yrosine hydroxylase (TH) deficiency is an
autosomal recessive neurotransmitter disorder that may have a
heterogeneous presentation[1]. We report an Indian family with this rare
disorder to sensitize pediatricians about the importance of clinical
suspicion and serum prolactin in diagnosing this condition. We also wish
to highlight its phenotypic variability and treatment-responsiveness.
Case Report
A 10-month-old boy presented with acute onset,
rapidly progressive loss of milestones. The child was term born to
non–consanguineous, healthy, Indian couple. His birth-weight was 2.8 kgs
and perinatal period was uneventful. Pre-morbidly, he was
developmentally normal. At nine months, the child had an episode of
low-grade fever with rhinorrhea for four days. Subsequently, he became
lethargic and rapidly lost abilities to sit, turn-over, reach for
objects or babble. He continued to track visually and smile back. He had
an episode of generalized seizure for five minutes on second day of
illness. On examination he was well built, lethargic with generalized
hypotonia and paucity of limb movements. He spontaneously recovered to
normalize over three weeks. Two weeks later, he had an acute,
unprovoked, rapid recurrence of milestone loss evolving over one week.
At the nadir, he could not hold his neck or voluntarily reach out with
his hands. He vocalized but could not coo. He recognized parents but
lost stranger-anxiety. Parents felt that the child was flaccid and had
difficulty swallowing solids. He did not have abnormal breathing,
vomiting, abnormal eye/ limb movements, posturing, seizures,
unconsciousness or abnormal urine odour.
On repeat examination, the positive findings were
significant generalized hypotonia and paucity of spontaneous limb
movements.
Child’s hematological and biochemical profile,
arterial ammonia, serum biotinidase, homocysteine, creatine
phosphokinase, anti-TPO antibody titers, cere-brospinal fluid study CSF
study, electroencephalogram, nerve conduction study, electromyography,
Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy
(MRS) brain, Tandem Mass Spectroscopy (TMS), urinary organic acid
profile by Gas Chromatography-Mass Spectroscopy (GC-MS) and serum
aminoacidogram were unremarkable. He was managed empirically with
carnitine, Coenzyme-Q, thiamine, riboflavin, folic acid besides
physiotherapy, multisensory stimulation, and nutritional support. On
follow up at two years of age, he had attained partial neck control,
voluntary reach, babbling and stranger anxiety . He now was noticed to
have intermittent dystonic upper-limb twisting which increased during
crying and disappeared during sleep. While this child was being followed
up, his younger sister was born and evaluated for being symptomatic.
The younger six-month-old female sibling was
term-born with uneventful perinatal period and was pre-morbidly
developmentally normal. She was first noticed to have episodes of brief,
paroxysmal, non-repetitive, abnormal, multi-directional eye movements at
the age of three months. She did not have frothing, sweating, flushing,
cyanosis, or pallor. Frequency of these episodes increased from once a
day to about ten per day by one month. The child also developed feeding
difficulty in the form of abnormal lip and tongue movements when milk
was offered with a spoon or feeding bottle. The child’s neck control
gradually deteriorated and she stopped gaining new milestones over next
three months. On examination, positive findings were truncal and axial
hypotonia. Child’s home videos suggested paroxysmal non-epileptiform
ocular movements, orolingual dyskinesias and dystonic limb posturing.
Her hemogram, serum biochemistry, arterial ammonia, lactate, acyl
carnitine profile, urinary organic acid profile, electro-encephalogram,
MRI brain and MRS were within normal limits.
Given the above profiles, a neurotransmitter disorder
was suspected. Serum prolactin and phenylalanine levels were obtained as
the suspicion of TH deficiency and Aromatic L amino acid decarboxylase
(AADC) deficiency were entertained. Phenylalanine levels were within
normal limits. Prolactin levels of both siblings were significantly
elevated [119.4 ng/mL (boy); 132.6 ng/mL (girl)] (reference
level:4.79-23.3 ng/mL)] .
The boy’s TH gene targeted sequencing revealed
two heterozygous missense variations in exon 6 and 12. Hence, he was
diagnosed to have TH deficiency due to a compound heterozygous
mutation. The girl was evaluated by targeted Sanger sequencing of exons
6 and 12 for TH gene. Both variations were detected in the
heterozygous state (Table I). Parents were evaluated for
mutations in TH gene. The variation in exon 6 was detected in
heterozygous state in the mother and the variation in exon 12 was
detected in heterozygous state in the father.
