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100 CASE REPORT 100

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Homocystinuria: Challenges in 0

diagnosis and management


Jennifer Garland MD1, Asuri Prasad MD FRCPC3, Cathy Vardy MD FRCPC2, Chitra Prasad MD FRCPC FCCMG4
1
Departments of Pediatrics and 2Child Development, Janeway Child Health Centre, St John’s, Newfoundland;
3
Section of Pediatric Neurosciences and 4Section of Genetics and Metabolism, Department of Pediatrics,
Children’s Hospital, Winnipeg, Manitoba

J Garland, A Prasad, C Vardy, C Prasad. Homocystinuria: Chal- Des défis en matière de diagnostic et
lenges in diagnosis and management. Paediatr Child Health de traitement
1999;4(8):557-562.
Deux patients atteints d’homocystinurie sont présentés. Tous deux af-
Two patients with homocystinuria are discussed. Both patients presented
fichaient des anomalies de comportement et un déficit de l’attention,
with behavioural abnormalities and deficits in attention – symptoms that
des symptômes souvent observés dans le cabinet des pédiatres. Dans
are frequently encountered in paediatric office practice. In both cases, the
les deux cas, le diagnostic d’homocystinurie n’a pas été posé à la pre-
diagnosis of homocystinuria was not made at initial presentation. Subtle
mière visite. Des traits phénotypiques subtils mais établis ont fini par
but definite phenotypic features eventually provided the first indication of
fournir la première indication d’homocystinurie entre l’âge de cinq et
homocystinuria between the ages of five to seven years. Laboratory
sept ans. Des examens de laboratoire ont confirmé la présence d’ho-
screening confirmed homocystine in the urine, and elevated methionine
mocystine dans l’urine, ainsi qu’une élévation du taux de méthionine
and homocysteine plasma levels in both patients. Patients with inborn er-
et d’homocystine plasmatique chez les deux patients. Les patients atte-
rors of metabolism such as homocystinuria are treated first by family phy-
ints d’une erreur innée du métabolisme comme l’homocystinurie sont
sicians and paediatricians. Without a high index of suspicion, physicians
d’abord traités par des médecins de famille ou des pédiatres. Sans un
can easily overlook a diagnosis of homocystinuria. The management of
indice de suspicion élevé, il est facile pour les médecins d’omettre la
patients with homocystinuria continues to pose a challenge to physicians
possibilité d’homocystinurie. Le traitement des patients atteints d’ho-
and care givers.
mocystinurie continue de représenter un défi pour les médecins et les
soignants.
Key Words: Attention deficit hyperactivity disorder; Cystathionine beta-
synthase deficiency; Developmental delay; Homocystinuria; Lens disloca-
tion

H ypermethioninemia and homocystinuria (hyperho-


mocyst[e]inemia) are terms used to describe bio-
chemical abnormalities arising as a consequence of
be considered in the differential diagnosis of children
presenting with the common symptoms of developmental
delay, and attention deficit and hyperactivity disorder
metabolic perturbation in the trans-sulfuration pathway (ADHD) (3).
(1) (Figure 1). These biochemical disturbances have both
genetic and nongenetic causes (Table 1). The present pa- CASE PRESENTATIONS
per describes two patients in whom the diagnosis of ho- Case 1
mocystinuria was made after the early childhood years. A six-year-old girl was referred to the Child Develop-
100 100
The patients’ clinical features were nonspecific, but bio- ment Clinic at the Janeway Child Health Centre,
95 chemical findings confirmed the diagnosis. Clinical vari- St John’s, Newfoundland for evaluation of impulsivity, 95
ability in the phenotypic features of homocystinuria is hyperactivity and poor school performance of one-year
75 well recognized (2,3); as a result, the condition may be duration. She was born at 39 weeks’ gestation with a birth 75

overlooked. Metabolic disorders, although rare, should weight of 4.2 kg to a Gravida II, Para I mother following an

