16.7. Adult Lysosomal Disorders with Dementia
GM1 Gangliosidosis (Type 3)
- General characteristics:
- Chromosome 3
- β-galactosidase:
- Requires a protective protein that is encoded on chromosome 20 (stabilizes β-galactosidase)
- Activates neuraminidase
- Activates saposin β:
- An activator protein
- A physiological detergent within the lysosome
- A defect in protective protein:
- Heads to galacto sialidosis
- Defect in saposin β:
- Causes a disorder similar to metachromatic leukodystrophy
- Adult form:
- Onset may be in the first decade
- Slowly progressive
- Dystonia
- Spasticity
- Ataxia
- Myoclonus
- No visceral involvement
- Pathology (adult type 3):
- Minimal storage of gangliosides in cerebral cortex
- Atrophy of the caudate, putamen and globus pallidus (neural loss and gliosis)
- Meganeurite formation noted in the basal ganglia and pyramidal neurons of the cortex
- Stored ganglioside is PAS positive
- No vacuolated lymphocytes
GM2 Gangliosidosis
- GM2 gangliosidosis diseases
- Tay Sachs disease:
- Deficiency of hexosaminidase A
- Sandhoff's disease:
- Deficiency of hexosaminidase A and B
- AB variant:
- Deficiency of ganglioside activator protein
- General characteristics:
- AR inheritance
- Hexosaminidase A locus:
- Alpha subunit
- Chromosome 15
- Hexosaminidase B locus:
- Beta subunit
- Chromosome 5
- Clinical features:
- Infantile form (all types same signs):
- Onset 3–6 months with developmental delay
- Mental retardation
- Macrocephaly
- Exaggerated startle response
- Blindness
- Cherry red spot in the retina
- Seizures
- Juvenile onset:
Hexosaminidase A Deficiency in Adults (Type B)
- General characteristics:
- Mutations in the ∞-subunit; does not associate with β subunit
- Type B:
- Low hexosaminidase A activity
- Clinical features:
- Slowly progressive deterioration from early childhood
- Most common presentation is motor neuron disease
- Ataxia
- Dysarthria
- Recurrent psychosis
- No seizures
- No ocular abnormalities
- Tremor
- Peripheral neuropathy
- Pathology:
- Large increase of GM2 ganglioside:
- Less storage in cortex of ganglioside than in infantile or juvenile form
- Storage in brainstem, cerebellum, basal ganglia and spinal cord
- Co-existent lipofuscin stage
- Laboratory evaluation:
- Enzyme assay of white blood cells or fibroblasts
- Assay for β-galactosidase activity
Adult Batten's Disease (Kufs' Disease)
- General characteristics:
- AR inheritance
- Chromosome; gene CLN4
- Clinical features:
- Type A:
- Onset at approximately age 30
- Progressive myoclonic epilepsy
- Dementia
- Ataxia
- Type B:
- Behavioral changes
- Dementia
- Facial dyskinesia
- Pathology:
- Excessive lipofuscin like substance in brain neurons and GI tract
- Deposition in mega neurites of the basolateral amygdaloid complex
- Storage may be layers III–VI of the cerebral cortex
- Involvement of basal ganglia and brainstem nuclei
- No vacuolated lymphocytes
Niemann–Pick Disease
- General characteristics:
- Group 1:
- Deficient sphingomyelinase:
- Type A. Neurovisceral:
- Occurs in infants, juveniles and adults
- Type B:
- Visceral only
- Occurs in infants, juveniles and adults
- Group 2:
- No sphingomyelinase deficiency:
- Clinical features:
- Type A: (infantile, juvenile and adult form):
- Clinical features (adult form):
- Variable hepatosplenomegaly
- Dementia
- Spasticity
- Seizures
Niemann–Pick Disease - Group II (Type C)
- General characteristics:
- Not sphingomyelinase deficient
- Clinical features:
- May be very late onset (age 59)
- Adults with dementia
- Ataxia
- May have unexplained splenomegaly
- Dystonia in 25% of patients
