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Clinical presentation of patients with Aromatic L-amino Acid Decarboxylase (AADC) deficiency

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AGE 6 DAYS

Onset of symptoms

  • Began experiencing temperature instability (hypothermia) and problems with breastfeeding
AGE 2 MONTHS

Pediatrician documents additional signs & symptoms

  • General pediatrician documented excessive irritability, including excessive startle to noises and sudden movements
AGE 3 MONTHS

Began exhibiting oculogyric crises

  • Oculogyric crises typically occurred in the late afternoon or evening, with increased frequency and severity over the following 2 months
AGE 5 MONTHS

Pediatric neurologist prescribes symptomatic treatment

  • Referred to a pediatric neurologist, who examined the patient and revealed:
    • Axial hypotonia
    • Right-sided head deviation
    • Inability to reach for objects, roll over, or lift head while in prone position
    • Ptosis, miosis, nasal congestion, and drooling
  • Pediatric neurologist then treated the patient with clonazepam, which was not effective in mitigating oculogyric crises
  • At this time, a physical therapist was added to patient’s supportive care team
DIAGNOSIS
Age 5 months

Normal MRI leads to additional labs to confirm diagnosis

  • Imaging: Brain MRI—normal
  • Laboratory findings1:
    • Metabolic screening: normal
    • Plasma AADC activity: undetectable
  • CSF neurotransmitter metabolite analysis:
    Metabolites Results
    3-OMD 1439 nmol/L High
    5-HIAA 9 nmol/L Low
    HVA 14 nmol/L Low
    Pterins Normal Normal
3-OMD=3-O-methyldopa; 5-HIAA=5-hydroxyindoleacetic acid; CSF=cerebrospinal fluid; HVA=homovanillic acid; MRI=magnetic resonance imaging.

AGE 3 MONTHS

Signs present since birth

  • Feeding difficulties since birth
  • Hypotonia documented
AGE 6 MONTHS

Misdiagnosed with cerebral palsy by a pediatric neurologist

  • Patient started experiencing episodes of oculogyric crises, which led to referral to a pediatric neurologist
  • Pediatric neurologist diagnosed the patient with cerebral palsy
TIME ELAPSED: 1 YEAR, 6 MONTHS
AGE 2 YEARS

Developed signs of autonomic dysfunction

  • Signs of autonomic dysfunction included temperature instability and hypotension
TIME ELAPSED: 2 YEARS
AGE 4 YEARS

No developmental milestones achieved

  • Those not achieved included:
    • Inadequate movement development
    • Lack of cognitive and communication abilities
  • Patient began exhibiting hypokinesia
TIME ELAPSED: 2 YEARS
AGE 6 TO 10 YEARS

Referred to physical medicine and rehabilitation specialist

  • Signs and symptoms during this time period included:
    • Continued inability to control head movement
    • Feeding and swallowing difficulties
    • Severe insomnia
    • Remained nonverbal
TIME ELAPSED: 3 YEARS
AGE 13 YEARS

Oculogyric crises worsen

  • Frequency and duration increased
TIME ELAPSED: 4 YEARS
AGE 17 YEARS

Evaluated by a new neurologist

  • After geographic relocation, evaluation by a new neurologist for adult patients led to consideration of an AADC deficiency diagnosis
DIAGNOSIS
Age 17 years

Lab findings help diagnose AADC deficiency

  • Laboratory findings1,2:
    • Metabolic screening: normal
    • Plasma AADC activity: undetectable
  • CSF neurotransmitter metabolite analysis:
    Metabolites Results
    3-OMD 539 nmol/L High
    5-HIAA 24 nmol/L Low
    HVA 50 nmol/L Low
    Pterins Normal Normal
3-OMD=3-O-methyldopa; 5-HIAA=5-hydroxyindoleacetic acid; CSF=cerebrospinal fluid; HVA=homovanillic acid.

