Key-words:
Dopa-responsive dystonia - Libya - nephrocalcinosis - sepiapterin reductase
Introduction
Dystonia is a movement disorder characterized by persistent and intermittent muscle
contractions that cause involuntary repetitive movements, leading to abnormal posture
in affected parts of the body.[[1]] Hermann Oppenheim (1858–1919) described the first case of dystonia in 1911. In1994,
the mutation in the GTP cyclohydrolase1 gene was discovered as a leading cause of
DRD.[[2]]
DRD constitutes a group of clinically and genetically different movement disorders
that typically manifest by dystonia of limbs with diurnal fluctuation and exhibit
a clear and continuous response to levodopa drugs.[[3]] DRD is caused by three different genes – GCH1, TH, and SPR. The most common are
the mutations in the GCH1 gene, followed by mutations in the TH and SPR genes.[[4]],[[5]]
The GCH1 gene regulates the synthesis of the GTP cyclohydrolase enzyme, responsible
for the first three steps in the production of tetrahydrobiopterin (BH4) molecule.
The SPR gene controls for the synthesis of the sepiapterin reductase enzyme, which
is involved in the last step of BH4 production.[[4]] The classical forms of BH4 deficiency manifest by hyperphenylalaninemia, while
DRD and SPR deficiency are not, and hence the neonatal screening for phenylketonuria
(PKU) cannot detect it.[[6]]
DRD, due to (SPR) deficiency (OMIM#612716), is a rare genetic movement disorder caused
mainly by an autosomal recessive [[5]] and rarely by dominant mutations.[[7]] The clinical manifestations of SPR deficiency range from a mild movement disorder
at one end to a severe progressive neurological disease at the other end.[[5]] The SPR enzyme converts a molecule called 6-pyruvoyl-tetrahydropterin to tetrahydrobiopterin
molecule. Tetrahydrobiopterin is involved in neurotransmitters' production; the neurotransmitters
carry signals between nerve cells in the brain. Most notably, tetrahydrobiopterin
is involved in the production of two neurotransmitters called dopamine and serotonin.
Among their many functions, dopamine transmits signals within the brain to smooth
physical movements, and serotonin is responsible for regulating emotion, mood, appetite,
and sleep.[[4]] The majority of affected individuals' clinical features include motor and speech
delay, axial hypotonia, dystonia, weakness, and oculogyric crises; symptoms usually
show diurnal fluctuation. Other standard features include parkinsonian signs (tremor,
rigidity, masked face, and bradykinesia), limb hyperreflexia, hypertonia, autonomic
dysfunction, intellectual disability, psychiatric and/or behavioral abnormalities,
and sleep disturbance (excessive sleep, difficulty initiating, or maintaining sleep).
The disease features are nonspecific in the first year of life, which includes developmental
delays and axial hypotonia; other features develop over time.[[5]]
Here, we report a new heterozygous variant c.207C>G, p. (Asp69Glu) in the SPR gene
(OMIM: 182125), which leads to an amino acid exchange. Nine out of ten bioinformatic
in silico programs predict a pathogenic effect for this variant.
Case Report
History
A 12-year-old girl presented at the age of 8 years with tiptoes walking and deteriorated
gait. She has no diurnal variation of her symptoms. She is a product of first-degree
consanguineous marriage with insignificant history. She has two sisters; the younger
one has global developmental delay, epilepsy, and bilateral nephrocalcinosis. Her
two uncles had severe axonal polyneuropathy and died in their forties of unknown cause.
This family is an Arab family from Libya. On examination, she had high-stepped and
broad-based gait. She was alert with normal higher mental function. She had mask face,
normal cranial nerves, normal head size, and average body built. Her muscle tone was
increased, and her tendon reflexes were exaggerated. She had sustained clonus. Her
muscle power was grade 5. Her systemic examination was unremarkable.
Investigations
The patient's initial workup was unremarkable. Her abdominal and renal ultrasound
showed bilateral nephrocalcinosis; complete investigations were done to find the cause
of here nephrocalcinosis, were all normal including serum calcium level, phosphorus,
alkaline phosphatase, parathyroid hormone, Vitamin D level, arterial blood gases,
serum sodium and potassium, blood urea, and creatinine. In addition, she had a normal
urinary anion gap, normal urine routine examination, and normal 24-h collection for
calcium to creatinine ratio. Hence, a diagnosis of idiopathic nephrocalcinosis was
most likely. Brain MRI showed periventricular leukomalacia with right frontal subcortical
lacunar gliosis [[Figure 1]]. Genetic DNA evaluation (whole-exome sequencing [WES]) identified the heterozygous
variant c.207C>G, p. (Asp69Glu) in the SPR gene (OMIM: 182125), which leads to an
amino acid exchange. Nine out of ten bioinformatic in silico programs predict a pathogenic
effect for this variant [[Figure 2]].
