Lysosomal Disorders

Def

Results in...

Describe the brain's appearance

Disruption of catabolic pathway, intracellular accumulation

Causes distention of nerve cell bodies, their processes, glia, BV walls, or visceral cells (can cause hepatomegaly or splenomegaly

Brain looks big and heavy due to distention and accumulation in nerve cell bodies

Peroxisomal Disorders

Def

Serum level of metabolites normal/abnormal?

Intracellular Storage?

A class of conditions which lead to disorders of lipid metabolism

Serum levels of metabolites are normal

Less tendency for intracellular storage

Mitochondrial Disorders

Serum level of metabolites normal/abnormal?

Serum levels of metabolites are normal

Impairment of oxidative phosphorylation may lead to elevation of lactic acid

Neuronal Lipidosis Diseases:

Pathology

Clinical Findings

Specific LSD's

Path:  Storage in the neuronal body and processes

Sx:  Neurological regression, seizures, blindness

LSDs:

Gangliosidoses

mucopolysaccharidoses

neuronal ceroid lipofuscinoses

Leukodystrophy Diseases:

Pathology

Clinical Findings

Specific LSD's

Storage in oligodendrocytes and Schwann cells

Sx. Neurological regression, spasticity, peripheral neuropathy (because its a white matter disorder)

LSDs:

Gangliosidoses (metachromatic leukodystrophy, Krabbe's disease)

Mucopolysarccharidosis Diseases

Pathology

Clinical Findings

Specific LSD's

Storage in extraneural tissues

Sx's: visceromegaly, soft tissue swelling, skeletal dysplasia, heart disease

LSD's:

glycoproteinoses

GM1 gangliosidosis

Storage Histiocytosis

Pathology

Clinical Findings

Specific LSD's

Storage in histiocytes

Sx's: Hepatosplenomegaly

hematopoietic abnormalities

Gangliosidoses:

Gaucher disease

Niemann-Pick disease

Gaucher Disease

What type of storage disease is it?

Inheritance?

Physiologic Explanation

What deficiency is present in rare cases?

What chromosome/gene?

Contrast Neuronopathic vs. Non-neuronopathic forms

Neuropath Features

What symptom is assoc w/ brain stem involvement?

Any assoc w/ cancers?

Sphingolipidoses

(Gaucher Disease is the most prevalent LSD)

Autosomal Recessive inheritance

Pathophys:  Deficiency of glucocerebroside B-glucosidase enzyme w/ accumulation of glucocerebroside

In rare cases:  deficiency of saposin C, a heat-stable enzymatic cofactor

Caused by mutation in the GBA gene on Chromo 1q21

Non-neuronopathic form:  Type I (Adult-onset)

Hepatosplenomegaly, pancytopenia (reduction in RBCs/WBCs/& platelets; skin

Bone deformities of the distal femur (Erlenmeyer deformity)

Neuronopathic Forms:

Type II - infantile form, rapidly progressive

Type III - Juvenile form, slowly progressive

Neuropath Features: Atrophy of cortex and basal ganglia (brain is smaller than normal);

Perivascular collections of cerebroside-laden MP's (Gaucher cells - wrinkled paper appearance), w/ some neuronal storage

Brain stem involvement in both Types 2 and 3 causes horizontal supranuclear gaze palsy: Paresis (partial loss of movement) of conjugate eye movements is called a gaze palsy. Horizontal supranuclear gaze palsy, will cause weakness of gaze toward the side of the lesion.

Occasional cases of leukemia, lymphoma, and glioma

Krabbe Disease

Type of storage disease

Inheritance

Chromosome location

Pathophys

Pathology in CNS/PNS; non-neuronal involvement?

Histopath

Prognosis

A sphingolipidosis

Autosomal Recessive

Chromosome 14q31

Pathophys: Deficiency of enzyme galactosyl ceramidase; results in globoid cells filled w/ galactocerebroside - shunting of galactocerebroside to phychosin (a galactosylsphingosine)

Pathology:

Demyelination in cerebrum and cerebellum

Perivascular Krabbe Cells (globoid cells), do not have wrinkled paper appearance

PNS Involvement

No storage in liver or spleen

Prognosis: death before age 2

Niemann-Pick Disease

type of storage disease

Histopath

A sphingolipidosis

Characterized by large neurons w/ distended cytoplasm and many pale, clear vacuoles

Farber lipogranulomatosis

Inheritance

Pathophys

Affects CNS/PNS/Both?

