Zellweger

Refsums

ALD

Gauchers

GM1 and GM2 gangliosidosis

Niemann Pick A, B, C

Oligosaccharidoses

Neuronal Ceroid Lipofuscinosis

Metachromatic Leukodystrophy

Krabbe

Fabry

Mucopolysaccharidosis

Zellweger disease

- Defective enzyme

- Inheritance

- Symptoms/signs

- MRI

Enzyme: defective import of peroxisomal enzymes

Inheritance: AR

Symptoms/signs: Flat face with high brow, hypotonia, seizure, large fontanelle

MRI: pachygyria polymicrogyria, bone calcification

Refsums

- Defective enzyme and result

- Inheritance

- Symptoms/signs

- MRI

- Treatment

Enzyme: Defective phytanoyl CoA hydroxylase

Result: elevated phytanic acid

Inheritance: AR

Symptoms/signs: retinitis pigmentosa, cardiomyopathy, anosmia, ataxia, peripheral neuropathy

MRI: corticospinal tract white matter disease

Treatment: avoid leafy vegetables

Pelizaeus Merzbacher

- Defective enzyme and result

- Inheritance

- Symptoms/signs

- MRI

- Defective enzyme and result: proteolipid 1 protein, causes dysmyelination

- Inheritance: X linked

- Symptoms/signs: Hypotonia, nystagmus, progressive motor (choreiform, ataxia, spastic)

- MRI: T2 tigroid areas. MR spec shows lower ?NAA and choline peaks.

Gauchers disease

- Defective enzyme and result

- Inheritance

- Symptoms/signs

- histo

- Treatment

- Defective enzyme and result: deficient glucocerebrosidase -> absent glucosylceramidase, accumulation of glucocerebrosides in macrophages (lysosomal)

- Inheritance: AR

- Symptoms/signs: hepatomegaly, anemia, thrombocytopenia

- Histo: wrinkled macrophages

- Treatment: enzyme replacement

GM1 gangliosidosis

- Defective enzyme and result

- Inheritance

- Symptoms/signs

- Defective enzyme and result: deficiency in Beta-galactosidase -> accumulation of GM1 gangliosides 

- Inheritance: AR

- Symptoms/signs: age <18 mo, coarse face, spasticity, sz, cherry red spot

Tay-Sachs

- Defective enzyme

- Inheritance

- Symptoms/signs

A GM2 disease

- Defective enzyme: Hexosaminidase A deficiency

- Inheritance: AR HEXA mutation

- Symptoms/signs: NO hepatosplenomegaly, YES increased startle, sz, optic atrophy, macrocephaly (CNS)

Sandhoff's disease

- Defective enzyme and result

- Inheritance

- Symptoms/signs

A GM2 disease

- Defective enzyme: Hexosaminidase B

- Inheritance: AR on HEXB

- Symptoms/signs: CNS (blindness, macrocephaly) AND hepatosplenomegaly

A: CNS (no viscera) : deficient sphingomyelinase in bone marrow biopsy

B: lung and viscera (no CNS): deficient sphingomyelinase in bone marrow biopsy

C: CNS and viscera: cholesterol accumulation in perinuclear lysosomes on Filipin test

Krabbe disease

- Defective enzyme and result

- Inheritance

- Symptoms/signs

- MRI

- Histology

- Defective enzyme and result: deficient galactocerebrosidase -> galactosylceramide accumulates in macrophages

- Inheritance: AR

- Symptoms/signs- (CNS and PNS) myelin destruction, opisthotonos (backward arching of head like in tetani), optic atrophy, demyelinating polyneuropathy

- MRI spares U fibers

- Histology: PAS+ globoid cells

Fabry disease

- Defective enzyme and result

- Inheritance

- Symptoms/signs

- Defective enzyme and result: deficient alpha-galactosidase = accumulation of ceramide trihexoside

- Inheritance: X-linked

- Symptoms/signs: dysestheisas, lancinating pain/burning, angiokeratomas (blue-black lesions), cardiac involvement, strokes in kids, retinal, corneal, and renal damage

Mucopolysaccharidosis

- Defective enzyme and result

- Inheritance

- Defective enzyme and result: defective enzymes resulting in deficiencies responsible for degrading GAGs

- Inheritance: AR except Type 2 which is X-linked

Sanfilipo Mucopolysaccharidosis (MPS3)

- Inheritance

- Symptoms/signs

- Diagnosis/ what accumulates

- Inheritance: AR

- Symptoms/signs: 2nd year cognitive impairment, hyperactive, sleep disorders, umbilical hernia, short stature, macrocephaly

- Diagnosis: mucopolysacchariduria, heparin sulfate in urine (but not dermatan sulfate)

Hurler's Syndrome (Mucopolysaccharidosis type I)

- Inheritance

- Symptoms/signs

- Diagnosis/ what accumulates

- Defective enzyme and result

- Inheritance: AR

- Symptoms/signs: Cognitive, macroglossia, distonia, short, coarse face, hepatosplenomegaly, corneal clouding

- Diagnosis: heparin sulfate and dermatan sulfate in urine

Hunter's Syndrome (Mucopolysaccharidosis type 2)

- Inheritance

- Symptoms/signs

- Diagnosis/ what accumulates

- Inheritance: X-linked

- Symptoms/signs: Cognitive, macroglossia, distonia, short, coarse face, hepatosplenomegaly, NO corneal clouding (hunter needs vision to hunt), extensive mongolian spots and skin papules (hunter needs camouflage) 

- Diagnosis/ what accumulates

Canavan disease

- Defective enzyme and result

- Inheritance

- Symptoms/signs

- Diagnosis

- Defective enzyme and result: deficient aspartoacylase-> leads to accumulation of N-acetylaspartic acid in the brain

- Inheritance: AR, Ashkenazi jews

- Symptoms/signs: infant with psychomotor arrest, hypotonia, spasticity, megalencephaly (enlarged brain)

- Diagnosis: White matter, INVOLVES U fibers, high urine N-ascetylaspartic acid

Alexander's disease

- Defective enzyme and result

- Symptoms/signs

- MRI

- Histology

- Defective enzyme and result: glial acidic protein (progressive disorder of astrocytes)

- Symptoms/signs: megalencephaly, sz, quadriparesis

- MRI: frontal lobe hyperintensity that INVOLVES U fibers, thinning C-spine

- Histology: Rosenthal fibers (elongated eosinophilic fibers associated with severe myelin loss)

Neuronal Ceroid Lipofuscinosis

- Defective enzyme (and gene) and result

- Symptoms/signs

- MRI

- Histology

- Defective enzyme and result: CLN1 encodes for palmitoyl protein thioesterase 1 (PPT1)- kids from Finland. CLN2 encodes for tripeptidyl peptidase 1 (TPP1)

- Symptoms/signs: normal birth then regression with microcephaly, sz, hypotonia, myoclonus

- MRI

- Histology: membrane bound granular osmiophilic deposits on electron microscopy

Metachromatic Leukodystrophy

- Defective enzyme and result

- Inheritance

- Symptoms/signs

- MRI

- Histology

- Defective enzyme and result: deficiency of lysosomal arylsulfatase A with accumulation of sulfatide= demyelination of CNS and PNS

- Inheritance

- Symptoms/signs: clumsy, falls, slurred speech, death

- MRI: T2 hyperintensity periventricular white matter that spares U fibers