These are references cited in the front page story from the Winter 1997 newsletter. All relate to the deleterious effects of high phenylalanine levels.
Abstracts presented for each paper are directly from the paper,
with occasional minor editorial changes. The other details cited,
are interesting notes also selected from the paper, with minor
editorial changes. No attempts have been made to provide definitions
of medical/scientific terms, which are numerous. Even for those
without knowledge of these specific terms, the overall message
of each paper cited should be understandable. Consult a medical
dictionary and/or PKU treatment program if you want further explanation
of the terms used. All of the papers are available in medical
Battistini, S, De Stefano, N., Parlanti, S, and Federico, A,
Unexpected white matter changes in an early treated PKU case and
improvement after dietary treatment, Functional Neurol. 6(2):
We report a case of classic phenylketonuria treated by dietary
restriction until the age of five years. At the age of 18 years,
she developed anxious-depressive symptoms and deterioration of
school performance. Neurophysiological investigations showed changes
in VEPs (Visual Evoked Potentials) and BAEPs (Brainstem Auditory
Evoked Potentials) and brain MRI (Magnetic Resonance Imaging)
showed white matter abnormalities. The return to a diet low in
phenylalanine reduced psychiatric disturbances and reversed neurophysiological
and MRI changes. Our data confirm previous observations of white
matter involvement in PKU and the utility of lifelong dietary
therapy to prevent neurological and/or psychiatric deterioration.
Psychomotor development and school performance was normal at age
five. The only problems reported until the age of 18 years were
several episodes of allergy. The patient in her late teens then
became subject to anxiety and depression. She also became anorectic
and lost 6 kg in 18 days. She was examined for anxious depressive
symptoms. Neurological examination showed generalized hypotonia
and weak abdominal reflexes. Depression, anxiety and hysterical
behavior were also present. Her I.Q. was 103 (normal). He phe
level was 15 mg/dl. A low protein diet was started. Follow-up
after 4 months on diet (phe level 3.4 mg/dl) showed marked improvement
in psychological symptoms, and improvement in BAEPs. Two years
later, phe levels, BAEPs, VEPs and MRIs were completely normal.
Bick, U, et.al., White matter abnormalities in patients with
treated hyperphenylalaninemia: magnetic resonance relaxometry
and proton spectroscopy findings, Eur. J. Ped. 152: 1012-1020,
In order to further clarify the pathogenesis and clinical significance
of MRI (Magnetic Resonance Imaging) white matter abnormalities in treated
hyperphenylalaninemia (HPA), ten patients (seven type I HPA, two type 11 and
one type 111) underwent T2 relaxometry (n = 8) and/or 1H spectroscopy
(n = 7) in addition to conventional MR spin-echo imaging
at 1.5 T. Two patients with severe MRI abnormalities had repeat
examinations during and after a 6- to 8-month period of strict
diet control. The clinical evaluation included a detailed neurological
examination. In nine out of ten patients visual evoked potentials
(VEP) were obtained parallel to the MR examination. MR imaging
demonstrated typical symmetrical areas of prolonged T2 relaxation
time predominantly in the posterior periventricular white matter
in all but one of type I and 11 patients. There was no consistent
relationship between MRI findings and time of diagnosis/initiation
of therapy, IQ or visual evoked potential changes. MRI abnormalities
tended to be more severe in patients with poor dietary control
and high current plasma phenylalanine levels, whereas a normal
MRI was found only in patients with plasma phenylalanine levels
continuously below 0.36 mol/l (that is, below 6 mg/dl
or 360 mol/dl). There was marked regression of MRI
abnormalities already after 3 months of strict diet control. T2
relaxometry showed a bi-exponential behavior of T2 in the
affected white matter, with a slow component of about 200-450
ms, indicating an increase in free (extracellular) water. 1H spectroscopy
revealed no signs of severe neuronal damage. We conclude, that
the observed white matter changes in treated HPA probably represent
reversible structural myelin changes rather than permanent demyelination.