- Loss of vertical eye movements
- Interfamilial variation of phenotype
- Pathology:
- Group I (sphingomyelinase deficient):
- Enlargement of the liver and spleen
- Slight brain atrophy
- neuronal and glial ballooning
- Foamy histocytes:
- Contain cholesterol esterase (sudanophilic)
- Globus pallidus; substantia nigra and the dentate nucleus
- Niemann–Pick cell:
- 20–90 μm; foamy histocyte
- Filled with uniform vacuoles
- Type II (sphingomyelinase is present):
- Cerebral atrophy
- Neuronal ballooning:
- Basal ganglia; brainstem and spinal cord are affected
- Axonal swelling (contains finely granular storage material)
- Defect of intracellular utilization of cholesterol
Gaucher's Disease
- General characteristics:
- Genetics:
- AR
- Chromosome 1 q 21 (mutation L444P)
- Deficient glucocerebrosidase
- Clinical features:
- Bone pain (vascular changes in the metaphysis of long bones)
- Collapse of vertebral bodies with spinal cord compression
- Other patients:
- Easy bruisability
- Myoclonic epilepsy (adult)
- Horizontal gaze palsy (juvenile)
- Spasticity
- Pathology:
- Gaucher cells are seen perivascularly
- Neuronal loss in cortex layer III and V of the cortex; the cerebellum and basal ganglia
- Gaucher cell:
- 20–100 μm
- Cytoplasmic fibrillar material; PAS positive
Metachromatic Leukodystrophy
- General characteristics:
- Chromosome 22; AR
- Deletion splice mutations and substitutions
- Deficit of aryl sulfatase A
- Clinical features:
- Age of onset is 20–50
- Present with subtle organic brain syndrome:
- Impaired concentration
- Memory dysfunction
- Schizophrenic behavior
- Emotional lability
- Seizures are rare:
- Duration of illness is approximately 14 years
- Unusual movements
- Increased reflexes
- Spasticity
- Rare presentation occurs without psychiatric symptoms
- Variant of arylsulfatase A gene mutation:
- D281 Y
- Adult patient
- Slowly progressive psychiatric and cognitive decline
- Pseudo deficiency of arylsulfatase A:
- Mutations in the gene
- No disease produced
- No disease produced
- Two patients reported with abnormal neurological findings with pseudo arylsulfatase A deficiency
- Pathology:
- Loss of myelin throughout the brain
- Neuronal depositions of sulfatide in:
- Basal ganglia
- Dentate nucleus
- Brainstem nuclei
- Spinal cord neurons
- μ fibers are spared
- Peripheral nerves:
- Loss of myelinated fibers
- Sulfatides in macrophages and Schwann cells
Mucosulfatidosis
- General characteristics:
- Pathological changes of MLD and gross neuronal storage of ganglioside coexist
- Adult onset forms described
- Multiple sulfatase deficiency (or Austin variant of MLD)
- Clinical features:
- Ichthyosis
- Retinitis pigmentosa
- Corneal clouding
- X-ray changes are subtle (spade ribs)
- Ataxia
- Increased reflexes
- Meningeal thickening with hydrocephalus
- Spasticity
- Pathology:
- Chemical deposits in the brain consist of:
- Increased sulfatides
- Gangliosides
- Ceramide galactoside
- Mucopolysaccharides
- Electron Microscopy:
- Lamellated inclusions within neurons
- Sulfatide inclusions within macrophage
- Membrane vacuoles within endothelial cells
- Diagnostic evaluation:
- urinary sulfatides and mucopolysaccharides
- Absence of arylsulfatase A and B in cultured fibroblasts
- Neutrophiles contain alder granules
Krabbe's Leukodystrophy
- General characteristics:
- Genetics:
- AR; chromosome 14q31
- Deficiency of galacto-cerobroside-β-galactosidase
- Clinical features:
- Adult disease:
- May have very late onset (up to 72 years)
- Gait abnormality
- Progressive spasticity
- Demyelinating peripheral neuropathy
