Neurology-Metabolic Disorders Flashcards
What are sphingolipidoses?
Progressive conditions that involve defective neuronal lipid metabolism. Ex:Tay-Sachs, Gaucher, Niemann-Pick, Fabry, Krabbe, Metachromatic leukodystrophy
What is the inheritance pattern and deficient enzyme of Tay-Sachs disease?
aka infantile GM2 Gangliosidosis. AR (more common in Ashkenazi Jews). Hexosaminidase A.
What builds up in Tay-Sachs disease and what is the presentation?
Neuronal gangliosides. 4-6 months old with hyperreflixa, seizures, hypotonia, blindness, macular cherry-red spots
What metabolic conditions have macular cherry-red spots?
Niemann-Pick, Gaucher and Tay-Sachs
What enzyme is deficient in Sandhoff?
Hexosaminidase A & B. Similar presentation to Tay-Sachs.
What is the inheritance pattern and deficiency in Gaucher’s disease?
AR. Glucocerebrosidase.
What are the three main forms of presentation of Gaucher’s?
Infantile- seizures, cherry-red spots, hepatosplenomegaly, early death.
Chronic non-neuronopathic- juvenile increase visceral storage
Juvenile neuronopathic- epilepsy, IQ decline, spasticity, hypersplenism around 5yo
Niemann-Pick inheritance and enzyme
AR. Sphingomyelinase
What is the presentation of Niemann-Pick?
hypotonia, cherry-red spots, MR, hepatosplenomegaly. Death by 4-5yo
What is the inheritance of Fabry disease and which enzyme is affected?
X-linked. Beta-Galactosidase
What is the presentation of Fabry disease?
extremity pain and paresthesias, telangiectasias, renal failure, cardiomyopathy, large purple macular skin lesions
What is the enzyme and inheritance pattern of Metachromatic leukodystrophy?
AR. Arylsulfatase A (lysosomal)
What accumalates in metachromatic leukodystrophy and what is the presentation?
Sulfatide.
Late infantile type- flaccid paralysis, dementia, slow nerve conduction velocities, optic atrophy, and death by 10
Juvenile- similar but slower progression
Adult- 4th decade with progressive dementia
What is the Krabbe disease?
A globoid cell leukodystrophy from deficient galactocerebrosidase. AR. Accumulates psychosine which is toxic to oligodendrocytes.
What is the presentation of Krabbe disease?
3-6mo. Hypertonic and Hyperreflexic with pregression to flaccid paralysis and death by 2-3yo.
What is the presentation of Alexander’s disease and what is the characteristic pathological finding?
Presents in 1st year of life: macrocephaly, spasticity, seizures, loss of milestones. Rosenthal fibers (start frontally)
What enzyme is deficient in Canavan’s disease? What is the inheritance pattern and what accumulates?
Aspartoacylase (amino-acidopathy). AR (Ashkenazi). N-acetylaspartate (seen on MR spect)
What is the presentation of Canavan’s disease?
2-4mo. hypotonia, optic atrophy and macrocephaly.
What does Canavan’s disease involve?
Subcortical U fibers (unlike most leukodystrophies).
What is Pelizaeus-Merzbacher disease and how is it inherited?
Deficient myelin proteolipid protein. X-linked recessive.
What is the presentation of Pelizaeus-Merzbacher?
Infancy: Spasticity, ataxia, optic atrophy, seizures, rotary nystagmus, delayed development. Survive into 30s
What is the inheritance pattern of Adrenoleukodystrophy? What is defective?
X-linked. Defective peroxisomal very long-chain fatty acid B-oxidation (lignoceroyl coenzyme A)
What is the presentation and skin appearance of Adrenoleukodystrophy?
5-8yo: Bronze skin, dementia, behavioral changes, optic atrophy, neuropathy
Which mucopolysaccharidoses is X-linked?
Hunter
Hurler Syndrome. Inheritance and enzyme?
AR. a-L-iduronidase. aka Mucopolysaccharidoses I (MPS I)
What is the presentation of Hurler?
Corneal clouding, MR, coarse facial features, cardiac disease. Fatal by 10.
Lab test for Hurler?
Increased urinary excretion of dermatan and heparan sulfate
Scheie syndrome. Inheritance and enzyme?
AR mild variant of Hurler. a-L-iduronidase.
What is the presentation of Scheie?
Mild version of Hurler. No MR and live long unless cardiac issues. Occassionally will have spinal cord compression or corneal clouding
Hunter’s syndrome. Inheritance and enzyme?
MPS II. X-linked recessive. iduronate-2-sulfatase
What is the presentation of Hunter’s.
Pebbled skin over the scapulae. Dwarf, hepatosplenomegaly, deaf, hydrocephalus (no corneal clouding). Slower progression than Hurler
Lab test for Hunter’s?
increased urinary excretion of dermatan sulfate
Sanfilippo syndrome. Inheritance and enzyme?
MPS III. AR. 4 different enzyme mutations involved with metabolism of heparan sulfate
What are the symptoms of Sanfilippo?
MR, ataxia, hirsutism, seizures, progressive quadriparesis. Affects juveniles and they live until 2nd decade
Morquio syndrome. Inheritance and enzyme?
AR. B-galactosidase (mild form) or galactose-6-sulfatase (severe form)
What is the presentation of Morquio?
AO subluxation leading to cervical SCI. dwarfism, joint laxity, deafness, cardiac and pulmonary disease
Increased urinary excretion of ________ is seen with Morquio syndrome?
keratan sulfate
What is the inheritance pattern of glycogen storage disease?
AR (except IX and a subtype of VIII X-linked)
What is the enzyme and presentation of Von Gierke’s disease?
