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NAME: Yvette Claire L. Borres II-AN

JOURNAL CRITIQUING

Homocystinuria: Diagnosis and Neuroimaging Findings of Iranian

Pediatric patients
Parvaneh KARIMZADEH, MD,1,2 Narjes JAFARI, MD,2 MohammadReza ALAI, MD,3 Sayena
JABBEHDARI, MSc,1and Habibeh NEJAD BIGLARI, MD2

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Introduction
Homocystine is an amino acid with sulfur that comes from methionine metabolism.
Homocystineis metabolized by two pathways as follows: transsulfuration or remethylation (1).
Gene abnormalities in the enzymes, which catalyze the reactions in trans sulfuration or
remethylation pathways, can cause hyper homocysteinuria. Homocystinuria can be caused by
abnormal DNA methylation during embryogenesis(2). Hyperhomocystinuria is causedbya rare
genetic error causedby deficiencies in methylenetetrahydrofolate reductase, cystathionine beta
synthase, or in enzymes involved in homocystine methylation andmethyl-B12 synthesis(3).
There is an association between mutations of elevated levels of homocysteine,
methylenetetrahydrofolate reductase, MTHFR C677T, and increased risk of thrombosis among
homozygous carriers. Heterozygote carriers for the above gene mutations with other major or
minor risk factors are prone to thrombosis (4).Mutation of the methylenetetrahydrofolate
reductase (MTHFR) and provides the folate derivative for homocystine to methionine
conversion. This mutation can cause mild hyperhomocysteinuria. The rationale (folate
supplementation) can be usedto over come the genetic deficiency in cases with low levels of
folate(5). High levels of homocystine in plasma are one of the risk factors for atherosclerosis
(6).It has been showed that early detection and treatment can be helpful and homocystine levels
can be controlled by vitamins B6, B12, cofactors needed for homocystine metabolism, and by
folic acid supplements (7-9).
In this study, we present 10 years of experience about homocystinuria fromthe Pediatric
Neurology Research Center of Mofid Children’s Hospital, Tehran, Iran. We describe clinical
symptoms and neuroimaging findings for20 cases with this disorder.
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Materials & Methods

This observational study was performed on patients who were diagnosed with homocystinuria at
the Neurology Department of Mofid Children’s Hospital in Tehran, Iran, from2004–2014. The
diagnosis was performed based on clinical manifestations, neuroimaging findings, homocystine
level assessments in Germany,and,finally,genetic study. The data collected wereage, gender, past
medical history, developmental status, general appearance, and clinical and neuroimaging
findings.
Treatment consisted of betaine, carnitine, folic acid, vitamin B12, vitamin B6 supplements, a
low-protein diet, and anti-convulsant drugs in cases with seizures. The children’s diet was
carefully controlled. The data were analyzed by descriptive methods and no statistical testing
was applied.
Institutional ethical approval for the conduct of this study was obtained from the Pediatric
Neurology Research Center of Shahid Beheshti University of Medical Sciences, Tehran, Iran.
All parents signed a written consent for participation in the study.
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Results
Twenty patients with homocystinuria who hadbeen assessed and followed over thelast 10 years
were included in this study. Sixpatients,in addition tohomocysteinuria, had
methylmalonicacidemia. There were 11 males and 9 females with an agerangefrom 6-months to
15-years. The earliest case was diagnosed in a neonate who presented with a sepsis-like illness
and the latest case was diagnosed in a 10 year-old with seizures due to cerebral thrombosis after
lens dislocation surgery. The average age of patients at final detection time was9.6 months. A
total of 75% of patients were offspring from consanguineous marriages. In addition, 5 patients
had a positive family history of similar disease and2 of them died without diagnosis.
One of our patients (39 months old) died about 2years after detection.The patient had not
received any treatment due to his parent’s decision.
Four patients had a history of neonatal hospitalization because of poor feeding in patient-number
1, was diagnosed at that time, and treatment of homocystinuria was started.Patient-number 2 had
continuous vomiting that was permanent until 4 months of age and homocystinuria was detected
at this time.Patient-number 3 had sepsis-like illness from12 days of age but was diagnosed at 9
months of age. Patient-number 4 had a neonatal hospitalization due to hyper bilirubinemia.
The chief complaints in patients at detection time were seizures in 11 patients and developmental
delays or regression in 7. Twocases had visual loss. In the developmental assessment, 19 patients
had developmental delay, 8 patients had developmental regressions with words and movements
stuck more than their recognition. Fifteen patients had seizures of which 9 patients had recurrent
and refractory. The types of seizures were as follows:5 patients had generalized tonic clonic
seizures; 5 had tonic seizures; 3 had partial seizures; and 2 patients had infantile spasms. The
body weightof4 patients was below the 3rd percentile and the height in 6 patients wasabove the
5th percentile.Three patients had microcephaly but another patient was in thenormal
developmental index. Three patients had erythematous scaling lesions on their skin. One patient
had alopecia and 4 patients with homocystinuria had blond hairs and light eyes. Five patients had
visual loss due to lens dislocation and secondary cataracts.One patient hadstrabismus and another
patient had optic atrophy. Two patients had valvular heart disease. Seven patients had central
hypotonicity . Two patients indicated stroke episodes. Six patients showed long fingers and long
limbs.
The lab data showed that all patients had increased levels of homocystine in their serum (from
48–1022 with maximum normal range of 16);6 patients had anemia;and 4 patients had
megaloblastic anemia. These patients also had methylmalonicacidemia. Serum amino acid was
assessedwiththe HPLC method and was showed elevated levels of glutamine in all patients, as
well as increases in a few nonspecific aminoacids in some of the patients.
From the neuroimaging data, we saw that 11 patients had brain atrophyand white matter
involvement;4 patients exhibited corpus callosum atrophy; 2 patients had only white matter
involvement; 4 patients had a previous stroke; 1 patient had cerebral thrombosis; and 1patient
had a normal brain MRI ( Figure 1).

