2.6: Storage and infiltrative disorders

Sudha Kiran Das, Rudresh Hiremath

Storage disorders are a heterogeneous group of inherited defects in metabolism characterized by accumulation of substrate within the cells, resulting in a wide spectrum of diseases that are classified based on the substrate accumulated and its clinical sequel. The commonly known diseases under this comprise Gaucher disease, lysosomal storage disorder, amyloidosis, glycogen storage disorders, mastocytosis.

Gaucher disease

Gaucher disease is one of the most common lysosomal storage disorders caused by deficiency of enzyme beta-glucocerebrosidase resulting in accumulation of undegraded lipids like glucocerebroside within the macrophages of reticuloendothelial system. It is rare disorder with autosomal recessive inheritance having more than 300 mutations in glucocerebrosidase gene.

Epidemiology: Disease is more commonly seen in Ashkenazi Jews with incidence of 1 in 500–1000, whereas in general population disease is quite rare with incidence of 1 in 50,000–100,000. No sex predilection.

Pathology

Depending on the severity, there is 70%–90% reduction in the enzyme activity of glucocerebrosidase resulting in accumulation of toxic glucocerebroside within the lysosomes. These lysosomes are in turn scavenged by the macrophages, resulting in increase in their size and morphological changes. Macrophages filled with unprocessed glucocerebroside are called as Gaucher cells which get accumulated in the reticuloendothelial system and affects organs like the bone marrow, spleen and liver resulting in downgrading of their function.

Clinical Features: Clinically, Gaucher disease is classified into three types:

Type 1: Known as nonneuropathic type with no central nervous system involvement. It is most common type of Gaucher disease seen predominantly in the second decade but can occur at any age. Patients present with symptoms of bone pain, pathological fractures, bone infarcts, osteonecrosis, hepatosplenomegaly and haematological disturbances. Patients with Gaucher disease will have haematological abnormalities like anaemia and thrombocytopenia with resultant clinical features of fatigue, easy bruising and nosebleeds.

Type 2: It is referred as acute neuropathic type and disease becomes evident by 6 months of life with progressive neurological deterioration. Death ensues by 1–2 years of life. Patients will have significant hepatosplenomegaly, seizures, mental retardation, strabismus and spasticity.

Type 3: This type is called as subacute neuropathic type with mild symptoms. Age of onset is 2–6 years and presents with variable hepatosplenomegaly and seizures.