25 25

5
Correspondence and reprints: Dr Chitra Prasad, Section of Genetics and Metabolism, Department of Pediatrics and Child Health, Children’s Hospital, 5
FE 229-820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9. Telephone 204-787-1317, fax 204-787-1419, e-mail cprasad@hsc.mb.ca
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Figure 1) The metabolism of methionine, homocysteine and cystathionine. The principal pathway for the metabolism of dietary methionine is through
conversion of homocysteine to cysteine. Folate and vitamin B6 (pyridoxine) are important cofactors in the metabolism of homocysteine, while introduc-
tion of betaine leads to remethylation of homocysteine to methionine and degradation of pathways other than trans-sulfuration

She had an inguinal hernia that was repaired at two years


of age. She was given shoe inserts for gait difficulties at
three years of age. Upon entering kindergarten, she was
noted to have a speech delay. She was prescribed correc-
tive eye lenses for myopia at school entry, but did not un-
dergo a detailed ophthalmologic evaluation at the time. Her
classroom behaviour, characterized by hyperactivity and at-
tention difficulties, prompted an evaluation by the school
psychologist, and a referral for further clinical evaluation.
There was no history of seizures, loss of consciousness or
developmental regression. Both maternal and paternal
families are of Aboriginal and Irish descent. Her parents
are third cousins (Figure 2).
Physical examination revealed a girl who was 130 cm
tall (98th percentile), weighed 26 kg (between 90th to
95th percentile) and had a head circumference of 51.5 cm
(50th percentile). Facial features showed subtle dysmor-
phism and mild frontal bossing. A livedo reticularis pat-
100 tern was present on her skin. Her scalp hair was thin, 100
Figure 2) Pedigree showing autosomal recessive inheritance of homo- brittle and lustreless. She had a high myopic refractive er-
cystinuria and inter-relationship between the two affected cases
95 ror (Figure 3). A high arched palate, mild pectus excava- 95

tum, long and slender fingers, joint hypermobility and flat


75 75
uncomplicated pregnancy, labour and delivery. The feet were also noted. Neurological examination revealed
mother was maintained on thyroxine supplements for a normal cranial nerves II to XII; motor and sensory exami-
previous history of hypothyroidism during pregnancy. The nations were normal. The patient’s hearing was normal.
25 infant received phototherapy for neonatal hyperbilirubine- There was no scoliosis on musculoskeletal examination. A 25

mia. Her developmental milestones were normal in the formal ophthalmologic examination showed bilateral lens
5 5
first year, but subsequently she was noted to be clumsy. subluxation. The combination of ocular findings and phe-
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Homocystinuria: Diagnosis and management

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95 TABLE 1: Differential diagnoses of homocyst(e)inemia 95

75 Genetic disorders Biochemical findings 75

Impaired activity of cystathionine beta-synthase enzyme • Increased plasma methionine, homocysteine


(homocystinuria) • Decreased cysteine, no cystathionine
5,10-Methylenetetrahydrofolate (MTHFR) deficiency and • Increased plasma homocysteine
25 25
thermolabile variant of MTHFR • Decreased or normal methionine
• Decreased folate, normal vitamin B12
5 5
Defects in vitamin B12 metabolism • Increased plasma homocysteine and methylmalonic acid in urine
Cobalamin defects (C,D,E,F and G) • Decreased or normal methionine, normal cysteine
0 0
Transcobalamin deficiency
Immerslund syndrome
Nongenetic disorders
Nutritional B12 deficiency • Increased homocysteine, methylmalonic acid
Renal insufficiency • Increased homocysteine
Pregnancy
Nutritional folic acid deficiency
Drug related
Isonicotinic acid hydrazide therapy

