Metabolic Flashcards
1
Q
What enzyme converts D-Glucose -> Glucose-6-phosphate
A
Hexokinase
2
Q
How many molecules of ATP and NADH and pyruvate are made via glycolysis
A
2 net molecules ATP (2 required, 4 produced)
2NADH
2 Pyruvate molecules
3
Q
What enzyme converts pyruvate to lactate
A
Lactate dehydrogenase
4
Q
What enzyme converts pyruvate to alanine
A
Alanine transaminase
5
Q
Which GLUT transporter transports glucose to the brain
A
GLUT1
6
Q
What GLUT transporter transports glucose to muscle and fat
A
GUT4
7
Q
What glucose transport transports glucose to kidney/liver/pancreas
A
GLUT 2
8
Q
What enzyme converts glucose –> glucose 6 phosphate
A
Hexokinase
9
Q
What base molecule makes up glycogen and what does it connect to
A
Gluogenin
UDP Glucose
10
Q
Which enzyme elongates the glycogen chain
A
Glycogen synthase
11
Q
In a glycogen molecule
-what enzyme makes branches and what is the bond
-what enzyme elongates the chain and what is the bond
A
-Branching enzyme; a1-6 glycosidic bond
-Glycogen synthase; a1-4 glycosidic bond
12
Q
What enzyme converts Glucose1phosphate to Glucose-6-phosphate
A
Phosphoglucomutase
13
Q
What enzyme allows Glucose-6-phosphate to be relased into the blood
What organs is it found
What organ is it NOT found in
A
Glucose-6-phosphatase
Liver/Kidney/GIT
Not found in muscle
14
Q
What pathway is used in the liver and RBC for glucose metabolism and to protect against oxidate stress
A
Pentose Phosphate pathway
15
Q
What glycogen storage defect is due to a deficiency in glucose-6-phosphotase
A
von Gierke Disease- type 1
16
Q
What causes Glycogen storage disease type 1: von Gierke disease and what are the symptoms
A
Glucose-6-phosphatase enzyme deficiency
Cannot convert G-6-P to free glucose so G-6-P builds up in cells
-hypoglycaemia
-G-6-P is shunted down glycolysis pathway to make pyruvate. Pyruvate converted ot
-Lactate (LDH)
-Alanine (ALT)
-Fatty acids –> hyperlipidaemia
Also get increased shunting of G6P down the pentose phosphate pathway –> increased purine synthesis –> increased uric acid
Conclusion
-Hypoglycaemia
-High lactate
-hyperlipidaemia
-Hyperalbuminaemia
-High uric acid
17
Q
What can Glucose-6-phosphate become
A
glucose
Glycogen
Pyruvate–> alanine, fatty acids, lactate
Pentose phosphate pathway –> purine and pyridines –> urate
18
Q
What features would you see in a child with GSD Type 1
what features on investigations
A
Hypoglycaemia –> seizures
Hepatomegally
Doll like facies + thin limbs
FTT
Investigations
-low BSL
-high lactate
-high alanine
-hyperlipidaemia
-hyperuraemia
-Liver biopsy: universal distension of hepatocytes with glycogen and fat
19
Q
What foods should be avoided in von Gipple disease
A
Fructose
Galactose
20
Q
What is the role of glucose-6-phosphate translocase
A
Glucose 6 phosphate is taken up into the ER
Dephosphorylated to glucose by glucose-6-phosphatase
Glucose-6-phosphate translocase allows the transport of G6P into the endoplasmic reticulum
21
Q
SLCA gene is associated with what glycogen storage disease defect
A
GSD Type 1b: Glucose-6-phosphate translocase deficiency
22
Q
What distinguishes type 1a via type 1b glycogen storage disease
A
Type1a= Von Gierke Disease- glucose-6-phosphatase deficiency
Type1b = Glucose-6-phosphate transferase deficiency due to SLCA gene
Both have accumulation of Glucose-6-phosphate –> hyperalanine, hyperlipidaemia, high lactate, hypoglycaemia
Type1b also has neutropenia and manage as per type 1a but also use prophylactic cotrimoxazole
23
Q
hypoglycaemia, lactic acidosis, hyperuricemia, hyperlipidaemia
what is the disease
A
Glycogen storage disease type 1a or b
24
Q
What is Pompe a disease of what enzyme
Where does glycogen accumulate
What are the symptoms
A
Pompe= GSD type 1
-disease of acidic alpha glucosidase (to break a1-4 and a-1-6 glycosidic binds)
-Accumulates in the liver and in muscle (skeletal, heart and smooth muscle)
Sx
-Hepatomegaly/ liver enlargement likely 2 to heart failure
-Cardiac: enlarged heart, Hypertrophic cardiomyopathy
-Skeletal: hypotonia, proximal myopathy in juvenile disease
-Smooth muscles of blood vessels and organs
-Enlarged tongue
Involvement of the diaphragm can cause respiratory distress
25
An infant presents with an enlarged heart and hypotonia/weakness
What metabolic disorder does this suggest
Pompe disease
26
What deficiency is present in Coris disease
What type of disorder is it
What are the symptoms
Deficiency of debranching enzyme
Glycogen storage disease
Sx: mild hypoglycaemia, hepatomegaly, skeletal muscle wasting and weakness, short stature
27
What is McArdle syndrome
What symptoms does it cause
What is the test for it
What is the treatment
A glycogen storage disease due to muscle phosphorylase deficiency
-Symptoms: cannot utilise glycogen so muscle fatigue with a second wind aka more energy once fatty acid is utilised
-test: ischaemic forearm test.
