MACROSCOPIC APPEARANCES

In the infantile forms, the brain size varies from excessively small to overlarge, but gyral atrophy and loss of white matter are evident. Changes are much less dramatic in the juvenile and adult variants, and amount at most to mild atrophy.

MICROSCOPIC APPEARANCES

In the older patients neuronal storage of excessive lipofuscin is confined to the basal ganglia, brain stem, cerebellum, and spinal cord. In infantile G_M2 gangliosidosis, ballooned neurons are found throughout the CNS and the peripheral nervous system. The foamy nerve cells stain strongly with Luxol fast blue and Sudan black, and in frozen sections the soluble ganglioside is periodic acid–Schiff (PAS)-positive (Fig. 23.1). Microglia are also PAS-positive, retaining stored material even in paraffin sections. Ultrastructural studies show membranous cytoplasmic bodies (MCBs) within neuronal somata.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Mild gyral atrophy is present in all three subtypes (Fig. 23.2a,b). Ballooned neurons with staining characteristics virtually identical to those seen in G_M2 gangliosidosis are widespread in the cerebrum (Fig. 23.2c,d), brain stem, and spinal cord, and in autonomic ganglia (in subtypes 1 and 2). Ballooned neurons are confined to the striatum and pallidum in the adult form. Ultrastructural studies show membranous cytoplasmic bodies.

VISCERAL PATHOLOGY

In type 1 G_M1 gangliosidosis only, highly water-soluble oligosaccharide storage produces vacuolation of hepatocytes, liver, spleen and lymph node histiocytes, renal glomerular epithelium, and endothelial cells.

MACROSCOPIC APPEARANCES

Cerebral atrophy is always present, but is at its most severe in the infantile form (Fig. 23.3a–c), manifesting as a walnut brain with shriveled cortex and rubbery white matter encased in a markedly thickened skull. Atrophy may also be considerable in infantile and juvenile Batten’s disease, and increases with the length of survival. In adult cases (Kufs’ disease), atrophy is more limited, and predominantly in frontal and cerebellar regions.

MICROSCOPIC APPEARANCES

The stored material, which is insoluble and therefore readily detectable in paraffin as well as frozen sections, is widespread in the nervous system and in many other tissues. Its tinctorial properties vary slightly between the various subtypes of the disease (Table 23.2). In infantile Batten’s disease, storage is evident in CNS neurons, astrocytes, and macrophages, and in autonomic ganglia from an early stage, but neuronal loss is relatively subtle to begin with, becoming obvious after 2 years. By 4 years of age virtually all cortical neurons have disappeared, and there is dense astrocytic gliosis, and myelin loss. Some astrocytes contain storage material.

In late-infantile and juvenile Batten’s disease (Fig. 23.3d,e) neuronal loss is less severe and myelin loss, if present, is slight. The rarity of adult cases and the accumulation of lipofuscin during normal aging have impeded the formulation of a consensus view of the histology of Kufs’ disease, although widespread storage is the principal element (Fig. 23.3f,g).

 Sphingomyelinase deficient.

 Not sphingomyelinase deficient (Table 23.3).

MACROSCOPIC AND MICROSCOPIC APPEARANCES

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The characteristic Gaucher cell (Fig. 23.6) is present in many tissues, is large (20–100 mm), and has one or more nuclei. Its cytoplasm is filled with finely or coarsely fibrillar material. The appearance of the cytoplasm in histologic sections has been likened to crumpled tissue paper. Gaucher cells are PAS-positive, negative with lipid stains, and sometimes contain iron pigment. Ultrastructurally, the fibrillar inclusions are membrane-bound elongated bodies containing a tubular arrangement of the glucocerebroside.

Gaucher cells are numerous in the spleen, lymph nodes, bone marrow, and hepatic sinusoids (hepatocytes themselves being spared), pancreas, thyroid, and lung.

Findings in the neuronopathic forms of Gaucher’s disease (types 2 and 3) are similar. Macroscopic changes are minimal. Perivascular clusters of Gaucher cells are present in the subcortical white matter and cerebellum, and are sometimes associated with myelin loss and gliosis. Gaucher cells are also prominent in the thalamus, hippocampus, and pons. Neuronal loss occurs in the cortex, cerebellum, and brain stem, and may be particularly severe in the cochlear nuclei, olives, and vestibular and cuneate nuclei. Neuronal storage is not detected by light microscopy.

