Metabolic Disorders

Question 1

Tay Sachs Disease
Infantile GM2 Gangliosidosis

Answer 1

• Hexosaminidase A* Deficiency

Question 2

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.

Answer 2

Tay Sachs Disease - Hexosaminidase Deficiency

Question 3

Gaucher Disease

Answer 3

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)

Question 4

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

Answer 4

Guacher Disease

Question 5

Niemann-Pick Disease

Answer 5

• Sphingomyelinase* Deficiency

Question 6

Presents with psychomotor retardation and cherry-red spot on the macula. Cerebral symptoms are often preceded by systemic signs such as hepatosplenomegaly and lymphadenopathy.

Answer 6

Niemann Pick Disease

Question 7

GM1 Gangliosidoses

Answer 7

Autosomal Recessive
Galactosidase Deficiency (GLB1 gene, chromosome 3)

Path: Lipid storage in the neurons and proximal axons = Neuronal Ballooning

Question 8

Presents with psychomotor retardation and cherry-red spot on the macula + Dysmorphic facial features (coarse facial features), bone changes, and hepatosplenomegaly

Answer 8

GM1 Gangliosidoses

Question 9

Krabbe Disease

Answer 9

• Galactocerebrosidase* Deficiency

Question 10

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.

Answer 10

Krabbe Disease

Question 11

Inferior lens subluxation + Marfanoid Habitus (long, slender fingers, and scoliosis)

Answer 11

Homocystinuria

Question 12

Attacks of abdominal pain, peripheral neuropathy with proximal muscle weakness, neuropsychiatric manifestations, and autonomic dysfunction.

Answer 12

Acute intermittent Porphyria

Diagnosis made by elevated urine porphyrin levels, along with urinary urobilinogen

Question 13

Which protein deficiency results in low carnitine levels?

Answer 13

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

Question 14

Hypoxanthine-Guanine Phosphoribosyl Transferase (HGPRT) Deficiency

Answer 14

Lesch-Nyhan Syndrome

Presentation: Self-mutilation, Hyperuricemia, and Dystonia

Question 15

X-linked Disorder
Alpha-galactosidase deficiency

Answer 15

Fabry Disease

Question 16

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

Answer 16

Fabry Disease

Question 17

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

Answer 17

Congenital Disorders of Glycosylation
Carbohydrate-deficient Glycoprotein Syndrome

Question 18

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

Answer 18

Type 1 Congenital Disorders of Glycosylation
(Carbohydrate-deficient Glycoprotein Syndrome)

Question 19

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

Answer 19

Cystathionine-Beta-Synthase Deficiency

Question 20

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

Answer 20

Ornithine Transcarbamylase (OTC) Deficiency

Question 21

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

Answer 21

Methylmalonic Acidemia

Question 22

Autosomal Recessive
Mutations in BTD on chromosome 3
Presentation: Developmental Delay, Hearing/Vision loss, cutaneous abnormalities (alopecia)
Labs: Ketoacidosis, Hyperammonemia, Organic Aciduria

Answer 22

Biotinadase Deficiency

Question 23

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

Answer 23

Canavan Disease

Question 24

Poor fixation and tracking
Psychomotor arrest and regression
Feeding difficulties
Hypotonia with poor head control and inability to sit
Megalencephay

Answer 24

Canavan Disease

Question 25

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

Answer 25

Nonketotic Hyperglycemia

Question 26

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

Answer 26

Krabbe Disease
Globoid Cell Leukodystrophy

Question 27

?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

Answer 27

Alexander Disease

Question 28

Megalencephaly, Developmental Delay, Seizures, Psychomotor delay, Spasticity + Quadriparesis

Answer 28

Alexander Disease