-Pretest venous CK/Ammonia/lactate
-inflate a blood pressure cuff to force arm to use glycogen and get person to do repetitive movements
-repeat ammonia/CK/lactate at 5, 10 and 20 min mark
-post test urine myoglobinuria
Treatment
-Avoid statins
-Pre work out protein and surcose
-Activity modification
28
What enzymes are responsible for converting galactose to Glucose 6 phosphate
Galactose kinase (Galactose --> Galactose-1-phosphate)
GALT (Galactose-1-phosphate-urodyltransferase)= Gal-1-Phosphate + UDP-Glucose --> Glucose-1-phosphate + UDP-Galactose
-UDP-Galactose Epimerase: converts UDP-Galactose --> UDP-Glucose
-Phosphoglucomutase = converts Glucose-1-phosphate --> Glucose-6-phosphate
29
What 3 enzymes cause galactosemia and what are the symptoms of each
1) GALT (Galactose-1-phosphate uridyltransferase) -
-onset of sx within a week due to milk consumption (lactose= glucose + galactose)
-E. coli sepsis
-lethargy
-jaundice
-coagulopathy
-oil drop cataracts
-faltering growth, tubulopathy, rickets
2) Galactosekinase- cataracts is the only issue
3) UDP-Galactose epimerise - only affects RBC
29
What 3 enzymes cause galactosemia and what are the symptoms of each
1) GALT (Galactose-1-phosphate uridyltransferase) -
-onset of sx within a week due to milk consumption (lactose= glucose + galactose)
-E. coli sepsis
-lethargy
-jaundice
-coagulopathy
-oil drop cataracts
-faltering growth, tubulopathy, rickets
2) Galactosekinase- cataracts is the only issue
3) UDP-Galactose epimerise - only affects RBC
30
What is deficient in Hereditary Fructose Intolerance
What sx does it cause
What is the treatment
Aldolase-B deficiency
F=Vomitting/hypoglycaemia on ingestion of fructose approx 6 months of age. Chronic= faltering growth, hepatomegaly, proximal renal tubulopathy
Investigations
-Reducing substances in urine
-Lactic acidosis
-Deranged LFTs and coagulation studies
Management: Avoid Fructose + Sucrose + Sorbitol
31
E. coli Sepsis and cataracts in a neonate is associated with what error of metabolism
Galactoseaemia
32
What deficiency results in phenylketonuria
Deficiency in phenylalanine hydroxylase OR biopterin deficiency
33
What amino acid is phenylalanine converted to
tyrosine
34
what is the amino acid tyrosine used in
protein synthesis
cathecolamine synthesis
thyroxine
melanin
35
What symptoms does PKU caused if left untreated
microcephaly
mental retardation
spastic cerebral palsy
albuminism
widely spaced teeth
musty odor
eczematous rash and dry skin
36
A baby has elevated succinylacetone- what is this pathopnemonic of
Tyrosinaemia
Tyrosine is covered to Fumerate and acetoacetate by fumaryl-acetoacetate. If this enzyme is deficient it is shunted to succinylacetone
37
What are the symptoms of tyrosinaemia
-peripheral neuropathy
-acute liver failure
-proximal renal tubulopathy
38
What is Maple syrup urine disease a deficiency of
Branched chain a ketoacid dehydrogenase
39
What effects does a deficiency in branched chain a-ketoacid dehydrogenase deficiency have
-high leucine --> outcompetes other amino acids to cross the BBB.
