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

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 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)

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

Functions of Citrin

Citrullinaemia Type I (classical)  Argininosuccinate synthetase (ASS) deficiency  Increased Citrulline  Decreased Arginine  Urine orotic acid  Classically presents with hyperammonaemia in newborn period

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

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

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’

Clinical course of NICCD

The Chubby Index

Disappears by one year!

Characteristic food preference  NICCD have a characteristic food preference  Carbohydrate avoidance  Prefer protein and fat rich foods  Markedly different from know UCD (protein avoid)

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

Case study  High CHO diet  Drowsy with increase NH4  ‘Normal’ diet, high protein/fat  Slight increase NH4  Linear relationship glucose to ammonia

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

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

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