notypic features suggested homocystinuria as the under-


lying metabolic cause for her developmental delay. The
diagnosis was confirmed by a quantitative analysis of
plasma amino acids, which showed elevated methionine
of 586 mmol/L (normal 7 to 47 mmol/L), homocysteine of
295 mmol/L (normal 0 to 17 mmol/L), and a low cysteine
value of 2 mmol/L (normal 5 to 45 mmol/L), while red
blood cell folate and serum vitamin B12 levels were nor-
mal. Urinary homocystine levels were elevated at
586 mmol/mmol creatinine (normal 0 to 9 mmol/mmol cre-
atinine). Methylmalonic acid was not detected during urine
organic acid analysis. A skeletal survey showed mild gen-
eralized osteoporosis. A cranial computed tomography
scan and electroencephalogram were normal.
The diagnosis of classic homocystinuria was conclu-
sively established with the confirmation of cystathionine
beta-synthase deficiency in cultured fibroblasts. The pa-
tient began pyridoxine 500 mg once a day, folic acid 5 mg
once a day and a low methionine diet. Dietary compli-
ance to date has been poor. The patient showed no bio-
chemical response to pyridoxine administration. With
the introduction of betaine at 3 g twice a day, plasma ho-
mocysteine values decreased marginally. She has also
been started on methylphenidate (Ritalin, Novartis Phar-
maceuticals Canada Inc, Dorval, Quebec) therapy. Her
attention span has shown some improvement since ther-
apy was initiated.
100 100
The mother of this patient subsequently delivered a
male infant who was found to have elevated methionine
95 95
levels during newborn screening. The parents had de-
Figure 3) Frontal views of patient in case presentation 1 showing relative
75 clined prenatal diagnosis. The diagnosis of homocystin- nonspecific facial features and the high myopic refractive error 75

uria in the male child due to cystathionine beta-synthase


deficiency was confirmed by enzymatic assay on fibro-
blasts. He is currently 11 months old and is receiving Case 2
25 A 30-year-old woman with homocystinuria from the 25
pyridoxine, folic acid and a low methionine diet. So far
same geographical region as the previous female patient
5 he has shown good clinical and biochemical response. 5
has been followed intermittently by the provincial genet-
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95 TABLE 2: Clinical features of homocystinuria TABLE 3: Suggested metabolic investigations for a patient 95