-In the brain, uses glutamine and alanine to convert back to other amino acids
-result = like glutamine = low GABA and glutamate (neurotransmitters) = impaired cell-cell communication
Also get elevated a-ketoacids which impair the kerbs cycle resulting in reduced ATP production
-Na/K ATP pump dysfunciton
-Cerebral oedema
40
what deficiency is present in homocysteinuria
what symptoms does it cause
what vitamins are given to help
if the vitamins don't work what is given
cystathionine-b-synthetase
Sx
-marfanoid like sx
-ectopic lentis- downward
-intellectual disability
-blood clots as homocysteine inflames endothelium
-behavioural issues
-osteoporosis
Vitamin B6
Folate
BETANINE - think making homocystINI Better --> Better-nine
41
what is the role of glycine in the brain and spinal cord
acts as a neurotransmitter
-in the brain: excitatory effect
-spinal cord and brainstem: inhibitory affect
42
Non-ketotic hyperglycinaemia is a defect in what
What are the symptoms
what would you see on investigation
what is the treatment
Defect in glycine cleave which allows glycine to accumulate
Glycine is a neurotransmitter
-excitory effect in the brain
-inhibitory affect on spinal cord and brain stem
Sx
-hiccups
-hypotonia
-apnoea and encephalopathy
-seizures
-marked developmental delay
Investigation
-elevated blood and urine glycine
-CSF plasma glycine >0.9
Tx: sodium benzoate
43
what is the treatment in non-ketotic hyperglycinaemia to reduce glycine
sodium benzoate
44
Tryptophan is an important precursor for what
niacin - vitamin B3
serotonin
45
Hartnup is a disease due to what
What sx are cause
what is the treatment
Disorder of non-polar amino acid absorption especially affecting the amino acid tryptophan
-do not absorb from GI tract
-unable to absorb in the kidneys --> high levels in the urine
Tyrptophasn is a precursor to Vitamin B3 (Niacin) and Serotonin
-Get pellegra sx (diarrhoea, dermatitis, dementia)
-Cerebellar ataxia
-Developmental delay
-muscle weakness
Serotonin supplementation
Nicotinic acid
46
what accumulates in Canavan disease
N-acetyl-L-aspartate
47
What gene and enzyme are deficient in Canavan disease
What does the enzyme do
what accumulates
ASPA gene
Enzyme: aspartoacylase
“what to get out of the caravan ASAP” canavan = ASPA = aspartoacylase”
enzyme: converts N-acetyl-L-aspartate --> acetate and L-aspartate
Accumulates: N-acetyl-L-aspartate
48
Canavan disease is a deficiency in Aspartoacylase (ASPA) which results in the accumulation of N-acetyl-L-aspartate
Why does this cause disease pathology
what are the symptoms
N-acetyl-L aspartate are converted to L-Aspartate and acetate by the enzyme Aspartoacylase.
