Keywords
encephalopathy - metabolic disease - genetic disorder
Introduction
Dihydropteridine reductase (DHPR) deficiency is a rare autosomal recessive genetic
disorder caused by the quinoid dihydropteridine reductase (QDPR) gene mutations located in Ch. 4p 15.32. QDPR gene missense mutations, insertions/deletions, and splice site mutations have been
reported in patients with this disorder.[1]
[2]
[3]
[4]
[5]
[6] The gene encodes the enzyme DHPR, which catalyzes the NADH-mediated reduction of
quinoid dihydrobiopterin, an essential component of the pterin-dependent aromatic
amino acids hydroxylating systems. DHPR deficiency impairs the synthesis of the tetrahydrobiopterin
(BH4), an essential cofactor for the hydroxylation of the aromatic amino acids phenylalanine,
tyrosine, and tryptophan, the deficiency of which causes: (1) increased levels of
phenylalanine in the blood (hyperphenylalaninemia [HPA] type 2) and in other tissues
and (2) reduced cerebrospinal fluid (CSF) synthesis of neurotransmitters (dopamine
and serotonin) and CSF folic acid.[5]
[6] Clinical manifestations may be observed since infancy, affecting equally both genders
and all racial and ethnic groups. Increased level of HPA found through neonatal metabolic
screening program may be a clue to this metabolic disorder, and early treatment may
prevent severe brain involvement.[7] When not precociously treated, the disorder may present with a series of neurologic
disorders including progressive developmental delay, microcephaly, seizures, speech
impairment, movement dysfunction, and spastic diplegia or tetraparesis.[8]
[9]
[10]
[11] DHPR deficiency is an extremely rare disorder and accounts for about one-third of
all forms of BH4 deficiencies, which are estimated to occur in 1 to 2% of all patients with HPA.[9] The incidence of HPA is estimated to be ¼,500 and BH4 deficiency identified by the Neonatal Screening Program of the State of Minas Gerais
is reported in 2.1 × 1,000,000 live birth with a frequency of 1.71% among HPA patients.[7] The treatment of DHPR deficiency includes the early lowering of blood phenylalanine
by dietary restriction, BH4 supplementation, and administration of methylfolate or folinic acid and of neurotransmitter
precursors such as L-DOPA/carbidopa and 5-hydroxytryptophan. Long-acting dopamine
agonists are also utilized in the treatment of this disorder.[11]
[12]
[13]
[14]
[15]
We reported here a 12-year-old girl who was previously hospitalized for a few days
to a local pediatric emergency section for two short episodes of seizures. One month
after the discharged, she came to Pediatric Department of Catania University (Italy)
presenting with episodes of vomiting, headache, irritability, acute confusional state,
seizures, and left lower limb hypotonia; she was known to be affected by DHPR deficiency
and in treatment since infancy. A thorough personal history revealed that the girl,
with the agreement of her parents, had suspended the folinic acid treatment due to
poor compliance since at least 6 months before the present admission. The relation
between the clinical signs presented by the girl and folic acid deficiency was confirmed
by the results of laboratory assessment and by the answer to the notable clinical
improvement with the renewal of folinic acid treatment.
This clinical report points out the following: the rarity of DHPR deficiency disorder;
the peculiar neurologic manifestations presented by the girl with signs previously
unreported in patients with folic acid deficiency; and the confirmation of the usefulness
of the folic acid treatment along the course of the disorder in patients with DHPR
deficiency as to avoid further neurologic complications.
Case Report
A 12-year-old female patient was the second born from healthy unrelated parents. Her
7-year-old younger brother is healthy. Family history is negative for neurological
disorders. The girl was born at the 39th week of gestation by normal delivery. The
mother mentioned to have felt fetal movements normally and did not suffer febrile
disorders throughout the pregnancy. Personal history of the girl started at the neonatal
period, since at the neonatal screening program for inherited metabolic disorders
a positivity for high level of phenylalaninemia (PHA) was found. On admission at Pediatrics
Department of Catania University, Neonatal Section, a diagnostic work-up for PHA was
started, and a serum phenylalanine level ranging between 492 and 756 nmol/L was reported.
A diagnosis of DHPR deficiency was performed, and based on BH4 loading test, measurements of urinary, serum, and CSF pterins, DHPR activity in dried
blood spots, and analysis of neurotransmitter metabolites in urine and CSF were conducteds.
Treatment was started with phenylalanine restriction diet, levodopa/carbidopa (2 mg/kg/day)
and 5-hydroxytriptophan (10 mg/mL), and folinic acid (3 mg/day). The girl has been
followed up since birth in ambulatory care by the doctor team of the regional center
for inherited metabolic disorders and by pediatric neurologists of this department.
