Citrin Deficiency- The chubby baby story Fiona Carragher, - - PowerPoint PPT Presentation

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Sep 23, 2022 288 likes •467 views

Citrin Deficiency- The chubby baby story Fiona Carragher, Biochemical Sciences GSTS Pathology, St Thomas Hospital London Citrin Deficiency First described in Japan/East Asia Now increasingly recognised worldwide Mutations in

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Citrin Deficiency- The ‘chubby baby’ story

Fiona Carragher, Biochemical Sciences GSTS Pathology, St Thomas’ Hospital London

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Citrin Deficiency

 First described in Japan/East Asia  Now increasingly recognised worldwide  Mutations in SLC25A13 gene (chr 7q21.3)

which encodes citrin

 Mitochondrial aspartate-glutamate carrier (AGC)  Two distinct disease entities

 Adult onset type II Citrullinaemia (CTLN2)  Neonatal intrahepatic cholestasis (NICCD)

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Citrin – two key roles

 Gluconeogenesis from lactate

 Transports cytosolic NADH-reducing equivalents in

mitochondria

 Part of malate-aspartate shuttle

 Ureogenesis from ammonia

 Provides aspartate from mito to cytosol  Required for synthesis of proteins, nucleotides and

urea

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Functions of Citrin

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Citrullinaemia Type I (classical)

 Argininosuccinate

synthetase (ASS) deficiency

 Increased Citrulline  Decreased Arginine  Urine orotic acid

 Classically presents with

hyperammonaemia in newborn period

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Citrullinaemia Type II (CTLN2)

 Liver specific decrease in ASS activity

 Secondary to citrin deficiency  Citrullinaemia present during hyperammonaemia  Exact cause not clear

 Hyperammonaemia in early adulthood

 Neuropsychiatric symptoms  Disorientation and delirium  Seizures and Coma  Mortality

 Non-alcoholic fatty liver disease

 Not-overweight

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Neonatal Intrahepatic Cholestasis (NICCD)

 Neonatal cholestasis

 Growth retardation /FTT  Severe intrahepatic Cholestasis

 Multiple metabolic abnormalities

 Aminoacidaemia (cit/thr/met/tyr/arg)  Galactosaemia  Hypoproteinaemia  Fatty liver

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NICCD- clinical course

 Severe symptoms during infancy  Symptoms often resolve in first year

 Healthy period may last decades

 Some patients develop severe CTLN2

 May require liver transplantation

 More recently symptomatic groups described

during ‘healthy period’

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Clinical course of NICCD

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The Chubby Index

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Disappears by one year!

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Characteristic food preference

 NICCD have a characteristic food preference

 Carbohydrate avoidance  Prefer protein and fat rich foods

 Markedly different from know UCD (protein avoid)

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Carbohydrate toxicity

 Yazaki et al (2005)

 14 cases with hyperammonaemic brain oedema  12/14 treated with glycerol died  2/14 treated with mannitol survived

 Case study 13yr old girl Citrin def

 Sister with CTLN2 – liver transplant  Fatigue, skinniness, abdominal disorder

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Case study

 High CHO diet

 Drowsy with increase

NH4

 ‘Normal’ diet, high

protein/fat

 Slight increase NH4

 Linear relationship

glucose to ammonia

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Ureagenesis in citrin def

 Under controlled state

 Glu formed from NH3 leaves mito instead of Asp  Converted in cytosol to Asp by aspartate aminotransferase  Formed Asp used by ASS and formation of citrulline

 Urea may be synthesised in citrin def

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Link to carbohydrate toxicity

 Oxaloacetate essential, formed from malate

 Reaction requires NADH to be oxidised

 If increased CHO load in citrin def NADH accumulates

 Urea cycle inhibited as asp cannot be formed  Glycolysis inhibited causing energy deficit

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Treatment options

 Standard therapy

 Low protein/ high CHO diet  May cause hyperammonaemia in Citrin def

 Most effective is Liver Tx

 Metabolically normal (but long term immunosup)

 Low CHO/high protein diet is effective  Sodium pyruvate may be effective

 Oxidises NADH