Radiological features

a. Skeletal system: Skeletal manifestations of Gaucher disease are prominent and debilitating secondary to accumulation of Gaucher cells into the bone of marrow leading to abnormal turnover of the bone and deranged haematopoiesis. Accumulated cells increase the pressure within the marrow cavity occluding the vascular structures with resultant pathology. Skeletal manifestations are picked up on radiography, CT, DEXA and MRI.
1. i. Osteopenia and endosteal scalloping: Accumulation of Gaucher cells within the marrow cavity leads to the marrow expansion with resultant endosteal scalloping and decreased bone density.
2. ii. Erlenmeyer flask deformity: Secondary to marrow accumulation, there is lack or abnormal remodelling of the bone resulting in relative constriction at diaphysis and flaring up of metaphysis depicting as Erlenmeyer flask. It is also called as metaphyseal flaring and seen most commonly in the distal end of femur (Fig. 2.6.1).
3. iii. Bone cries: Also known as pseudoosteomyelitis or aseptic osteomyelitis presenting in children and adolescence with history of fever, severe bone pain and leucocytosis with no evidence of obvious infection.
4. iv. Osteonecrosis: Avascular necrosis of femoral and humeral heads is noted. H-shaped vertebrae are noted, secondary to osteonecrosis resulting in complete collapse of vertebral body with interim peripheral regrowth.
5. v. Pathological fractures: Fractures are common with diseased bones.
6. vi. Lytic and sclerotic lesions: Bones may show lytic or sclerotic lesions.
7. vii. Marrow signal changes: Apart from above mentioned features, MRI has advantage of detecting marrow signal changes. Bone marrow is infiltrated with Gaucher cells replacing the normal marrow contents. On MRI, infiltrated marrow appears hypointense on both T1- and T2-weighted images replacing hyperintense marrow. On STIR sequences, marrow appears hyperintense. Two cautions in declaring the marrow infiltration are paediatric marrow is normally hypointense on both T1- and T2- weighted images due to red marrow and second if marrow is hyperintense on both T2 and STIR then we are dealing with inflammation like bone cries or osteomyelitis.
8. viii. Bone scintigraphy: Technetium 99m methylene diphosphonate is used to evaluate subtle pathological fractures and to differentiate bone cries from the osteomyelitis. Bone cries show absent uptake of tracer in contrast to osteomyelitis which shows increased uptake. Leucocyte-labelled Indium 111 is used to localize the infection. Similar to MRI, some radiotracers can be used to detect the marrow infiltration by Gaucher cells. Technetium-labelled sulphur colloid accumulates normally within the marrow cavity and shows reduced or patchy accumulation in Gaucher disease. On other hand, technetium-labelled sestamibi gets accumulated in the areas infiltrated by the Gaucher cells.
b. Abdominal visceral manifestations:
1. i. In the abdomen, the most commonly involved organ is liver followed by the spleen. In the liver, Gaucher cell accumulates within the Kupffer cells causing significant increase in the volume. Conglomeration of Gaucher cells can lead to formation of nodules which can be hypo, hyper or mixed echogenic on ultrasonography. On MRI, the nodules are hypointense on T1 and hyperintense on T2-weighted images. Differential diagnosis for these focal lesions is extramedullary haematopoiesis.
2. ii. Similar to the liver, the spleen will show increase in volume up to 5–15 folds to the normal. Splenic nodules are seen secondary to conglomeration of Gaucher cells. These nodules can be hypo, hyper or mixed echogenic on sonography and hypodense with peripheral calcifications on CT. The nodules are hypointense on T1 and hyperintense on T2-weighted images. On gradient sequences, the nodules show significant hypointensity secondary to iron accumulation. Splenic infarcts are known complications secondary to massive splenomegaly.
c. Pulmonary manifestations:
- Pulmonary manifestations of Gaucher disease are rare and are either due to direct infiltration of Gaucher cells into the interstitial spaces or secondary to the hepato-renal syndrome or aspiration pneumonia. Chest radiographs are usually normal. HRCT may reveal intralobular and interlobular septal thickening, ground glass opacities, consolidations and bronchial wall thickening.
- Complications: Pathological fractures, avascular necrosis femoral and humeral heads, osteomyelitis, myelosclerosis, repeated pulmonary infections and predisposition to malignancies like multiple myeloma.
- Treatment and prognosis: Bone marrow transplantation and enzyme replacement therapy is the mainstay of treatment. Clinical course is highly variable and with strong relationship between splenic volume and disease severity.

Fig. 2.6.1 Erlenmeyer flask deformity (Gaucher).

Lysosomal storage disorders

Lysosomal storage diseases are a group storage disorders comprising of nearly 51 genetically identified disorders and a small subset of acquired disorders, the latter because of inhibition of a-mannosidase II either drug induced or due to ingestion of certain plant materials. Owing to different mutations of the same gene, there is marked clinical heterogeneity, and they are further classified as infantile and adult type.

Pathology

Deficient activity of the lysosomal enzymes either due to altered property or absence is caused by genetic mutations, leading to substrate accumulation in different cell types and tissues that is one of the major causative pathways. Nonenzymatic mutations can also result in storage of substrates. Normally, most lysosomal hydrolases are present in sufficiently high amount that their respective substrate does not accumulate. Accumulation of undegraded substrate occurs only when the residual enzyme activity is less than the critical threshold of 10%–15% of the normal enzyme activity. Usually, the residual enzyme activity results in juvenile or adult onset of the disease, and absence of enzyme activity is manifested as severe infantile onset.