Fig 1
A-15-year –old male with brain involvement due to Homocystinuria
Genetic analysis was done on 3 patients and reported mutant polymorphism of C677T
heterozygote and mutant allele of C homozygote.
Patients were treated with a low protein diet, betaine, carnitine, folic acid, vitamin B12, vitamin
B6, and anti-convulsant drugs in cases with seizure. Seizures were controlled in13 patients after
starting anti-convulsant drugs. Regression in our patients was stopped after starting treatment
with 5 out of 8 patients progressed to have the ability again.Even white matter involvement and
brain atrophy improved after treatment. Also further strokes after treatment did not occur. Only
one patient who was 39 months old did not receive special treatment anddied due to a refractory
seizure.
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Discussion
Homocystinuria is a rare inborn error of the metabolismwith autosomal recessive inheritance that
is caused byenzyme deficiencies(3). Homocystinuria is caused by genetic mutations in the
enzymes and may contribute to increases in plasma homocystine. First, Carson and Neill
reported the association between mental retardationand homocystinuria in two Irish brothers in
1962 (10). In 1964, Gerritsen and Waisman first identified homocystine in the urine and defined
homocystinuria (11). Prior to the 1960s, in 1933, homocystinuria had already been described in
an eight-year-old child with mental retardation, dislocation of the lens, and skeletal abnormalities
with coxavara and who died from a stroke (12). Homocystinuria was diagnosed in this child’s
nephew in 1965 (13). Normal levels of plasma homocysteine are between 5–15 nmol/ml and
concentrations between 16–30 nmol/ml is mild, 31- 100nmol/ml is moderate, and greater
than100 nmol/ ml is severe hyperhomocystinuria(14). MuddSHet al reported that around half of
their cases had a good laboratory and clinical response to high doses of vitamin B6 (15). Fonseca
et al had no known relevant clinical findings in family members (16). Treatment for elevated
homocystine levels is simple and innocuous. High doses of pyridoxine (B6) were used initially
with success in children with homocystinuria (17).
The clinical features include subluxation of the lens, which are characteristic for connective
tissue disorders (15). Our results were similar and five patients had visual loss from lens
dislocation and secondary cataracts. Twenty patients (11 males and 9 females) with
homocystinuria were included in this study. A total of 75% of cases were fromconsanguineous
parents and 25% had similar diseases in their families. Therefore, in suspected cases of
homocysteinuria, having consanguineous parents can contribute to the diagnosis because of
autosomal recessive inheritance of homocysteinuria. A total of 15% of patients had a history of
hospitalization due to period of sepsis-like illness that metabolic disease assessment can be
helpful indetection forill neonates. A total of 95% of patients had a history of developmental
delay and 40% had developmental regression. Patients with these symptoms who are referred to
a pediatric neurologist, it is our suggestion to for the pediatric neurologist to consider
homocysteinuria. A total of 35% of patients had heights greater than normal and 40% of patients
had skin and hair involvement, i.e. skin lesions and blond hair, among others.
From brain MRIs, 75% of patients had brain involvement (generalized atrophy, white matter
involvement, previous infarct pattern, and venous sinus thrombosis). In follow-up imaging,
which was done in 6 patients, 50% of them had improvements in white matter involvement and
brain atrophy. Sachdeva Vet al reported that all patients had ischemic lesions in the brain MRI
with contrast (18).
A total of 75% of patients had seizures and 45% of these seizures werere current and refractory.
Seizures were controlled for13 patients after starting anti-epileptic drugs and special treatment
for homocysteinuria. Regression in our patients was stopped after starting treatment and 62% of
patients regained that ability.In addition, further strokes after treatment did not occur.
Our patients with homocystinuria came to our specialist center and exact evaluationswere done.
In conclusion, based on our results, patients with developmental delay or regression, long limbs
and tall, recurrent seizures, skin lesions, blond hair, eye involvement such as secondary cataracts
due to lens dislocation, hypotonia, brain involvement in MRI include brain atrophy or white
matter involvement, and having a positive family history of homocystinuria thenhomocystinuria
disorder should be considered.
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Acknowledgment
We thank Wagnester laboratory in Germany for conducting laboratory tests for neurometabolic
disorders. In addition, we thank the parents of our patients for their cooperation and permission
to publish this study.
Declaration of conflicting interests: None declared.
Funding: The authors received no financial support for the research and publication of this
article.
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Author contribution
Dr. Karimzadeh was responsible for the study design, collection, and interpretation of clinical
data and oversaw all stages of revision and editing.
Dr. Jafari contributed in the collection of data and wrote the first draft of this manuscript. Other
coauthorswereinvolved in the data collection and interpretation. All authors reviewed the draft of
this article and agreed to submit this final version of the manuscript.
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Articles from Iranian Journal of Child Neurology are provided here courtesy of Shahid Beheshti
University of Medical Sciences