Cranial CT and MRI in malignant phenylketonuria F. G u d i n c h e t 1, P h . M a e d e r I , R . A . M e u l i 1, Th. D e o n n a 2, a n d J. M. M a t h i e u 2
Department of Radiology and 2 Department of Pediatrics, CHUV, Lausanne, Switzerland Received: 18 September 1991; accepted: 30 October 1991
Abstract. Malignant phenylketonuria is a rare disease caused by a deficiency in dihydropteridine-reductase which induce a hyperphenylalaninemia and a deficiency of neurotransmitters such as 3,4,dihydroxyphenylalanine (DOPA) and 5 hydroxytriptophan. The case of a patient with malignant phenylketonuria (PKU) who underwent both CT and M R Imaging is reported. CT demonstrated the characteristic calcifications of the basal ganglia. M R I demonstrated areas of hypersignal on T1 images in the basal ganglia, subcortical frontal and occipital white matter and cortex probably corresponding to calcifications. The M R findings are not specific but could be useful in monitoring the diet and neurotransmitter substitution therapy.
Malignant P K U is a rare cause of elevated serum phenylalanine due to a cofactor deficiency in the phenylalanine hydroxylase system, which affects the synthesis of tyrosin related neurotransmitters such as Dopamine and Norepinephrine. The treatment includes a low phenylalanine diet and nenrotransmitter substitution. The CT pattern of classical and malignant P K U have been reported, but the M R I features of classical and malignant P K U are less well known. Repeated CT a n d M R I w e r e performed in a 5 year old girl under substitution therapy for dihydropteridine deficiency in order to correlate the clinical statuswithmorphologicalmodifications. Case report
This young girl was delivered normally after an uneventful gestation. The father and mother were first grade cousins. A Hyperphenylalaninemiawas diagnosed in the first week of life and a low phenylalaninemia diet was started. The psychomotor development began to stagnate at 4 months of life and a dihydropteridine reductase deficiency was diagnosed 3 months later. Seizures, chor eiform and dystonic movements of the whole body were then noted. A neurotransmitter sub-
stitution was started without improvement of the psychomotor lag. Brain CF was performed at 8 month showing a hypodensity of the frontal and occipital white matter and a widening of the pericerebral spaces. A second CT of the brain performed 2 years later showed almost symmetrical calcifications of the basal ganglia, frontal subcortical regions (Fig. l) and diffuse atrophic processes of the brain. A third cranial CT performed a 4 years of age confirmed a diffuse brain atrophy with ventricular dilatation. A first MRI was done on a 0.35 T. MR unit a 4 y. 5 m.. The frontal and occipital calcifications appeared as isosignal areas on TlWI. The myelinisation of the frontal, parietal and occipital lobes were diminished onT2WI, which showed an associated hyperintense signal of the frontoparietal and occipital white matter. A treatment of Sinemet (Carbidopa 10 mg/kg/d), 5 hydroxytriptophane (10rag/d) and Carbamazepin (20 mg/d) was initiated and followed by some decrease of motor spasticity and seizures. Follow up MRI performed with a 1.5 T MR unit at 5 y. showed a progressive cerebral and cerebellar atrophy, and hyperintensity of the ffontoparietal and occipital white matter on T2WI. The basal ganglia showed two well delineated lesions: a focus of hyperintensity which appeared in the globus pallidus on TlWI and Proton Density Images, corresponding to the hyperdensity seen on CT, and disappeared on T2WI, confirming its calcified nature. In the putamen, a linear area of hypersignal was seen on Proton Density and T2WImages corresponding to a slight hypointensity on T1WI and hypodensity on CT (Fig.2). Hyperintensity of the cortex of the frontoparietal and temporooccipital regions was present on TIWI and remained unenhanced after Gadolinium DTPA I.V. Injection (Fig.3). The child died after multiples episodes of pneumonia due to aspiration. Unfortunately no autopsy was performed. Discussion
Classical and atypical P K U are due to Phenylalanine hydroxylase deficiency resulting in diminished conversion to Tyrosine, leading to neurological impairment and psychomotor retardation. Dihydropteridine reductase deficiency or malignant P K U is a rare entity which makes up to 3 % of all PKU. It is caused
