cells (Niemann –Pick cells). In NPD type C, ASM activity is usually normal, the metabolic block in type C is in the intracellular trafficking of cholesterol.The biochemical defects in type D and type E NPD remain undetermined.
Disease is characterized by failure to thrive, hepatosplenomegaly and a rapidly progressive neurodegenerative course that leads to death by 2 –3 years of age. Type B NPD is a heterogeneous non-neuronopathic form observed in children andadults. The disease shows hepatosplenomegaly, hyperlipidemia, interstitial pulmonary disease, variable survival to adulthood and absence of neurodegeneration. NPD type C has a sub acute clinical course and presents in infancy with neonatal hepatitis or later in childhood with moderate splenomegaly and gradual neurologic deterioration. Most patients have seizures and limitation of vertical gaze. The presence of downgaze paresis and ataxic athetosis is characteristic. NPD type D and E have slower neurodegenerative course.
In NPD-A most striking ocular finding is the presence of cherry-red maculae
(Fig. 1 – figure provided is of brao and not cherry red spot). Occasionally, a macular halo with grey granular appearing macula is observed. Optic atrophy developsovertime. Subtle lens opacities and corneal clouding can occur. ER G is usually abnormal.
In NPD-B cherry-red spot is present in small number of patients and not associated with neurodegeneration.
11,12Macular halo is a more common finding.
Type C is characterized by ophthalmoplegia with limitation of vertical gaze. Horizontal eye movements may be affected with total supranuclearophthalmoplegia.There is no macular cherry-red spot or macular halo in type C NPD. There are no ocular abnormalities in NPD type D. Patients with type E variant may have macular cherry-red spot.
The absence of ganglion cellsat fovea is responsible for
cherry red spot. Lipid storage in the macular region appears as a grayish white halo that results from the swelling and loss of transparency of multilayered ganglion cell ring. When significant lipid accumulation occurs in the ganglion cells, a white ring of lipid-laden neurons encircling the red, ganglion cell –free fovea can be observed as the characteristic macular cherry red spot.
The presence of characteristic NPD cells in bone marrow aspirate supports the diagnosis of NPD.
Confirmation of diagnosis is done by measuring acid sphingomyelinase activity in peripheral leukocytes, cultured fibroblasts or lymphoblasts which shows markedly decreased activity (1 –10%) in both type A and type B NPD. Prenatal diagnosis can be done by measuring sphingomyelinase activity in cultured amniocytes or chorionic villi.
Currently there is no specific treatment for NPD. Enzyme replacement therapy for NPD is under study for therapeutic use.
Fabry’s disease is an X-linked inborn error of glycosphingolipid metabolism due to deficient activity of alpha-galactosidaseA. Prevalence is estimated to be 1 in 50,000 males. Enzyme defect leads to the systemic accumulation of neutral glycosphingolipid, primarily globotriaosylceramide (‘Maltese cross’ crystals) in plasma and lysosomes of vascular endothelium and smooth muscle cells. This leads to ischemia, infarction and major disease manifestations.
Disease related complications can develop in heterozygotic females due to random X- inactivation.
Fabry’s disease is characterized by angiokeratoma (telangiectatic skin lesions), hypohidrosis, acroparesthesias (
agonising, burning pain in extremities “Fabry crisis ”), vascular disease of kidney, heart and brain with ocular changes.
Fabry’s disease can involve cornea, lens andconjunctival and retinal vessels. They correlate with the progressive deposition of glycosphingolipid in ocular structures.
13Vortex keratopathy (cornea verticillata) is the most common ocular manifestation reported in the disease and represents high sensitivity and specificity for Fabry’s disease. 14It should be differentiated from amiodaroneandchloroquine toxicity. In lens, patients exhibit typical lens opacity with a “spoke like ” pattern at the level of posterior capsule, referred as “Fabry’s cataract ”. Corneal opacities and lenticular changes, observed under slit-lamp examination, are present in affected males and 90% of heterozygotes.
Conjunctival vessels are abnormally dilated.Retinal vessels are tortuous and show aneurysmal dilatation and occlusion.
15 Disruption of vascular architecture is due to substrate accumulation within the vessel wall resulting in endothelial dysfunction, abnormal blood flow andhypercoagulability. Conjunctivaland retinal vessel tortuosity may represent a clinically significant marker of diffuse microvascular disorder leading to end organ pathology and increased vascular tortuosity correlates with severity of systemic disease. Ophthalmological manifestations ofFabry’s disease do not result in visual symptoms. 12Other ocular findings include lid edema, myelinated nerve fib ers, mild optic atrophy, papilledema, nystagmus , and internuclearophthalmoplegia.
In affected males, diagnosis is made from history of painful acroparesthesia, hypohidrosis
, and characteristic skin, corneal and lenticular lesions. Diagnosis is confirmed by markedly decreased alpha-galactosidase-A activity in plasma, isolated leukocytes, cultured fiboblasts or lymphoblasts. Prenatal diagnosis can be done by chorionic villus or cultured amniocytes.
Recombinant alpha-galactosidase (Fabrazyme) is a safe and effective enzyme replacement therapy. Medical management of acroparesthesiaand renal transplantation in patients of renal failure is done.
Gangliosidoses are inherent disorders of metabolism caused by defective activity of a lysosomal enzymecharacterized by progressive mental and motor deterioration due to the storage of GM1or GM2gangliosides in neurons.
16 GMs are classified in 2 groups: GM1 and GM2; Gm1 has two subtypes, while Gm2 has four subtypes.
- GM1 generalized form: It is caused by deficiency of isoenzymes A, B
,and C β-galactosidase.