In some cases of the non-neuronopathic form (type 1), perivascular Gaucher cells can be found in the brain, cord, and pituitary.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

There is intralysosomal storage of mucopolysaccharides within most types of cell and there may also be storage of gangliosides within neurons. The mucopolysaccharides are not protein-bound and are extremely water-soluble, and therefore not demonstrable in fixed tissue.

Macroscopic appearances are usually nondescript, but there may be considerable widening of the skull, dural and meningeal thickening, and sometimes cerebral atrophy. Hydrocephalus may occur (see Chapter 4). A characteristic finding in sectioned brain is the presence of small perivascular cavities in the white matter (Fig. 23.7a–d), which are shown microscopically to contain foamy macrophages.

Neuronal storage (Fig. 23.7e–g) is very variable, but usually parallels the severity of mental retardation. The stored material in neurons is ganglioside, and therefore PAS-positive, sudanophilic, and strongly positive with Luxol fast blue. However, neuronal storage of mucopolysaccharide cannot be demonstrated.

In other tissues, cryostat sections of snap-frozen tissue are required to demonstrate stored mucopolysaccharide in vacuolated cells by a suitable metachromatic method, but this is hampered by the tendency of the material to diffuse into surrounding tissue. Storage is especially marked in hepatocytes and Kupffer cells, cartilage, lymph nodes, tonsils, spleen, kidney, heart (notably the valves), fibroblasts in skin, conjunctiva, cornea, and vascular endothelial cells.

In blood, Alder granulation, which is a coarse reddish violet granulation in neutrophils stained with May–Grünwald–Giemsa or Wright stain is found in MPS VI and MPS VII.

Ultrastructurally, large membrane-bound vacuoles in many tissues are usually empty, but some fine granular material and lamellae are occasionally noted. Various neuronal storage bodies are seen including MCBs, and loosely arranged parallel lamellae juxtaposed with spaces to form ’zebra’ bodies (Fig. 23.7 h).

MACROSCOPIC AND MICROSCOPIC APPEARANCES

In α-mannosidosis, vacuolated neurons are plentiful in the cerebral cortex, brain stem, and spinal cord, and in the peripheral nervous system. Astrocytes, endothelial cells, and pericytes are also vacuolated. Gliosis, myelin depletion, and cerebellar degeneration may also occur.

The stored mannose-rich oligosaccharides are so water-soluble that they can be demonstrated only in cryostat sections of snap-frozen tissue stained by the alcoholic PAS reaction or following protection with celloidin.

Lymphocytes have large or small discrete vacuoles, both in peripheral blood and in bone marrow aspirates, which also contain large foamy storage cells. Morphologic descriptions of β-mannosidosis are sparse, but vacuolated lymphocytes are not found.

MICROSCOPIC APPEARANCES

Granulovacuolar storage is present in many tissues, including kidney, spleen, lymph nodes, lungs, heart, endocrine glands, hepatocytes, Kupffer cells, vascular endothelial cells, fibroblasts, and sweat glands. There are foam cells in the bone marrow. The stored material is extremely soluble, and impossible to characterize histochemically.

Neurons in many areas of the CNS are vacuolated and enlarged. The olives and thalamus are particularly affected. Purkinje cells may be depleted. In some cases, the white matter is extensively demyelinated and gliotic, and the presence of many Rosenthal fibers (Fig. 23.8) produces an appearance reminiscent of Alexander’s disease.

Ultrastructurally, there are membrane-bound vacuoles, which are either empty or contain parallel or concentric lamellae at their periphery.

MICROSCOPIC APPEARANCES

In frozen sections vascular endothelium and smooth muscle contain PAS- and Sudan black-positive birefringent deposits. Although deposits in all sites are generally removed during processing, frozen or cryostat sections retain considerable material, and sometimes there is residual staining in paraffin sections.

