Metabolic Disorders Flashcards
Tay Sachs Disease
Infantile GM2 Gangliosidosis
- Hexosaminidase A* Deficiency
Presents in the early neonatal period with delayed or regressive psychomotor development, lack of response to visual stimuli, hyperresponsiveness to acoustic stimuli, and irritability. A cherry-red spot on the macula is seen in over 90% of affected neonates.
Tay Sachs Disease - Hexosaminidase Deficiency
Gaucher Disease
Autosomal Recessive
Mutation in gene GBA on chromosome 1
Glucocerebrosidase Deficiency
Common in Ashkenazi Jews
Gaucher Cells: Lysosomal storage of glucocerebroside in macrophages. Large cytoplasm with striated appearance (wrinkled tissue paper)
Present with psychomotor retardation, abnormal responses to stimuli, and irritability + Systemic signs and symptoms such as hepatosplenomegaly, yellow discoloration of the skin and sclera, and trouble with speech
Guacher Disease
Niemann-Pick Disease
- Sphingomyelinase* Deficiency
Presents with psychomotor retardation and cherry-red spot on the macula. Cerebral symptoms are often preceded by systemic signs such as hepatosplenomegaly and lymphadenopathy.
Niemann Pick Disease
GM1 Gangliosidoses
Autosomal Recessive
Galactosidase Deficiency (GLB1 gene, chromosome 3)
Path: Lipid storage in the neurons and proximal axons = Neuronal Ballooning
Presents with psychomotor retardation and cherry-red spot on the macula + Dysmorphic facial features (coarse facial features), bone changes, and hepatosplenomegaly
GM1 Gangliosidoses
Krabbe Disease
- Galactocerebrosidase* Deficiency
Onset 4-6 months of age.
Irritability: Episodes of inconsolable crying.
Hypersensitivity to stimuli
Increasing hypertonicity with eventual Opisthotonos
Psychomotor developmental arrest: Regression of previously achieved milestones.
Krabbe Disease
Inferior lens subluxation + Marfanoid Habitus (long, slender fingers, and scoliosis)
Homocystinuria
Attacks of abdominal pain, peripheral neuropathy with proximal muscle weakness, neuropsychiatric manifestations, and autonomic dysfunction.
Acute intermittent Porphyria
Diagnosis made by elevated urine porphyrin levels, along with urinary urobilinogen
Which protein deficiency results in low carnitine levels?
Acetoacetate
It is a ketone produced by the liver during fasting periods. Carnitine deficiency impairs fatty acid transport into mitochondria and prevents β-oxidation of fatty acids leading to cardiac and skeletal muscle injury due to lack of ATP.
Clinical presentation: Myopathy, cardiomyopathy (S3 gallop), hypoketotic hypoglycemia, and decreased carnitine
Hypoxanthine-Guanine Phosphoribosyl Transferase (HGPRT) Deficiency
Lesch-Nyhan Syndrome
Presentation: Self-mutilation, Hyperuricemia, and Dystonia
X-linked Disorder
Alpha-galactosidase deficiency
Fabry Disease
Renal Failure, Cardiomyopathy
Cutaneous: Purplish angiokeratomas in the groin/hips/periumbilical region/LE
Neuropathy: Cold-induced painful paresthesias
CNS: Stroke 2/2 vascular ectasia , dolichoectatic enlargement of the basilar artery
Fabry Disease
Autosomal recessive
Marked by a defect in the synthesis, modification, transport, and/or processing of the carbohydrate moieties or glycans of glycoproteins
Characterized by the presence of of carbohydrate-deficient transferrin in the serum and CSF
Congenital Disorders of Glycosylation
Carbohydrate-deficient Glycoprotein Syndrome
Abnormal synthesis of Glycans (PMM2-CDG)
Failure to thrive, Developmental delay, Cerebellar atrophy, Dysmorphic features, Hypotonia, Ataxia, Retinitis Pigmentosa,
Short stature with skeletal abnormalities, Stroke-like episodes, Hypogonadism
Lipodystrophy with prominent fat pads in the buttocks & suprapubic areas + inverted nipples
Type 1 Congenital Disorders of Glycosylation
(Carbohydrate-deficient Glycoprotein Syndrome)
Autosomal Recessive
Mutations in gene CBS at chromosome 21 which encodes for enzyme that produces an elevation of serum & urine levels of homocystine, homocysteine, methionine.
Presentation: Developmental delay, Intellectual disability, Collagen disability
- Marfanoid Habitus: Tall/Thin, Pectus Carinatum, Pes Planus, Genu Valgum, Scoliosis, Osteoporosis
- Ectopia Lentis
- Intimal thickening of blood vessels, Thromboembolism
Treatment:
- Pyridoxine, Low protein diet, Betaine
Cystathionine-Beta-Synthase Deficiency
X-linked recessive
Mutations in the OTC gene at chromosome X
Presentation: Hyperammonemia, Encephalopathy, Respiratory Alkalosis
– Ammonia induces Glutamine accumulation resulting in astrocyte swelling and brain edema
Ornithine Transcarbamylase (OTC) Deficiency
Autosomal Recessive
Deficiency in Methylmalonyl-CoA Mutase in chromosome 6 which requires 5’-Deoxyadenosylcobalamin as a cofactor.
Presentation: Metabolic Acidosis, Ketosis, Hyperglycinemia, Hyperammonemia
Labs: Elevated MMA in plasma & urine
Methylmalonic Acidemia
Autosomal Recessive
Mutations in BTD on chromosome 3
Presentation: Developmental Delay, Hearing/Vision loss, cutaneous abnormalities (alopecia)
Labs: Ketoacidosis, Hyperammonemia, Organic Aciduria
Biotinadase Deficiency
Autosomal Recessive
Mutation in ASPA gene on chromosome 17
Deficiency in Aspartoacylase
Labs: Urinary N-acetylaspartic Acid elevated
MRI: Diffuse symmetric T2 hyperintensities in WM + Involvement of U-Fibers
MR Spectroscopy: Increased peak N-acetylaspartic Acid
Canavan Disease
Poor fixation and tracking
Psychomotor arrest and regression
Feeding difficulties
Hypotonia with poor head control and inability to sit
Megalencephay
Canavan Disease
Autosomal Recessive
Due to defects in at least one of the 3 proteins that make up the mitochondrial glycine cleavage system resulting in complete absence of function and accumulation of glycine in all body tissues:
- P-protein (Glycine Carboxylase)
- T-protein (Aminomethyltransferase)
- H-protein (GCSH)
Labs: Elevated serum and CSF glycine levels
MRI: Hypoplastic/Absent Corpus Callosum, Gyral malformations, Cerebellar Hypoplasia
Nonketotic Hyperglycemia
Autosomal Recessive
Mutation in Galactocerebrosidase gene in chromosome 14
Results in accumulation of galactocerebrosides in macrophages leading to formation of Globoid Cells and progressive demyelination.
MRI: Symmetric demyelination of WM with sparing of subcortical arcuate or U-fibers.
Path: Clusters of Globoid Cells - PAS+ multinucleated macrophages with cytoplasmic accumulation of galactocerebrosidase
Krabbe Disease
Globoid Cell Leukodystrophy
?Autosomal Dominant
Mutation in GFAP gene
MRI: Diffuse WM T2 hyperintensities in the frontal lobes and anterior cerebral regions involving U-Fibers
Path: Rosenthal Fibers - elongated eosinophilic fibers. Deposition associated with sever myelin loss and cavitation of WM
Alexander Disease
Megalencephaly, Developmental Delay, Seizures, Psychomotor delay, Spasticity + Quadriparesis
Alexander Disease
