homocystinuria presentation

1. HOMOCYSTINURIA
Tee ty

2. Homocystinuri
a
A recently discovered cause of mental defect and cerebrovascular thrombosi
s
Henry G. Dunn, Thomas L. Perry, Clarisse L. Dolma
n
Neurology Apr 1966, 16 (4) 407; DOI: 10.1212/WNL.16.4.407

3. HOMOCYSTINURIA
An IEM assoc with mental retardation
Urine gives a positive cyanide nitroprusside reaction for cystine
Urine excretes large amount of homocysteine and moderate methinine
Clinical features:skeletal deformities, mental retardation, dislocation of
lens, fine fair hair,malar flush,livedo reticular,shuffling gait

4. Homocystinuri
a
Response to pyridoxin
e
Ellen S. Kang, Randolph K. Byers, Park S. Geral
d
Neurology May 1970, 20 (5) 503; DOI: 10.1212/WNL.20.5.503

7. CASE REPORT
9-year-old girl presented with right-hand dystonia and gait dif
fi
culty.
At 4 yrs old,she experienced blurred vision and was operated for lens dislocation 3 years later.
At 8 yr old,she had a history of severe low back pain and experienced right femur fracture.
There was a family history of undiagnosed progressive motor disability in her older brother, which
fi
nally resulted in seizure and death.
Her parents had consanguineous marriage.
On physical examination, she had fair and wooly hair and mild
fi
xed oromandibular dystonia presenting as
fi
xed smiling.
On chest examination, pectus carinatum was evident.
There was no eye deviation in primary position. All types of horizontal and vertical eye movements were preserved.
At rest, she had dystonic posture in her limbs on both sides, with more severity on the right side.
Attempted movements of the right hand worsened the abnormal postures. There was mild motor de
fi
cit on rt side

8. CASE REPORT
Deep tendon re
fl
exes were prominent on right side as well. She was unable to stand unsupported. While aiding in walking her dystonic
gait was revealed.
Her blood cell count, liver function test, thyroid function test, calcium, serum ceruloplasmin, 24-hour urine copper, and serum B12 were
within the normal range. Serum homocyteine was measured as 200 nmol/mL.
Carotid Doppler sonography demonstrated left carotid narrowing without evidence of thrombosis. Carotid intima–media thickness (IMT)
was within normal range on both sides.

9. RADIOLOGICAL
Her brain magnetic resonance imaging (MRI) revealed deep
watershed infarct in left centrum semiovale
.
Basal ganglia were normal.

10. RADIOLOGICAL
Previous MRI of lumbosacral vertebrae was suggestive of severe
degenerative changes

11. TREATMENT
The patient was treated with high dose of oral pyridoxine (360 mg daily) and put on methionine-restricted diet.
She was followed up monthly for clinical evaluation and response to treatment.
She attained the ability of standing and walking without help.
She showed a remarkable recovery from her limb dystonia, although nothing was completely normal
.
After 3 months and 9 months of treatment, serum Hcy decreased to 40 nmol/mL and 26.5 nmol/mL,
respectively.
The second carotid Doppler did not show any change.

12. DICUSSION
Homocystinuria is the second most common treatable aminoacidopathy after phenylketunuria.
Homocysteine, an intermediate metabolite of methionine catabolism, can be removed in 2 ways.
Cystathionine b-synthase (CBS) is an enzyme that catalyzes Hcy irreversibly by the means of B6 as the
cofactor. This is called transsulfuration
.
In the second way, methionine is rebuilt through remethylation, by means of either methylenetetrahydrofolate
reductase or methionine synthase. In the
fi
rst pathway, Hcy is converted into methionine in the presence of
coenzyme, methylcobalamine. Folic acid is the substrate in this reaction.