by a genetic defect of dihydropteridine reductase resulting in a decrease of Dihydropteridine (DH4). This substance is essential to the biosynthesis of neurotransmitters such as 3,4,dihydroxyphenylalanin and 5 hydroxytriptophan. Classical P K U may be asymptomatic as long as the neonatal brain is protected by the maternal liver. Early vomitting, mental retardation after 6 months and seizure before ten years of age are frequent symptoms. Growth impairment, stooped posture rigidity and microcephaly are common. The phenotype is characteristic with a fair complexion, blue eyes, pale skin and blond hair. The neurological disorder in D H P R deficient patients is thought to be due to a D H 4 deficiency resulting in low levels of neurotransmitters. Previously, neuroimaging studies have been of little help in patients with P K U and no specific CT pattern has been described. In malignant P K U however, Schmidt and Sugita reported a pattern of symmetrical calcifications in the lentiform nucleus [1, 2], which were present in our patient on CT. The cause of basal ganglia calcifications in these cases remained unctear and a wide range of causes may produce similar images: acute conditions (encephalitis, hypoxia, etc), inborn errors of metabolism among others Leigh's disease, lactic acidemia, Maple syrup urine disease, demyelinating diseases and degenerative diseases (juvenile Huntington's disease and the T O R C H infections). The M R appearance of classical P K U is now well known and non specific images as hyperintense periventricular white matter on T2WI are reported, consistent with the spongiosis and demyelination that is described pathologically. The severity of the lesions on M R could be correlated with dietary control. However, the clinical severity of the disease does not parallel its imaging severity. The M R patterns of malignant P K U have been recently reported in two siblings  and in seven patients of the same tribe . The M R findings con-
224 cortex appeared hyperintense and are unenhanced by Gadolinium D T P A I. V. Injection. The lesions of the globus pallidus dissapeared on T2WI. The high signal intensity occasionally disclosed by calcified brain tissue on T l W I has been reported  and the absence of modifications of the M R signalpattern during a long time span and the correlations with the CTimages led us to speculate that the progressive lesions of the cortical and basal ganglia lesions could be attributed to calcifications rather than to hemorrage. A very similar pattern of cortical laminar streaks of increased attenuation on CT associated to increased intensity on T l W I and decreased intensity on T2WI has been described by Flodmark  in 4 children after diffuse cerebral edema but was attributed to cortical hemorrage. The hyperintensity of the frontoparietal and occipital white matter observed in our patient on T2WI is comparable to that of previous reports [2, 3] and consistent with the demyelination and spongiosis described pathologically. In spite of adequate treatment and substitution, we did not observe the partial reversibility of the lesions reported in several patients . Although both CT and M R demonstrated abnormalities in our patient, the lesion extent appeared greater with MR, making it the imaging modality of choice.
Fig. 1 a, b. Brain CT performed at 2 years 8 months: transverse slice at the level ofthelateralventricles (a) and basal ganglia (b) showing diffuse cerebral atrophy, calcifications of the lenticulate nucleus (arrows), calcifications and hypodensity of the subcortical frontal and occipital white matter (curved arrows) Fig.2a, b. Transverse MR images (2500/20/90) corresponding respectively to a T1 and T2 image showing T1 hyperintensity (a)and T2 hypointensity (b)of both globus pallidus corresponding to calcified regions (short arrows). Hypersignal in both putamen and subcortical frontal and occipital white matter believed to represent gliosis (longarrows) Fig.3. SagittalT1 MRimage (600/15) showing cortical gyriformhypersignalprobably representing calcifications (curvedarrows)
sisted in subcortical hypointense cystic lesions on T1WI and hyperintense signal of the periventricular white matter. The classical pattern of calcifications of the basal ganglia appeared in one case as mottled hyperintensity areas on T1WI
and heterogeneous areas of signal loss on T2WI. In our patient, CT showed symmetrical calcifications of the basal ganglia and frontal subcortical regions. On T I W images, the globus pallidus, the frontoparietal and temporooccipital
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