Congenital Metabolic Disorders

• Phenylketonuria – most frequent; deficiency of phenylalanine hydoxylase in liver; phenylalanine accumulates; autosomal recessive on chromosome 12; increased urine phenylpyruvic acid, increased serum phenylalanine
• Homocysteinuria – defect metabolism of methionine; decreased collagen and elastin; like Marfans but with mental retardation and strokes
• Maple syrup urine disease – branched chain amino acids, autosomal recessive, death in 4 weeks unless intake stopped
• Spongolipidoses – lysosomal accumulation of glycolytic/peptide degradation products; spingomyelin = phospholipid + sphingosine = ceramide + phosphocholine; ganglioside = ceramide + sialic acid; gray matter has more gangliosides, less phospholipids than white matter; accumulation damages neurons and myelin sheaths; cherry-red macules due to ganglion cell degeneration of retina allowing visualization of vascular choroid behind it
• Nieman-Pick – deficiency of sphingomyelinase, accumulation of sphingomelin and cholesterol
• Autosomal recessive, Ashkenazi Jews
• 3-9 months, death 2 years
• Cherry-red macula, hepatosplenomegaly, normal head size, psychomotor retardation
• Nieman-Pick cells (foam cells) – large vacuolated histiocytes and lymphocytes in brainstem, cerebellum, spinal cord, visceral organs
• Gaucher – deficiency of glucocerebrosidase, accumulation of glucocerebroside
• most frequent of all sphingolipidoses
• Autosomal recessive, Ashkenazi Jews
• Late childhood, no neurological symptoms, liver/spleen/bone marrow/lung symptoms (hypersplenism, anemia, thrombocytopenia)
• Gaucher cells – wrinkled tissue paper appearance from stored glucose
• Fabry – deficiency alpha galactosidase, accumulation of ceramide trihexose
• X-linked recessive
• Adolescents; dysesthesia; deposits in cornea, blood vessel walls, kidneys, non-cortical neurons, cardiac muscle fibers
• Associated with hypertension, renal failure, CHF, MI, stroke by 6^th decade
• Painful sensory neuropathy
• Eruption of dark macules/papules (angiokeratoma corporis diffusum)
• Tay-Sachs – deficiency hexosaminidase A, accumulation of GM2 gangliosides
• Autosomal recessive, Ashkenazi Jews
• 6 months, death by 4 years
• gray matter affected more than white matter
• cherry-red macule, macrocephaly
• Sandhoff – deficiency hexoxaminidase A and B, accumulation of GM2 gangliosides
• Like Tay-Sachs but visceral storage in liver, spleen, kidney, heart
• GM1 gangliosidosis – deficiency acid beta-galactosidase, accumulation GM1 gangliosides
• Autosomal recessive, onset 3 months-2 years, CNS/visceral accumulation with dysmorphic face, cherry-red macula, hepatosplenomegaly, bone abnormalities, contractures
• Mucopolysaccharidoses – defective mucopolysaccharide degeneration with accumulation of lipids in gray matter lysosomes culminating in neural death; also accumulation of polysaccharides in connective tissue
• Hurler’s (MPS1H) – deficiency alpha-L-iduronidase, accumulation of mucopolysaccharides
• Heparin and dermatan in urine
• Autosomal recessive
• Onset 1 year, death 5-10 years (cardiorespiratory death)
• Gargoyle face, mental retardation, corneal opacities, conduction deafness, hepatosplenomegaly, cardiac dysfunction, skeletal abnormalities, thick meninges with spinal cord compression
• Sheie’s (MPS1S) – milder form of Hurler’s with no mental retardation or neuronal storage; spinal cord compression, carpal tunnel syndrome, and corneal opacities are present
• Hunter’s (MPS2) – deficiency of iduronate sulfatase
• X-linked recessive
• Heparin and dermatan in urine
• Similar to Hurler’s except survive to adulthood, no mental retardation, less corneal clouding, slower progression
• Skin pebbling, peripheral nerve entrapment
• San Fillippo (MPS3) – defect in multiple enzymes
• Autosomal recessive
• Heparin in urine
• Mental retardation, less clouding clouding and fewer skeletal abnormalities than others
• Morquio’s (MPS4) – deficiency galactose-6-sulfatase and beta galactosidase
• Autosomal recessive
• Keratin in urine
• No mental retardation
• Severe skeletal abnormalities, ligamentous laxity, odontoid hyperplasia, thick cervical dura
• Muroteaux-Laury (MPS6) – deficiency arylsulfatase B
• Autosomal recessive
• Dermatan in urine
• No mental retardation
• Compressive myelopathy, hepatosplenomegaly
• Sly (MPS7) – deficiency beta-glucuronidase
• Autosomal recessive
• Dermatan, heparin, chondroitin in urine
• Moderate mental retardation, corneal clouding, hepatosplenomegaly, bony changes