The alterations in MRI were confined to the cerebral white matter
and were more pronounced in the parieto-occipital and peritrigonal
region. In severely affected patients, the lesions extended to
the frontal and subcortical white matter. The MRI findings observed
are rather characteristic of PKU. Some of the abnormalities may
be observed in any type of cerebral edema as well in a variety
of myelin disorder.Similar findings have been described in PKU
by numerous other groups. Although the findings may be demonstrated
in the majority of classical PKU patients, a large degree of inter-individual
variation exists regarding the extent of MRI abnormalities. In
general, changes are less pronounced in patients with good dietary
control at the time of MRI examination. Regression of MRI abnormalities
after reinstitution of strict diet treatment has also been reported
by several other groups. The data in this study as well as the
data from the literature indicate that a significant regression
of MRI white matter abnormalities under diet may only be expected
with plasma phe levels below 0.36 mol/L (6 mg/dl or 360 mol/dl).
Clarke, J.T.R., Gates, RD, Hogan, SE, Barrett, M, and MacDonald,
GW, Neuropsychological studies on adolescents with phenylketonuria
returned to phenylalanine-restricted diets, Amer. J. Mental
Retard. 92 (3): 255-262, 1987.
Nine adolescents with phenylketonuria who had been on unrestricted
diets for 2 to 11 years, underwent serial neuropsychological testing
over two consecutive 4- to 5-week periods, during which each was
maintained on a low-phe diet supplemented in a triple-blind fashion
either with L-phe (high phe) or L-alanine (low phe). Assignment
to the initial condition was done randomly, and the alternate
condition was substituted at the end of the first 4- to 5- week
period. In 6 of 7 subjects with PKU, baseline median choice reaction
times (RTs) were slower than those of controls matched for age,
sex, handedness, and Full-Scale IQ (WISC-R). A highly significant
improvement occurred during the low-phe phases of the study. Results
suggest that adolescents with PKU on unrestricted diets have neuropsychological
deficit that is out of proportion to their overall intellectual
handicap. Moreover, this deficit appears to be at least partly
reversible by return to dietary phe restriction despite years
Cleary, MA, Walter, JH, Wraith, JE, White, F., Tyler, K and
Jenkins, JP, Magnetic resonance imaging in phenylketonuria: reversal
of cerebral white matter change, J. Ped. 127(2): 251-255,
Our objective was to investigate the extent to which the abnormalities
in cerebral white matter in adolescents and adults with phenylketonuria
are reversible. Magnetic resonance imaging (MRI) of the brain
was repeated in 41 patients with PKU (age range 14-49 years) after
an interval (median 9 months: range 3-12 months) of dietary intervention.
Scans were scored according to the extent of the white matter
involvement. After an initial MRI, five patients returned to a
strict low-phenylalanine diet with amino acid supplement; 21 patients
started a low-protein diet (1 gm/kg) with amino acid supplement;
and 15 patients made no dietary alteration. Scans improved in
all five patients who returned to a strict low-phe diet, in 5
of the 21 patients on the low-protein diet plus animo acid supplement,
and in 4 of the 15 patients who made no dietary change. There
was a significant association between change in the MRI findings
and in the blood phe concentration (Pearson correlation: r = 0.55;
p < 0.0001). Improvement was seen primarily in those in whom
phe levels were reduced to less than 900 mol/L (or 15 mg/dl)
There was no obvious change in MRI score after 3 weeks of strict
phe restriction for the two adults who underwent serial scanning.
We conclude that the MRI changes in PKU are at least partially
reversible by lowering the blood phe concentration.
The abnormalities observed in PKU are common in patients older
than 10 years. The severity of white matter involvement is most
closely determined by blood phe levels around the time of scanning,
and the changes are seen in both early-treated and untreated patients
with PKU. In this study, the largest change in MRI was seen in
patients who returned to a strict diet and had lowered phe levels
to less than 400 mol/L (6.6 mg/dl). It appears that the extent
of reduction in phe levels relates not only to the amount of change
in blood phe levels but also to the level attained. For example,
reducing the phe level from 1800 to 1000 mol/L (29.7 to 16.5
mg/dl) may not result in any improvement in MRI appearance. This
finding supports those of Bick et al, whose patients with normal
scans had levels consistently lower than 360 mol/L (6 mg/dl),
and those of Weglage, et al, who reported normal MRI scans for
a group of patients whose average phe levels were less than 600
mol/L (9.9 mg/dl).