The girl's growth was normal, and anthropometric measurements were just below the
normal range for her age. During the course of the disease, physical examination was
normal and no malformation anomalies were found. The thorax, heart, and abdominal
organs were normal. At the age of 2 years, the stage of neurodevelopment was delayed
as regards motor and language skills. Doses were adjusted according to the age of
growth. At the scholastic age, the girl attended school regularly but with poor benefit
and with support. At the age of 8 years, she showed an IQ of 56 at the Wechsler Intelligence
Scale for Children (WISC)-III test. Laboratory analysis performed along the course
of the disease displayed normal electrolytes, plasma and urine amino acids including
phenylalaninemia, plasma purine, thyroid and celiac markers, and sialotransferrin.
At the present age of 12 years, the girl came to a pediatric emergency of a local
hospital due to the sudden onset of afebrile focal epileptic seizures lasting a few
minutes, which was preceded by frontal headache. After 2 hours, the seizures reappeared,
lasting again a few minutes with spontaneous resolution. Computed tomography (CT)
scan was normal and EEG recording showed basic theta activity at 5 to 6 c/s on the
posterior regions and at hyperventilation high-voltage activities and intermittent
light stimulation at 20-Hz frequency on the posterior region bilaterally. Levetiracetam
therapy at the initial dosage of 500 mg/day (18 mg/kg/day) was started, and she was
discharged by the hospital in good condition. About a month later, the girl presented
with new sudden episodes of acute blurred consciousness, vomiting, headache, and again
epileptic seizures lasting a few minutes and was admitted to the Pediatric Department,
University of Catania, Italy. On admission, the general condition of the girl was
unsatisfactory: refill time, 2 seconds; weight, 27 kg; height, 132 cm; and head circumference,
49 cm—all within the 3rd percentile. At physical examination, the girl showed confusional
state, with poor behavioral interaction and no seizures. She was able to reply to
the question with poor and dull voice. Cranial nerves were normal. She was unable
to walk without support because of hypotonia involving the left lower limb. Meningeal
signs were absent with patellar tendon reflexes present and brisk. Routine laboratory
analyses were normal including electrolytes, plasma and urine amino acid, vitamin
B12, organic acid, thyroid and celiac markers, sialotransferrin, plasma purine, and total
cholesterol. Systemic lupus erythematosus panel, proteins C and S, factor V Leiden,
antiphospholipid antibodies, and antithrombin III and coagulation profile as well
as inflammatory markers and urinalysis were in the normal range. Plasma PHA was 56 nmol/L
(normal range, 25–100 nmol/L), and plasma folic acid was 7.5 nmol/L (normal range,
3.89–26.8 nmol/L). CSF analysis gave the following results: cultures were normal,
PHA 60 nmol/L (normal range, 23–95 nmol/L), 5-5-Hydroxyindoleacetic acid (HHA) 34 nmol/L
(normal range, 84–360 nmol/L), Homovanillic Acid (HVA) 86 nmol/L (normal range, 140–780 nmol/L),
5-MTHF 97 nmol/L (normal range, 150–170 nmol/L), BH4 24 nmol/L (normal range, 18–40 nmol/L), and N-PHA 22 nmol/L (normal range, 5–25 nmol/L).
Otoacoustic examination, electrocardiogram (ECG), and echocardiogram were normal.
A new EEG recording showed medium focal time slowdown specifically in the left centrotemporal
and right temporo-occipital region and a generalized slow activity. Brain magnetic
resonance imaging (MRI) showed the presence of altered signal areas at the cerebellar
level bilaterally with diffusion restriction as for vasogenic and cytotoxic edema.
Other lesions of the altered signal were seen at the temporo-occipitoparietal right
level, with swelling of the convolutions and reduced differentiation between white
and gray matter, temporomandibular left, and right thalamic ([Fig. 2A–C]). In consideration of the interrupted folinic acid treatment, as informed by her
family members and again confirmed by the laboratory assessment, and excluding the
stroke nature of the brain MRI lesions, a new cycle of intravenous folinic acid treatment
was started (initially at the dosage of 10 mg/day and then 15 mg/day orally) associated
with dexamethasone therapy resulting in progressive clinical benefit. The daily dosage
of levetiracetam was also increased. No episodes of headache, vomiting, seizures,
or other neurologic signs were observed, and progressive regain of consciousness and
improvement in the left lower limb hypotonia were observed albeit with residual hypoesthesia.
A new brain MRI performed after 2 months from the admission showed a notable improvement
of the lesions previously reported ([Fig. 3A–C]). At 1-year follow-up, the girl had good clinical condition. No other similar episodes
were registered. She can walk normally but scholastic performance is poor and IQ test
persisted at the precedent levels.
Fig. 1 Phenylalanine hydroxylating system. BH4, tetrahydrobiopterin; GTP, guanosine triphosphate. (Reproduced with permission from
van Spronsen et al.[13])
Fig. 2 (A–C) MRI images related with acute neurological symptoms.
Fig. 3 (A–C) MRI imaging performed after reintroduction of folinic acid and adjustment of antiepileptic
therapy.