• Leukodystrophies – abnormal formation, destruction, and maintenance of myelin; widespread confluent myelin loss with astrocytosis, minimal inflammation (except adrenoleukodystrophy which has perivascular lymphocytes); most spare subcortical U fibers (they myelinate later)
• Krabbe (globoid cell leukodystrophy) – deficiency galactocerebrosidase-beta-galactosidase, accumulate galactocerebroside (from myelin sheaths)
• Autosomal recessive
• Globoid macrophages around blood vessels
• Onset 3-6 months, death 2 years
• Motor delay, microcephaly
• Psychosine accumulation kills oligodendrocytes (spares subcortical U fibers)
• Basal ganglia and thalamus hyperdense on CT
• Metachromatic leukodystrophy – accumulation arylsulfatase A, accumulate sulfatides
• Most common
• Autosomal recessive, chromosome 22
• Onset 1-4 years, death 3 years later
• Motor delay, degeneration of peripheral myelin
• Damage to liver/spleen/kidney
• Hirsch-Pfeiffer reaction – stain with acidic cresyl violet aniline dye; arylsulfatase is brown, background purple
• Adrenoleukodystrophy – deficiency of lipid oxidation in peroxisomes, accumulate long chain fatty acids
• X-linked recessive
• Onset 3-10 years, death 3-5 years later
• Cavitation of parieto-occipital white matter
• Motor, behavioral, intellectual, visual, auditory delay
• Adrenal insufficiency with bronze skin
• Pelizaeus-Merzbacher – deficiency of synthesis of proteolipid apoprotein (myelin basic protein required for oligo differentiation and survival)
• X-linked recessive
• Onset infancy, death adult
• Atrophic brain, demyelination sparing perivascular white matter (opposite of most demyelinating diseases)
• Tigroid MRI due to degeneration of myelin
• Abnormal eye movements (100% have nystagmus)
• Spasticity, ataxia, mental retardation
• Canavan – deficiency N-acetyl-aspartoacylase
• Increased urine N-acetyl-aspartic acid
• Autosomal recessive in Ashkenazi Jews
• Onset infancy, death in 5 years
• Spongy white matter degeneration with vacuoles
• Does not spare U fibers
• Brain enlarged, motor regression, spasticity, blindness
• Alexander’s disease – unknown deficiency
• Sporadic
• Onset infancy, death 5 years
• Frontal hemispheric demyelination front to back, macrocephaly, mitochondrial dysfunction
• Rosenthal fibers (eosinophilic hyaline bodies representing glial degeneration products) especially periventricular, perivascular, and subpial
• Motor and sensory changes
• Sudanophilic dystrophy
• Can be early onset (3 months, death 2 years) or delayed onset (7 years, chronic)
• Diffuse degeneration of medullary fibers, phagocytosis of sudanophilic myelin products
• Spasticity, blindness, motor regression
• Other Metabolic Diseases
• Menke’s kinky hair disease – defect copper absorption in GI tract
• X-linked recessive, death by 2 years
• Diffuse loss of all neurons, mental retardation, seizures, tortuous vessels
• Hair brittle, twisted, colorless
• Leigh disease (subacute necrotizing encephalomyelitis) – deficiency mitochondrial cytochrome c oxidase
• Autosomal recessive
• Onset before 1 year
• Decreased muscle tone and head control, seizures, myoclonus, ophthalmoplegia, respiratory problems, swallowing problems
• Bilateral symmetric spongiform degeneration and necrosis in thalamus, basal ganlia, brainstem, spinal cord; peripheral nervous system demyelination
• Lowe syndrome (oculo-cerebral-renal syndrome)
• X-linked recessive
• Bilateral cataracts, motor delay, large eyes, nystagmus
• Death from renal failure
• Zellweger (cerebro-hepato-renal) syndrome – decrease in peroxisomes, accumulation long chain fatty acids in white matter and gray matter dysgenesis
• Autosomal recessive
• Hepatorenal dysfunction
• Death in few months
• Ataxia-Telangiectasia – defective DNA repair
• Autosomal recessive
• conjunctival telangiectasias, ataxia, and recurrent infections
• Cerebellar atrophy, basal ganglia calcifications, pachygyria, impaired immunity (decreased antibodies), increased lymphatic cancers
• Death by 20 years due to infection or lymphoma
• Leisch-Nyham – deficiency HGPRT, elevated uric acid
• X-linked recessive
• Self-mutilating behavior, choreoathetosis
• Pelizaeus Merzbacher Disease – defective synthesis of myelin basic protein
• X-linked, pendular nystagmus, ataxia, choreiform movements, corticospinal and white matter signs
• Can resemble Cochayne’s syndrome; this and Cochayne’s are the only leukodystrophies that always have nystagmus
• Tigroid pattern of degenerated and intact myelin in cerebrum
• Cochayne’s Syndrome
• Autosomal recessive
• Photosensitivity of skin, retinitis pigmentosa, pendular nystagmus
• Ataxia, demyelination; prognathism, anhidrosis, decreased lacrimation
• Striatocerebellar calcifications