Acetate converted to Acetyl-CoA and used in fatty acid synthesis in the myelin sheath
Defect - interfers with white matter tract
Result= leukodystrophy
Symptoms
-Regression of motor skills
-Macrocephaly (think child with a caravan on top of their head)
-hypotonia
-seizures
-paralysis
-blindness
49
Glutaric acid is an intermediate in the degradation of what amino acid
Lysine
50
Glutaric aciduria type 1 is due to a efficiency in what
What are the symptoms of GAT-Type 1
Glutaric acid is an intermediate in the degradation of lysine
Converted to Acetyle CoA via glytayl-CoA-dehydrogenase
Onset during illness/times of stress
-acute increase in Glutaryl-CoA-COA
-rigidity, dystonia
-metabolic decompensation --> vomitting, ketosis, seizures, death
51
What should be avoided in Glutaric aciduria type 1
Lysine
Tryptophan
52
What antibiotic is used in organic academia and why
Metronidazole- works on gut bacteria - reduces production of propionic acid
53
What medication is given in organic academia that binds the organic acids to reduce them and allow excretion
L- carnitine
54
What enzyme is deficient in Methylmalanoic aciduria
methylmalonyl CoA mutatase "MCM"
55
Raised propionylcarnitine (C3) is elevated in what disease
Organic acidaemia
Proprionic acid + methymalanoic-CoA bind to carnitine to form methymalonlycarnitine (C4DC) and propionlycarnitine (C3)
56
What are the symptoms of methymalanic acaemia
what enzyme is deficient
what do you see on blood testing
what is the treatment
enzyme: MCM = methymalanoic-CoA mutatse
symptoms
-first week of life
-poor feeding, lethargy
-vomitting
-encephalopathy
-dilated cardiomyopathy
-pancreatitis
-if untreated, basal ganglia necrosis
tests
-metabollic acidosis
-raised ketones
-neutropenia and thrombocytopenia
-elevatated C3 (propionylcarnitine)
Treatment
-L-carnitine
-B12 supplementation
-Sick day plan with 10% dextrose to prevent catabolism
-Special formula with no isoleucine, methionine, threonine or valine
56
What are the symptoms of methymalanic acaemia
what enzyme is deficient
what do you see on blood testing
what is the treatment
enzyme: MCM = methymalanoic-CoA mutatse
symptoms
-first week of life
-poor feeding, lethargy
-vomitting
-encephalopathy
-dilated cardiomyopathy
-pancreatitis
-if untreated, basal ganglia necrosis
tests
-metabollic acidosis
-raised ketones
-neutropenia and thrombocytopenia
-elevatated C3 (propionylcarnitine)
Treatment
-L-carnitine
-B12 supplementation
-Sick day plan with 10% dextrose to prevent catabolism
-Special formula with no isoleucine, methionine, threonine or valine
57
58
what enzyme is deficient in propionic acidaemia
What treatment is used
propionyl CoA dehydrogenase
Tx
-L) carnitine
-Liver transplant
-Biotin
-Metronidazole
59
Smelly feet odour is associated with what metabolic disorder
Isovaleric acidaemia
60
A child has bilateral subdural and encephalopathy
what metabolic condition should be excluded
what enzyme is deficient
Glutaric aciduria Type 1
Glutaryl-CoA-dehydrogenase
61
What are symptoms of Glutamic aciduria type 1
Pre crisis: asymptomatic with frontal bossing
During crisis: encephalopathy, dystonia, chorea, feeding issues, irritability, bilateral subdural haemorrhages
62
What metabolic condition causes this and why
Hartnup disease - cannot absorb tryptophan which forms niacin (B3) and serotonin so you get Pellegra (dermatitis, dementia, diarrhoea)
63
What is the pneumonic of the urea cycle
/ what is the urea cycle
“ Carbs combine with oranges to make a citrus appetizer that makes you full argaine but Urea continue to crave oranges”.
Carbomoyl phosphate + Ornithine Citrulinne Arginosuccinate Fumrate + Arginine Ornithine + urea
64
What is the only urea cycle defect that is inherited in an x-linked fashion
Ornithine Transcarbamoylase deficiency is X-linked recessive
The remainder are Autosomal recessive
65
In a urea cycle defect you have a deficiency in ornithine transcarbamylase (OTC). what does this cause in blood tests
Increased glutamate and ammonia
increased ornithine (orotic acid) and carboxyl phosphate
reduced citrulline
reduced arginine
66
What deficiency causes citurllinaemia
what is seen in the blood
Argininosuccinate synthase
Increased citrulline and increased orotic acid (ornithine)
reduced arginine
66
What deficiency causes citurllinaemia
