ABSTRACT
II = sweaty feet ●● Multiple carboxylase deficiency = cat urine
●● Most commonly diagnosed metabolic disorder
●● Symptoms begin in first month of life, progressive
●● Autosomal recessive except for Hunter, Fabry, and Danon disease (X-linked recessive)
●● Diagnosis by biochemical assay for deficient enzyme
●● Leukocytes, fibroblasts, and amniocytes assessed for enzyme levels
●● Electron microscopy studies detect morphological evidence of stored material
GAUCHER DISEASE
(infantile cerebral form), type III (adolescent form)
decade of life, bone pain, easy bruising, fever, and pneumonia
●● Enlarged lipid-laden histiocytes (Gaucher cells) throughout reticuloendothelial system
●● E/M: Glucocerebroside storage material = rod-shaped/tubular lipid-bilayer stacks, up to 4 µ diameter
FABRY DISEASE (ANGIOKERATOMA CORPORIS DIFFUSUM UNIVERSALE)
vascular disease ●● Glomeruli show mesangial expansion by
PAS positive material, pale-staining podocytes (visceral epithelial cells)
●● EM: Epithelium expanded by osmiophilic, lamellated leaflets, and tubules (glycolipid and cholesterol storage)
NEURONAL CEROID LIPOFUSCINOSES (BATTEN DISEASE)
●● Progressive encephalopathies, premature death
atrophy, neuronal loss, and apoptosis
●● EM: Infantile (granular bodies), late infantile (curvilinear bodies), juvenile (fingerprint bodies)
POMPE DISEASE (GLYCOGEN STORAGE DISEASE TYPE II, GSD-II)
Note: Explained in detail in the section of “Glycogen storage disease”
DANON DISEASE, X-LINKED VASCULAR CARDIOMYOPATHY AND MYOPATHY
●● Mental retardation, hypertrophic cardiomyopathy, skeletal myopathy
MUCOPOLYSACCHARIDOSES
●● Storage of undegraded glycosaminoglycans (GAG) in lysosomes
●● Progressive psychomotor delay, coarse facial features, short stature, dysostosis multiplex
●● Autosomal recessive disorders except Hunter syndrome (X-linked)
●● Type I = Hurler syndrome, type II = Hunter syndrome
metachromatic Alder-Reilly granules ●● EM: Fibrillogranular lysosomal storage
material
MUCOLIPIDOSES
I-cell disease (ML-II) and pseudo-Hurler polydystrophy
●● Defective N-acetylglucosamine I-phosphotransferase activity
●● Clinical features mimic MPS and sphingolipidoses
●● PAS +ve and Hale’s colloidal iron +ve vacuoles in fibroblasts, endothelial cells, and lymphocytes
●● EM: Fibroblast cytoplasm expanded by numerous membrane-bound vacuoles containing fibrillar material
OLIGOSACCHARIDOSES/ GLYCOPROTEINOSIS
saccharides in tissues ●❑ Alpha-mannosidosis ●❑ Beta-mannosidosis ●❑ Fucosidosis ●❑ Sialidosis (Mucolipidosis I) ●❑ Aspartyglycosaminuria
GANGLIOSIDOSES
●● Lysosomal accumulation of glycosphingolipids (gangliosides)
GM1 gangliosidosis
tral nervous system (CNS)
GM2 gangliosidosis
neurons
GM2 type I, Tay-Sachs disease, B variant
●● Hexosaminidase A enzyme deficiency, accumulation of substrate GM2 ganglioside
●● Ashkenazi Jews. Mental/motor deterioration begins in infancy, blindness, cherry red spot on macula, death by 2-3 years
●● CNS and retina; enlarged cerebral gyri, narrow sulci, atrophy of cerebellum/brainstem
●● Neurons ballooned with cholesterol, phospholipids, and GM2 gangliosides
GM2 type II, Sandhoff disease, O variant
●● Sphingomyelinase enzyme deficiency, sphingomyelin substrate is accumulated
●● Type A is common (infantile neuronopathic form of Niemann-Pick disease)
tal/motor functions, and death by third year ●● Ashkenazi Jews ●● Brain atrophy, neuronal loss, gliosis, and
demyelination ●● 25-75 µ histiocytes in bone marrow, splenic
pulp, and lungs ●● Histiocytes have vacuolated cytoplasm,
pale-yellow/tan on H&E ●● Vacuoles positive for Sudan black B and
oil-red-O ●● Stored material composes lipofuscin, sphin-
gomyelin, ganglioside, and cholesterol
METACHROMATIC LEUKODYSTROPHY (MLD)
CNS/extraneural sites ●● Excessive urinary sulfatides ●● Metachromatic material accumulates in cells
(stains with cresyl violet/toluidine blue) ●● EM: Tuftstone inclusions