AGE 4 MONTHS

Hypotonia, spontaneous movements, and other signs and symptoms are documented

  • Signs and symptoms included:
    • Hypotonia
    • Little spontaneous movement
    • Irritability
    • Weight loss
AGE 6 TO 12 MONTHS

Pediatric neurologist prescribes antiepileptic medications

  • Admitted to hospital multiple times due to movements resembling epileptic spasms and is finally seen by a pediatric neurologist
  • Pediatric neurologist:
    • Ordered an EEG, which came back normal
    • Treated patient with antiepileptic medications
  • Patient was then seen by a developmental pediatrician, who conducted a metabolic screening that yielded normal results
AGE 14 MONTHS

Epileptic spasms are reclassified as dystonic movements

  • New pediatric neurologist reviewed medical history and conducted a physical exam, documenting:
    • Developmental delay
    • Inability to sit without assistance or grasp objects
    • Limb hypertonia and exaggerated deep tendon reflexes
    • Difficulty swallowing, recurrent vomiting, and constipation
    • Hypersalivation, hyperhidrosis
    • Disturbed sleep
  • Pediatric neurologist:
    • Ordered imaging:
      • Brain MRI—normal
      • EEG—normal (repeated several times)
    • Reclassified the patient’s epileptic spasms as dystonic movements
    • Referred patient to movement disorder specialist
    • Helped develop the patient’s supportive care team:
      • Gastroenterologist
      • Physical therapist
      • Occupational therapist
TIME ELAPSED: 10 MONTHS
AGE 2 YEARS

Evaluated for neurotransmitter disorder

  • After considering mitochondrial disease diagnosis, patient was evaluated for neurotransmitter disorder
DIAGNOSIS
Age 2 years

CSF neurotransmitter metabolite panel and plasma enzyme activity assay help pediatric neurologist make a diagnosis

  • Laboratory findings3:
    • Plasma AADC activity: low
  • CSF neurotransmitter metabolite analysis3:
    Metabolites Results
    3-OMD 961 nmol/L High
    L-dopa 157 nmol/L High
    5-HTP 67 nmol/L High
    5-HIAA 10 nmol/L Low
    HVA 26 nmol/L Low
    Pterins Normal Normal
3-OMD=3-O-methyldopa; 5-HIAA=5-hydroxyindoleacetic acid; 5-HTP=5-hydroxytryptophan; EEG=electroencephalogram; HVA=homovanillic acid; L-dopa=L-3,4-dihydroxyphenylalanine; MRI=magnetic resonance imaging.

WATCH: Why screen for levels of 3-O-methyldopa (3-OMD) in the blood of patients suspected of having Aromatic L-amino Acid Decarboxylase (AADC) deficiency?

Keith Hyland, PhD, explains what 3-OMD is and why physicians should screen for it in patients who may have AADC deficiency

AGE 3 MONTHS

Seen by a general pediatrician

  • Pediatric examination documented patient’s hypotonia and inability to lift her head
AGE 5 MONTHS

Onset of severe oculogyric crises leads to consideration of cerebral palsy diagnosis

  • Oculogyric crises affecting the entire body led to referral to a pediatric neurologist, who considered a diagnosis of severe cerebral palsy
AGE 9 TO 13 MONTHS

No achievement of developmental milestones leads to a new pediatric neurologist

  • Patient did not achieve any developmental milestones, remained inactive, and experienced severe insomnia, which led to a referral to another pediatric neurologist
  • New pediatric neurologist:
    • Ordered a brain MRI
      • Imaging: Brain MRI—normal
    • Added developmental pediatrician to the patient’s supportive care team
AGE 14 MONTHS

Referred to specialized center for genetic testing

  • After there is no improvement in the patient’s condition and there is no definitive diagnosis, the patient is referred to a specialized center for genetic testing
DIAGNOSIS
Age 15 months

Genetic testing confirms diagnosis of AADC deficiency

  • Genetic testing:
    • Mutations in the DDC gene
  • Laboratory findings1,4:
    • Plasma AADC activity: undetectable
DDC=dopa decarboxylase; MRI=magnetic resonance imaging.

WATCH: What are common misdiagnoses of Aromatic L-amino Acid Decarboxylase (AADC) deficiency?

Keith Hyland, PhD, details common misdiagnoses of AADC deficiency and explains what physicians should look for to differentiate AADC deficiency from other conditions

Access resources that can help with the diagnosis of AADC deficiency

References: 1. Swoboda KJ, Hyland K, Goldstein DS, et al. Clinical and therapeutic observations in aromatic L-amino acid decarboxylase deficiency. Neurology. 1999;53(6):1205-1211. 2. Anselm IA, Darras BT. Catecholamine toxicity in aromatic L-amino acid decarboxylase deficiency. Pediatr Neurol. 2006;35(2):142-144.3. Gücüyener K, Kasapkara CS, Tümer L, et al. Aromatic L-amino acid decarboxylase deficiency: a new case from Turkey with a novel mutation. Ann Indian Acad Neurol. 2014;17(2):234-236. 4. Wassenberg T, Molero-Luis M, Jeltsch K, et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis. 2017;12(1):12. 
doi: 10.1186/s13023-016-0522-z.