Hyperphenylalaninemia in Cerebral Malaria
Condition: Plasmodium Falciparum Malaria
MeSH terms: Malaria; Malaria, Falciparum; Malaria, Cerebral; Phenylketonurias
Study type: Observational

Summary: 
      The purpose of this study is to see if children, who develop coma from malaria, are not
      making enough of a vitamin-like chemical, tetrahydrobiopterin (BH4), which is required for
      the brain to function normally. This information may help to identify new ways to treat
      malaria in the future. Study participants will include 512 children, ages 6 months to 6
      years. Participants will be placed into one of 4 groups: well children; children with mild
      malaria; children without malaria, but with a medical problem involving the brain that
      requires a lumbar puncture for diagnosis (a procedure in which a needle is placed into an
      area surrounding the spinal cord and a sample of cerebral spinal fluid is removed); and
      children with a severe form of malaria affecting the brain called cerebral malaria. Study
      procedures will include blood samples, urine samples and lumbar puncture, only if necessary
      for diagnosis as part of standard practice procedures. Participants will be involved in study
      related procedures for up to 3 weeks.
    

Detailed description: 
      The mortality in severe malaria remains between 12-30% despite antimalarial therapy. The
      overwhelming majority of deaths from malaria occur in children in impoverished countries of
      the world with cerebral malaria (CM) and metabolic acidosis as the most important negative
      prognostic indicators. CM is a serious complication of falciparum malaria. It is
      characterized by fever, coma (not attributable to hypoglycemia), seizures (not attributable
      to febrile seizures) and abnormalities of muscle tone (rigidity, hypotonia) and body posture
      (decerebrate, decorticate, opisthotonic posturing). This observational prospective cohort
      study will enroll 512 Tanzanian children, 6 months to 6 years old, admitted to the hospital
      with CM (Group 1) as defined by World Health Organization criteria and uncomplicated malaria
      (UM-Group 2). Healthy children who are not acutely ill (healthy control, HC-Group 4) and
      children with coma and/or central nervous system (CNS) illness not attributed to malaria
      (NMC-Group 3) will serve as controls. Children will be recruited from 2 hospitals in Dar es
      Salaam, Amana Hospital in the Ilala District (AHID) and Mwananyamala Hospital (MDH)in the
      Kinondoni District. Children presenting to AHID or MDH, who are diagnosed with CM or a
      non-malarial CNS condition will be transferred by ambulance to the Clinical Research Unit
      (CRU) at Hubert Kairuki Memorial University (HKMU). Before transfer the child will be
      stabilized and treatment will be initiated. A lumbar puncture will be performed. Transfer to
      the HKMU-CRU will take place only with the parent(s)/guardian(s) permission and the parent(s)
      and/or guardian(s) will be transferred to HKMU with the child. Comatose children admitted to
      the hospitals will be evaluated by the house physician and/or member of the study team.
      Febrile children admitted to the hospital with high level Plasmodium falciparum parasitemia,
      no other cause of fever identified, nor evidence of severe malaria and no co-infection with
      other malaria species will be enrolled in the UM group. Health control children will be
      enrolled from outpatient well-baby clinics at AHID and MDH. All ill (groups II, III,
      IV)children will have complete blood picture, urinalysis, blood culture, and a blood smear
      for malaria. Lumbar puncture will be performed for diagnosis of meningitis or hemorrhage (in
      groups I and III) if there are no contraindications (e.g. papilledema or focal neurological
      signs suggesting a CNS mass lesion). Children will be treated according to Tanzanian
      standards based on the initial evaluation. Those subjects agreeing to enter the study will
      have portions of the blood, urine and CSF preserved for study purposes. Study subjects will
      be followed from the time of hospital admission until death or 1-2 weeks post hospital
      discharge. Primary study objectives are to: determine whether African children with cerebral
      malaria (CM) have sufficient levels of systemic tetrahydrobiopterin (BH4) by analyzing their
      urine for metabolites of BH4; determine whether these children have sufficient levels of BH4
      in their CNS by analyzing their cerebrospinal fluid for BH4 metabolites; and determine
      whether these children have sufficient levels of BH4-dependent biogenic amine
      neurotransmitters in their CNS by analyzing their cerebrospinal fluid (CSF) for metabolites
      of the neurotransmitters. Secondary objectives are to: determine natural history of
      hyperphenylalaninemia in CM and correlate with outcome (i.e., death or recovery); and
      determine whether BH4 deficiency is due to low expression of genes encoding de novo BH4
      synthesis in peripheral blood mononuclear cells from children with CM.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        The study is a prospective cohort study involving Tanzanian children 6 months to 6 years
        old admitted with UM and CM as defined by World Health Organization (WHO) criteria (Section
        5.2). Healthy children who are not acutley ill (healthy control, HC) and children with coma
        and/or CNS illnesses not attributed to malaria (NMC) will serve as controls. Children will
        be recruited from 2 hospitals in Dar es Salaam (AHID,MDH).
      
Biospecimen description: 
      urine, CSF, blood
    
Keywords: Cerebral malaria, phenylalanine, Tanzania