Chromosome location implicated

Histopath - Describe what you'd see; where does accumulation occur? - extra-neuronal (4) and neuronal (3)

Auto recessive

Deficient activity of enzyme acid ceramidase (converts ceramide into sphingosine and fatty acids)

Affects CNS and PNS

On chromosome 8p22-p21

Histopath:

Banana-shaped Farber Bodies, eg in Schwann cell next to a myelinated PNS axon

Periarticular and Perivascular nodules of lipid-filled macrophages w/ associated granulomatous inflam reaction

Lipogranulomas found in:

Skin

Joints

Bones

Kidneys

Neuronally:

In the neurons of the anterior horns

Peripheral sensory ganglion cells

Peripheral Autonomic ganglion cells

Fabry Disease

Characteristic symptom?

Pathophys

Inheritance

Affects CNS/PNS/both? Affects what 3 extra-neural organs/systems

What 5 portions of the CNS does it affect?

Angiokeratoma corporum diffusum (a characteristic skin rash)

Alphagalactosidase enzyme deficiency

X-linked recessive inheritance 

Affects CNS and PNS

Also affects Kidneys, Heart, GI

Affected portions of the CNS:

Amygdala

Hippocampus

Hypothalamus

Entorhinal Cortex

Brainstem nuclei

Tay Sachs Disease

Most heavily affected pop?  Heterozygote incidence in this pop?

Age of onset? Two Characteristic features of onset?

Four defining symptoms; what do their faces look like?

Any visceromegaly?

What anatomically changes late in the course of the disease?

Histopath (light microscopy and EM)

Ashkenazi Jewish ancestry have heterozygote freq of 1 in 30

Onset occurs between 3 and 6 months

Onset assoc. w/ heightened startle response and hyperacusis (oversensitivity to certain sound frequencies)

Symptoms:  

Doll-like faces

Cherry red spots in maculae

Weakness

Psychomotor retardation

NO visceromegaly

Head becomes enlarged late in course of disease

Histopath:

Swollen neurons w/ clear peripheral vacuoles seen in LM

Membranous cytoplasmic bodies on EM

Metachromatic leukodystrophy

Inheritance

Pathophys

Describe pathophys effects of I, O, A, and R mutations;  which are late infantile forms, which are adult onset?

Describe histopath

Auto recessive

caused by deficiency of arylsulfatase A

I and O mutations - no active enzyme (late infantile form)

A and R mutations - low enzyme activity (adult onset form)

Massive demyelination in brain, but w/ sparing of U fibers

(The subcortical U-fibers are, as the name implies, myelinated fibers just at the junction of the gray matter and the white matter which travel in a tangential, rather than radial, fashion connecting areas of cortex to other areas of cortex. What's special about these U-fibers, and why they are either spared or not in leukodystrophies, is that they comprise the slowest myelinating fibers within the nervous system. These U-fibers begin myelination early in gestation and often aren't completely myelinated until the third or fourth decade of life. Therefore, leukodystrophies in which the pathology is dependent on myelin turnover will demonstrate relative sparing of these fibers as the turnover is extremely slow; while in leukodystrophies which depend on toxic damage to the oligodendroglial cell, subcortical U-fibers are as vulnerable as other myelinated fibers within the nervous system." )

Also, Metachromasia of white matter (different coloration of different tissues produced by the same stain)

Neuronal Ceroid Lipofuscinosis

What is it?

Describe the associated Clinical Tetrad

Pathophys

Histopath for Late infantile vs. juvenile vs adult NCL

Accumulation of pigment, various causes

Clinical Tetrad:  

Visual distrubances (retinal degeneration)

Ataxia

Seizures

Dementia

Pathophys:  Loss of nerves w/ cerebral and cerebellar atrophy and intra-neuronal accumulation of lipopigment

Histopath: (EM)

Curvilinear bodies and granular deposits for Late infantile NCL

Fingerprint profiles in juvenile and adult NCL

The Peroxisome

What cells are they found in?

How to ID peroxisomes (3 ways)

Where are they found in the mature human CNS (2 places)?

4 Functions; All of these are necessary for metabolism in what 3 organs/systems?

Found in all nucleated cells of plants and mammals

ID them by:

1. Structure

2. Positive Histochemical reaction for Catalase

3. Immunohistochemistry

Found in neurons and oligodendrocytes of mature mammalian CNS

Functions:

1. Plasmalogen biosynthesis (important components in cell membranes and myelin

2. Cholesterol Biosyn

3. Bile acid biosyn

4. Beta-oxidation of FA's

***All these functions are necessary for metabolism of nervous system, adrenals, and liver

Zellweger Disease

Incidence and Inheritance

A disorder of what cellular component?

