Clinical features of PKU probands.
Family 1: A male child aged 1 year and 8 months, the third offspring of second degree
consanguineous parents, was referred with history of global developmental delay since early
infancy. The child attained head control by 7 months, rolling over by 9 months, sitting with
support by 1 year and bi-syllable speech by 19 months but was unable to sit without support or
stand with support. There was no history of seizures, hearing or visual deficits or any other focal
neurological deficits nor any adverse events in the antenatal or perinatal period. On examination,
there was microcephaly (head circumference 44 cm) and failure to thrive (weight 9 kgs). The
child’s scalp hair was hypopigmented. Tone was slightly reduced but deep tendon reflexes were
normal in all 4 limbs. Urine metabolic screen revealed a positive ferric chloride test. There was
history of similar profound developmental delay and intellectual disability in an older sister aged
9 years.
Family 2: A male child aged 1 year, the second offspring of third degree consanguineous
parents, was referred with history of right focal seizures since the second month of life and
significant global developmental delay which was noted by the parents since early infancy. Even
by age 1 year, the child had not attained social smile, head control, or ability to roll over or sit
with support. His hearing and visual perception were also poor. On examination; there was
microcephaly (head circumference 40 cm) and failure to thrive (weight 6.5 kgs). The child’s
scalp hair and irises were hypopigmented. Tone was increased and deep tendon reflexes were
exaggerated in all 4 limbs. There was no history of any other similarly affected family member.
Interestingly, the proband also exhibited classical symptoms of Metachromatic leucodystrophy.
Family 3: A female child aged 7 years, the only offspring of third degree consanguineous
parents, was referred with history of global developmental delay which was noted by the parents
since around 6 months of age. She started walking by 2 years of age, attained bisyllablic speech
by 3 years and a few meaningful words by 5 years. There was no history of seizures, hearing or
visual deficits or any other focal neurological deficits. There was no history of any other
similarly affected family member. On examination; Head circumference was at the 3rd centile 49.5 cm; weight & height were normal. The child’s scalp hair and irises were hypopigmented.
Tone and deep tendon reflexes were normal in all 4 limbs. Cardiovascular system was normal
and per abdomen there was no organomegaly. Urine metabolic screen revealed a positive ferric
chloride test. Plasma amino acid HPLC showed significantly elevated phenylalanine levels.
Family 4: A male child aged 2 years, born to non-consanguineous parents, was referred with
history of global developmental delay and light colored hair. There was no history of any other
similarly affected family members.
Family 5: A female child aged 1 year and 2 months, born to third degree consanguineous
parents, was referred with global developmental delay and microcephaly. The child’s scalp hair
was hypopigmented. Her thyroid profile was normal. Plasma amino acid HPLC showed
significantly elevated phenylalanine levels.
Family 6: A female child aged 6 months, the first born to 1st cousin consanguineous parents
with refractory seizures, presented with classical PKU symptoms. Head circumference indicated
microcephaly. There was no following of objects, and social smile was not attained. EEG
showed generalized seizure disorder and brain MRI was normal except for microcephaly.
Family 7: A male child, first in birth order, aged 2 years and 6 months, born to nonconsanguineous parents by forceps delivery, was referred with history of delayed milestones,
motor and cognition. The child was sitting at 8 months and walking at 22 months, exhibited
speech delay, was hyperactive and possessed mildly hypopigmented hair.
Family 8: The proband, a female child aged 2 years and 6 months and the first offspring of third
degree consanguineous parents, was referred with history of global developmental delay which
was noted by the parents since early infancy. She had attained head control by 9 months, rolling
over by 1 year, sitting with support by 1 year and 6 months, standing/walking by 2 years and
occasional bi-syllable speech by 2 years. There was no history of seizures, hearing or visual
deficits, no adverse events in the antenatal or perinatal period and no history of acute worsening
episodes or stroke or regression. On examination, head circumference was 44 cm with lusterless
brown color hair. The proband’s karyotype was found to be 46, XX. Similar profound global
developmental delay and brownish colored hairs since birth were noticed in a younger sister aged
8 months.
Family 9: A male child aged 2 years and 6 months, born to non-consanguineous parents, was
referred with history of global developmental delay, behavioral problems and hyperactivity since
the age of 1 year.