what is seen in the blood
Argininosuccinate synthase
Increased citrulline and increased orotic acid (ornithine)
reduced arginine
67
What key features are seen in a urea cycle defect
-ammonia level
-blood gas
-urine
Ammonia level >1000
Blood gas: respiratory alkalosis as urea is a strong stimulate of the respiratory centre
-urine: increased orotic acid
68
A child has a urea cycle defect
-what is acute treatment
-what is long term medication
-acute: harm-filtration, IV dextrose to stop catabolism of proteins
-long term: sodium benzoate and sodium phenylbutyrate which conjugate with glutamate and glycine to allow urine excretion and removal of nitrogen
-Arginine supplementation
69
What indicates a fatty acid oxidation defect in terms of blood sugar and ketones
low blood sugar and inappropriately low ketones
70
Which fatty acid required carnitine to enter the mitochondrial matrix
Long chain fatty acids
71
What deficiency causes medium chain fatty acid oxidation defect
medium chain fatty acid CoA dehydrogenase
72
what causes raised C8 + C10 carnitine
medium chain fatty acid oxidation defect
73
a mother has liver dysfunction during pregnancy- what fatty acid oxidation defect is this linked to
Long chain fatty acid CoA dehydrogenase deficiency
74
What are the clinical features of VLCFA defect
All the 'opathies'
-myopathy- muscle weakness and fatigue, rhabdomyolysis
-cardiomyopathy (hypertrophic)
-peripheral neuropathy
-pigmentary retinopathy
75
What is elevated Carnitine 16 (CD16) and Carnitine-20 (CD-20) associated with
Long chain fatty acid defect
Very long chain fatty acid defect
76
What should be tested in all babies born to mothers with AFLP (Acute fatty liver of pregnancy) and HELLP syndrome
Acylcarnitine profile
77
which anti-epileptic forms a complex with carnitine
sodium valproate
78
What are causes of carnitine deficiency
What is the result
Causes
1) Primary- genetic defect that results in a failure of intake/synthesis/transport of carnitine
2) Secondary- due to excessive loss of carnitine
-organic acidaemia
-disorders of fatty acid oxidation
-sodium valproate which forms a complex with carnitine
Result- inability to transport long chain fatty acids into the mitochondrial matrix for oxidation
79
What is the role of carnitine in fatty acid oxidation
What defects are involved in defects of fatty acid oxidation
transports LCFA into the mitochondria
All are Medium/Short/Long/Very long CoA dehydrogenase defects
80
what causes familial hypertriglyceridaemia
what causes familiar hypercholesterolaemia
VLDL overproduction or reduced destruction
LDL receptor mutation
81
what is the major constituent of LDL
cholesterol - 70%
82
what is the major constituent of VLDL
triglycerides
83
what are features of hypercholesterolaemia in children
tendon xanthomas / thickening of the achilles tendon
corneal acrus
xanthomata
Premature CVD
84
what 2 medications are used in the support of familial hypercholesterolaemia
-statins- HMG-CoA reductase inhibitor which is the rate limiting step in cholesterol production
-Ezetimbe= selective blockage of cholesterol uptake
85
Abetalipoproteinaemia:
-what gene defect
-deficiency in what
-result of deficiency is what
-symptoms
MTP gene defect
Defective Apoenzyme B (ApoB)
Unable to absorb fat
Sx
-fat malabsorption --> steatorrhoea, failure to thrive
-Vitamin E deficiency
-Retinitis pigmentosa
86
what is the role of peroxisomes
metabolism and synthesis of bile acids
Vitamin A brakdown
Oxidation of long chain fatty acids
Synthesis of plasmogens (consitutents of cell walls)
87
what disorders are the below genes involved in
MTP gene
PEX1 gene
PEX6 gene
ABCD1 gene
-Abetalipoproteinaemia
-Zellweger syndrome + Neonatal adrenoleukodystrophy
-Neonatal adrenoleukodystrophy
-X-linked adrenoleukodystrophy
88
what are the symptoms of Zellweger syndrome
what is it a disorder of
sx
-large forehead with frontal bossing and large fontanelle
-hypotonia
-seizures
-hepatomegally with cirrhoses
-cystic kidney disease
-calcific stippling and punctate lesions around the body
89
What accumulates in Refusm syndrome
Phytanic acid (Vitamin A)
90
In X-linked adrenoleukodystrophy
-Gene
-Age of presentation
-Symptoms
Finding on:
-Blood test
-MRI
-Short synacthen test
Treatment
ABDC1
5-15 years
Sx: developmental regression, visual impairment, hyperpigmentation, adrenal crisis