Similar storage is present in renal glomerular and tubular epithelia, which are vacuolated (Fig. 23.9a). Urinary deposit derived from desquamated distal tubules contains intensely PAS-positive, mulberry-like cells (Fig. 23.9b,c), which can be analysed biochemically. Glomerular sclerosis supervenes in the later stages of the disease. Cardiac muscle, cells of the mononuclear/phagocyte series (Fig. 23.9d), and peripheral nervous system ganglion cells also exhibit storage.

Neuronal storage is notable in the amygdala, hypothalamus, brain stem, and cord, but neuropathology is largely the consequence of vasculopathy, which manifests as small infarcts.

Ultrastructurally, cytoplasmic inclusions are composed of tightly packed concentric or parallel lipid lamellae arranged in stacks or as interwoven curved segments.

MICROSCOPIC APPEARANCES

The hallmark of the disease is a vacuolar degeneration of skeletal myofibers: extreme in infants, moderate in juveniles, and modest or mild in adults. The vacuoles contain excessive soluble β-particle glycogen and strong acid phosphatase activity. Excess glycogen is also present in capillary endothelium and smooth muscle, and in the infantile form in cardiac muscle fibers in association with cardiomegaly. Neuronal glycogen storage is a feature of the infantile and juvenile forms, but not the adult-onset form. It is found in anterior horn cells (Fig. 23.10) and motor cranial nerve nuclei, basal ganglia, and gastrointestinal tract plexuses. Glycogen is also abundant in astrocytes in the cerebral cortex.

In blood films, lymphocytes have small discrete cytoplasmic glycogen-containing vacuoles.

MICROSCOPIC APPEARANCES

Neuronal loss and gliosis are associated with marked neuronal storage in the basal ganglia, brain stem, and anterior horns, and to a lesser degree in the cerebral cortex and gastrointestinal tract plexuses (Fig. 23.11a–c). The stored material is strongly PAS-positive, weakly sudanophilic, and birefringent in polarized light.

Foamy cells are numerous in the spleen, lungs, and lymph nodes. The subcutaneous nodules are aggregates of foam cells or granulomas with macrophages, lymphocytes, and multinucleate giant cells. Granulomas may also be present in the lungs.

Neurons and endothelial cells contain zebra bodies (Fig. 23.11d). Hepatocytes contain membrane-bound collections of lipid lamellae. Subcutaneous foam cells contain small curvilinear tubular structures (Farber bodies or banana bodies) (Fig. 23.11e).

MACROSCOPIC APPEARANCES

The changes are similar in both the typical infantile form and in the rarer examples with late or adult onset. Externally, there is moderate to severe atrophy, widened sulci and marked weight reduction, while on palpation the firm white matter surrounded by normal cortex gives the impression of an ‘iron fist in a velvet glove’. On cut section the white matter is extensively discolored and grayish, though subcortical white fibers are spared, and the ventricles are dilated (Fig. 23.12a). Cerebellar white matter is similarly affected.

MICROSCOPIC APPEARANCES

Principal changes are extensive myelin and oligodendrocyte loss, astrocytic gliosis, and the pathognomonic presence of globoid macrophages which early in the course of the disease are mononuclear but later form perivascular clusters of multinucleated cells with as many as 20 peripheral nuclei. Eventually myelin, axons, and even globoid cells may disappear, leaving only an intense gliosis. Globoid cells are PAS-positive, faintly sudanophilic, but not metachromatic (Fig. 23.12b). They show strong acid phosphatase activity, and ultrastructurally contain straight or curved tubular profiles which are irregularly crystalloid on cross-section (Fig. 23.12c). Demyelination affects most of the cerebral white matter, usually the optic tracts, and the brain stem and cord variably with preservation of cranial and spinal roots. There is no neuronal storage but there may be severe neuronal loss from the dentate and olivary nuclei, and more moderate involvement of other brain stem nuclei and Purkinje cells. Peripheral nerves also show demyelination, fibrosis, and the presence of macrophages containing tubular inclusions.

MACROSCOPIC APPEARANCES

In the late infantile form the brain may appear externally normal, slightly enlarged, or atrophic (changes are slight in juvenile and adult cases). On section the white matter is a dull chalky white, firm to touch, and sharply demarcated from the cortex (Fig. 23.13a). Cerebellar atrophy may also occur.

