Genetics & metabolism

Question 1

Menke disease
vs.
Moubis dynrome

Answer 1

Twisted, fractured hair (kinky hair), wormian bones, cerebral deterioration, saggy lips, joint laxity. –> copper transport
x-link recessive.

Moubis: 6th, 7th cranial nerve palsy, mental deficiency.

Question 2

Dwarfism: what gene and what inheritance pattern

Answer 2

FGFR3 mutation

Autosomal dominent
but A LOT de novo

Question 3

Most inborn errors of metabolism follows what inheritance pattern

Give an exception

Answer 3

autosomal recessive.

Exception:
Ornithine carbamyl transferase (also most common)
(high urine orotic aice, high glutamine/alanine. low citrulline and arginine) –> Urea cycle defect
THIS IS X-Link Recessive

Question 4

x-linked disorders among inborn errors of metabolism

Answer 4

OTC deficiency
X-linked ALD
Hunter Syndrome

x-linked, not inborn errors of metabolism:
incontinentia pigmenti

Question 5

For each of the following group of disorder, give the basic presentation

• Fatty Acid Oxidation Disorders
• Organic Acidemia
• Aminoacidopathy
• Urea Cycle Disorders

Answer 5

• Fatty Acid Oxidation Disorders
  Hypoketotic hypoglycemic
• Organic Acidemias
  Metabolic acidosis with anion gap
• Aminoacidopahties
  No acidosis or hyperammonemia
• Urea Cycle Disorders
  Hyperammonemia without acidosis.

Question 6

Organic Acidemias

Answer 6

Metabolic acidosis with anion gap
Urine Ketone

Question 7

plasma lactate is elevated in what

Answer 7

mitochondrial disease
glycogen storage disease 1 A

Question 8

Plasma Amino Acids can help with what disorders?

Answer 8

PKU
MSUD
Urea Cycle Disorders

amino aciodpahties

Question 9

Urine Organic Acids
helps diagnose what disorders

Answer 9

Mehtymalonic Acidemia
Propionic Acidemia
Isovaleric Acidemia

Organic Acidemia

Question 10

Plasma Acylcarnitine and Carnitine can pick up a lot of disorders

Question 11

Tandem Mass Spectroscopy is used for NBS

Question 12

is OTC screened on NBS

Answer 12

no

(neither is cholesterol disorder)

Question 13

PKU (Phenylketonuria)

Answer 13

This is amino and organic acidopathies.

autosomal recessive

metabolism of Phenylalanine (no phenylealanine hydroxylase -> classic type.
Hence: cannot convert from phenyalanine to Tyrosine.

mousy urine order or musty urine order.

elevated:
Phenyalanine
AND Phe/Tyr ratio

no symptoms in newborn period

if mom has PKU and cannot control diet, elevated phenylalanine is teratogenic (microcephaly, IUGR, intellectual disability, congenital heart disease)

Question 14

MSUD

Answer 14

autosomal recessive

elevated Leucine, Valine, isoleucine.
(Leucine toxic to brain. )

branched chain ketoacid dehydrogenase deficiency.
> elevated ketones in urine

– Poor feeding, lethargy, coma, apnea.
Can present BEFORE NBS

maple odor.

Hypoglycemia and hyperammonemia UNUSUAL
very HIGH urine Ketone.

Question 15

Transient Tyrosinemia of the Newborn

Answer 15

elevated Tyrosinemia but no succinylacetone in urine.

Type 1 tryosinemia is autosomal recessive and has succinylacetone in urine.

Question 16

Nonketotic Hyperglycinemia

Answer 16

measure CSF/Plasma glycine
hiccups, seizure, myoclonus.

Question 17

Propionic Acidemia

Answer 17

This is organic acidemia

Defect in propionyl CoA Carboxylase.

Autosomal recessive.

severe, lethargy, coma, neutropenia, thrombocytopenia.

