Metabolics Flashcards
Kearns - Sayre Syndrome
Mitochondrial defect
Onset by age 20
External opthalmaplegia
Heart block
Retinitis pigmentosa
Multiple endocrine abnormalities
Cerebellar syndrome/ataxia
Elevated CSF protein
Leigh Disease (Subacute Necrotising Encephalopmyopathy)
Mitochondrial defect
Progressive degenerative disorder presenting in infancy
Developmental delay and regression - strokes in basal ganglia
Decompensation during periods of stress Generalised seizures, weakness, hypotonia, ataxia, tremor, pyramidal signs and nystagmus
Intermittent respiratory with associated sighing or sobbing
External ophthalmoplegia, ptosis, retinitis pigmentosa, optic atrophy, and ↓visual acuity
Hepatic and renal failure
HOCM
Ix: Lactic acidosis, MRI brain: necrotising areas in brainstem
MELAS = Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis + Stroke-Like Episodes
Mitochondrial defect
Initially normal –> progressive motor and cognitive deficits due to recurrent stroke like episodes
At least 2 of the following
i. Focal or generalised seizures
ii. Dementia
iii. Recurrent migraine headaches
iv. Vomiting
Other possible features exercise intolerance, myopathy, ophthalmoplegia, cardiac conduction defects, hypertrophic or dilated cardiomyopathy, deafness, diabetes and proximal renal tubular dysfunction
Investigations
a. Lactic acidosis
b. Ragged red fibres (muscle biopsy)
Metachromatic leukodystrophy
The clinical manifestations of the late infantile form of MLD, which is most common, usually present between 12 and 18 months of age as irritability, inability to walk, and hyperextension of the knee, causing genu recurvatum. The clinical progression of the disease relates to the pathological involvement of both central and peripheral nervous system, giving a mixture of upper and lower motor neuron and cognitive and psychiatric signs. Deep tendon reflexes are diminished or absent. Gradual muscle wasting, weakness, and hypotonia become evident and lead to a debilitated state. As the disease progresses, nystagmus, myoclonic seizures, optic atrophy, and quadriparesis appear, with death in the first decade of life
Smith- Lemi- Opitz
Gene- DHCR7
7-dehydrocholesterol reductase deficiency
Poor growth, microcephaly, intellectual disability, syndactyl/webbing of toes, photosensitivity, ambiguous genitalia (hypospadias + cryptochordism), cardiac defects
Ix: elevated 7-DDHC, low serum cholesterol, sequence gene mutation
Rx: cholesterol supplementaiton
Causes normal anion gap metabolic acidosis
Loss of bicarb
Renal losses
Gastro losses - eg diarrhoea
Causes high anion gap metabolic acidosis
in metabolics- organic acidurias (addition of acid)
Acylcarnitine profile can be used to investigate ..
fatty acid oxidation defects
Organic academies
B12 disorders
What does urinary GAGs test for?
Muchopolysaccharidosis
Galactoseaemia investigations
urine reducing substances, coagulopathy, low albumin, mildly abn LFTs, may or may not have hypoglycemia
Increased RBC galactose 1 phosphate concentration (not affected by blood transfusion)
Definitive: RBC GALT activity (affected by blood transfusion)
Which metabolic conditions are x linked?