with developmental delay and attention deficit


75 Major features Minor features Other features hyperactivity disorder 75

Lens dislocation Long and slender Fair skin


fingers Investigations Disorders

25
Myopia Glaucoma Malar flush Plasma and urine Aminoacidopathies 25
Thin, long bones: Seizures Livedo reticularis aminoacids Phenylketonuria
5 dolichostenomelia Homocystinuria 5
Osteoporosis Psychiatric Brittle, thin hair Branched chain
0 disturbances aminoacidopathies 0
Urea cycle defects
Mental retardation Genu valgum Inguinal hernia
Serum uric acid levels Lesch-Nyhan syndrome
Arterial and venous Scoliosis High arched palate
thromboembolism Plasma ammonia levels Urea cycle defects
Organic acidemias
Plasma lactate levels Mitochondrial cytopathies
Urinary mucopolysaccharides Lysosomal storage disorders
and oligosaccharides
ics program. The diagnosis of homocystinuria was made Skeletal survey Dysostosis multiplex in
mucopolysaccharidoses
at seven years of age. The patient is a third cousin to the
Ophthalmic slit-lamp Lens dislocation in homocystinuria
first case, and one of her first cousins has two children
examination Corneal clouding in
with homocystinuria (Figure 2). She was born at term
mucopolysaccharidoses
with a weight of 4 kg following a normal pregnancy and la-
bour. At three weeks of age, she developed seizures that
remitted spontaneously. Developmental milestones were
delayed. The patient sat without support at one year of age,
and walked independently at two years of age. She re- nitive abilities, she was performing at a five to six year
quired orthopedic intervention for her flat feet and varus level. An analysis of the patient’s most recent quantitative
deformity of her hips. At seven years of age, she under- plasma amino acids revealed normal cysteine value of
went investigations for developmental delay and attention 26 mmol/L (normal five to 45 mmol/L), elevated methio-
problems. Plasma amino acid analysis demonstrated ele- nine levels of 555 mmol/L (normal 7 to 47 mmol/L) and ho-
vated methionine and homocysteine levels, and a skeletal mocysteine levels of 231 mmol/L (normal 0 to 17 mmol/L).
survey revealed osteoporosis. Ophthalmologic evaluation Serum vitamin B12 and red cell folate levels were normal.
revealed dislocated lenses bilaterally. The diagnosis of ho- The patient remains severely affected by homocys-
mocystinuria was, thus, established. Pyridoxine and folate tinuria, and requires constant supervision to perform
therapies were initiated. Compliance to treatment was activities of daily living and infant care tasks. As with
not strict, and she was lost to follow-up. the previous case, compliance with diet and medica-
The patient completed a grade one education. At tions is poor.
21 years of age, she was re-evaluated for mental retarda-
tion, psychiatric problems with multiple suicide attempts, DISCUSSION
aggressive behaviour and problems with the law. She re- Homocystinuria due to cystathionine beta-synthase de-
quired management with antipsychotic medication. Other ficiency is an inborn error of metabolism with phenotypic
medical issues included headaches, asthma, chest pain features that for the most part are readily identified (2,3).
and deep vein thrombosis in her legs. For the most part, The principal clinical features of homocystinuria are sum-
the patient remained in a group home, and treatment marized in Table 2. Because of numerous complications,
compliance was a major problem. At 29 years of age, she such as increased tendency to strokes, ocular symptoms
delivered a normal male infant after an unremarkable and neuropsychiatric abnormalities, regular medical fol-
pregnancy. At 30 years of age, she was re-evaluated to op- low-up is imperative. Recently, there has been renewed in-
timize metabolic control. On examination, she appeared terest in the relationship between elevated homocysteine
obese, her weight was 90 kg (above the 95th percentile) levels and the occurrence of vascular complications (4,5).
100 100
and her height was 175 cm (above the 95th percentile). The inheritance pattern of homocystinuria is autoso-
95 She did not have a Marfanoid habitus. She was strongly mal recessive, and the reported incidence varies from 95

myopic. Facial dysmorphism was not present. The patient 1/67,000 to 1/200,000, with a higher risk in individuals
75
had long and slender fingers without hypermobile joints. A who are of Irish descent or from New South Wales, Aus- 75

scar from the surgical removal of a clot was present on tralia (1,6). The gene for cystathionine beta-synthase is lo-
her left ankle. A formal psychological assessment was not cated on the long arm of chromosome 21 band 22.3.
25 done. Neurological evaluation was significant for poor Sixty-four mutations affecting this gene have been de- 25

comprehension, limited reading and writing skills, and a scribed (7); the most frequent are 1278T (24%) and
5
marked inability to perform fine motor skills. In her cog- G3075 (31%). The importance of molecular analysis lies 5

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Homocystinuria: Diagnosis and management

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95
in establishing a genotype-phenotype correlation that is with a better prognosis (16), thus providing evidence for 95
helpful in predicting a patient’s response to pyridoxine, including the detection of homocystinuria in the newborn
75 which in turn may have implications for long term out- screening programs (2). More studies to examine the inci- 75

come. Vitamin B6 responsive patients are likely to have a dence of this disorder and to confirm the effectiveness of
lower incidence of complications, while mental retarda- early intervention are necessary.
25
tion occurs more often in patients who are nonrespon- Dietary methionine restriction and vitamin supple- 25
sive to vitamin B6. Aggressive behaviour and conduct ments have been ineffective in both patients described.
5 disorders are also seen more commonly in this sub- There are, in addition, a number of social and behav- 5