Epidemiology and classification

The prevalence of these individual disorders ranges from 1 in 57,000 for Gaucher disease to 1 in 4.2 million for sialidosis. As a group of disorders, the prevalence is 1 per 7700 live births.

Most lysosomal storage diseases affect different cell types, tissues and organs. The brain lesions are particularly prevalent, which comprises two-thirds of all lysosomal diseases. Constellation of disorders grouped under LSD can be classified as detailed in Table 2.6.1.

Disease	Deficient Enzyme	Storage Products	Organs Involved
MUCOPOLYSACCHARIDOSIS
MPS-I Hurler, Scheie syndrome	α-l-iduronidase	Dermatan sulphate, Heparan sulphate	CNS, Connective tissue, heart, skeleton, cornea
MPS-II hunter syndrome	Iduronate sulfatase	Dermatan sulphate, heparan sulphate
MPS-III sanfilippo syndrome Subtype A Subtype B Subtype C Subtype D	Sulfaminidase α-N-Acetylglucosaminidase Acetyl Co A aglucosaminide acetyltransferase N-acetylglucosamine 6-sulfatase	Heparan sulphate	CNS
MPS-IV Morquio syndrome Type A Type B	Galactose 6-sulfatase β-Galactosidase	Chondroitin-4 sulphate, keratan sulphate Keratan sulphate	Cartilage, skeleton, cornea, heart Cartilage, bone, cornea
MPS-VI Maroteaux–Lamy syndrome	Arylsulfatase β-Nacetylgalactosamine 4-sulfatase	Dermatan sulphate	Skeleton, cornea, heart
MPS-VII sly syndrome	β-Glucuronidase	Dermatan sulphate, heparan sulfate, chondroitin 4-8-sulphate	CNS, connective tissue, skeleton, heart
MPS-IX hyaluronidase deficiency	Hyaluronidase	Hyaluronan	Periarticular soft tissue
Sphingolipidoses (LIPID STORAGE DISEASES)
Glucocerebrosidosis (Gaucher disease) Infantile type 2 Juvenile type 3 Adult type 1	β-Glucocerebrosidase	Glucosylceramide	CNS, spleen, liver, bone marrow Spleen, liver, bone marrow
Fabry disease	α-Galactosidase	Trihexosylceramide	Blood vessels of skin, kidney and brain
Schindler disease (type I)	α-N-acetylgalactosaminidase	Sialylated and asialopeptides and oligosaccharides	CNS, PNS
Metachromatic leukodystrophy Late infantile form Late onset form Multiple sulfatase deficiency	Arylsulfatase A Arylsulfatase A At least 7 lysosomal sulfatases and a microsomal sulfatase	Galactosylsulfatide	CNS, liver, kidney, gallbladder CNS, visceral organs and skeleton
Niemann–Pick disease Type A Type B Type C (NPC-1 and NPC-2)	Sphingomyelinase Proteins required for lipid transport through late endosome	Sphingomyelin Unesterified cholesterol and spingolipids	CNS, liver, spleen, bone marrow CNS, liver, spleen
GM1-gangliosidosis	β-galactosidase	GM1-ganglioside, oligosaccharides, keratan sulphate	CNS, skeleton, viscera
GM2-gangliosidosis Tay–Sachs disease, A variant Sandhoff disease AB variant Galactosialidosis Globoid cell leukodystrophy (Krabbe disease)	β-hexosaminidase A β-hexosaminidases A and B Deficiency of GM2 – activator protein Protective protein/cathepsin A, resulting in deficiency of bgalactosidase and aneuraminidase Galactosylcerebroside, β galactosidase	GM2-ganglioside GM2-ganglioside, oligosaccharides GM2-ganglioside Glycolipids and oligosaccharides Galactosylsphingosine	CNS CNS CNS CNS, spleen, liver, skeleton CNS
