MSE 2020 L14

Lysosomal Storage Disease

What is an inherited metabolic disease? (IDM)

Diseases that are associated with deficiencies in enzymatic steps associated with metabolism

• buildup of precursor/intermediary metabolites

• product deficiency

How is IDM categorised?

• Disorders that give rise to intoxication

• Disorders involving energy metabolism

• Disorders involving complex molecules

IDM that give rise to intoxication examples

• Phenylketonuria (PKU)

• Porphyrias

• Organic acidurias (MMA)

• Urea cycle defects

• Wilson disease

IDM involving energy metabolism examples

• Mitochondrial defects

• Fatty acid oxidation defects (MCADD)

• Respiratory chain defects

IDM involving complex molecules

• Lysosomal storage disorders

• Gaucher disease

What is the heel prick test?

Part of post-natal screening for blood spots offered to babies five days after they’re born, used to check for IDM

What diseases would a heel prick investigate?

• Phenylketonuria

• Hypothyroidism

• Cystic fibrosis

• Sickle cell disease

• MCADD aka fatty acid oxidation defect

• Galactosaemia

• Cogenital adrenal hyperplasia

What are some non-specific symptoms to look for when diagnosing babies?

• Lethargy

• Hypotonia (floppy baby)

• Vomitting

• Seizures

• Poor feeding

• Irritability

• Odour

What should be considered in diagnosing babies?

• Association with time of onset

  • e.g. fasting, increased exercise, infection, changes in carb and protein intake

• Family history e.g. multiple miscarriages, unexplained death

How do you perform pre-natal genetic screening?

• FISH can be used to run multiple tests on a singular cell

• When embryo @ 8-cell stage, a single blastomere can be removed and analysed

• Probes are then used for chromosomes X, Y, 13-16, 18, 21, 22

Aneuploidy

The presence of an abnormal number of chromosomes in a cell, can be identified in prenatal screening

• Trisomy 21, Down syndrome

What are the ethical issues surrounding prenatal genetic screening?

• Designer babies

• Sex-selection

• Reproductive beneficence

What things should be tested first in suspected IMD?

• Hypoglycaemia

• Hyperammonaemia

• Hyperbilirubinaemia

• Lactic acidosis

• Creatine kinase

• FBC

• Blood gases

• Urine ketones

Lysosomal disorders

• Result as toxic buildup of partially denatured substrates

• Most are recessive

• Disease is progressive

• Early presentation in life

What categories are lysosomal storage disorders grouped into?

• Lipid/sphingolipidoses (Gaucher, Tay-Sachs)

• Glycoproteinoses/mucolipidoses (Mannosidosis, I-cell disease)

• Mucopolysaccharidoses (MPS disorders, Hurler, Hunter)

• Others (Pompe, cystinosis, Battens)

What are the clinical features of lysosomal storage diseases?

• Neurological

• Opthalmological

• Craniofacial

• Skeletal

• Abdominal

• Haematological

What are the Neurological Features of LSD?

• Developmental delay/regression

• Behavioural disturbances (Sanfilippo)

• Intellectual disabikity

• Hypotonia (floppy), can develop into spasticity

• Seizures (Tay-Sachs, Sandhoff)

What are the Opthalmological Features of LDS?

• Macular cherry-red spots (red spot in eye)

• Optic atrophy

• Corneal clouding

What are the Craniofacial Features of LSD?

• Coarse, can be mild or prominent

• Macroglossia (large tongue)

• Large, low-set ears

What are the Skeletal Features of LSD?

• Spinal abnormalities

• Broad hands and feet

• Brachydactyly (abnormally short fingers)

What are the abdominal Features of LSD?

• Hepatosplenomegaly (large liver and spleen)

• Inguinal hernia (when intestine protrudes through weak spot in the groin area)

What are the haematological features of LSD?

• Vacuolated or granulated lymphocytes

• Foam cells

• Bone marrow abnormalities

• Cytopenias

How would you manage LSD?

• Bone marrow transplant aka haematopoietic stem cell transplantation

• Enzyme replacement therapy

• Substrate reduction therapy

• Gene therapy

What is Tay-Sachs?

• An example of an LSD

• Autosomal recessive disease caused by a deficiency in the HEXA gene on Chromosome 15

What happens in Tay-Sachs disease?

Gangliosides (glycosphingolipid) accumulate in neuronal cells and lead to cell death

In which populations is Tay-Sachs common?

• Ashkenazi Jews

• French Canadians

• Cajun

What is the HEXA gene?

• Encodes for HEXA aka Hexaminidase A, a hydrolytic enzyme which is part of the lysosome complex

• Degrades sphingolipids

What does sphingolipids have a role in?

• Cell signalling

• Cholesterol metabolism

• Cell membrane e.g. trafficking, cell polarity, signal transduction

• Apoptosis

What is the most classic mutation of HEXA?

1278insTATC

• 4 base pair insertion in exon 11

• Causes a frameshift

Tay-Sachs Mutations

• Majority cause protein misfolding

• Compound heterozygosity (two different, mutated alleles) is important

How can Tay-Sachs be categorised?

• Infantile (Age of onset 6months)

• Juvenile (Age of onset between 2-10 years old)

• Late-onset

What is the HEXA enzyme assay?

• Tay-Sachs diagnosis tool before FISH development

• WBC incubated with sphingolipids and rate they are processed is measured

Why do we not use the HEXA enzyme assay anymore?

• Doesn’t work on pregnant women - due to increase of an intermediate isoenzyme (HEX I)

• Doesn’t work on woman who are on the pill - the pill can effect enzyme activity

• Only select mutations will result in defective white cell HEXA - doesn’t account for other mutations

Can we cure Tay-Sachs?

• No

• Available management is only supportive

• Infantile average age of mortality is 4 years old

What is Hurler’s syndrome?

• Autosomal recessive condition

• Mutation in α-L iduronidase gene (IDUA)

• A type of mucopolysaccharidsosis LSD

What is prognosis like for Hurler’s Syndrome?

• Life expectancy is around 9 years old

• Incidence of 1 case per 100,000

What symptoms are associated with Hurler’s syndrome?

• Skull/skeletal changes e.g. enlarged skull, shortened fingers

• Airway/blood vessel occlusion can occur

• Cataracts

What causes Hurler’s?

• IDUA hydrolyses uronic acid, a constituent of glycosaminoglycans (GAG)

  • heparan sulfate

  • dermatan sulfate

• Deficiency in this gene causes aminoglycans to build ↑ within tissues and cause cells to swell

How do we diagnose Hurler’s?

Urinealysis, reveals abnormal levels of suplhated GAGs

What LSDs are associated with IDUA?

• 1H Hurler

• !H-S Hurler Scheie

• 1S Scheie syndrome

How can we manage Hurler’s?

• Aldurazyme (laronidase) - enzyme replacement therapy

• May improve breathing and walkability

• Otherwise not curable