WOLMAN DISEASE AND CHOLESTEROL ESTER STORAGE DISEASE (CESD)
cholesterol esters ●● Liver enlarged, greasy, bright orange, pro-
gresses to cirrhosis ●● EM: Lipid droplets and cholesterol clefts ●● CEST: Some residual acid lipase activity
(disease is milder)
FARBER DISEASE (DISSEMINATED LIPOGRANULOMATOSIS)
●● Acid ceramidase deficiency leading to accumulation of ceramide
●● Symptoms in infancy; failure to thrive, deformed joints, respiratory insufficiency
●● Multivisceral involvement, PAS positive storage material
●● EM: Curvilinear membrane bound storage material = banana bodies (Farber bodies)
KRABBE DISEASE (GLOBOID CELL LEUKODYSTROPHY)
ciency leading to accumulation of undigested psychosine
●● Monocyte/macrophage cells in nervous system (globoid cells positive for PAS and acid-phosphatase)
CYSTINOSIS
●● Cystinosin deficiency leading to accumulation of cysteine in multiple viscera
●● Nephropathic form is most severe, kidneys involved
●● Cysteine crystals in interstitium, glomeruli, and tubular cells
●● Progressive interstitial fibrosis, swan-neck deformity of the proximal convoluted tubule, renal failure
●● Unfixed frozen tissue shows rhomboid cysteine crystals by polarizing light
●● Ophthalmologic demonstration of cysteine crystals
●● Blockage of amino acid breakdown (due to enzyme deficiency) leading to accumulation of specific amino acids
PHENYLKETONURIA
ing to elevated phenylalanine/deficiency of tyrosine
●● Deficiency of tyrosine (melanin precursor); patients are fair skinned/fair haired/blue eyes
retardation/seizures
●● Diagnosis: Tandem mass spectrometry (MS/MS) for blood phenylalanine levels
TYROSINEMIA TYPE I (HEPATORENAL TYROSINEMIA, CONGENITAL TYROSINOSIS)
●● Fumarylacetoacetate hydrolase deficiency leading to accumulation of tyrosine
ure, cirrhosis, renal Fanconi syndrome ●● Hepatocellular carcinoma at young age ●● Liver transplantation recommended by
2 years of age (to prevent carcinoma)
TYROSINEMIA TYPE II (OCULOCUTANEOUS TYROSINEMIA, RICHNER-HANHART SYNDROME)
mental retardation ●● No liver involvement
HOMOCYSTINURIA
●● Cystathionine beta synthetase deficiency with increased level of homocysteine and methionine (serum and urine)
tion
NON-KETOTIC HYPERGLYCINEMIA (NKH)
tissues (including brain) ●● No ketosis
MAPLE-SYRUP URINE DISEASE (MSUD, BRANCHED-CHAIN KETOACIDURIA)
●● Accumulation of leucine, isoleucine, and valine in plasma
sweat, and saliva (sotolone induced)
GALACTOSEMIA
●● Deficiency of enzymes that convert galactose to glucose: GALT, GALK, and GALE
●● Severe galactose intolerance (after milk feed)
●● Escherichia coli sepsis (due to depressed neutrophil function)
●● Extensive liver damage, CNS disorders, ovarian failure
HEREDITARY FRUCTOSE INTOLERANCE (HFI)
●● Fructose-1-phosphate aldolase deficiency leading to accumulation of fructose-1-phosphate
mation, ductular proliferation, cholestasis, fibrosis, and necrosis
GLYCOGEN STORAGE DISEASE (GSD)
mas, growth retardation, hypoglycemia, hyperlipidemia
into HCC
Type II (Pompe disease)
Infantile
acid-
skeletal muscle and myocardium ●● Cardiac myocyte enlargement leads to
hypertrophic gross appearance of the myocardium
●● Hepatocytes enlarged with vacuolar rarified cytoplasm
●● EM: Lysosomal and extra-lysosomal glycogen storage
Childhood
Adult
Type 3 (Cori disease, limit dextrinosis)
Type 4 (Anderson disease, branching enzyme deficiency)
●● Amylopectinosis (brancher enzyme deficiency)
●● Hepatosplenomegaly, cirrhosis, muscle wasting
●● Liver resembles Lafora disease, progresses to fibrosis and cirrhosis
●● Hepatocytes enlarged with cytoplasmic inclusions
●● Inclusions have halo around them and are PAS +ve/diastase resistant
●● Inclusions are green with colloidal iron, brown/blue with Lugol’s iodine
Type 5 (McArdle)
Type 6 (Her)
●● Mosaic pattern of non-distended and distended hepatocytes
Other types are Type 7 (Tarui disease), Type 8, Type 9, and Type 10 (Fanconi-Bickel).
