Metabolics and genetics

Question 1

Homocysteinuria epidemiology and aetiology

Answer 1

Autosomal recessive, one in 200,000

Involves connective tissue, brain, vascular system.
Caused by deficiency of cystathionine-B-synthase (conversion of methionine to cysteine - homocysteine is an intermediate) therefore increased levels of methionine

Question 2

Homocystenuria clinical presentation

Answer 2

Dislocated ocular lens [down and in], long slender extremities [marfanoid – but there lenses dislocate up and out]
Malar Flushing, livido reticularis, scoliosis, psychiatric illness, and are, AV thrombosis

Diagnosis: elevated homocysteine in blood
Plasma AA: elevated methionine

Question 3

Homocysteinuria treatment

Answer 3

Two forms:
- 50% activity of deficient enzyme can be enhanced by large doses of pyridoxine, folate supplement added + diet and betaine (trimethylglycine) to control homocysteine levels –> more likely to be missed on NBS because methionine levels aren’t always above cut off

• Second form is not responsive to pyridoxine therapy. Elevated homocysteine levels controlled by methionine-restricted diet and cystine and folate supplement

Question 4

MSUD epi/etiology

Answer 4

AR, rare (1:250,000)
Branched chain ketoaciduria
Deficiency of decarboxylase –> degradation of ketoacid analogues of the 3 crunches chain AA - leucine, isoleucine, valine
Pennsylvania Mennonites (1:150)

Question 5

MSUD presentation

Answer 5

Typically begins within 1 to 4 weeks of birth
For feeding, vomiting, incr RR
Hallmark is profound CNS depression, alternating hypotonia/hypertonia (extensor spasms), opisthotonos and seizures
Urine has the odour of maple syrup

There are also intermittent and late onset forms

Investigations:
Hypoglycemia and ketonuria
Variable presence of metabolic acidosis with AG (from plasma beached chain organic acids and ketone bodies, B-hydroxybuterate and acetoacetate)
Plasma AA and urine OA

Question 6

MSUD diagnosis

Answer 6

Definite diagnosis made by ^^ plasma leucine, isoleucine, and valine
And alloisoleucine in excess
Abnormal urine OA profile with ketoacid derivatives and beached chain AA

Question 7

MSUD treatment

Answer 7

Nutrition: adequate calories, protein, excluding branched chain amino acid’s
Intake of the branched chain amino acids [all three are essential] is restricted to amounts required for growth in severely affected infants. Restriction is continued for life.
Acidotic crisis: hemodialysis, hemp filtration and PD life saving. Crisis precipitated by ordinary catabolic stresses e.g. infection
Liver transplantation treats MSUD!!!

Question 8

MCAD aetiology and epi

Answer 8

Most common of the fatty acid oxidation disorders, founder effect [missense mutation]

Question 9

Mcad presentation.

Answer 9

Presents at three months to three years of life with episodes of acute illness triggered by prolonged fasting (>12-16hrs)
Attacks are rare in the first few months because babies feet so often, but has been seen in breast-fed infants.
Symptoms: nausea, vomiting, lethargy with rapid progression to coma or seizures with cardiorespiratory collapse. SIDS can occur
Hepatomegaly can occur with fat deposition

Question 10

MCAD labs

Answer 10

Hypoglycemia usually with acute episodes
Hypoketotic (because of the relative hypoketonemia there is little or no metabolic acidosis)
LFTs abnormal, incr PTT and INR
During acute episode urine organic acid profile will show low concentration of key tones and increased medium chain dicarboxylic acids
Plasma and tissue total Carnitine levels are 25-50% of normal (secondary Carnitine deficiency)

Question 11

Mcad treatment

Answer 11

Avoid fasting, acute illness give d10w to suppress lipolysis
Restricting dietary fat or treatment with Carnitine is controversial

Testing of sibling of affected pt is important to detect asymptomatic family members, as many as half have never had an episode

Question 12

PKU aetiology and epi

Answer 12

AR, primarily affects brain
1:10,000

Classic: results from defect in hydroxylation of phenylalanine to tyrosine (so high phenylalanine and low tyrosine)

Question 13

PKU untreated

Answer 13

Normal at birth, but severe MR [I Q 30] develops in first year of life
Blonde hair, blue eyes, eczema, mousy odour of urine
This is rarely seen because of newborn screening

Question 14

Tetrahydrobiopterin defect

Answer 14

Severe form of PKU,

Question 15

PKU screening

Answer 15

Positive screen–> quantitative plasma AA, measure phenylalanine and tyrosine levels
PAH gene testing reveals >400 mutations, some mutations are mild

Plasma PA > 360 uM is diagnostic and req prompt treatment. Untreated PA >600

Prems and a few full term infants have transient elevations in phenylalanine

Once ^PA diagnosed deficiency of BH4 (tetrahydrobiopterin) needs to be ruled out

Question 16

PKU treatment

Answer 16

Goal to keep plasma phenylalanine in range of 120 to 364 first 10 years of life at least. This is sometimes harder as teens/adults

Foods to eliminate: high protein milk/dairy, meat, fish, chicken, eggs, beans, nuts
Milk substitute: phenyl free formula

Excellent prognosis if diet started in first 10 days

Question 17

Maternal PKU

Answer 17

Maternal hyperPA needs management before conception to prevent fetal brain damage, CHD, microcephaly

Question 18

Tyrosinemia I etiology

Answer 18

Due to fumarylacetoacetate hydrolase deficiency
Rare
Accumulated metabolites produce severe liver disease associated with bleeding disorder, hypoglycemia, low albumin, elevated LFTs and defects in renal tubular function
HCC may occur eventually