13. DICUSSION
Mutation in the encoding gene of each of these enzymes can result in homocystinuria
.
The most common genetic disorder is CBS de
fi
ciency (homocystinuria type I)
.
The reported world- wide incidence of this rare autosomal recessive disorder is between 1 in 50 000
and 1 in 200 000
The clinical manifestation of CBS de
fi
ciency is diversely heterogenou
s
4 organs are dominantly affected, namely ‘‘central nervous system, eye, skeletal, and vascular system.’
’
These patients are often normal at birth.
Homocysinuria, due to CBS de
fi
ciency, usually manifests itself as ocular lens subluxation, which results
in severe myopia and iridiodonesis.
In a large number of patients, ectopic lentis occurs by the age of 8 years

14. CLINICAL FEATURES
Skeletal abnormalities -a common manifestation as in Marfan syndrome.
Eg: fair wooly hairs, blue eyes, livedo reti- cularis, limitation of joint mobility, scoliosis, high-arched palate,
pes cavus, pectus excavatum or pectus carinatum, and genu valgum and osteoporosis, especially of vertebrae
and long bones.
Central nervous system involvement includes progressive mental retardation, seizure, dystonia, behavioral and
personality disorder, and stroke due to thromboembolic syndromes.
Premature vascular events are the major causes of early death and morbidity
.
Vascular injury is proposed to be due to ‘‘endothelial dysfunction, smooth muscle proliferation, extracellular
matrix modi
fi
cation, lipoprotein oxidation, and increased thrombin production.’
’
Endothelial dysfunction is the result of nitric oxide release impairment, thereby disturbing vasodilation and
facilitating platelet aggregation.
Earlier studies=hyperhomocysteinemia provokes intima hypertrophy and resultant increased intima media
thickness

15. TREATMENT
Early diagnosis and treatment might prevent ectopic lentis and other serious complication including thrombotic
events
.
Since in half of the patients with homocystinuria 1% to 5% of CBS activity is normal, high dose of pyridoxine
(B6) with a dosage of 200 mg/d, can ameliorate clinical and laboratory signs signi
fi
cantly
.
Even in cases with certain CBS gene mutation and nonresponsive to B6, high dose of B6 administration (500-1000
mg daily) is recommended
.
In addition to methionine restriction, betaine is the second treatment that lowers plasma Hcy through Hcy
remethylation
.
Finally, folate and cobalamine are other adjunctive treatments that help reducing serum Hcy concentration
.
Normal range of plasma Hcy concentration between 5 and 15 nmol/mL,(recommended <11nmol/mL)

16. Atypical BECTS and homocystinuria
S. Buoni, R. M. di Bartolo, M. Molinelli, et al. Neurology 2003;61;1129-1131
DOI 10.1212/01.WNL.0000090460.77321.B0

17. INTRODUCTION
Benign childhood epilepsy with centrotemporal spikes (BECTS) consists of a peculiar EEG pattern with migratory spikes originating over the rolandic
(centrotemporal or midtemporal) regions.
The annual incidence is 21/ 100,000 in children < 15 years.
Typical BECTS patients are characterized by absence of neurologic or intellectual de
fi
cits, motor partial seizures with or without generalization
recurring mostly during sleep, and a peculiar EEG pattern with centrotemporal spikes.
In general, BECTS is associated with excellent prognosis, seizures being dif
fi
cult to control in only a small number of cases.
Atypical BECTS symptoms are seen in 50% of patients
.
The atypical clinical manifestations include hemifacial seizures, dysarthria or anarthria, and persistent drooling
.
Fortuitous associations have been found between BECTS and nonprogressive brain lesions (e.g., unilateral opercular neuronal migration disorders)and
brain tumors

18. CASE 1
Patient 1 is an 11-year-old girl, apparently healthy
.
She was referred to our clinic when she was 6, with a history of seizures since she was 3.5 years old
.
The seizures were characterized by clonic jerks of the right arm accompanied by twitching of the right corner of the
mouth, on one instance with loss of consciousness.
Treatment with valproate (up to 40 mg/kg/day) was started, and the seizures were apparently controlled for 3 months.
Later, she experienced brief partial seizures with speech arrest, clonus of the right arm, sometimes loss of consciousness,
and transient right arm paresis (Todd’s paresis).
Valproate was substituted by carbamazepine up to 30 mg/kg/day without producing any improvement.