X linked aderenoleukodystrophy
Hunter disease
Fabry disease
OTC deficiency
what is the treatment for tyrosinemia type 1
Nitisinone
Low protein (esp low tyrosine and phenylalanine ) diet
Liver transplant
what causes elevated succinylacetone
tyrosinemia type 1
3 manifestations of tyrosinemia type 1
liver failure - (cirrhosis), high risk HCC
Fanconi syndrome —> hypophosphatemic rickets
nephromegaly
Neurological issues - variable
which metabolic defect is most likley to not be picked up by newborn screening
lysosomal storage disordrs
which enzyme is affected in pompe disease
acid alpha glucosidase
Tyrosinemia 1
Disease of liver, kidneys and peripheral nerves
Usually presents 2-6 mo of age with progressive liver disease/acute hepatic crisis - hepatomegaly, transaminitis, cholestasis –> jaundice, ascites, hypoglycemia, coagulation abormalities/GI bleeding
often precipitated by illness
Renal- fanconi syndrome –> hypophosphatemic rickets
Mild to severe neurological dysfunction
Ix: elevated succinulacetone (plasma organic acids)
Rx:low tyrosine + phenylalanine diet
Nitisinone
Liver transplant
Chediak Higashi syndrome
- immune disorder, increased risk infection esp sinopulmunary
Ix: giant granules in granulocytes
Slightly increased bleeding tendancy
hypopigmentation
Maple syrup urine disease
Aminoacidopathy
Presents within first week of life
Deficiency in BCKDC
Build up of leucine, isoleucine, valine (leucine the one that causes encephalopathy)
Present with irritability, poor feeding, vomiting, hypertonia/dystonia, abdnomal movements, seizures,
Ix: may have hypoglycemia/metabolic acidosis, always have ketones +++ in urine. Elevated urine and plasma amino acids (leucine, isoleucine, valine)
METABOLIC EMERENCY
Rx: dialysis to remove toxic metabolites, then diet low in branched chain amino acids
Liver transplant
Organic acidemia
Acute form: present in first 2 weeks of life, lethargy, seizures, vomiting, sweaty feet odor
Chronic: acute episodes of metabolic decompensation during capabolic states eg infection
Ix: metabolic acidosis classically with wide anion gap, +/- hypoglycemia, elevated ketones, mild-mod hyperammonemia
Urine- elevated organic acids, acylcaritine profile
Rx a. Decrease substrate – low protein diet (protein completely withheld during acute illness- 10% dextrose +0.9% n/saline)
b. Enhance enzyme activity – biotin, B12 (for MMA)
c. Disposal of toxic metabolites – L-carnitine (life saving) (especially for proprionic acidemia)
i. Carnitine binds to organic acids then can be excreted in the urine
d. Ammonium scavengers- sodium benzoate or sodium phenylbutyrate
Hemofiltration/dialysis
Niemman pick
lysosomal storage disease
A and B: deficinecy in activity of sphingomyelinase –>accumulation of sphingomyelin which accumulates in CNS and non-neural tissue
A: classic form. FTT, HSM, progressive rapid neurodegeneration that leads to death by 2-3 years of age. Psychomotor retardation is evident by 6mo. Absent reflexes. Cherry red spot.
B: non neuronopathic, may present older. HSM. May have pulmunary involveement. Normal IQ
C: neuronopathic, defect in cholesterol transport. May present as prolonged neonatal jauncdice. Appear normal for 1-2 years, then slowly progressive neurodegeneration. HSM less severe than Type A or B. Can have ataxia, delayed motor milestones, galastic cataplexy, vertical supranuclear gaze palsy
Galactosemia
GALT deficiency after the onset of galactose-containing feedings (eg, human or cow’s milk)
Presents within first few days of life
Liver- conjugated and unconjugated hyperbilirubinemia, deranged LFTs, coagulopathy, +/-hypoglycemia
E.coli sepsis
Fanconi syndrome (renal tubular acidosis)
Cataracts
Rx: soy formula (avoid galactose containing products)
which gene encodes GLUT1
SLC2A1
Mutation leads to GLUT1 deficiency (inability to transport glucose into brain, low glucose in CSF)
Netherton syndrome
Mutations in the SPINK5 gene.
Children have “bamboo hair” (trichorrhexis invaginate) and are predisposed to atopy
most sensitive metabolic marker of neuroinflammation in CSF
Neopterins are products of guanosine triphosphate (GTP) catabolism that result from cellular immune activation by pro-inflammatory cytokines. They are non-specific with regard to aetiology.
what would you see on hypo screen with hyperinsulinemia
no acidemia
low free fatty acids (inhibition of lipolysis)
low ketones (inhibition of fatty acid oxidation)
detectable insulin levels in face of low BSL
what length of carbon chain metabolism is affected by MCAD
C6-8
therefore in MCAD plasma acylcarnitine profile may show elevated c6, c8, c10
miglustat
competitive inhibitor of glucosylceramide synthase
treatment for neimenn pick type c and gaucher disease
treatment cystinosis
mercaptamine (cysteamine) = oral form + eye drops, high water intake, Na + K supps, HCO3 sups, phosphate supps, vit D supps
