6.2.9  Farber Lipogranulomatosis

Farber disease is a disorder of lipid metabolism caused by a deficiency of lysosomal acid ceramidase which results in abnormal tissue accumulation of ceramide. Subcutaneous and periarticular nodules, progressive arthropathy and hoarseness are a hallmark of the disease. Several phenotypes occur and the clinical manifestations are variable. The classic form of the disease involves progressive deterioration of neurologic function and death occurs within the first few years of life. A cherry-red spot is seen within the macula.

6.2.10  The Mucopolysaccharidoses

The conditions genetically referred to as the mucopolysaccharidoses result from the deficiency of specific lysosomal enzymes involved in the metabolic degradation of dermatan sulfate, heparan sulfate, or keratan sulfate, either singly or in combination. The incompletely degraded mucopolysaccharides accumulate in various tissues and organs throughout the body and are excreted in the urine.

As a group, the mucopolysaccharidoses are characterized by a rather distinctive spectrum of clinical manifestations. Skeletal deformity, resulting from changes in both the bones and the joints, is a prominent feature. There is also a characteristic facies with coarse, often somewhat grotesque features. Visceromegaly, cardiac disease, respiratory problems, deafness, and mental deficiency occur in some of the syndromes. The principal ocular manifestations of the various mucopolysaccharidosesareprogressivecornealclouding,pigmentary retinal degeneration, optic atrophy, and in some cases glaucoma.

All forms of MPS are recessively inherited; one mucopolysaccharidosis, MPS type II (Hunter syndrome), is X-linked, and the others are autosomal. The diagnosis of the various mucopolysaccharidoses is made on the basis of the distinguishing clinical features, the presence of excessive mucopolysaccharide substances in tissue and urine, and demonstration of the enzyme deficiency, particularly in cultured fibroblasts.

6.2.10.1  MPS I: Hurler Syndrome, Scheie

Syndrome and Hurler/Scheie Syndrome

The disorders grouped together as MPS I represent a spectrum of clinical severity from the very severe (Hurler syndrome, MPS I H) through an intermediate (Hurler/Scheie syndrome, MPS I H/S) to a more mild form (Scheie syndrome, MPS I S). All forms of MPS I are due to a mutation of the gene encoding alpha-L- iduronidase (IUDA). Different mutations encoding for IUDA account for the variable activity of the enzyme, leading to the spectrum of clinical features represented by the three disorders [31]. All three disorders are autosomal recessive.

6.2.10.1.1  MPS I H: Hurler Syndrome

Hurler syndrome is the prototype of the mucopolysaccharidoses. The disorder is severe and progressive. There is accumulation of acid mucopolysaccharide in virtually every system of the body, producing both somatic and visceral abnormalities and leading to early death, usually by age 10 years.

In MPS I H there is a profound deficiency of IUDA, with excessive urinary excretion of both dermatan sulfate and heparan sulfate. It occurs in many races and is probably the most common of the mucopolysaccharidoses.

Manifestations develop in infancy and early childhood and become more apparent with increasing age. Theheadtendstobelargeandmisshapen.Scaphocephaly from premature closure of the sagittal suture is common, and there is often a prominent longitudinal ridge along the sagittal suture. The facial features characteristicallyarecoarseandtheexpressionisdull.Hypertelorism is usual, and the orbits are shallow; the eyes appear wide-set and prominent. The lids tend to be puffy, the brows prominent. The nose is broad with wide nostrils and a flat bridge. The ears may be large and low-set. The lips usually are patulous; the tongue is large and protuberant. The teeth generally are small, stubby, and widely spaced, and the gums are hyperplastic.