19. CASE 1
At 6 years of age, her clinical and neurologic examinations and brain MRI were normal
.
Her IQ was 78 (Wechsler Intelligence Scale for Children–Revised), and waking EEG showed a symmetric, well-organized, and normal reactive back- ground
activity. Migratory negative diphasic spikes and spike and slow wave patterns at high voltage (100 to 150
􏰁
V) were present in her centrotemporal regions,
increasing during drowsiness and sleep. This EEG pattern is suggestive of BECTS.
Homocystinuria was diagnosed 18 months later, when she came again to our observation because of a cerebral venous thrombosis and we commenced screening
for risk factors associated with venous thromboembolism. The biochemical
fi
ndings are suggestive of homocystinuria (MIM *236200).8 She proved
homozygous for a C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR) and heterozygous for the A114V polymorphism in the
cystathionine
􏰂
-synthase gene
.
Serum levels of homocysteine and methionine normalized after a trial of treatment with pyridoxine at 300 mg/day for a week. Continued treatment with
pyridoxine (300 mg/day) and folic acid (7 mg/day) was therefore added to that with carbamazepine (25 mg/kg/day). Since then, the girl was wel
l

21. CASE 2
Patient 2 is an apparently healthy 23-year-old man. He had a single simple febrile seizure when he was 3 years old.
When he was 9, he was referred to our clinic because of two afebrile seizures, characterized by motor and speech arrest, star- ing, and generalized
hypertonia. His clinical and neurologic exam- inations were normal.
Brain MRI scans showed glial tissue areas in the white matter of both the cerebral hemispheres.
His IQ was 57 (Wechsler Intelligence Scale for Children–Revised).
Several waking EEG showed a pattern suggestive of BECTS , very similar to that described for Patient 1 The biochemical
fi
ndings were suggestive for
homocystinuria (MIM *236200).8 There were no C677T polymorphisms in the MTHFR gene.
Analysis for mutations in the cystathionine
􏰂
-synthase gene was not available. His serum abnormalities were not modi
fi
ed by treatment with pyridoxine
(300 mg/day for a week), so this was stopped.
We started a low-methionine diet, and he did not develop any further seizures.

22. CASE 3
Patient 3 is an apparently healthy 16-year-old boy.
Seizures had presented since he was 4 years old with deviation of his eyes and head to the left,
vomiting, and sometimes loss of consciousness and generalized hypertonia.
The seizures occurred one to six times per year. They were unresponsive to treatment with valproate
(up to 40 mg/kg/day) and phenobarbital (up to 4 mg/kg/day)
.
Clinical and neurologic examinations and brain MRI scans were normal. His learning skill was poor.
Several waking EEG showed a pat-tern suggestive of BECTS . The biochemical
fi
ndings were
suggestive for homocystinuria (MIM *236200)
.
Analyses for C677T polymorphisms in the MTHFR gene and for the cystathionine
􏰂
-synthase gene
were not available. Treatment with pyridoxine (900 mg/day) and folic acid (7 mg/day) was added to
phenobarbital (1.5 mg/kg/day).
Since then, he has not developed any further seizures. The drugs were slowly withdrawn after 1 year.

24. DISCUSSION
Homocystinuria, as de
fi
ned in Online Mendelian Inheritance in Man (MIM *236200), is a metabolic disorder caused by a
cystathionine -synthase gene de
fi
ciency, with increased serum concentrations of homocysteine and methionine.
The worldwide frequency is 1 in 344,000.
CNS impairment is present with mental delay, psychiatric disturbances, and evidence of other CNS problems (seizures, abnormal
unspeci
fi
ed EEG, extrapyramidal signs, and cerebrovascular accidents).
Seizures are reported in 21% of patients, most often as a grand mal type.To the best of our knowledge, no speci
fi
c EEG pattern has
ever been described. The only report on an association between homocystinuria and EEG pattern was by Del Giudice et al.Ten of their
19 patients showed abnormalities in their EEG, the most frequent being a nonspeci
fi
c slowing of background activity.

25. DISCUSSION
In all our patients, the EEG were suggestive of BECTS, although the clinical features were not.
The patients experienced partial complex seizures, which are uncommon in BECTS, although they
can be present in a small proportion (4.3%) of cases
.
Other features atypical of BECTS were the intelligence impairment and the resistance to drug
treatments in two of the patients
.
Resistance to drug treatment was not detected in Patient 2, as his homocystinuria was diagnosed
very soon after the seizures started.
The absence of typical BECTS somatic appearances (i.e., the absence of short body, long arms and
legs, and lens ectopia), yet the EEG pattern suggestive of BECTS, led to a delay in the diagnosis of
homocystinuria for several years, until metabolic evaluations could be performed.
Screening for homocystinuria needs to be considered in the presence of the nonspeci
fi
c nature of
BECTS EEG traits if these are observed together with borderline mental normality.

26. THANK YOU