group (8). ioural issues such as disruptive and aggressive behav-


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A condensed version of the principal pathways in- iours; these were encountered in our second patient and
volved in homocysteine metabolism, and the role of folic required multiple psychiatric interventions. Psychiatric
acid and pyridoxine (important cofactors) are depicted in manifestations are well recognized in patients with homo-
Figure 1. Longhi et al (9) reported that half of the patients cystinuria, and include: episodic depression, chronic be-
studied were responsive to pyridoxine, which improves haviour disorder, obsessive compulsive disorders and
the residual enzyme activity. Folic acid is helpful as an ad- personality disorders (8).
junct therapy in patients who are responsive to pyridox- There are very few reports of pregnancies in females
ine (10). Betaine, which uses an alternative pathway of re- with homocystinuria. Pregnancy in an affected female car-
methylation of homocysteine to methionine, has been ries an increased risk of miscarriage, as well as a definite
used in patients who are unresponsive to pyridoxine risk of a thromboembolic event (17). In spite of her poor
(11,12). Evidence demonstrates that the appropriate treat- metabolic control and no anticoagulation treatment, the
ment of homocystinuria markedly reduces the risk of vas- second patient had an almost uneventful pregnancy with
cular complications, even if biochemical control is subop- a normal outcome.
timal (13).
The two female patients described above were referred CONCLUSIONS
for an evaluation of their attention problems and develop- The consideration of metabolic etiologies in the inves-
mental disabilities, and not for an evaluation of the classi- tigation of ADHD and developmental delay in the pre-
cal features of homocystinuria described in the literature. school and childhood periods is essential for the early
ADHD is a relatively common disorder, occurring in 5% identification of patients with homocystinuria. Because
to 6% of school age children (14). Boys are more com- routine newborn screening is not available for many meta-
monly affected than girls. ADHD is diagnosed on the basis bolic disorders including homocystinuria, basic guidelines
of criteria outlined in the Diagnostic and Statistical for metabolic testing are outlined in Table 3. The authors
Manual of Mental Disorders, Fourth Edition (DSM-IV) recommend careful clinical evaluation in order to direct
(15). Attention and behavioural issues in the first patient the investigations appropriately, which may include other
masked the subtle physical features of homocystinuria. genetic investigations such as a karyotype and/or molecu-
In the second patient, the diagnosis of homocystinuria lar studies to rule out fragile X syndrome. Apart from the
was similarly established during investigation of devel- management of the individual patient and the complica-
opmental delay at seven years of age. Despite a positive tions that can arise during his or her lifespan, parents of a
history of homocystinuria in the second patient’s cous- child with homocystinuria should be made aware of the
ins, a diagnosis of homocystinuria was not considered 25% recurrence risk in a subsequent pregnancy, and the
until she was seven years of age. In both instances, the likelihood that other individuals in the extended family
abnormal amino acid profile obtained on screening are potential carriers.
pointed to the diagnosis of homocystinuria. In both pa-
tients, the ophthalmic findings, skeletal changes and bio- ACKNOWLEDGEMENTS: The authors thank Ann Duff and
chemical abnormalities were similar. The clinical course David Macgregor of the Newfoundland and Labrador Medical Ge-
of both patients illustrates the difficulties inherent in ini- netics Program for their help with data collection, Dr E Randell,
tiating treatment at a late stage and the challenges in of the Janeway Child Health Centre, St John’s, Newfoundland for
his help with the biochemical analyses on the patients; Dr Cheryl
management. The first case presented with ADHD, while R Greenberg and Louise Dilling, Section of Genetics and Metabo-
the second, the presentation was significant for develop- lism, Department of Pediatrics, Children’s Hospital, Winnipeg,
100 100
mental delay and attention problems during childhood Manitoba for their comments and suggestions. We are grateful to
95 and psychiatric manifestations in later life. Both pa- our patients and their families for their cooperation. 95

tients are unresponsive to pyridoxine, and are severely


75 affected. REFERENCES
75

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