Characteristically there are marked skeletal changes. Moderate dwarfism, short neck, kyphoscoliosis, and gibbus are typical, and on plain-film examination the vertebral bodies (particularly those of the lower dorsal and upper lumbar region) are wedgeshaped with an anterior hook-like projection referred

to as beaking. The extremities are short, the hands and feet are broad, and the phalanges are short and stubby. Thoracic deformity is another regular feature of the syndrome; the chest appears large and wide with flaring of the lower ribs over the abdomen. The abdomen is protuberant, owing in part to abnormalities in supporting tissues and to visceromegaly. As a rule there is enlargement of both the liver and spleen. Diastasis recti, umbilical hernia, and inguinal hernias are common. Recurrent hernias may be a presenting sign [32].

Manifestations of cardiac involvement, including murmur, angina, myocardial infarction, and congestive heart failure, are common. Respiratory problems develop in virtually every patient. Recurrent upper respiratory tract infection, bronchitis, and chronic nasal congestion are common, and the patients almost always are noisy mouth breathers.

The principal neurologic manifestation is mental deficiency. The course is one of progressive mental and physical deterioration. Death most frequently results from cardiac or respiratory disease.

The principal ophthalmologic manifestations of MPS I H are progressive corneal clouding, retinal degeneration, optic atrophy, and vision loss. It appears that the corneal and retinal changes are related to the pattern of mucopolysacchariduria – that is, corneal changes are greater in conditions characterized by higher levels of dermatan sulfate in the urine, as in Hurler syndrome. The retinal degeneration appears to correlate with the degree of heparan sulfaturia; the retinal changes are more severe in Hunter and Sanfilippo syndromes and less in Hurler syndrome [33].

Progressive corneal clouding may prevent visualization of the fundus, but signs of retinal involvement and optic atrophy have been documented in Hurler syndrome. The ERG findings are abnormal, usually markedly reduced, in Hurler syndrome. Histologic findings include enlargement and vacuolization of cells of the nuclear layer of the retina, vacuolization of the ganglion cells, atrophy of the optic nerve, and thickening and infiltration of the arachnoid with foam cells.

6.2.10.1.2  MPS I S: Scheie Syndrome

The predominant manifestations of MPS I S are corneal clouding, joint stiffness, clawhand deformity,

carpal tunnel syndrome, and aortic valve disease, principally aortic stenosis and regurgitation. The facial features are coarse and the mouth is broad. Other somatic and visceral changes characteristic of mucopolysaccharidosis tend to be minimal. Stature is normal, and the patients do not develop the distorted habitus characteristically seen in Hurler syndrome. Intellect is normal or nearly normal, although psychiatric disturbances have been reported. There may be hearing impairment. The life span of those affected is relatively normal.

Corneal clouding is a prominent manifestation of the Scheie syndrome. Developing early in life, sometimes present at birth, the corneal clouding tends to worsen with age and may ultimately interfere with vision. The pathologic corneal changes are similar to those in Hurler syndrome.

Although retinal changes have not been documented in all reported cases, retinal degeneration is a recognized feature of the Scheie syndrome. Manifestations include vision impairment, particularly progressive night blindness, field changes such as ring scotoma, retinal pigmentary changes (“RP-like”), and subnormal or extinguished ERG responses.

6.2.10.1.3  MPS I H/S: Hurler–Scheie Syndrome

A number of patients with features intermediate between those of the Hurler and the Scheie syndromes have been reported. As in MPS I H and MPS I S, in MPS I H/S there is deficiency of IUDA and urinary excretion of both dermatan sulfate and heparan sulfate. The prominent clinical manifestations are skeletal changes (dysostosis multiplex) with dwarfing and progressive joint stiffness, scaphocephaly, hypertelorism, and progressive coarsening of facial features. In addition, a receding chin (micrognathia) appears to be a distinctive feature. Patients with this syndrome may survive into the teens or twenties.

As in both MPS I H and MPS I S, corneal clouding occurs in MPS I H/S. The corneal haze is diffuse (sometimes denser peripherally) and progressive; it may be evident in childhood and ultimately may interfere with vision.

Bone marrow transplantation has been used in the treatment of patients with MPS I with variable success. A beneficial effect on the visceral features, but not the ocular abnormalities, may be seen [34].