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.

23.2 G_M1 gangliosidosis.
(a) Coronal section of cerebral hemisphere from a patient with the type 2 (late-infantile and juvenile) form of G_M1 gangliosidosis, who died aged 10 years. There is mild cortical atrophy and ventricular dilatation. (b) Cortical atrophy and poverty of myelination are more evident in a stained section from the occipital lobe. (c) In the cerebral cortex there is extensive neuronal and glial storage. The granular storage bodies fill the neuronal cytoplasm and distend the proximal dendrites. Note also the myelin pallor. (d) Heavy neuronal storage is also present in the pontine nuclei.

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.

G_M1 GANGLIOSIDOSIS

Type 1: Infantile G_M1 gangliosidosis

Onset: failure to thrive evident from birth, hepatosplenomegaly, bony changes and dysmorphism similar to those of mucopolysaccharidoses, cardiomyopathy, peripheral edema.

Course: psychomotor retardation and epilepsy, cherry red macular spots, death before 2 years of age.

Type 2: Late-infantile and juvenile G_M1 gangliosidosis

Onset: at 1–5 years of age with progressive psychomotor retardation, epilepsy, spastic tetraplegia, cerebellar signs, no visceral changes, and bony changes confined to the vertebrae.

Course: decerebrate rigidity and death at 3–10 years of age.

Type 3: Adult G_M1 gangliosidosis

Starting during the first decade, patients develop slowly progressive weakness, ataxia, extrapyramidal signs, myoclonus, dysarthria. There are no bony changes.

ETIOLOGY OF G_M1 GANGLIOSIDOSIS

The accumulation of G_M1 ganglioside is due to deficiency of β-galactosidase activity.

Functional defects occur as a result of mutations of the β-galactosidase gene, GLB1.

GALACTOSIALIDOSIS

In this autosomal recessive lysosomal storage disorder, a combined deficiency of β-galactosidase and neuraminidase is secondary to a defect in protective protein/cathepsin A (PPCA) leading to accumulation of sialyloligosaccharides in lysosomes and their excessive urinary excretion. Mutations in the gene encoding PPCA (CTSA) map to 20q13.1. Clinical features include coarse facies, macular cherry red spots, dysostosis multiplex, foam cells in bone marrow, and vacuolated lymphocytes. Infantile, late infantile and juvenile/adult presentations are known. Cytoplasmic vacuolation occurs in many cell types: hepatocytes, Kupffer cells, Schwann cells, fibroblasts, endothelial cells, and lymphocytes. Neuropathologic data are sparse. Neuronal storage can be observed in spinal and trigeminal ganglia, anterior horn cells, cranial nerve nuclei, basal forebrain and Betz cells. Variable degrees of gross atrophy of central gray structures, cerebellum, and brain stem have been reported.

BATTEN’S DISEASE, NEURONAL CEROID LIPOFUSCINOSIS (NCL, CLN)

This group of disorders has a confusing set of eponyms (Table 23.1). Classification is further complicated by newer terminology related to the molecular genetics of the disorders. The classification used here combines clinical presentation, age of onset, pathology, and electrophysiology. The diagnosis is most readily obtainable for all forms except Kufs’ disease by cutting cryostat sections of a suction rectal biopsy to examine neurons and other cell types (i.e. smooth muscle, histiocytes, vascular endothelium) for the characteristic accumulations of autofluorescent ceroid lipofuscin, while ultrastructural examination for the various specific types of inclusions is most easily accomplished using buffy coat preparations of lymphocytes. In JNCL (CLN3) numerous vacuolated lymphocytes are demonstrated in the trails of a routine peripheral blood film, and in the right clinical setting this is virtually confirmatory. Skin biopsy is also routinely used: examination of eccrine but not apocrine glands is informative (if the biopsy is from the axilla note that many of the sweat glands will be of apocrine type).

Table 23.1

Classification scheme for Batten’s disease

ETIOLOGY OF BATTEN’S DISEASE

All subtypes show recessive inheritance except for some families with autosomal dominant form of CLN4 (Kufs).

BATTEN’S DISEASE

INCL (CLN1)

Onset: at 8–18 months with rapidly progressive psychomotor retardation, irritability, visual failure, hypotonia, ataxia.

Course: myoclonic jerks, hyperkinesia, microcephaly, flat electroencephalogram (EEG) by 3 years of age, and death at 3–10 years of age.

LINCL (CLN2)

Onset: at 18 months to 4 years of age with epilepsy.

Course: regression, visual failure, spastic tetraplegia, bulbar paresis, characteristic EEG with large polyspike response to low rates of photic stimulation, attenuated electroretinogram (ERG) and enlarged visual evoked potentials (VEPs); death at 4–10 years of age.

JNCL (CLN3)

Onset: at 4–9 years of age with deteriorating vision and pigmentary retinopathy.

Course: dementia, epilepsy, gait disorder, and dysarthria; hallucinations in older patients; attenuation of ERG and VEPs; death at 15–30 years of age.

ANCL (CLN4)

Onset: at about 30 years of age – either type A with progressive myoclonic epilepsy, dementia, and ataxia, or type B with behavioral disturbance, dementia, motor disorder, and facial hyperkinesia.

Course: may survive for several decades.

Finnish variant LINCL (CLN5)

Onset: at 4–7 years of age with clumsiness, retardation, and visual failure.

Course: ataxia, myoclonic epilepsy, and cerebellar signs. Electrophysiology similar to that of CLN2; death by early 20s.

Variant late infantile/early juvenile NCL (CLN6)

Onset and course: similar to those of CLN5, but a wider age range of onset.

Variant late infantile with GROD/variant juvenile with GROD (both CLN1)

Onset and course: similar to those of classical LINCL and JNCL respectively despite differing pathology.

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.

Table 23.2

Histochemical and ultrastructural abnormalities in Batten’s disease

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).

NIEMANN–PICK DISEASE

This comprises autosomal recessive disorders that show common clinical features, but a diversity of underlying biochemical mechanisms. There are two main groups:

Sphingomyelinase deficient.

Not sphingomyelinase deficient (Table 23.3).

Table 23.3

Classification of Niemann–Pick disease

Group I: sphingomyelinase deficient	Group II: not sphingomyelinase deficient
Type A: neurovisceral (infantile, juvenile, and adult)	Types C and D (Nova Scotia): neurovisceral
Type B: visceral only (infantile, juvenile, and adult)	Possible pure visceral form

This classification incorporates the earlier four alphabetically defined groups.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Niemann–Pick disease group I

While hepatosplenomegaly is striking in both types, CNS abnormalities are not found in type B. In type A, cerebral atrophy may be slight or absent. Microscopically (Fig. 23.4), there is generalized enlargement of neurons and glia, and storage extends to white matter, which is demyelinated and gliotic. Gastrointestinal tract neuronal plexuses are also affected. Sudanophilic foamy histiocytes containing cholesterol esters, but not ballooned neurons, are numerous in the globus pallidus, substantia nigra, and dentate nucleus. Niemann–Pick cells (Fig. 23.4b) are present throughout the mononuclear phagocyte system, and can fill the alveolar spaces of the lungs. The lymphocytes of patients with type A Niemann–Pick disease contain cytoplasmic vacuoles, which are small and discrete. In contrast, in patients with type B there is minimal or no lymphocytic vacuolation. Bone marrow aspirates show collections of Niemann–Pick cells in patients with type A and in younger patients with type B. In older patients with type B disease there are fewer foamy Niemann–Pick cells, and more prominent ’sea-blue histiocytes’, in which the cytoplasm is filled with small granules that stain intensely blue with the Giemsa or Wright histochemical method.