(Type I glycogenosis) Glucose-6-phosphatase. Hepatomegaly and hypoglycemia
What is the enzyme and presentation of Pompe’s disease?
(Type II) Acid maltase (a-glucosidase).
Infantile- hypotonia, macroglossia, cardiomegaly (death by 2)
Juvenile/Adult- myopathy
What is the enzyme and presentation of Cori’s disease?
Type III. amylo-1,6-glucosidase (debranching enzyme). Hepatomegaly, seizures, growth retardation
What is the enzyme and presentation of McArdle’s disease?
Type V. Myophosphorylase. Muscle Cramps and myoglobinuria
What is the enzyme and presentation of Tauri’s disease?
Type VII. Phosphofructokinase. Early fatigue with exercise
What is the inheritance pattern of mitochondrial disorders?
Maternal inheritance
What is MELAS?
A mitochondrial disorder: generalized seizures, migraines, strokes
What is associated with ragged-red fibers?
MELAS and MERRF (myoclonic epilepsy with ragged-red fibers)
What is the triad of Kearns-Sayre syndrome?
Progressive ophthalmoplegia, pigmentary retinopathy, onset before 20. Deletion of mtDNA with cardiomyopathy and conduction defects
What is Leber’s hereditary optic neuropathy?
Mitochondrial disorder with progressive, painless central visual loss and cardiac conduction abnormality in the 3-4 decade
What are the amino acidopathies?
PKU, Maple syrup urine disease, Homocystinuria, hartnup. All autosomal recessive.
What is the enzyme and presentation of PKU?
Phenylalanine hydroxylase. MR, seizures, hyperreflexia, abnormal skin/hair pigmentation.
What is the enzyme and presentation of Maple Syrup Urine disease?
Defect in branched chain aa metabolism. Hypertonia, seizures, opisthotonos, sweet smelling urine
What is the enzyme and presentation of Homocystinuria?
Cystathionine B-synthase. Intimal thickening and fibrosis of blood vessels leading to stroke and dural sinus thrombosis. Seizures, ectopia lentis (malpositioned eye lense), glaucoma, Marfanoid
What accumulates in homocystinuria
Methionine and homocystine
What do you supplement in Homocystinuria?
Cysteine
What do you supplement in MSUD?
Thiamine
What do you avoid in MSUD?
Leucine, isoleucine, valine
What do you avoid in Homocystinuria?
Methionine
What is the defect and presentation of Hartnup disease?
defect in transport of neutral a.a. MR, Ataxia, photosensitive dermatitis, nystagmus, renal aminoaciduria.
What do you supplement Hartnup? Does it get better with age?
Niacin supplement (like pellagra) and a high protein diet. Gets better with age.
Lesch-Nyhan syndrome
X-linked disorder of purine metabolism with increased levels of uric acid
What is defective in Lesch-Nyhan syndrome
Hypoxanthine-guanine phosphoribosyltransferase (HPRT)
What is the presentation in Lesch-Nyhan
Self mutilation, choreoathetosis, MR, death from renal failure
What is the deficiency and presentation of Glucose transporter protein syndrome (GTPS)?
GLUT-1 (moves Glu across BBB). Decreased CSF glu (hypoglycorrhachia).
Seizures, MR, microcephaly, ataxia.
How do you treat GTPS?
Ketogenic diet
What is Zellweger syndrome?
AR peroxisomal disorder with abnormalities in very-long-chain fatty acids.
Present with hypotonia, seizures, pigmentary retinopathy, characteristic face.
Wilson’s disease. What chromosome and what is impaired
Hepatolenticular degeneration. AR Chr 13. Formation of Ceruloplasmin is impaired (decreased serum ceruloplasmin) and biliary excretion of copper is decreased.
What is the presentation of Wilson’s disease?
Increased serum copper, cirrhosis, Kayser-Fleischer rings, seizures, ataxia, tremor
What is the MRI and pathologic appearance of Wilson’s disease
T-1- hyperintense BG and abundant Alzheimer Type II astrocytes
What is the treatment of Wilson’s disease?
Penicillamine or ammonium tetrathiomolybdate and zinc
Acute intermittent porphyria (AIP)
abnormal metabolism of heme and increased urinary excretion of d-aminoevulinic acid. Presents with severe abdominal pain, psychosis, and peripheral neuropathy (similar to lead poisoning)
What is the treatment and what exacerbates AIP?
Treatment: Propranolol, hematin, diazepam (for seizures)
Preciptates: barbiturates
What is Hallervorden-Spatz disease?
AR with motor abnormalities: hyperreflexia, dystonia, ataxia, stiff arms/legs and a frozen face
What is the imaging feature of Hallervorden-Spatz?
T2 MRI hypointense GP (“eye of the tiger”)
What is neuroacanthocytosis?
Levine-Critchley syndrome. Progressive multisystem neurodegenerative d/o. AD Chr 9
What is the presentation of neuroacanthocytosis?
Psychiatric, dementia, hyperkinesis, acanthocytes
What are the neuroimaging features of neuroacanthocytosis?
Severe atrophy of the Striatum
What is superficial siderosis?
Chronic deposition of hemosiderin over the surface of the brain and SC. Secondary to chronic CNS hemorrhages
What is the presentation of superficial siderosis?
Hearing loss, ataxia, myelopathy, anosmia, dementia
What is Laurence-Moon-Biedl syndrome?
AR: Impaired night vision (retinitis pigmentosa), obesity, MR, hypertension
What does a defect in phytanic acid metabolism cause?
Refsum disease (an AR hypertrophic sensorimotor neuropathy). Progressive night blindness, hearing loss, ataxia, pes cavus, ichthyosis, cardiac conduction abnormalities
What enzyme is defective in Refsum’s disease?
Phytanoyl-coenzyme A hydroxylase