Pathophys

8 Components of the Clinical Presentation

Anatomic Brain abnormalities (2)

Auto recessive, incidence of 1 in 50,000 births

A disorder of Peroxisomal Function

Caused by mutations in 1 of 6 genes involved in biogenesis of peroxixomes

Its a neuronal migration disorder

Clinical Symptoms:

1. Dismorphic features

2. severe hypotonia

3. cataracts

4. retinitis pigmentosa

5. deafness

6. hepatomegaly

7. small renal cysts

8. pulmonary hypoplasia

Did Hymen's cat retrieve Dean's liver, kidney, and lungs?

Anatomic Brain abnormality: Pachygyria, exposed insula

Polymicrogyri

Def/description of brain architecture

Cobblestone appearance of brain

Cortex w/ only 4 layers instead of the normal 6

Large pyramidal neurons intermixed in layers 2 and 3 (not normally here)

Cerebellum has an abnormally busy architecture

Prototypical Peroxisome Biogenesis Disorder/Neuronal Migration Disorder

Describe the Gray matter:

2 areas of dysplasia

What cells are present that stain PAS +?

Location of pyramidal neurons

What neuron classes are affected?

Describe the White matter:

Myelin status

What cells are present/absent?

Physiologic effect

(Zellweger Syndrome)

Gray Matter:

Olivary dysplasia and dysplasia of dentate nucleus

PAS + MP's

Pyramidal neurons destined for deep cortical layers are found in outer cortex, w/ reduced #'s of the characteristic neurons in layers II and III;  many of the layer 2/3 neurons are found within the deep cortical layers

All neuronal classes are affected

White matter:

Reduced myelin, equal to 7 weeks post-natal life

Some oligodendrocyte loss, reactive astrocytosis, PAS + MP's

Results in developmental problems (hypo/dysmyelination)

A.  Peroxisomal biogenesis disorders

(multiple deficiencies, abnormal peroxisomes)

B.  Single enzymatic disorders

(morphologically-intact peroxisomes)

A. Peroxisome Biogenesis Disorders (PBD)

Give 4 Specific associated Diseases

Zellweger cerebrohepatorenal syndrome

Neonatal adrenoleukodystrophy

Infantile Refsum's disease

Rhizomelic chondroplasia punctata

X-linked Adrenoleukodystrophy (ALD)

Class A or B peroxisomal disorder?

Inheritance

Gene implicated and its function

What 2 body tissues are affected (hint: its in the name)

What protein(s) are involved

Histopath

3 visible immune rxn characteristics

Class B, disorder of peroxisomal function

X-linked recessive

Implicated gene is ABCD, member of the ATP binding cassette, subfamily D member 1

Protein is located in the peroxisome and is involved in transporting VLCFA's into peroxisomes

Deficient proteins:  VLCFA CoA synthetase, and ALD protein

Histopath:  Pallor of brain when staining for white matter

Severe myelin loss w/ MP's, reactive astrocytosis, and perivascular inflammatory infiltrate (all to clean up the myelin mess)

Mucopolysaccharidoses

Pathophys (what accumulates, where, and why?)

2 defining physical characteristics of affected patients

7 Physiologic/Anatomic effects

Appearance on EM

Gross path appearance

Glycosaminoglycans are abundant in CT (due to impaired recycling)

Characteristic appearance: Macroglossia, facial deformity, coarse facial features due to lots of CT

Physiologic/Anatomic effects:

1. Cardiomyopathy (due to very thickened CT)

2. Thickening of the intima (CT) in BV's

3. Dysostosis multiplex - severe abnormalities in development of skeletal cartilage and bone and mental retardation

4. Corneal Clouding

5. Thickening of dura and distortion of vertebrae (compressive myelopathy)

6. Communicating hydrocephalus

7. Neuronal lipidosis = storage of gangliosides in neurons

Stacks of membranes (zebra bodies) see on EM

Brain is glistening due to high mucopolysaccharide content, also hydrocephaly

Hunter's disease

what type of storage disease?

Inheritance

Pathophys (enzyme defect?)

What disease is it similar to?

3 Clinical Characteristics

Gross path

A mucopolysaccharidosis

X-linked recessive inheritance

Iduronate sulfatase enzyme deficiency

Severe form is similar to Hurler's disease

Presents as:

1. Pebbling of skin

2. Peripheral nerve entrapment syndromes

3. Retinal Degeneration

Gross Path:  glistening brain w/ fine peri-vascular pits thruout the white matter