- Visual dysfunction
- No seizures
- Pathology:
- Gross loss of myelin
- Astrocytic gliosis
- Globoid macrophages; generally around blood vessels
- Late onset patients the appearance of globoid cells may be delayed
- Globoid cells are PAS positive
- Cortex may be relatively normal:
- Loss of neurons in the dentate
- Inferior olives
- Straight or curved tubule crystalloid inclusion in Krabbe's globoid cells
- Diagnosis:
- Enzyme assay of leukocytes or fibroblasts
- Increased CSF protein
- MRI:
Mucopolysaccharidosis (Adult Form)
- General characteristics:
- Storage of mucopolysaccharides within liposomes of most tissues
- Early death or survival in all forms
- Mucopolysaccharidosis are AR:
- Exception is MPS II (Hunter) which is X-linked recessive
- Adult forms with dementia
- Clinical features:
- Severe and mild disease for all various forms
- Hepatosplenomegaly
- Coarse features
- Mild to severe mental retardation
- Skeletal changes that may cause spinal cord compression
- Corneal clouding (I, IV, VI and VII)
- Carpal tunnel syndrome
- Cardiomyopathy
- Aortic and mitral valve incompetence
- Normal intelligence in Schie's disease; Morquio's; Maroteaux–Lamy
- Sanfilippo:
- Severe behavioral disturbance
- No skeletal abnormality
- Adult forms of Mucopolysaccharidosis
- I-Hurler:
- Chromosome 4p16.3
- Deletions; substitutions
- Enzyme defect
- Urinary excretion of glucosaminoglycans (GAG):
- Dermatan sulfate
- Hunter's II:
- X-linked recessive Xq27–28
- Enzyme defect; alpha-L0 iduronate sulfatase
- Deletions/insertions/point mutations
- Excretion of dermatan sulfate
- Sanfilippo (type III):
- Chromosome 12 q 15 (type D)
- Enzymes involved:
- Heparin N sulfatase (type A)
- Alpha-N-acetyl glucosaminidase (type B)
- Acetyl CoA
- N-acetyl glucosamine-6-sulfatase (type D)
- Galactase-6-sulfatase (type D)
- Urinary excretion of heparin sulfate
- Morquio (type IV):
- Type IV:
- Point mutations/deletions
- Pathology:
- Neuronal storage throughout the brain, spinal cord, ganglia of the GI tract
- Older patients:
- Diagnosis:
- Urinary excretion of glycosamine glycans
- Enzyme assay of leukocytes or cultured fibroblasts
Neuraminidase Deficiency
Sialidosis Type I
- General characteristics:
- Deficient X-neuraminidase
- Chromosome 10 at 10 per q 23
- Clinical features:
- Cherry red spot myoclonus
- Presentation in first decade
- Slight intellectual decline or normal intelligence
- Alternating periodic nystagmus
- Myoclonus
- Bilateral macular cherry red spots
- Cystic long bone changes
- No hepatosplenomegaly
- Corneal clouding in some patients
- Pathology:
- Minimal neuronal storage in cortex
- Marked in GI tract
- Some vacuolation of neurons in:
- Cortex
- Basal ganglia
- Thalamus
- PAS positive foam cells in the marrow
- Diagnostic evaluation:
- Urinary excretion sialyl oligosaccharide most often
Sialidosis Type II
- General characteristics:
- Genetics:
- AR
- Chromosome 10 at 10 p ter–q 23
- Clinical features:
- Coarse facial features
- Skeletal dysplasia
- Progressive loss of vision
- Corneal cloudiness
- Bilateral macular cherry red spots
- Deafness
- Mild to moderate mental retardation
- Pathology:
- Neuronal storage of ganglioside like substance in brain and GI tract
- Neuronal storage (adult case):
- Brainstem
- Anterior horn cell
- Nucleus of Meynert (substantia innominata)
Galactosialidosis
- General characteristics:
- Deficiency of neuraminidase/B-galactosidase:
- Chromosome 20 at 20 q 13.1
- Codes for a protective protein:
- Required for aggregation of B-galactosidase monomers
- Activates neuroaminidase
- Carboxypeptidase activity
