Metabolics and genetics Flashcards
Homocysteinuria epidemiology and aetiology
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
Homocystenuria clinical presentation
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
Homocysteinuria treatment
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
MSUD epi/etiology
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)
MSUD presentation
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
MSUD diagnosis
Definite diagnosis made by ^^ plasma leucine, isoleucine, and valine
And alloisoleucine in excess
Abnormal urine OA profile with ketoacid derivatives and beached chain AA
MSUD treatment
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!!!
MCAD aetiology and epi
Most common of the fatty acid oxidation disorders, founder effect [missense mutation]
Mcad presentation.
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
MCAD labs
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)
Mcad treatment
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
PKU aetiology and epi
AR, primarily affects brain
1:10,000
Classic: results from defect in hydroxylation of phenylalanine to tyrosine (so high phenylalanine and low tyrosine)
PKU untreated
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
Tetrahydrobiopterin defect
Severe form of PKU,
PKU screening
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
PKU treatment
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
Maternal PKU
Maternal hyperPA needs management before conception to prevent fetal brain damage, CHD, microcephaly
Tyrosinemia I etiology
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
Tyrosinemia diagnosis
Positive NBS –> quantitative measurement of tyrosine and blood/urine succinylacetone (elevated)
Dna testing available for some mutations
Tyrosinemia treatment
Nitisinone (NTBC) –> inhibitor of oxidation of parahydroxyphenylpyruvic acid –> eliminates production of toxic succinylacetone
- low phenylalanine low tyrosine diet
Tyrosinemia II and III
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
CHARGE syndrome
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
MURCS
Mullarian duct aplasia
Renal aplasia
Cervicothoracic somite dysplasia
VAcTERL syndrome
Vertebral Anal atresia Cardiac defect (vsd most common) TEF Esophageal atresia Renal abn Limb defects
1/5000, risk factor: IDM
Normal development and intelligence
Cri du chat syndrome inheritance and characteristics
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
DiGeorge acronym
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)
Galactosemia characteristics
Jaundice, FTT, E. coli sepsis, bleeding, cataracts, met acidosis (hyperchloremic)
Disorder of galactose metabolism
Galactosemia types
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
Galactosemia diagnosis
Urine reducing substances (galactose)
Dx made by showing reduction in activity of GALT and dna testing for mutations to GALT confirms
Kallman syndrome
Isolated gonadotropin deficiency (most common form)
Xlinked form: KAL gene
Other forms AR, AD
Hyposmia/anosmia
Hemophilia inheritance
A (factor viii deficiency) : X linked
B (factor IV deficiency): X linked
C (factor xi): autosomal recessive (ashkenazi Jews)
Osteogenesis imperfecta testing
Culture fibroblasts for COL1A1 and 1A2 gene mutation will pick up 90% Majority AD (often spontaneous mutation)
OI triad
Fragile bones
Blue sclerae
Early deafness
Beckwith-wiedemann syndrome
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
Beckwith-weidemann tumour association
Wilms, hepatoblastoma, adrenal carcinoma, gonadoblastoma, rhabdomyosarcoma
Beckwith-weid treatment
Diazoxide, somatostatin and frequent feedings for hypoglycemia
May require surgery (resect pancreas)
Abdo ultrasound q3months until age 7-8
Soto syndrome associations
Cleft palate, mental retard Asian, seizure disorder and possible congenital heart defects
Bardet-Biedl syndrome
Ciliopathic genetic disorder characterized principally by obesity, retinitis pigmentosa, polydactyly, hypogonadism, and renal failure in some cases
POMC deficiency
Severe early onset of obesity, adrenal insufficiency (low acth levels), red hair
Very rare
POMC is responsible for satiety
McCune Albright Syndrome triad
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
QT syndrome
deafness, long QT
Axenfeld Rieger syndrome
anterior segment eye abnormalities can develop glaucoma hypertelorism extra periumbilical skin AD inheritance