Fisch, RO, Chang, PN, Weisberg, S, Guldberg, P, Guttler, F,
Tsai, MY, Phenylketonuric patients decades after diet, J. Inher.
Metab. Dis. 18:347-353, 1995.
Nineteen early-treated phenylketonuric patients, whose diet was
discontinued between 4.5 and 13 years of age, and who have been
off the diet for 1228 years, were reassessed in 1992-93. There
was little change in mean IQ between end of diet and follow-up,
less than one IQ point on the average, with no change for any
individual exceeding 12 IQ 12 IQ points. Both prior and current
IQ correlated slightly negatively with mean phenylalanine (Phe)
concentration, and positively with parents' education. The phenylalanine
level at follow-up was significantly lower on average by about
9OO mol/L. Five of the subjects (26%) have evidence of
mental disease. However, the data suggest that the discontinuation
of the diet did not cause intellectual deterioration. Nonetheless,
the patients' intellect cannot be the only consideration for maintenance
of diet. The occurrence of psychopathology among phenylketonuric
patients and the possible unknown effects of toxic elevation of
phenylalanine during their lifetime suggest the need to maintain
the diet. The use of DNA for diagnostic and prognostic purposes
might assist in decisions about dietary quality and duration,
and in anticipation of psychopathology.
Ishimaru, K.Tamasawa, N, Baba, M, Matsunaga, M, Takeg, K, Phenylketonuria
with adult-onset neurological manifestation, Clinical Neurol.
33(9): 961-965, 1993.
We report a male patient with phenylketonuria who developed multisystem
neurological manifestation in his fourth decade. He was born in
1957 when a neonatal mass screening had not been available. His
neuropsychological development was entirely normal and he was
a good athlete during his high school days. He was in good health
until the age of 32, when his vision was blurred. In four months
his gait progressively deteriorated to bind him to a wheel chair.
On physical examination he had red hair and gray eyes. IQ was
68. Visual field showed concentric narrowing and his visual acuity
was impaired. The limbs were spastic and weakened. He complained
of pain in the extremities. He suffered from pollakisuria. Routine
blood tests and CSF findings were normal. He was also found to
be normal in peripheral nerve conduction. Studies and central
conduction studies of SEP and VEP. EEG showed diffuse slowing
in background activities. T2-weighted MRI of the head revealed
widespread high-intensity areas in the deep white matter especially
in bilateral occipital lobes. Serum aminogram disclosed the remarkable
elevated phe level of 1663 mol/L (27.7 mg/dl) and reduced
tyrosine. Urinary secretion of endogenous tetrahydroxy-biopterin
(BH4--coenzyme of phe hydroxylase) remained in a normal range.
Despite a strict dietary control (oral intake of phe less than
0.5 g/day) the serum phe level remained high (around 500 mol/L
or 8.3 mg/dl) and he still deteriorated neurologically.
Koch, R.A., Azen, C, Friedman, EG, Fishler, K, Baumann-Frischling,
C, Lin, T, Care of the adult with phenylketonuria, Eur.J. Ped.
155[Suppl 1]: 90-92, 1996.
Forty-three adults with classical phenylketonuria were identified
by neonatal screening and treated with a phenylalanine (Phe) restricted
diet. Nineteen have remained on dietary treatment with varying
levels of blood Phe control and 24 have discontinued the diet
at an average age of 7.8 years. Follow up at an average age of
22 years revealed that the cohort remaining on dietary treatment
have achieved substantially better social and academic achievement
than the 24 who discontinued dietary treatment. Another group
19 adults who were not diagnosed until an average age of 2.5 years
have also been evaluated after an average of 22 years on
a Phe restricted diet. This report is based upon Wechsler Adult
Intelligence Revised Test scores, attendance at college, employment
and marital status.
Article summarized in more detail in Winter 1997 issue of National
McCombe, P.A., McLauglin, DB, Chalk, JB, Brown, NN, McGill,
J, Pender, MP, Spasticity and white matter abnormalities in adult
phenylketonuria, J. Neurol. Neurosurg. Psychiatry 55(5):
A 19 year old male with phenylketonuria developed a spastic paraparesis
8 months after stopping his restricted phenylalanine diet. CT
and MRI showed abnormalities of the deep cerebral white matter,
and visual evoked response latencies were prolonged. The spasticity
gradually improved over several months after resuming the PKU
diet. A repeat MRI scan was unchanged. His brother also had PKU
and ceased dietary restrictions, but his only neurological abnormality
at this time was a slight increase in the deep tendon reflexes
of the lower limbs. CT and MRI of his brain were normal. DNA analysis
showed that both brothers were homozygous for the same PKU mutation.