Bloods:
-high ACTH
-low cortisol -- hypoglycaemia
-low aldosterone - low sodium, high potassium and low blood pressure
-MRI: bilateral posterior white matter involvement
-Short synacthen test blunted
Treatment
-BMT
-Lorenzo oil
-Steroid replacement
91
what are the 5 conditions that cause developmental regression in school aged children
1. Subacute Sclerosing Panencephalitis
2. X – Linked Adrenoleukodystrophy
3. Batten Disease (Seizures + Regression)
4. Wilson Disease (Jaundice + Regression)
5. Niemann – Pick C Disease
92
What type of disorder is Tay-sach and Sandhoff disease
What enzyme is affected
What are their symptoms
What is the key difference on exam
Lysosomal disorder of glucoliosides
Due to deficiency in Hexosaminase A (Tay-each) and Hexoaminase A+B (Sandhoff)
Cherry red spots
Spasticity and quadraplegia
Progressive blindness
Seizures
Death within 2 years
Key difference= sandhoff- hepatomegaly, tay-sach does not
93
What type of disorder is Gaucher Disease
What enzyme is affected
What are the symptoms
Cerebroside disorder- gluco-sphingolipid involved in most cell membranes
Enzyme -glucocerebrosidase deficiency
Features: think an Obese G (child with big belly)
-Hepatosplenomegaly
-Boney involvement - pancytopenia, avascular necrosis, erlenmeyer flask deformity
-peripheral neuropathy
-seizures
Treatment-
-Enzyme replacement therapy for types 1+3
-No effective treatment for type 2
94
What enzyme is deficient in Krabbe disease
What are the symptoms
GALC ('Krabbes belong in Genitalia And Long Cocks)
Enzyme: galacetocerebrosidase enzyme
Destruction of myelin - a type of leukodystrophy
Seizures
Absent reflexes
Progressive blindness
Opisthotonus
Death by 2
95
What enzyme is involved in Fabry disease
What are the symptoms
a-galactosidase enzyme
Flakey skin- hypohydrosis
Angiokeratoma
Burning pain- nephropathy
Renal nephropathy
Y chromosome- boys affected as X-linked
Cardiovascular involvement
Corneal opacities
96
What enzyme is deficient in metachromic leukodystrophy and what does it do
What is the age of onset
What symptoms does it cause
What do you see on MRI
alpha-sulfatasa A enzyme
Desulfatation of sulfate in Glycolipid of myelin
Lack of enzyme results in central and peripheral myelin destruction
Age: 1-2 years old
Developmental regression
Hypotonia
Muscle wasting
Lack of deep tendon reflexes
Death by age 5
MRI: frontal and peri-ventricular white matter lesions
97
What is the symptoms of Cysteinosis
Accumulation of cysteine in cells
-destruction of proximal renal tubular cells --> Fanconi syndrome with hypophosphataemia, hyponatraemia, loss of bicarbonate so acidosis, hypoalbuminaemia, low urate
-accumulation in cornea --> cataracts
-accumulation of Kuppfer cells - hepatomegaly
98
What are the enzyme issue and symptoms of Wolfman disease
Lysosomal acid lipase deficiency
LIPA gene
Cannot break down cholesterol esters
FTT, Hepatomegaly, adrenal calcifications
Fatal in infancy
99
a-iduronidase and Idurisulfase are enzymes in what 2 disorders
-Hurler
-Hunter
100
which mucopolysaccarhoides is associated with corneal clouding
Hurler syndrome
101
heparan sulfate sulfatase is associated with what mucopolysaccharide disorder
San Fillippo
102
X-linked leukodystrophy
-what type of disorder
-what do you screen for
-what is the age of onset
-what are the symptoms
-what do you see on MRI
-what is the treament
-perioxosmal disorder with an inability to break down very long chain fatty acids
-Serum VLFCAs
-5-15 years
-Learning difficulties, progressive blindness, hyper-reflexia, Addisons disease
-Parito-occipital white matter demyelination
TX
-stem cell transplant
103
What is Smith-Lemi-Opitz Syndrome a defect of?
What are the symptoms
How is it diagnosed
What is the treatment
Defect of cholesterol biosynthesis- deficiency in 7-dehydrocholesterol reductase
Sx; microcephaly, syndactly of 2nd and 3rd toes, light sensitivity, ambitious genitalia for boys, renal abnormalities, learning difficulties
Diagnosis: raised 7-dehydrocholesterol
TX: cholesterol supplementation + statins to prevent precursor build up
104
What is not synthesised in a disorder of glycosylation
What are the symptoms
Oligosaccharides
SX:
-Inverted nipples
-Fat pads
-Muscular hypotonia
-Faltering growth
-Cerebellar hypoplasia
-MR, cardiomyopathy
-Effusions
-Endocrine
