Longitudinal Study of Mitochondrial Hepatopathies (MITOHEP)

1. Children and young adults with suspected or documented hepatic RC defector FAO defectbirth to 18 years old (through 18 years).
2. Both genders, all races and ethnic groups.
3. Participants must meet one of the following sets of criteria (A or B):
   1. Potential subjects presenting with acute or chronic liver disease or acute liver failurebut who have not had a liver transplant must meet one of Clinical Criteria 1 and one ofClinical Criteria 2 listed below:
4. Clinical Criteria 1 (any one of the following)
   • 1.Acute liver failure,defined as severe liver dysfunction and either 1) INR >1.5hrombin time > 15 seconds with encephalopathy or 2) INR > 2.0 orhrombin time > 20 seconds with or without encephalopathy; occurring within 8weeks of onset of illness; with no known underlying chronic liver disease, or
   • 2.Acute liver disease defined as elevated AST or ALT >1.25 ULN and CK <1000u/L orjugated bilirubin >2.0 mg/dl and >20% of total bilirubin, or
   • 3.Chronic liver disease defined as:
     • elevated ALT or AST (>1.25 ULN) for > 6 months, or
     • conjugated hyperbilirubinemia (conjugated [direct] > 2.0 mg/dl and > 20% ofbilirubin) for > 6 months or
     • clinical stigmata of chronic liver disease, including chronic hepatomegaly,dings or complications of cirrhosis or portal hypertension,d liver synthetic function, intractable pruritus explainable only byver disease or end-stage liver disease, or
     • abnormal liver histology including hepatic fibrosis or cirrhosis,vesicular steatosis, canalicular cholestasis, ballooned granular redhepatocytes (AKA onocytes), intralobular collapse/regeneration And
5. Clinical Criteria 2 (any one of the following:
   • 1.Prior history of extra-hepatic organ involvement accompanied by any one or morehe signs and symptoms associated with mitochondrial dysfunction (e.g.

hypotonia, neuro-developmental delay, seizure disorder requiring treatment with valproic
    acid, nystagmus, cardiomyopathy, renal tubulopathy, bone marrow failure,myopathy, hearing
    loss), or
     - 2.Lactic acidosis (arterial blood or free-flowing venous blood level >2.5 mmol/L or
       >22.5 mg/dl at any age and increased lactate:pyruvate ratio [>25.0]) or
     - 3.Hypoglycemia (blood glucose <45 mg/dl on any measurement) and hypoketonuria (<1+ for
       urine ketones by dipstick on urine specimen obtained within 4 hours after collecting
       blood with low glucose concentration), or
     - 4.Abnormal acyl carnitine profile, or
     - 5.Documented biochemical (enzymatic) or genetic diagnosis 3b. Potential participants
       who have undergone a liver transplantation because of acute liver failure or end stage
       liver disease due to suspected or confirmed mitochondrial hepatopathy; the
       transplantation may have been performed at a non-ChiLDREN medical center or at a
       ChiLDREN Clinical Site.
    B. Potential subjects who have already had a liver transplant must meet criteria 1 and
    either criteria 2 or criteria 3 below:
     - 1.Previous liver transplantation, AND
     - 2.Suspected mitochondrial liver disease, based upon meeting one or more of the
       following criteria:
        - Had a prior history of extra-hepatic organ involvement accompanied by signs and
         symptoms associated with mitochondrial dysfunction (e.g., hypotonia,
         neuro-developmental delay, seizure disorder requiring treatment with valproic
         acid, nystagmus, cardiomyopathy, renal tubulopathy, bone marrow failure,
         myopathy, hearing loss), OR
        - A prior history of lactic acidosis (arterial blood or free-flowing venous blood
         level >2.5 mmol/L or >22.5 mg/dl at any age and increased lactate:pyruvate ratio
         [>25.0]), OR
        - A prior history of hypoglycemia (blood glucose <45 mg/dl on any measurement) and
         hypoketonuria (≤1+ for urine ketones by dipstick on urine specimen obtained
         within 4 hours after collecting blood with low glucose concentration), OR
        - A prior history of an abnormal acyl carnitine profile, OR
        - Documented biochemical (enzymatic) or genetic diagnosis of a mitochondrial
         disorder
     - 3.A documented (confirmed) mitochondrial disorder based upon the confirmation criteria
       specified in protocol.
    Subjects in Group 2 (Suspected Mitochondrial Hepatopathy not meeting Group 1 enrollment
    criteria) must meet the following inclusion criteria:
     1. Children and young adults with suspected hepatic RC defect or FAO defect between birth
       through 18 years but who do not meet clinical inclusion criteria listed above for
       acute or chronic liver disease or acute liver failure.
     2. Both genders, all races and ethnic groups.
    Subjects in either Group 1 or 2 must not have any of the following exclusion criteria:
     1. Inability to comply with the longitudinal follow-up described below.
     2. Failure of a family/patient to sign the informed consent/assent document or the HIPAA
       authorization form.
     3. Known Medium Chain Acyl CoA Dehydrogenase deficiency (MCAD).
     4. Other known causes of liver disease.