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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

PTC Pinpoint™ offers no-cost genetic testing for individuals who have symptoms consistent with AADC deficiency

Learn more or order a test

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.