These patients demonstrate that reversibly neurological signs
may develop in patients with classic PKU after ceasing dietary
restrictions and that these may be associated with abnormalities
seen on neuro-imaging.
Thompson, A.J., Tillotson, S, Smith, I, Kendall, B, Moore,
SG, Brenton, DP, Neurological deterioration in young adults with
phenylketonuria, Lancet, pp. 602-605, Sept. 8, 1990.
Seven patients with phenylketonuria who developed neurological
disability in adolescence or early adult life are described. Four
had been diagnosed by routine neonatal screening and started a
low phenylalanine diet in infancy. Three were diagnosed in early
childhood because of developmental delay and then started dietary
treatment. Dietary control deteriorated in later years and was
withdrawn in mid to late childhood. The late neurological deterioration
cannot be directly ascribed to poor compliance with or cessation
of dietary treatment in this small, retrospective studyóbut
other likely causes have been excluded and two patients showed
a striking clinical improvement when a strict diet was resumed.
Serial magnetic resonance images from one of these patients show
abnormalities that appeared after cessation of dietary treatment
and resolved after diet was resumed. If these findings are confirmed,
strict dietary control into adult life would be indicated for
at least some patients with phenylketonuria.
Thomson, A.J., et.al., Brain MRI changes in phenylketonuria,
Brain 116(pt 4): 811-821, 1993.
Following the introduction 30 years ago of neonatal and early
dietary treatment for phenylketonuria there has been a dramatic
decrease in the severity of neurological dysfunction associated
with this disorder. However, there is evidence that subtle neurological
impairment remains common in early-treated subjects and in the
last 3 years there have been a number of reports of overt neurological
impairment with white matter abnormalities on MRI. The frequency
of white matter changes in phenylketonuria, and the relation of
these changes to dietary management, have remained unclear. The
present study examines MRI findings in 34 subjects aged 8-33 years.
Twenty-five subjects had been detected by routine neonatal screening
and nine had been missed in the screening program. At the time
of the investigation 16 of the early treated and two of the late-treated
subjects were still receiving a diet low in phenylalanine. All
but two of the 34 subjects showed abnormalities n MRI. In the
early diagnosed group it could be shown that the severity of MRI
changes (graded 1-5) was significantly and independently associated
with phenylalanine concentrations at the time of investigation
and the time since dietary treatment had been withdrawn. These
data are consistent with studies in animals showing that hyperphenylalaninemia
increases myelin turnover in a dose-dependent manner. It is suggested
that the effects of phenylalanine on myelin pose a lifelong hazard
to the nervous system.
Villasana, D., Butler, IG, Williams, JC, Roongta, SM, Neurological
deterioration in adult phenylketonuria, J. Inher. Metab. Dis.
12: 451-457, 1989.
A 28 year-old man with classical phenylketonuria had increased seizure frequency and rapidly progressive spasticity. There was a marked reduction of biogenic amine neurotransmitter metabolites in cerebrospinal fluid. Dietary therapy reduced serum phenylalanine levels, improved symptoms of hypertonicity, and cerebrospinal fluid neurotransmitter metabolites became normal. An adolescent male with classical phenylketonuria, treated by dietary restriction until age 6 years, was assessed for decreasing school performance at 18 years. Cerebrospinal fluid biogenic amine neurotransmitter metabolites were significantly reduced. Magnetic resonance imaging in both subjects showed multiple areas of increased signal intensity in cerebral white matter.
Neuropathological changes in classical phenylketonuria have been
characterized as a dysmyelinating or demyelinating process. Neurochemical
studies show a defect in brain lipids and biogenic amine metabolism.