Family 10: A female child aged 1 year and 4 months, the 4th offspring of third degree
consanguineous parents, was referred with history of global developmental delay, fair
complexioned skin and hypopigmented (golden brown) hair. There was no history of seizures.
On examination, there was microcephaly (head circumference 42 cm, < 2 SD) with no
neurological abnormality. Qualitative plasma and urine amino acid assays have shown spot of
elevated intensity in the phenylalanine region. Urine metabolic screen revealed a positive ferric
chloride test. There was family history of similar symptoms in an elder sister aged 12 years who
was diagnosed to have phenylketonuria and at present has severe intellectual disability.
Family 11: A female child aged 10 months, was born by In vitro fertilization to consanguineous
parent (uncle-niece marriage) after 12 years of infertility. The child presented with history of
developmental delay, myoclonic jerks, microcephaly and failure to thrive due to persistent
vomiting. Plasma amino acid HPLC showed very high elevated phenylalanine levels and
Phe/Tyr ratio was 27.
Family 12: A male child aged 11 months, the only offspring of third degree consanguineous
parents, was referred with history of developmental delay and light brown color hair. He had
attained social smile at 3 months, head control at 3 months, rolling over at 6 months, grasping
objects at 9 months but was unable to sit up. He suffered from stiffening of arms and legs with
flexion of the neck lasting for 5 seconds during sleep and sudden dropping of the neck when
awake. There was excessive weight gain, abnormal urine odor at 3 months of age and myoclonic
seizures at 5 months of age. The pregnancy, labor and neonatal period were uncomplicated.
Proband birth weight was 2.7 kg. On examination there was microcephaly (head circumference
44 cm) with weight of 13.1 kg (>97th centile WHO growth standards) and length of 73 cm (1550th centile WHO growth standards). There was hypotonia, normal deep tendon reflexes, flexor
plantar response and no involuntary movements.
Family 13: A female child 22 days old, born to 1st cousin consanguineous parents, was referred
based on newborn screening. Her plasma amino acid HPLC showed very high elevated
phenylalanine levels.
Family 14: The proband, a male child aged 10 months presented with history of global
developmental delay which was noted by the parents since early infancy. He was the third
offspring of second degree consanguineous parents. He had attained head control by 5-6 months,
rolling over by 5 months, and sitting with support by 9 months. He had not attained ability to sit
without support or stand with support. There was no history of seizures. He had bilateral hearing
deficit. There were no adverse events in the antenatal or perinatal period. There was history of
similar profound developmental delay and intellectual disability in an older brother aged 7 years.
On examination, there was sparse hipopigmented scalp hair. A Perianal rash was present. Tone
and deep tendon reflexes were normal in all four limbs. Cardiovascular system was normal and
per abdomen there was no organomegaly. MRI of the brain showed hypomyelination. Plasma
amino acid HPLC analysis showed significantly elevated phenylalanine levels.
Family 15: A male child aged 2 years born to 1st cousin parents was referred with
developmental delay and myoclonic seizures. At 2 months of age, he started getting seizures and
did not develop social smile at 5th month of life. Motor development was delayed and at 9
months there was no eye contact and the child was autistic. At 2 years, he was evaluated by the
geneticist and neurologist for developmental delay and seizures. EEG revealed generalized
seizure disorder, MRI brain showed leucodystrophy and leucomalacia. He presented with the
typical mousy odour of PKU with fair complexion and blond hair. Plasma amino acid analysis
showed high Phe/Tyr ratio. Urine metabolic screen revealed a positive ferric chloride test.
Family 16: A male child aged 10 months, the only offspring of third degree consanguineous
parents, was referred with history of delayed milestones. On examination; head circumference
was 40 cm. Proband had hypotonia, fair skin and silky blonde hair. There was no previous
history of any other similarly affected family member.
Family 17: A male child aged 6 years and 6 months, born to consanguineous parents was
referred with history of global developmental delay. There was no history of any other similarly
affected family member.
Family 18: A male child aged 10 months, born to 1st cousin consanguineous parents, was
referred with history of delayed motor mile stones and myoclonic seizures; social smile was
present. Child’s weight was 8.14 kgs (birth weight was 2.2 kgs) and the height was 75 cms.
Plasma amino acid HPLC analysis showed significantly high Phe/Tyr ratio.