Cerebrosidoses

Cerebrosides are composed of a ceremide and hexose molecule. There are three forms of cerebrosidosis or Gaucher's disease: type I (adult), type II (infantile), and

TABLE 30-3 - SPHINGOMYELINOSES (NIEMA

NN-PICK DISEASE) AND CEREBROSID

OSES(GAUCHER'S DISEASE)

Type

Name

Enzyme Defect

Storage Product

Genetics

Age at Onset

Primary Clinical Features

SPHINGOMYELINOSES

Type A

Classic Niemann-Pick

Sphingomyelinase

Sphingomyelin

Autosomal recessive; prenatal detection available

Infants

Hepatosplenomegaly, Niemann-Pick cells in bone marrow Prominent neurological findings, motor and mental retardation, cherry-red spot in 25 percent

Type B

Non-neurological variant

Sphingomyelinase

Sphingomyelin

Autosomal recessive; prenatal detection available

Chronic progressive

No neurological signs and massive hepatosplenomegaly

Type C

Childhood or adult

Sphingomyelinase

Sphingomyelin

Autosomal recessive

2-4 yr; chronic and progressive or adult onset

Hepatosplenomegaly, Nieman-Pick cells in bone marrow Prominent neurological findings, especially dystonia

Type D

Nova Scotian variant

No defect yet identified

Sphingomyelin

Autosomal recessive

2-4 yr; chronic and progressive

Clinically similar to type C. Most neurological signs may be secondary to hepatosplenopathy

CEREBROSIDOSES

Type I

Classic Gaucher's, chronic, non-neuropathic form

Glucose cerebrosidase

Glucose cerebroside

Autosomal recessive

Adults

Chronic disease involving viscera and blood-forming tissues, non-neurological

Type II

Infantile or neurological Gaucher's disease

Glucose cerebrosidase

Glucose cerebroside

Autosomal recessive

Infants

Prominent neurological signs with early opisthotonos, severe mental and motor retardation and death by 2 yr

Type III

Juvenile

Glucose cerebrosidase

Glucose cerebroside

Autosomal recessive

Juveniles

Hepatosplenomegaly and moderate neurological signs of motor and mental retardation

type III (juvenile) (see Iable 30:3 ). Gaucher's disease is the most frequently reported of the lysosomal storage disease, and particularly frequent among Ashkenazi Jews.'si It is the result of inherited defects in acid beta-glucosidase metabolism and accumulation of the substrate glucosylceramide in cells of monocytic-macrophage origin.

Type I disease, so-named because it was first described by Gaucher, is the chronic, non-neuropathic form. y Ihis form is usually found in adults and is a predominantly chronic disease involving the viscera and blood-forming tissues. Type II, on the other hand, is an acute neuropathic disease found in infants. It is almost always apparent by 6 months of age but may present as early as the newborn period, frequently with hyperextension or opisthotonic posturing of the head. Ihe posturing is believed to be due to Gaucher's cells in the meninges at the base of the brain. Affected babies have early strabismus or heterotropia, generalized hypertonia, and difficulty in swallowing, a fairly consistent neurological clinical triad. Profound psychomotor retardation develops, and laryngospasm, myoclonus, bulbar impairment, and seizures may be evident. Rapidly progressive central nervous system (CNS) deterioration occurs combined with splenomegaly, and most patients with this form of cerebrosidosis die by the age of 2 years. Ihe course of disease is similar in many respects to the fulminating course of type A sphingomyelinosis. Ihe infantile neuronal form of Gaucher's disease does not have a proclivity toward Jewish ancestry. Type III cerebrosidosis, most often found in juveniles, is heterogeneous, usually associated with hepatosplenomegaly, bone marrow containing Gaucher's cells, and neurological difficulties including hypertoxicity, opisthotonos, and mental decline. Ihese patients may also have myoclonus, and the diagnosis should be considered in children with the progressive myoclonic epilepsies (see ChaptĀ§L5.2,). Although this classification of Gaucher's disease into three entities is accepted, exceptions to it do occur, y such as a rare non-neuropathic form occurring in early infancy and a neuropathic form seen in adults.

In all forms of Gaucher's disease, although the spleen is greatly enlarged, it is not tender. Hypersplenism may occur. Anemia, thrombocytopenia, and leukopenia are frequent findings. Hepatomegaly is usually present, and there is laboratory evidence of hepatic malformation. Ihere may be pulmonary infiltrates. Bony fractures are common, possibly due to infiltration of the medullary space by Gaucher's cells, which weaken the bone.

Full clinical assessment includes a careful neurological examination, a detailed funduscopic examination, routine laboratory assessment including a hemogram, bone marrow, and liver assessment, and a family history. Ihereafter, a battery of liposomal enzyme and tissue analyses can be used to identify the specific storage defect.

Gaucher's cells, found in the bone marrow and other reticuloendothelial tissues, are the hallmark of the disease. Ihese monocytic-histiocytic cells are large, with an average weight of 20-60 pg, and have a distinctive cytoplasm that appears wrinkled or pleated. Ihe abnormalities are best recognized by a supravital technique and phase microscopy. Histochemistry shows abundant acid phosphatase activity, and on electron microscopy Gaucher's cells show many membrane-enclosed sacs containing long slender tubules. Ihe cells are rare in the central nervous system but occasionally may be seen along vessels. Pathological changes in neurons are most pronounced in the bulbar nuclei, where numbers of neurons are decreased, secondary neuronal phagia by histiocytes and macroglia occurs, and excessive cellular glycoprotein is present.

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