MICROSCOPIC APPEARANCES

Demyelination and considerable axon loss are extensive in cerebral and cerebellar white matter and corticospinal tracts. There is oligodendrocyte loss, intense astrogliosis, and accumulation of PAS and Luxol fast blue positive macrophages which, in frozen sections, demonstrate brown metachromasia with acidified cresyl violet, toluidine blue or thionine (Fig. 23.13c,d). This sulfatide deposition also occurs in neurons in the basal ganglia, dentate nucleus, some brain stem nuclei and dorsal root ganglia, as well as within macrophages and Schwann cells, in peripheral nerves, within renal tubular epithelium, macrophages in lymph nodes and spleen, liver, Kupffer cells, biliary duct epithelium, adrenal medulla, islets of Langerhans, and many other organs. Ultrastructurally, there are three types of inclusion: prismatic, tuffstone, and laminated.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The weight of the brain is often increased and there are widespread gyral abnormalities with both widened pachygyric convolutions and polymicrogyria (Fig. 23.14b).

Extensively deranged cortical migration manifests as pachygyria, polymicrogyria, and neuronal heterotopias (see Chapter 3). Focal gray heterotopias are present in cerebellar white matter, the dentate nucleus is dysplastic, and the inferior olivary nuclei show a characteristic malformation (Fig. 23.14c) (see Chapter 3). The white matter shows decreased myelin and evidence of myelin breakdown with lipid deposition (cholesterol esterified to very long chain fatty acids) in astrocytes and macrophages in some cases. A neuronal lipidosis and neuroaxonal dystrophy in the spinal nucleus of Clarke and in the lateral cuneate nucleus have also been reported.

Ultrastructural examination shows that macrophages in white matter contain lipid clefts, lamellae, and lamellar lipid profiles.

The adrenal gland may show striated cortical cells, which ultrastructurally contain trilaminar and lamellar lipid profiles. In the kidney, there may be renal cysts, which are mostly dilatations of Bowman’s space of the glomerulus, lined by flat or cuboidal epithelium. Hepatic pathology varies, but usually there is progressive fibrosis leading to micronodular cirrhosis, and sometimes cholestasis, giant cell change, or paucity of bile ducts. Peroxisomes are absent. Ultrastructurally, some angular lysosomes include trilaminar bodies.

ZELLWEGER VARIANTS

Infantile Refsum’s disease presents with a mild Zellweger phenotype and survival into adolescence. The liver shows absent peroxisomes and micronodular cirrhosis. Cerebellar cortical atrophy has been reported in one case.

Pseudo-Zellweger syndrome: Despite the clinical and pathologic features of classic Zellweger syndrome, there are abundant hepatic peroxisomes. The typical histology of Zellweger syndrome is found in the brain, adrenals, and kidneys.

MACROSCOPIC APPEARANCES

Externally relatively normal, the sliced brain shows an extensive symmetric white matter abnormality which in the fixed state is firm and gray. There is a caudal to rostral gradient of severity with the frontal areas often less severely involved (Fig. 23.15a,b).

MICROSCOPIC APPEARANCES

Demyelination is severe in the central cerebral white matter, optic nerves, internal capsule, and commissures, while U-fibers and stria of Gennari are relatively spared (Fig. 23.15c,d). There may be some involvement of the descending brain stem tracts (much more evident in the adrenomyeloneuropathy variant). Histologically, three zones of abnormality may be discerned. In the most recent there is demyelination with preservation of axons, and scattered sudanophilic PAS-positive macrophages (Fig. 23.15e). Older lesions also demonstrate a pronounced perivascular mononuclear infiltrate and numerous macrophages (Fig. 23.15f,g). The most ancient lesions are without macrophage or inflammatory activity, depleted of axons and oligodendroglia, and heavily gliotic.

Adrenal atrophy may cause severe difficulty in identifying the adrenals at autopsy: histologically, ballooned cells with striated cytoplasm replace the cortex (Fig. 23.15 h,i). With electron microscopy, adrenal, testis, peripheral nerves, and brain show cytoplasmic inclusions comprising needle-like trilaminar bodies of very long chain fatty acid esters (Fig. 23.15j).