- GM1 juvenile form: It is caused by deficiency of isoenzymes B
,and C β-galactosidase.
Gangliosidosis is an autosomal recessive disorder due to deficient activity of beta-galactosidase,characterized by pathologic accumulation of GM1 ganglioside in neural and visceral cells, which is most marked in the brain.
GM1 shows hepatosplenomegaly, edema, skin eruptions (angiokeratoma) and skeletal abnormalities.
Up to 50% of patients show macular cherry-red spotwhich is associated with neurodegeneration. Other ocular manifestations include nystagmus, retinal hemorrhages, optic atrophy and mild, diffuse corneal clouding.
Diagnosis is suspected in infants by typical clinical features andconfirmed by deficiency of beta
–galactosidase activity in peripheral leukocytes.
Currently only supportive treatment is available for the disease.
Gangliosidosis includesTay –Sachs disease andSandoffdisease resulting from deficiency of beta-hexosaminidase activity andlysoso smal accumulation of GM2 ganglioside especially in CNS. Beta-hexosaminidase has two isoforms A and B. Beta hexosaminidaseA is a trimeric protein composed of 1alpha and2 beta subunitsand isoform B has four beta subunits.
–Sachs disease results from mutation in alpha subunit causing deficiency of beta hexosaminidase A and is the most common storage disease causing macular cherry-red spot (Fig. 1). It is autosomal recessive in inheritance and has been classified into infantile, juvenile and adult forms. Infantile form is fatal neurodegenerative disease with microcephaly, loss of motor skills, increased startled reactionassociated with neurodegeneration and optic atrophy. Juvenile onset form presents with ataxia, dementia and death by 10 –15 years. Adult onset disease shows progressive motor weakness,dysarthria, spinocerebellar and lower motor neuron symptoms.
Sandhoff disease results from mutationin beta subunit causing deficiency of both
beta hexosaminidase A and B. Clinical manifestations are similar to Tay –Sachs disease with additional presence of hepatosplenomegaly, cardiac abnormality and bone dysplasia.
Ocular manifestations can be in the form of bilateral optic atrophy and a cherry- red spot at macula.
Krabbe disease, also known as globoid cell leukodystrophy, is a fatal disorder of infancy. Disease follows autosomal recessive pattern of inheritance.
Deficiency of enzymegalactocerebroside β-galactosidaseleads to accumulation of galactosylceramide in the white matter.Galactosylceramide is present exclusively in myelin sheath causing affection of both peripheral and central myelin, leading to severe degeneration of motor and mental skills.
Krabbe disease presents in early infancy with irritability, seizures, hypertonia and death before 3years of age. Ocular manifestations seen in this disorder are constant wandering eye movements and sluggish pupillary light reflexes.
17 Cherry-red spot is inconsistent but optic atrophy is seen very often. 1
Diagnosis is established by demonstration of deficient enzymatic activity in white blood cells or cultured skin fibroblasts.
Sulphatedglycosphingolipidtreatment of disease has been reported with umbilical cord blood cell transplantation in newborn and infants.
M etachromatic leukodystrophy (MLD )is an autosomal recessive white matter disease caused by deficiency of liposomal enzyme arylsulfataseA (ASA). 1 The enzyme is required for hydrolysis of sulphatedglycosphingolipid. Sulphatedglycosphingolipid accumulation in the white matter leads to demyelination andneurodegeneration.
Both central and peripheral nervous systems are involved giving upper and lower motor neurons, cognitive and psychiatric signs. Disease shows infantile, juvenile and adult forms. Infantile form presents between 12
– 18 months of age with irritability, inability to walk and hyperextension of knee. Juvenile form is seen in late twenties with gait disturbance and mental retardation. In adult form emotional difficulties and psychosis are more common.
Marked foveal atrophy with chorioretinal atrophy and progressive retinal pigment degeneration has been reported in this condition.
Cherry-red spot is inconsistent. Optic atrophy is seen in all three forms of disease. 19
The diagnosis of MLD in suspected patients is suggested by decreased nerve conduction velocities, increased cerebrospinal fluid protein, metachromatic deposits in sampled segments of sural nerve and metachromatic granules in urinary sediment.
Confirmation of the diagnosis is based on the demonstration of reduced activity of ASA in leukocytes or cultured skin fibroblasts.
Bone marrow transplantation has been tried, but clear evidence of clinical efficacy is lacking. Supportive care remains the primary intervention.
Disorder of neutral lipid
This is a rare autosomal recessive disorder that results from the deficiency of the lysosomal enzyme acid ceramidase and the accumulation of ceramide in various tissues, especially the joints. It is also known as Farberlipogranulomatosis.
The onset of Farber disease is typically in early infancy but may occur later in life and is characterized by painful joint swelling and nodule formation,breathing difficulties, failure to thrive and moderate
central nervous systeminvolvement.
The most common ophthalmic manifestation is cherry red-spot at the macula but is not as striking as seen in Niemann
–Pick and Tay–Sachs diseases.
Cogan and co-workers have demonstrated accumulated lipid-like material with inclusions in the ganglion cells of macula and midperiphery of retina.
20 Patients may have decreased visual acuity.
The diagnosis of this disorder should be suspected in patients who have nodule formation over the joints but no other findings of rheumatoid arthritis. In such patients, ceramidase activity should be determined in cultured skin fibroblasts or peripheral
Currently there is no specific therapy for Farber disease.
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