Farber granulomatosis	Ceramidase	Ceramide	Subcutaneous nodules, joints, larynx, liver, lung, heart
Wolman disease	Acid lipase/cholesterol esterase	Triglycerides, cholesteryl esters	Liver, spleen, adrenal
DISORDERS OF GLYCOPROTEIN DEGRADATION
Aspartylglucosaminuria	Aspartylglucosaminidase	Fragments of glycoprotein, aspartyl-2-deoxyl-2- acetamide glycosylamine, N-linked oligosaccharides	CNS, connective tissue, bone marrow
a-Mannosidosis	α-Mannosidase	N-linked oligosaccharides	CNS, skeleton, liver, spleen
b-Mannosidosis	β-mannosidase	N-linked oligosaccharides	CNS, skeleton, liver, spleen
Fucosidosis	α-fucosidase	Oligosaccharides and glycolipids	CNS, spleen, liver
Sialidosis (mucolipidosis I)	Neuraminidase	Fragments of glycoprotein	CNS, spleen, liver, skeleton
NEURONAL CEROID LIPOFUSCINOSIS (NCL)
Infantile NCL (CLN-1)	Palmitoyl protein thioesterase	Protein, saposins A and D	CNS, heart, endothelial cells, retina
Congenital NCL (CLN-10)	Cathepsin D (CTSD)	Protein	CNS, liver
Classic late infantile NCL (CLN-2)	Pepstatin-sensitive protease, tripeptydylpeptidase	Mitochondrial subunit C of ATPase synthase	CNS, retina
Late infantile (Indian variant) NCL (CLN-6)	Endoplasmic reticulum transmembrane protein		CNS, heart, endothelial cells
Late infantile (Turkish variant) NCL (CLN-7)	Protein		CNS
Late infantile (Finnish variant) NCL (CLN-5)	Transmembrane protein		CNS, heart, endothelial cells
Juvenile NCL (CLN-3)	(Battenin) lysosomal transmembrane protein		CNS, heart, endothelial cells, retina
Adult NCL (CLN-4)	Unknown		CNS, heart, endothelial cells
Progressive epilepsy with mental retardation, Northern epilepsy (CLN-8)	Transmembrane protein		CNS
Juvenile variant (CLN-9)	Unknown		CNS
GLYCOGEN STORAGE DISEASE
Pompe disease, type IIEarly and late onset	a-Glucosidase (acid maltase)	Glycogen	CNS, muscle, heart
DISORDERS OF PROTEIN DEGRADATION
Pycnodysostosin	Cathepsin K	Collagen	Osteochondrodysplasia
Experimental dilated cardiomyopathy	Cathepsin L	Sarcomeric protein	Heart
Papillon–Lefeʹvre syndrome	Cathepsin C	Proteins	Periodontal disease and palmoplantar keratosis
Neuronal loss and brain atrophy	Cathepsins B and L	Proteins	CNS
ABNORMAL LYSOSOMAL MEMBRANE TRANSPORT
Mucolipidosis-II (I-cell disease)	N-acetylglucosaminylphosphotransferase resulting in multiple enzyme deficiencies	Mucopolysaccharides, lipids, glycoproteins	CNS, connective tissue, skeleton, heart, kidney
Mucolipidosis-III (pseudo-Hurler polydystrophy)		Mucopolysaccharides, lipids, glycoproteins	Joint and connective tissue predominantly
Mucolipidosis-IV	TRPML-1	Lipids	CNS, connective tissue
Danon disease	Deficiency of LAMP-2	Glycogen	CNS, muscle, heart
Infantile osteopetrosis and neurona	OSTM1 Chloride Channel 7	Glycoproteins and glycolipids	CNS, skeleton
DISORDERS OF LYSOSOMAL EFFLUX
Cystinosis	Cysteine efflux mediator	Cysteine	Kidney
Salla disease	Sialic acid efflux mediator	Free sialic acid	CNS
Infantile dialiuria	Sialic acid efflux mediator	Free sialic acid	CNS, kidney, liver
OTHERS
Acid phosphatases	Acid phosphatases		CNS, skeleton