The father’s 20-year-old paternal first cousin has
history of episodic generalized weakness and involuntary twisting of
wrists from thirteen years of age. These episodes were triggered by
tension and fatigue. She was advised tablet L-dopa empirically to which
she responded. As these episodes were infrequent and non-impairing, she
was not on regular medication or follow-up. She was interviewed
telephonically. Clinical examination could not be organized as she
resided in a distant city. Her genetic testing revealed the variation in
exon 12 in heterozygous state.
The children were started on gradually increasing
dosage of L-Dopa (0.6 mg/kg/day), carbidopa (1mg/kg/day), selegiline (3
mg/kg/day) and trihexyphenidyl and were kept on follow-up. They have
been followed up for one more year.The boy has minimal decrease in
dystonia while the girl has demonstrated a significant decrease in oro-lingual,
ocular and limb dyskinesias. Both are gaining new milestones.
Discussion
Tyrosine Hydroxylase (TH) deficiency (MIM No: 191290)
is also called ‘autosomal recessive Segawa Syndrome’ [1]. TH catalyzes
conversion of L-tyrosine to L-dihydroxyphenylalanine (L-dopa). This is a
rate-limiting step in the formation of dopamine, norepinephrine and
epinephrine [2].
Our index case (boy) presented with neuroregression
with trivial illness while his younger sibling (girl) had more prominent
extrapyramidal movements. In such clinical scenarios a host of
differentials including amino-acidopathies, organic acidurias, urea
cycle disorders, respiratory chain disorders and rarely neurotransmitter
disorders need to be considered. Normal biochemical investigations
including arterial ammonia, lactate, acyl carnitine and urinary organic
acid profile, and unremarkable MRI brain and MRS made the diagnosis of
inborn errors of metabolism and respiratory chain disorders seem less
likely. These laboratory findings in addition to the core symptom of
extrapyramidal movements made the possibility of neurotransmitter
disorder more likely.
Investigations for neurotransmitter disorders begin
with CSF analysis of neurotransmitter level. CSF analysis in TH
deficiency reveals low homovanillic Acid (HVA) and normal levels of
5-hydroxyindole acetic acid (5-HIAA),neopterin, and biopterin [3]. The
HVA: 5-HIAA ratio is less than 1 (normal 1.0-3.7) [4].CSF analysis could
not be performed in our cases due to non-availability.
Hyperprolactinemia is noted in about 50% of severely affected patients
[5]. This surrogate marker was helpful in both of our children. This
serum marker is widely available and useful for evaluation of
neurotransmitter disorders.
Type A TH deficiency manifests after infancy with
hypokinesia, rigidity , dystonia with diurnal fluctuation [1]. Symptoms
respond to L-Dopa [1]. Type B TH deficiency manifests in early infancy
with encephalopathy, hypotonia, hypokinesia, dystonia, tremor, myoclonus
and oculogyric crises, dystonic crises and dysautonomia [4]. Our cases
had features of Type B TH deficiency of varying severity. A remarkable
feature seen in the family we report is the phenotypic variability, as
has also been reported previously [6]. Heterozygous carriers of TH
gene mutation may have intermittent symptoms of mild severity
[1].This was seen in one of the heterozygous carriers in the family
while other carriers were asymptomatic. Diagnosis of TH deficiency is
established by demonstrating TH gene mutations. The gene mutation
at exon 6 of TH gene was first reported in three unrelated Dutch
families [5]. However, the gene mutation at exon 12 seen in this family
is novel.
TH deficiency is a treatable neurotransmitter
disorder. L-Dopa is the key drug for treatment of this condition. Low
dose L-dopa/carbidopa with selegiline and trihexyphenidyl are more
effective than plain L-dopa/carbidopa [3,7]. Folinic acid
supplementation reverses secondary folate deficiency [8]. The affected
and unaffected family members need long term followup as rapid
dose-escalation, fever and stress may paradoxically increase dyskinesias.
Dose reduction and amantadine combats this adverse effect [8].
To conclude, the report highlights the clinical
heterogeneity of this newly described group of neurotransmitter
disorder. With a clue from widely available investigation like prolactin,
this potentially treatable condition may be suspected and proven in the
correct clinical context.
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