- Clinical features:
- Wide clinical heterogenicity
- Infantile, late infantile, juvenile, adult forms
- Adult:
- Variable retardation
- Angiokeratomata
- Ataxia
- Myoclonus
- Cherry red macular lesions
- Juvenile adult forms common in Japanese patients
- Pathology:
- Atrophic brain
- Loss of cortical neurons
- Lipofuscin accumulation in layers III, V, and VI of the cortex
- Demyelination
- Stored material (resembles membrane cytoplasmic bodies)
- Vacuolated lymphocytes
- Foamy cells in the bone marrow
- Diagnostic evaluation:
- Sialyloligosaccharides in the urine
- Vacuolated lymphocytes and foamy cells in bone marrow
- Enzyme analysis of cultured fibroblasts
Mucolipidosis I and III
- General characteristics:
- Located on chromosome 4q21–q23
- Enzyme defect:
- N-acetlglucosamine-1-phosphotransferase
- Clinical features:
- Present in early childhood
- Restriction of joint mobility
- Mild skeletal dysphasia
- Rare corneal clouding
- Mild mental retardation
- Laboratory evaluation:
- Both ML II and III:
- Elevated levels of serum lysosomal enzymes (B-glucosidase and amylosulfate A)
- Decrease of B-galactosidase and alpha-fucosidase in cultured fibroblasts
- Vacuolated lymphocytes and foam cells noted in bone marrow
- Pathology:
- Disorder primarily affects mesenchymal tissue
- Myelination is normal in PNS and CNS
- Brains is normal; no neuronal storage
Mucolipidosis II (I-Cell Disease)
- General characteristics:
- Chromosome 4q21–q 23
- N-acetylglucosamine 1-phophotransferase
- Clinical features:
- Similar Hurler's disease
- Skull and skeletal deformities
- Short stature
- Psychomotor retardation
- Corneal clouding
- Infantile form:
- Cardiac
- Skeletal deformities
- Diagnostic evaluation:
Mucolipidosis III
- General characteristics:
- Pseudo Hurler polydystrophy
- Chromosome 4q21–q23
- Clinical features:
- Presents in early childhood
- Increasing restrictions of joint mobility
- Carpal tunnel syndrome
- Mild cognitive deficits
- Rare corneal clouding
- Pathology:
- To any endothelial cells
- Myelination is normal in both PNS and CNS
- Primarily a disease of mesenchymal tissue
- Laboratory evaluation:
- In both MLP II and III there are high levels of serum lysosomal enzymes:
- Arylsulfatase A
- β-glucuronidase
- Decreased levels of alpha-fucosidase and β-galactosidase in fibroblasts
Mucolipidosis IV
- General characteristics:
- No skeletal abnormalities
- Clinical features:
- No skeletal abnormalities
- Infantile patients:
- Psychomotor retardation
- Hepatosplenomegaly
- Milder patients (juvenile adult):
- Diagnostic evaluation:
- Pathology:
- Neuronal storage in CNS and PNS with PAS positive granules
- Phospholipids and gangliosides
- Increased autofluorescent lipofuscin
- Neuronal loss with astrocytosis
- Membranous cytoplasmic bodies in endothelial cells of blood vessels
Mannosidosis (Juvenile Adult Type II)
- General characteristics:
- Two forms:
- Alpha mannosidosis
- β-mannosidosis
- Severe infantile form type I
- Milder juvenile–adult type II form
- AR inheritance
- Clinical features:
- Resembles Hurler's syndrome
- Coarse fascias
- Psychomotor retardation
- Dysostosis multiplex
- Gingival hyperplasia
- Recurrent bacterial infection
- Deafness
- Corneal and lenticular opacities
- Pathology:
- Vacuolization of nerve cells in:
- Cerebral cortex
- Brain stem
- Spinal cord
- Loss of cerebellar granular layer
- Vacuoles in astrocytes and endothelial cells
- Diffuse gliosis and loss of myelin
- Diagnostic evaluation:
- Vacuolated lymphocytes
- Alpha mannosidosis in leukocytes
β-Mannosidosis
- General considerations:
- Decreased activity of lysosomal β-mannosidase