Question 19

Tyrosinemia diagnosis

Answer 19

Positive NBS –> quantitative measurement of tyrosine and blood/urine succinylacetone (elevated)
Dna testing available for some mutations

Question 20

Tyrosinemia treatment

Answer 20

Nitisinone (NTBC) –> inhibitor of oxidation of parahydroxyphenylpyruvic acid –> eliminates production of toxic succinylacetone

• low phenylalanine low tyrosine diet

Question 21

Tyrosinemia II and III

Answer 21

More benign forms of hereditary tyrosinemia

Blocked metabolism of tyrosine at earlier steps in the pathway and succinylacetone is NOT produced

Hyperkaratosis of palms and soles of feet and keratitis with visual disturbance

Treat with low phenylalanine and low tyrosine diet

Question 22

CHARGE syndrome

Answer 22

Coloboma
Heart disease
Atresia (choanal)
Retarded growth and development 
GU abn (+/- micropenis)
Ear abn deafness/CN abn (1, 2 and 8 most commonly)

1/10,000
70% if pts will have mutation on CHD7 gene
Autosomal dominant

Question 23

MURCS

Answer 23

Mullarian duct aplasia
Renal aplasia
Cervicothoracic somite dysplasia

Question 24

VAcTERL syndrome

Answer 24

Vertebral 
Anal atresia 
Cardiac defect (vsd most common)
TEF
Esophageal atresia 
Renal abn
Limb defects

1/5000, risk factor: IDM
Normal development and intelligence

Question 25

Cri du chat syndrome inheritance and characteristics

Answer 25

Deletion of material from short arm of chromosome 5
De novo 85%, 15% due to balanced translocation in parent

-growth retardation
- microcephaly
- severe MR
Characteristic cat-like cry during infancy
Low birth wt and low tone
Facial features: hypertelorism, low set ears, small jaw, round face
May have heart defect

Question 26

DiGeorge acronym

Answer 26

Aka velocardiofacial syndrome
CATCH 22
-Cardiac: outflow tract obstructions (TOF, truncus, DORV, interrupted aortic arch)
-Abnormal face: hypertelorism, low set prominent ears, notched pinnae, mucrognathia, bifid uvula, high arched palate)
-Thymus hypo/aplasia (t cell deficiency)
-Cleft palate
-Hypocalcemia (hypoparathyroid)
22q11 micro deletion (usually sporadic de novo)

Question 27

Galactosemia characteristics

Answer 27

Jaundice, FTT, E. coli sepsis, bleeding, cataracts, met acidosis (hyperchloremic)

Disorder of galactose metabolism

Question 28

Galactosemia types

Answer 28

Classic: AR results in deficient activity of GALT enzyme (1/60,000)
Newborn: high amounts of lactose = glucose and galactose –> not able to metabolize and accumulates and causes injury to kidney and liver and brain

Start lactose free diet in first 10 days to avoid complications, but still at risk of DD and speech problems

Partial transferase deficiency: asymptomatic generally, more frequent than classic, diagnosed on NBS

Question 29

Galactosemia diagnosis

Answer 29

Urine reducing substances (galactose)

Dx made by showing reduction in activity of GALT and dna testing for mutations to GALT confirms

Question 30

Kallman syndrome

Answer 30

Isolated gonadotropin deficiency (most common form)
Xlinked form: KAL gene
Other forms AR, AD
Hyposmia/anosmia

Question 31

Hemophilia inheritance

Answer 31

A (factor viii deficiency) : X linked
B (factor IV deficiency): X linked
C (factor xi): autosomal recessive (ashkenazi Jews)

Question 32

Osteogenesis imperfecta testing

Answer 32

Culture fibroblasts for COL1A1 and 1A2 gene mutation will pick up 90%
Majority AD (often spontaneous mutation)

Question 33

OI triad

Answer 33

Fragile bones
Blue sclerae
Early deafness

Question 34

Beckwith-wiedemann syndrome

Answer 34

Omphalocele, umb hernia 
Gigantism
Macroglossia
Visceromegaly
Hemihypertrophy
Facial features: infant - round with prominent cheeks and relative narrowing or forehead 
Teen- normalizes 
Hypoglycemia 3-6 months

Question 35

Beckwith-weidemann tumour association

Answer 35

Wilms, hepatoblastoma, adrenal carcinoma, gonadoblastoma, rhabdomyosarcoma

Question 36

Beckwith-weid treatment

Answer 36

Diazoxide, somatostatin and frequent feedings for hypoglycemia
May require surgery (resect pancreas)
Abdo ultrasound q3months until age 7-8

Question 37

Soto syndrome associations

Answer 37

Cleft palate, mental retard Asian, seizure disorder and possible congenital heart defects

Question 38

Bardet-Biedl syndrome

Answer 38

Ciliopathic genetic disorder characterized principally by obesity, retinitis pigmentosa, polydactyly, hypogonadism, and renal failure in some cases

Question 39

POMC deficiency

Answer 39

Severe early onset of obesity, adrenal insufficiency (low acth levels), red hair
Very rare
POMC is responsible for satiety

Question 40

McCune Albright Syndrome triad

Answer 40

Café au lait spots with irregular bone scar tissue (polyostotic fibrous dysplasia)
Endocrine hyper function (^tsh, ^GH) precocious puberty

Also ricketts (renal losses secondary to ^po4

Question 41

QT syndrome

Answer 41

deafness, long QT

Question 42

Axenfeld Rieger syndrome

Answer 42

anterior segment eye abnormalities 
can develop glaucoma 
hypertelorism 
extra periumbilical skin
AD inheritance