Discussion
In our patient, DHPR deficiency was diagnosed in the neonatal period through the presence
of a high level of PHA at the neonatal screening program and subsequently by appropriate
diagnostic laboratory assessment including blood and CSF results. Soon after the diagnosis
of DHPR deficiency, the girl was treated and followed up according to the classical
protocol for DHPR deficiency. During the course of the years, the treatment was effective,
as no complaints were reported with the exception of poor growth and poor scholastic
performance. The first clinical episode happened at the age of 12 years and was characterized
by a sudden onset of headache and by a focal epileptic seizure lasting a few minutes
not preceded by febrile temperature and followed by a second epileptic episode presenting
with the same features. Initially, the clinical signs and EEG recording pointed toward
the diagnosis of focal epilepsy. One month later, further clinical manifestations
occurred with features of acute encephalopathy with headache, vomiting, confusional
state, and seizures and admission to the Pediatric Department of Catania University.
The brain MRI allowed us to exclude the diagnosis of acute arterial ischemic or thrombohemorrhagic
stroke together with the negativity of specific laboratory analysis for this disorder.
The information given by the parents on the interruption of the folinic acid treatment
in the girl and subsequently the results of the blood and CSF laboratory analyses
led us to better clarify the origin of the clinical disturbances presented by the
girl.
Early and correct treatment for patients affected by DHPR deficiency is essential,
as a delay or an inadequate treatment may result in severe neurologic impairment including
developmental delay/intellective disability (DD/ID), microcephaly, seizures, movement
disorders, cerebral palsy, and other neurological impairments. Bozaci et al[12] reported on nine patients: three affected by DHPR deficiency and six by BH4 deficiency. All the three patients affected by DHPR deficiency were females. One
of these (patient 7) was referred at the age of 18 months for walking difficulty and
at her last visit showed hypotonia, seizures, and slight ID. Another patient (patient
8) showed DD and slight ID. In this patient, hypersalivation, apathy, dysarthria,
and gait disturbances became worse when the blood Phenylalanine (PHA) levels were
high, particularly when over 6 mg/dL. The third case (patient 9) was diagnosed at
the age of 9 years with ID, seizures, and inability to stand, walk, or even sit without
assistance. Miladi et al[16] report on seven members of a large family affected by DHPR deficiency. In this family,
a sister and four brothers died between the age of 3 and 7 years. In the sister, a
neuropathologic exam showed diffuse demyelination throughout the white matter and
spongy vacuolation in the subthalamic nuclei, superior cerebellar peduncles, and tegmentum
tracts of the brain stem. The anterointernal part of the putamen was completely necrotic
with nearly total nerve cell loss. Abnormal vascular proliferation and calcification
of the walls of small, medium, and large arteries and veins and diffusely scattered
pericapillary and isolated calcospherites were also reported in the necrotic region.
The clinical and neuroradiologic anomalies observed in the present case were unusual.
The girl manifested signs of acute encephalopathy, and brain MRI showed diffuse lesions
characterized by vasogenic and cytotoxic edema, swelling of the convolutions, and
reduced differentiation between white and gray matter. Anomalies were also reported
at cerebellar level bilaterally. In this girl, the failure of folic acid as found
in spinal liquor and the improvement of clinical and radiological manifestations after
the renewed treatment with folinic acid are suggestive of a highly probable correlation
between clinical manifestations presented by the girl and folic acid deficiency. It
is well known that brain folate has an important role in myelin formation, and this
is supported by the fact that brain folate deficiency is manifested by several neurological
manifestations.[17]
[18]
[19] In nontreated DHPR deficiency patients, the neuroradiological characteristics usually
observed consist of brain atrophy, basal ganglia calcification, white matter changes,
ventricular dilatation, areas of hypodensity, and global demyelinating signs.[20] Woody et al[21] reported on a child with DHPR deficiency presenting with seizures and a progressive
basal ganglia and other subcortical calcifications. After the use of folinic acid,
an excellent seizure control was obtained, suggesting either a direct or indirect
anticonvulsant effect of this treatment. Sugita et al[22] reported two siblings with HPA due to DHPR deficiency. The siblings were examined
using MRI and CT of the brain. MR images showed white matter changes, whereas CT scan
showed characteristic calcifications in the basal ganglia and subcortical region bilaterally.
In a 16-year-old boy with DHPR deficiency, the brain MRI displayed high-intensity
areas in bilateral frontal and posterior deep white matter on fluid-attenuated inversion
recovery (FLAIR).[23] Coronal FLAIR image revealed a high signal in pyramidal tracts. The patient clinically
showed moderate DD, parkinsonism, and spastic paralysis.
In our patient, the failure to continue the treatment with folinic acid has caused
neurological dysfunction manifesting with acute encephalopathy and correlated with
severe symptoms including epileptic seizures. The therapeutic intervention with folinic
acid achieved a notable clinical and imaging improvement. The present case shows that
the clinical presentation and MRI anomalies of the cerebral folic acid deficiency
may be various and unusual compared with those reported in the literature, and it
clearly confirms the usefulness of the continuation of folinic acid treatment during
the course of the disorder in patients with DHPR deficiency.