- Clinical features:
- Mental retardation
- Deafness
- Mild dysmorphic features
- Peripheral neuropathy (one patient)
- Angiokeratoma (2 brothers)
- Diagnostic evaluation:
- Vacuolated lymphocytes are not seen
- Fibroblasts vacuolated
- Direct enzyme assay of leukocytes
Fucosidosis
- General characteristics:
- Type I-infantile severe form with death by age one
- Type II-juvenile–adult form
- Deficient alpha-fucosidase
- Clinical features:
- Facial dysmorphisms are similar to the mucopolysaccharidoses
- Angiokeratomas are present
- Vascular tortuousities in conjunctiva and retina
- Pathology:
- Enlarged or small brain
- Neural ballooning in all areas; olivary nuclei and thalamus in particular
- Granulovacuolar storage in all organs
- Foam cells in the bone marrow
- Vacuolated lymphocytes in the blood
- Diagnostic evaluation:
- Foam cells in the bone marrow
- Fucose compounds in the urine
Aspartylglycosaminuria
- General considerations:
- Chromosome 4; several mutations
- Aspartylglycosaminidase enzyme activity decreased
- Clinical features:
- Common in Finland; described widely
- Coarse facies
- Sagging coarse skin (cheeks)
- Mental retardation
- Joint laxity
- Macroglossia
- Short stature
- Systolic murmur
- Dysostosis multiplex
- Rare hepatosplenomegaly
- Excitable, psychotic behavior in adults
- Spondylosis/spondylolisthesis (3 adolescents)
- Angiokeratomata noted in some patients
- Pathology:
- No consistent brain macroscopic changes
- Cranial hyperostosis
- Some patients thickened and crenated mitral valves
- Neuronal cytoplasm is filled with vacuoles:
- Cerebral cortex
- Basal ganglia
- Less evident in the brainstem
- Neurons and glial cells contain increased lipofusion
- Diagnostic evaluation:
- Leukocytes demonstrate no activity of aspartoglucosaminidase
- Large excretion of aspartylglycosamine
Sialuria
- General considerations:
- Genetics:
- AR
- Long arm of chromosome 6
- Salla disease:
- Occurs primarily in Finland
- Defect of transport of sialic acid with secondary defect of glucuronic acid
- Clinical features:
- Usually psychomotor retardation in first two years of life
- Survive to adulthood
- Adults IQ less than 30
- Spasticity
- Ataxia
- Athetosis
- Mild coarse facies
- Pathology:
- Vacuolated lymphocytes in peripheral blood
- Gyral atrophy (adult autopsy); atrophy of the cerebellar folia
- Loss of nerve cells in the cortex, astrocytosis, increased lipofusion
- Occasional NFT (neurofibrillary tangles)
- Thalamus, basal ganglia, spinal cord involved
- Diagnostic evaluation:
- Large increase of free urinary sialic acid
- MRI:
- Reduction of white matter; normal cortical ribbon; thin corpus callosum
Fabry's Disease (Alpha Galactosidase Deficiency)
- General considerations:
- Genetics:
- X-linked recessive
- Chromosome X q22.1
- Alpha galactosidase A deficiency
- Clinical features:
- Angiokeratoma corporis diffusum:
- Punctate red black telangiectasias bathing suit distribution
- Mucous membranes
- Rarely absent
- Proteinuria to renal insufficiency
- Retinal, conjunctival, corneal abnormalities
- Burning pain and paresthesia of the extremities (small fiber neuropathy)
- Fever with paresthesia
- Autonomic dysfunction:
- Decreased sweating
- Decreased saliva and tear formation
- Decreased intestinal motility
- Hypertrophic cardiomyopathy, mitral insufficiency
- Minor to major manifestations may occur in female heterozygotes
- Mental deterioration from renal failure, cardiomyopathy and stroke
- Differential diagnosis of angiokeratoma:
- Fucosidosis
- Sialidosis (ML1)
- Galactosialidosis