METABOLIC ACIDOSIS, ANION GAP, HYPERAMMONEMIA

Question 18

why carnitine for organic acidemias

Answer 18

Carnitine becomes covalently bound to the organic
acid and facilitates excretion in urine.

Carnitine needed for fatty acid oxidation of long chain fats

Question 19

Methylmalonic Acidemia

Answer 19

AR
methylmalonylCoA Mutase

neonatal onset, lerthargy, coma

metabolic acidosis, anion gap
hyperammonemia, hyperglycinemia

neutropenia, thrombocytopenia,

Treatment: Diet, carnitine, B12,

if mom has vegan diet and low B12, baby will screen positive.

Question 20

Ornithine Transcarbamylase Deficiency (OTC)

IMPORTANT

Answer 20

X-link
Male severe.
(female can have milder form)
classic urea cycle.

normal for 24-48 hours. then poor feeding, grunting, lethargy, coma, cerebral edema.

Orotic acid elevates in urine

Question 21

Citrullinemia in Urea cycle defect

Answer 21

argininosuccinate synthase or argininosuccinit lyase deficiency.

Brittle hair, hyepr-ammonia
very high citrulline, orotic aciduria

need to supplement arginine.

Question 22

Arginase deficiency -> Argininemia

Answer 22

AR,
can have neonatal hyperammonemia.
But often with Spastic Quadriplegia, delay milstone.
orotic aciduria.

Question 23

How to tell difference between OTC deficiency and CPS deficiency

Answer 23

Orotic acid high –> OTC deficiency
Orotic Acid low (and low Citrulline) –> CPS deficiency
(carbamyl phosphatate synthase deficiency)

Question 24

know slight 67-68 (genetic 1)

Question 25

Neonate with liver failure: ddx

Answer 25

Tyrosinemia Type 1 Classic Galactosemia HFI (Hereditary Fructose Intolerance)

Question 26

Mucopolysaccharidosis I (MPS Type 1)

Answer 26

Lysosomal Storage Disease Hurler, Hurler-Schei, Schei autosomal recessive, alpha-L-Iduronidase deficiency (cannot break down glycosaminoglycans) normal at birth, but has coarse facial features, hepatosplenomegaly, dysostosis multiplex, corneal clouding.

Question 27

which has corneal clouding

Answer 27

Hurler syndrome NOT Hunter Both are lysosomal storage disease

Question 28

Myotonic Dystrophy

Answer 28

CGT repeat, and severity classification

Question 29

22q11.2 Deletion DiGeorge Velocardiofacial syndrome

Answer 29

Conotruncal defect in DiGeorge ToF, Interrupted aortic arch, +/- Truncus in Velocardiofacial syndrome.

Question 30

Fanconie Anemia

Answer 30

Prenatal/postnatal short stature  Microcephaly  Hypoplastic thumb/radius  GU anomalies  Hyper or hypopigmentation  Eye anomalies  GU anomalies AR (19 genes), AD (one gene), one X-linked. Genomic instability syndrome associated with congenital abnortmalities, bone marrow failure, cancer predisoposition can be associated with VACTERL (won't test)

Question 31

enzyme deficiency in Type I glycogen storage disease and Type II

Answer 31

Type I: **Glucose-6-Phosphatase** (liver, kidney, GI, metabolic acidosis and hypoglycemia) Type II: Pompe **Lysosomal alpha-glucosidase** cardiomegaly, CNS.

Question 32

hypoketotic, hypoglycemic crisis

Answer 32

fatty acid oxidation disorder CPK and Uric acid are often elevated

Question 33

cataract, hepatomegaly, poorly breast feed baby Dx what enzyme deficient

Answer 33

Galactesemia Galactose-1-phosphate uridyltransferase (GALT)

Question 34

hypotonia, high forhead, flat orbital bridge, flate nasal bridge, hepatomegaly, calcifcation in poplteal area

Answer 34

zellweger syndrome (cerebro-hepato-renal syndrome) very long chain fatty acid accumulation hepatic and renal peroxisome issue