In the past, dietary therapy was directed at reducing hyperphenylalaninemia
only during the first decade of life. This report, as well as
other studies, indicates that dietary therapy should be lifelong
in patients with classical phenylketonuria in order to prevent
progressive and insidious neurological deterioration in later
Subject A: This man had started diet treatment late, at
age 3 years, and had borderline mental retardation. He was maintained
on a restricted diet until age 12 and attended special education
classes in public school until the age of 20. In 1980 he had a
seizure and an EEG was reportedly abnormal but no structural lesions
were seen on CT scan. In 1986, his mother noted difficulty in
his gait with a painless limp affecting the right leg. Symptoms
progressed over the following days with posturing of the right
arm. Within 10 days the patient was unable to walk more than 10
meters without rest. The weakness resolved partially but he was
virtually wheelchair-bound presentation. His mother also noted
increased seizure frequency. On examination, he had mild to moderately
increased tone in all extremities, more marked in the legs, with
minimal weakness in the major muscles. A mild postural tremor
of the right hand became more evident with finger-to-nose testing.
He walked with spasticity and mild unsteadiness, but no truncal
ataxia. All reflexes were at least 3+ with clonus at the ankles
and knees. There were abnormalities in visual evoked responses
and he had a phe level of 27.8 mg/dl (4633 mol/L). He was
placed on a restricted phe diet (20 mg/kg/day). Two months after
starting the diet, there was subjective improvement of his gait
and he could walk 1.6 km. Muscle tone had decreased but spasticity
was still apparent. Serial CSF neurotransmitter metabolite analysis
showed improvement as his phe levels was further lowered.
Subject B: An adolescent male with classical phenylketonuria diagnosed
at neonatal screening was assessed at 18 years of age, having ceased
schooling several years earlier for failing grades. He was treated
with the restricted diet until age 6 and maintained a regular
diet thereafter. He had been assessed previously at a local clinic
for episodic abdominal pain and scoliosis. There was gradual deterioration
in his school performance and behavior over the next several years.
Mental retardation had become apparent and he was educated in
special classes until the eighth grade. On examination he had
a fine tremor of the outstretched hands and an action tremor.
Tandem walking was performed with some difficulty. Deep tendon
reflexes were normal. He had difficulties in concentration and
a dull effect (I.Q. 81). Attempts at reinstitution of diet were
unsuccessful and he was lost to subsequent assessment.
Waisbren, S.E. And Levy, H.L., Agoraphobia in phenylketonuria,
J. Inherit. Metab. Dis. 14(5): 755-764, 1991.
We describe agoraphobia as a complication of phenylketonuria (PKU) in young adults. The five patients have classic PKU and received phenylalanine-restricted diet only in childhood. Only one has normal intelligence. All but one were also depressed. All were anxious. Three of the five had initiated the phenylalanine-restricted diet after 3 months of age. Two returned to the phenylalanine-restricted diet with dramatic reduction of symptoms.
The frequency of manifestations of agoraphobia was also examined in 50 young women with PKU enrolled in a longitudinal study of psychosocial factors in maternal PKU, 47 of their acquaintances and 49 women with diabetes. All were administered a test of agoraphobic-avoidant behavior. The women with PKU appeared to be more prone to social withdrawal and fear of leaving home. Twenty per cent were within the agoraphobia range of the Mobility Inventory. Those still on diet and those with non-PKU hyperphenylalaninemia reported less avoidant behavior than those who had terminated the diet in childhood.
These results suggest that young adults with PKU are at risk for
agoraphobia but that return to the phenylalanine-restricted diet
may be an effective treatment.
Waisbren, S.E. And Zaff, J., Personality disorder in young women
with treated phenylketonuria, J. Inher. Metab. Dis. 17:
Twenty-eight young women with phenylketonuria (PKU) attending a Maternal PKU Summer Camp were interviewed and administered a personality inventory, the Minnesota Multiphasic Personality Inventory (MMPI). The 12 young women who were either late-treated (treatment initiated after 90 days) or who had terminated the diet for a period of at least 5 years (the extended exposure group) were compared to the 16 women who were early-treated and had remained continuously on diet (the continuously treated group). Although the mean blood phenylalanine and tyrosine concentrations at the camp for the two groups were comparable (973 + 344 and 1033 + 284 mol/L for phenylalanine and 43 + 16 and 40 + 25, mol/L for tyrosine), the women in the extended exposure group evidenced significantly greater psychopathology as measured by the MMPI and self-report; thought disorder and mood disturbances were associated with diet termination in PKU.