- Aspartylglycosaminuria
- Adult alpha-N-acetylgalactosaminidase deficiency
- Dermatological conditions
- Pathology:
- Accumulation of ceramide trihexoside and dihexoside in blood vessels and endothelial cells
- Foam cells in bone marrow aspirates
- Accumulation of ceramide trihexoside:
- Amygdala
- Hypothalamus
- Brain stem
- Anterior horn cells
- Brain pathology related to vascular changes; small infarcts
- Involvement of leptomeninges
- Peripheral nerves are involved; particularly small fibers
- Diagnostic evaluation:
- Biopsy demonstrates PAS positive deposits in the walls of blood vessels which also stain with Luxol fast blue
- Absent alpha-galactosidase in fibroblasts
Alpha-N-Acetylgalactosaminidase Deficiency (Schindler's Disease)
- General considerations:
- Deficiency of alpha-N-acetylgalactosaminidase activity
- Chromosome 22q3.1–q13.2
- Clinical features:
- Children
- Pyramidal tract signs
- Hypotonia
- Myoclonus
- Early visual impairment
- MRI evaluation:
- Atrophy of cerebellum, brainstem and cervical spinal cord
Type II Glycogenosis (Acid Maltase Deficiency)
- General considerations:
- Genetics:
- AR; chromosome 17q23
- Deficient acid alpha-1,4-glucosidase
- Clinical features:
- Marked respiratory muscle weakness
- Presents in second and third decade
- Weakness of skeletal muscle:
- Vacuoles filled with soluble B-particle glycogen
- Some adults do not have myopathy
- No excess glycogen noted in adult heart
- Pathology:
- No neuronal glycogen storage in adults
- Cerebral vasculature demonstrates glycogen in the adult form
- Diagnostic evaluation:
- Muscle biopsy with characteristic vacuoles (subsarcolemmal)
- Peripheral blood; lymphocytes show small discrete cytoplasmic granules
Farber's Disease (Farber's Lipogranulomatosis)
- General characteristic:
- Genetics:
- Defect in lysosomal ceramidase activity
- Increased free ceramide; also increased glycolipids, mucopolysaccharides, GM3
- AR inheritance
- Clinical features:
- Infantile form:
- Onset early months of life
- Painful swelling of joints
- Subcutaneous nodules over affected joints
- Hoarse cry
- Feeding difficulties
- Psychomotor or retardation
- Prolonged survival reported
- Pathology:
- Neuronal storage:
- Brainstem
- Basal ganglia
- Anterior horn cells of spinal cord
- Cortical neurons and those of GI tract involved to a lesser extent
- Subcutaneous nodules:
- Formed by collection of foam cells
- Stored material and neurons (PAS positive)
- Zebra bodies in neurons
Wolman's Disease and Cholesteryl Ester Storage Disease
Wolman's Disease
- General characteristics:
- Genetics
- AR; LIPA gene mutations
- Enzyme defect is acid lipase
- Infantile form:
- Diarrhea, vomiting, failure to thrive
- Hepatosplenomegaly
- Adrenal calcification
- Anemia and fever
- Death by six months
- Milder form in infants:
- Abdominal distention
- Diarrhea and vomiting
- Survive with mild hepatomegaly
Cholesteryl Ester Storage Disease
- General characteristics:
- Genetics:
- AR: chromosome 10q23–q23.3
- Defect of acid lipase
- Clinical features:
- Hepatitis like illness
- Adrenal calcification
- Pulmonary vascular obstruction
- Atherosclerosis in longstanding survivors
- Pathology:
- Deposition of glycerol esters (triglycerides) and cholesteryl esters
- Brain demonstrates no gross changes
- Calcification of the deeper layer of the adrenal gland
- Lipid laden foamy cells of the mononuclear phagocyte system
- Fibrillary gliosis of the white matter
- Diagnosis of Wolman's or cholesteryl storage disease:
- Increased triglyceride and cholesteryl esters are present in liver and adrenal gland
Cystinosis