Figure 1: Magnetic resonance imaging brain performed using a dedicated head coil on a 1.5 tesla
scanner, the fluid-attenuated inversion recovery images revealed bilateral cerebral
hemisphere periventricular deep white matter high signal intensity going with periventricular
leukomalacia with right frontal subcortical lacunar gliosis
Figure 2: An alignment view of the variant gene SPR leading to a frameshift mutation indicted
by a vertical shadow line (cytogenetic location: 2p13.2, which is the short [P] arm
of chromosome 2 at position 13.2)
Discussion
To the best of our knowledge, the association of this variant with nephrocalcinosis
has not been described previously. However, a similar variant has already been described
in the literature in a family with autosomal dominant DRD with incomplete penetrance
(PMID: 29147684). The variant is found in 0.01% of the overall population (12 heterozygous,
0 homozygous; gnomAD), and this is the first time the variant was detected in the
internal laboratory database. Considering the available information, the variant was
classified as a variant of uncertain significance (Bioscientia International). Molecular
genetic study for parents showed that the father carries c.207C>G, P.(Asp69Glu) in
SPR in a heterozygous state, while the mother is not a carrier of the same gene.
More than 20,000 genes in the human genome were enriched using Roche/NimbleGen technology
(SeqCap EZ MedExome Library) and sequenced on an illumine HiSeq 1500 system (WES).
The aberrations listed were identified by filtering the exome data for homozygous/putatively
compound–heterozygous variant, bioinformatically extracted homozygousity-by-descent
regions and by a literature-based survey against the indication of interest.
DRD comprises a genetically heterogeneous group of movement disorders with both autosomal
dominant and recessive traits,[[4]],[[8]] The phenotypic spectrum of SPR deficiency has not been completely elucidated due
to the small number of affected people. In 2015, a total of fifty cases were reported
all over the world.[[5]] Focusing on the Middle Eastern and North Africa (MENA) region, ten more cases from
Saudi Arabia and Egypt were reported in 2017.[[7]],[[9]] Also another case was reported from Jordan in 2019.[[9]]
Comparing our case with those from the same MENA region may be of particular interest.
Our patient carries a heterozygous SPR variant (c.207C.G, p. Asp69Glu, chr2:73114768_C.G.),
a mutation has also been described in one Egyptian family.[[7]] Our patient's father carries the same gene, supporting the autosomal dominant inheritance
with incomplete penetrance in this family.
Also, comparing our case with the five affected children in the Egyptian family [[7]], reveals a similarity in the age of onset with most of the cases seen between childhood
and puberty. The clinical presentation of all cases was with lower limb dystonia (tiptoe
walking) and rigidity that started early in childhood and had a progressive course.
Regarding the response to treatment, the first patient in the Egyptian family has
improved markedly with L-DOPA, however, with low-threshold drug-induced dyskinesia.
His current medications include fractionated L-DOPA doses (750 mg/day), anticholinergic,
and amantadine (400 mg/day). The second and third children experienced symptomatic
benefit with L-DOPA and continued on pramipexole. Children 4 and 5 were not treated
with L-DOPA because of their age, minor symptoms, and fear of L-DOPA-induced dyskinesia.
Treatment of our patient with levodopa/benserazide 4:1 (Madopar) has not changed her
condition. She has not shown any improvement in fractionated L-DOPA doses (750 mg/day)
for a 6-month duration.
Nephrocalcinosis, which is seen in our case, has never been reported previously in
any published cases of DRD due to the SPR deficiency, and its relation to the child's
condition seems to be unclear. Further research is required to confirm the relationships
and elucidate its mechanisms.
Conclusions
We suggest that the new variant (207C>G, p[Asp69Glu]) of the gene responsible for
DRD due to SPR deficiency detected in our patient and the Egyptian patient is likely
to be pathogenic rather than of uncertain significance. This is supported by the phenotypic
and the genotypic similarities, both being inherited as autosomal dominant with incomplete
penetrance. DRD due to SPR deficiency is infrequent, but the real number of cases
may be underestimated due to a lack of diagnosis. WES is an essential tool for diagnoses,
but it is costly, especially in the third world. The association of nephrocalcinosis
and DRD is not clear, but further researches are needed.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form, the legal guardian has given consent for the patient's images and other
clinical information to be reported in the journal. The guardian understands that
the patient's name and initial will not be published, and due efforts will be made
to conceal patient identity, but anonymity cannot be guaranteed.
Authors' contributions
All authors were involved in the clinical care of patients, undertaking the investigative
studies and drafting and finalizing of the manuscript.
Compliance with ethical standards
No prior ethical approval is required for single case reports. However, the patient
provided consent for publication as stated above.
Reviewers:
Hussein Al Saffar (Muscat, Oman)
Wanis H Ibrahim (Doha, Qatar)
Editors:
Salem A Beshyah (Abu Dhabi, UAE)
Elhadi Aburawi (Al Ain, bu Dhabi)
