Although gangliosides are found throughout the body, they are found in highest concentration in the neurons and in the brain. Therefore, affected individuals suffer from an excess accumulation of glycolipid in the central and peripheral nervous system. Two major forms of gangliosidoses exist: GM1 and GM2. Both are autosomal recessive.

6.2.2  GM1 Gangliosidosis

The GM1 gangliosidoses occur secondary to deficiency of acid b-galactosidase activity. The clinical presentation of GM1 is variable. Several subtypes occur and are described as infantile, late infantile/juvenile, and adult/chronic types. The infantile form is characterized by infantile onset, rapid neurologic degeneration and dysmorphic features. Early development may appear to be normal. This is followed by an arrest in development and then neurologic regression. Seizures are frequent and the course is invariably a progressive neurologic deterioration with increasing spasticity. Decerebrate rigidity with spastic quadriplegia, blindness, deafness and unresponsiveness develops. Death usually occurs by age 2 years and is often due to bronchopneumonia.

Loss of vision occurs early in the course of the disease and ophthalmologic findings may help lead to a diagnosis. A cherry-red spot occurs in approximately half of affected patients (Fig. 6.4). Tortuosity of the retinal vessels, retinal hemorrhages, and optic atrophy have also been reported [28]. These findings are less consistently seen in the late infantile/juvenile and adult/chronic forms of GM1.

6.2.3  GM2 Gangliosidosis

6.2.3.1  Tay–Sachs Disease

Tay–Sachs disease occurs due to a deficiency of hexosaminidase A which is responsible for the hydrolysis of ganglioside GM2. As a result, lipidosis can be seen throughout the nervous system but are most prominent in cortical, autonomic and rectal mucosal neurons. The initial clinical presentation may be subtle and demonstrate a deterioration of both motor and mental function that begins in infancy, usually by 3–5 months of age. Irritability and feeding difficulties may be early symptoms. Exaggerated startle reactions is a typical early sign. Rapid progression begins after 10 months of age and the child becomes less responsive. A vegetative state will eventually develop and death generally occurs by 3 years of life.

Cherry-red spots develop in virtually all cases and are usually present when the neurologic signs first appear. Therefore, ophthalmologic examination may play an important role in helping to diagnose these patients.

6.2.4  Sandhoff Disease

The clinical manifestations and pathologic changes of Sandhoff disease are like those of Tay–Sachs disease. The genetic defect involves a deficiency of both hexosaminidase A and hexosaminidase B activity. As in Tay–Sachs disease, a cherry-red spot occurs. Optic atrophy and progressive vision loss leading to blindness early in the course of the disease occurs.

Fig. 6.4  Cherry-red spot seen in a patient with Tay–Sachs disease

6.2.5  Niemann–Pick Disease

Niemann–Pick (NP) disease includes two biochemically distinct entities: the primary sphingomyelin lipidoses, designated NPA and NPB and a cholesterol lipidosis, designated NPC. NPA and NPB are caused by a deficiency of acid sphingomyelinase (ASM). NPC is secondary to a defect in intracellular transport of cholesterol from the lysosome to the plasma membrane.

6.2.6  Types A and

B Niemann–Pick Disease

Sphingomyelin is a phospholipid that is found in plasma membranes, subcellular organelles, endoplasmic reticulum, mitochondria and in myelin sheaths. The enzyme defect leads to lysosomal accumulation of sphingomyelin, cholesterol, and other metabolically related lipids throughout the body.

Patients with NPA demonstrate severe neurologic and visceral manifestations. Hepatomegaly and splenomegaly develop in infancy. Presenting neurologic signs often include hypotonia and muscle weakness along with failure to thrive. The neurologic dysfunction is progressive and patients become debilitated. Death usually occurs by 3 years of age. Patients with NPB also demonstrate visceral involvement but do not develop the neurologic dysfunction seen in NPA. The difference between the two subtypes is due to the level of deficiency of sphingomyelinase activity found in each type, with NPA showing significantly less activity than NPB.

The most common ocular manifestation seen in patients with NP disease is a cherry-red spot of the macula that is seen in up to 50% of cases. Some patients may also develop a gray-white opacification of the macular ring which surrounds and accentuates the red blush of the central foveal region. This has appearance has been termed the macula halo syndrome [29]. Diagnosis of NP disease can be made by bone marrow biopsy which shows lipid-laden foamy cells (NP cells) along with enzyme studies of ASM.

6.2.7  Type C Niemann–Pick Disease

NPC leads to an accumulation of cholesterol in lysosomes. A vertical ophthalmoplegia occurs in affected individuals. Cherry-red spots and macular halos do not develop in NPC.

6.2.8  Fabry Disease

of the skin, cerebrovascular abnormalities, peripheral neuropathy and autonomic dysfunction. It is caused by a deficiency of the enzyme a-galactosidase A. Affected males demonstrate a profound deficiency of enzyme activity and heterozygous females demonstrate a partial deficiency. Due to the enzyme deficiency, ceramide trihexoside accumulates throughout the body including endothelial and smooth muscle cells of blood vessels, myocardial cells, epithelial cells of the kidney, cornea and adrenal glands. Deposition also occurs in the ganglion cells of the brain and peripheral nervous system and in the peripheral cells of the autonomic nervous system.

Affected males present with episodes of severe burning pain in the extremities. Skin lesions develop and are characteristic of the disease. These angiokeratomas develop in the superficial layers of the skin and increase in number and size with age. They do not blanch with pressure and are flat or slightly elevated. The lesions typically occur between the umbilicus and the knees. Cardiovascular involvement occurs over time and manifests as angina, arrhythmias, valvular disease and congestive heart failure. Renal disease leads to systemic hypertension and uremia.

Ocular involvement develops early in the course of the disease and may aid in diagnosis. Corneal opacification results from accumulation of lipid in the corneal epithelial cells. The deposition occurs in a whorl-like pattern that is characteristic. The lens may develop granular anterior capsular or subcapsular opacities arranged in a radiating wedge-shaped pattern which leads to a spoke-like cataract. The lens findings may be seen in the carrier female [30]. The retinal blood vessels are often dilated and tortuous (Fig. 6.5).