- General considerations:
- Genetics:
- Chromosome 17q
- Defect of carrier mediated transport of cysteine
- Clinical features:
- Infant nephropathic form:
- Failure to thrive
- Fanconi syndrome
- Death first decade
- Photophobia due to crystals within the conjunctiva and cornea
- Depigmentation of the retina:
- Slight decrease of visual acuity
- Fair complexion and hair
- Hypothyroidism by age 10
- Intermediate form:
- Later onset of renal disease
- Survival to age 30 possible
- Benign cystinosis:
- No renal involvement
- Corneal and retinal changes
- Long survivors (on dialysis)
- Swallowing problems
- Neurological deterioration
- Pathology:
- Necrosis of internal capsule and brachium pontis
- Multifocal cystic necrosis and spongy change in cerebrum (28 yo adult)
- Vascular disease with cystine deposition
- Deposition of crystals widespread and is mainly within the mononuclear phagocyte system
- Diagnostic evaluation:
- Bone marrow aspiration
- Electron microscopy:
- Crystals are within lysosomes
Differential Diagnosis of Lysosomal Storage Diseases
Most of the lysosomal storage diseases have an adult form that will display seminal neurological features. They are rare and will be mixed with other dementing illnesses which make their diagnosis difficult.
Outstanding neurological features that suggest these disorders are:
- Dysmorphisms of the face
- Clouded cornea
- Cherry red spot in the retina
- Spasticity
- Myoclonic epilepsy
- Adrenal dysfunction or calcification
- Angiokeratoma
GM1 gangliosidosis has the combination of dystonia, ataxia and spasticity. The adult form of GM2 (hexosaminidase A) deficiency presents as anterior horn cell disease. Behavioral and psychiatric episodes strengthen the diagnosis. Niemann Pick (sphingomyelinase) type C is striking due to the vertical gaze ophthalmoparesis that is seen. Gaucher's disease in adults often is suspected due to long bone changes, myoclonic epilepsy and bleeding. Metachromatic leukodystrophy should be suspected in an adolescent or young adult with psychiatric problems and spasticity.
Facial coarseness, corneal clouding, skeletal dysostosis with normal intelligence suggest Morquio's, Schie's or Maroteaux–Lamy forms. Deficiency of neuraminidase formally sialidosis I and II are suggested by cherry red spot myoclonic epilepsy, cystic long bone changes, skeletal dysplasia and deafness. Galactosidases have myoclonic seizures and cherry red spots in the retina, but angiokeratoma of the skin as well.
Abnormalities of joint mobility, corneal clouding suggests mucolipidosis II and III. Angiokeratoma are distinctive and suggest fucosidosis, sialidosis, galactosialidosis and alpha-N-acetylgalactosaminidase. Fabry's disease will be encountered and has angiokeratoma in the bathing suit distribution. The overwhelming complaints of these patients are burning hands and feet from their small fiber neuropathy. They also are very heat sensitive due to failure to sweat and have suffered coma during hot weather. The mucosulfatidoses have ichthyosis, retinitis pigmentosa and corneal clouding.
Wolman's disease and cholesteryl ester storage disease are associated with calcification in the adrenal glands. The latter is also associated with accelerated atherosclerosis.
Adult Krabbe's disease has the unusual combination of spasticity and features of a demyelinating neuropathy with normal MRI and no protein elevation in the CSF.
Kuf's disease (neural ceroid lipofuscinosis) is suspected in a middle aged patient with myoclonic epilepsy, dementia and ataxia.
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