J Neurol (2014) 261:2446–2448 DOI 10.1007/s00415-014-7492-7
LETTER TO THE EDITORS
Adult-onset phenylketonuria revealed by acute reversible dementia, prosopagnosia and parkinsonism Francesca Rosini • Alessandra Rufa • Lucia Monti • Letizia Tirelli • Antonio Federico
Received: 3 April 2014 / Revised: 2 September 2014 / Accepted: 3 September 2014 / Published online: 31 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Dear Sirs, Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficiency of phenylalanine hydroxylase (PAH) enzyme [1], usually manifesting in infancy; however, rare cases of adult onset of PKU symptoms have been described [2–6]. A 46-year-old female, with mild learning difficulties (middle-school degree achieved), was observed for rapidly progressive dementia, walking difficulties and visual impairment started 1 month before, at the end of 6-month unbalanced diet for slimming. Her older sister, presenting with fair hair and skin (similarly to their unaffected mother), mental retardation and spastic tetraparesis, was diagnosed with PKU in infancy. Patient’s newborn screening was reported as negative. Her physical examination disclosed fair hair with blue eyes. Neurologic examination showed inability to walk, aphasia, prosopagnosia, extrapyramidal signs and brisk tendon reflexes. Fundoscopy revealed pale optic disks. Brain MRI evidenced diffuse bihemispheric white matter hyperintensity, mild cortical atrophy, and decreased N-acetyl-aspartate/ creatine (NAA/Cr) ratio at MR spectroscopy (Fig. 1a). Electroencephalogram showed diffuse slowing of cerebral biorhythms. Among serum and CSF testing, CSF total TAU protein was increased (997 pg/ml, nv \ 275), betaF. Rosini A. Rufa L. Tirelli A. Federico (&) Department of Medical, Surgical and Neurological Sciences, Medical School, University of Siena, Policlinico Santa Maria Alle Scotte, Viale Bracci 2, 53100 Siena, Italy e-mail: [email protected] L. Monti Unit NINT Neuroimaging and Neurointervention, AOU Senese, Policlinico Santa Maria Alle Scotte, Viale Bracci 2, 53100 Siena, Italy
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amyloid was 529 pg/ml, (nv [ 600), phosphorylated-TAU was normal (21 pg/ml, nv \ 50). Amino acid analysis evidenced increased phenylalanine (Phe) (serum 947 lmol/ L, nv 37–94, urinary 49 mmol/mol-creatinine, nv 2–19), with normal tyrosine. Molecular analysis of the proband and her sister confirmed a compound heterozygosity for the mutations IVS10-11G[A/IVS4?4A[G of PAH gene, reported with classical PKU phenotype. Immediately after Phe-restricted diet with amino acid supplementation introduction (daily Phe intake: 600 mg), patient showed rapid improvement; 6 months later (still under Pherestricted diet), only mild cognitive deficit and visual reduction remained, despite unvaried Phe levels (serum 868 lmol/L, urinary 55 mmol/mol-creatinine). One-year brain MRI and MR spectroscopy follow-up showed marked reduction of white matter abnormalities and increased relative NAA/Cr ratio (Fig. 1b). Adult-onset PKU represents an uncommon event after the late 1960s, since newborn screening identifies the affected individuals; however, up to 10 % false negatives have been reported before the recent use of tandem-mass spectroscopy method. Few patients with cognitive, motor and visual disturbances were described with adult onset of PKU symptoms [2–6]; diffuse white matter abnormalities have been reported [3–5], either related to hypomyelination or intramyelinic edema [7]. Clinical and MRI changes are often reversible after therapy [8]. In our patient, the learning difficulties may have been a not-recognized disease sign that should have been evaluated and treated before; during the acute phase, beside dementia and extrapyramidal changes, she showed prosopagnosia, as a prominent sign. Brain MRI evidenced mild cortical atrophy, unusual for the age. H1-MR spectroscopy showed different NAA/Cr ratio before and after diet, without increased choline/creatine (Cho/Cr) ratio: this finding,
J Neurol (2014) 261:2446–2448
2447
Fig. 1 a Brain MR imaging and MR spectroscopy before therapy. Coronal T2-weighted, axial FLAIR images demonstrate a diffuse leukoencephalopathy. Multivoxel MR spectroscopy data set (TE 30 ms; 135 ms) using spin-echo (SE) acquisition was acquired. Spectroscopy (TE 135 ms) shows a decrease of the relative ratio NAA/Cr without an increase of Cho/Cr relative ratio. b After therapy the diffuse white matter signal abnormalities are strongly reduced and MR spectroscopy confirmed the metabolic recovery of the white matter by a significant increase of the relative ratio NAA/Cr
uncommon in PKU, in which only increased Phe values are usually present, could have been related to intramyelinic edema [9]. Increased levels of CSF TAU protein, related to axonal damage, were similarly described in many neurodegenerative diseases [10]. Despite carrying the same mutation, our patient showed a different disease progression, compared to her sister. This phenotypic heterogeneity has been previously observed in other PKU families and could be partly related to different brain uptake of Phe [1, 2, 11]. In our case, the unbalanced diet performed for slimming might have altered the unstable metabolic equilibrium. Rapid improvement of clinical and MRI abnormalities confirms this hypothesis, despite persistence of elevated Phe levels, possibly due to not-perfect home adherence to therapeutic diet. In conclusion, genotype–phenotype discordance is to be contemplated among members of the same family. Adult onset of PKU symptoms, not previously present (asymptomatic individuals) or recognized (as in our patient), should be considered in differential diagnosis of acute dementia, motor and visual disturbances, MRI white matter changes. Biochemical amino acid analysis should be performed in patients and family members, despite eventual negativity of family history and/or newborn screening. Prompt, life-lasting Phe-restricted diet leads to clinical amelioration, preventing brain damages. Acknowledgments This research has been in part supported by a grant from Regione Toscana and National Ministry of Health to AF. Authors kindly thank Dr. F. Calı`, Laboratorio di Genetica Molecolare, U.O.C. di Genetica Medica, Associazione OASI Maria SS. ONLUS— IRCCS, Troina, EN, for the execution of the genetic testing.
Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical standard report.
Patient’s anonymity was protected in this case
References 1. Weglage J, Mo¨ller HE, Wiedermann C, Cipcic-Schmidt S, Zschocke J, Ullrich K (1998) In vivo NMR spectroscopy in patients with phenylketonuria: clinical significance of interindividual differences in brain phenylalanine concentrations. J Inherit Metab Disord 21:81–82 2. Kasim S, Moo R, Zschocke J, Jinnah HA (2001) Phenylketonuria presenting in adulthood with progressive spastic paraparesis and dementia. J Neurol Neurosurg Psichiatry 71:795–797 3. Weglage J, Oberwittler C, Marquardt T, Schellscheidt J, von Teeffelen-Heithoff A, Koch G, Gerding H (2000) Neurological deterioration in adult phenylketonuria. J Inherit Metab Dis 23:83–84 4. Ishimaru K, Tamasawa N, Baba M, Matsunaga M, Takebe K (1993) Phenylketonuria with adult-onset neurological manifestation. Rinsho Shinkeigaku 33:961–965 5. Jousserand G, Antoine JC, Camdessanche´ JP (2010) Musty odour, mental retardation, and spastic paraplegia revealing phenylketonuria in adulthood. J Neurol 257:302–304 6. Narayanan D, Barski R, Henderson MJ, Luvai A, Chandrajay D, Stainforth C, Bradley J, Rogozinski H, Sharma R (2014) Delayed diagnosis of phenylketonuria—a case report of two siblings. Ann Clin Biochem 51:406–408 7. Anderson PJ, Leuzzi V (2010) White matter pathology in phenylketonuria. Mol Genet Metab 99:S3–S9 8. Cleary MA, Walter JH, Wraith JE, White F, Tyler K, Jenkins JP (1995) Magnetic resonance imaging in phenylketonuria: reversal of cerebral white matter change. J Pediatr 127:251–255 9. Pietz J, Kreis R, Schmidt H, Meyding-Lamade´ UK, Rupp A, Boesch C (1996) Phenylketonuria: findings at MR imaging and
123
2448 localized in vivo H-1 MR spectroscopy of the brain in patients with early treatment. Radiology 201:413–420 10. Oka M, Hasegawa S, Matsushige T, Inoue H, Kajimoto M, Ishikawa N, Isumi H, Ichiyama T (2014) Tau protein concentrations in the cerebrospinal fluid of children with acute disseminated encephalomyelitis. Brain Dev 36:16–20
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J Neurol (2014) 261:2446–2448 11. Weglage J, Wiedermann D, Denecke J, Feldmann R, Koch HG, Ullrich K, Moller HE (2002) Individual blood-brain barrier phenylalanine transport in siblings with classical phenylketonuria. J Inherit Metab Dis 25:431–436
LETTER TO THE EDITORS
Adult-onset phenylketonuria revealed by acute reversible dementia, prosopagnosia and parkinsonism Francesca Rosini • Alessandra Rufa • Lucia Monti • Letizia Tirelli • Antonio Federico
Received: 3 April 2014 / Revised: 2 September 2014 / Accepted: 3 September 2014 / Published online: 31 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Dear Sirs, Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficiency of phenylalanine hydroxylase (PAH) enzyme [1], usually manifesting in infancy; however, rare cases of adult onset of PKU symptoms have been described [2–6]. A 46-year-old female, with mild learning difficulties (middle-school degree achieved), was observed for rapidly progressive dementia, walking difficulties and visual impairment started 1 month before, at the end of 6-month unbalanced diet for slimming. Her older sister, presenting with fair hair and skin (similarly to their unaffected mother), mental retardation and spastic tetraparesis, was diagnosed with PKU in infancy. Patient’s newborn screening was reported as negative. Her physical examination disclosed fair hair with blue eyes. Neurologic examination showed inability to walk, aphasia, prosopagnosia, extrapyramidal signs and brisk tendon reflexes. Fundoscopy revealed pale optic disks. Brain MRI evidenced diffuse bihemispheric white matter hyperintensity, mild cortical atrophy, and decreased N-acetyl-aspartate/ creatine (NAA/Cr) ratio at MR spectroscopy (Fig. 1a). Electroencephalogram showed diffuse slowing of cerebral biorhythms. Among serum and CSF testing, CSF total TAU protein was increased (997 pg/ml, nv \ 275), betaF. Rosini A. Rufa L. Tirelli A. Federico (&) Department of Medical, Surgical and Neurological Sciences, Medical School, University of Siena, Policlinico Santa Maria Alle Scotte, Viale Bracci 2, 53100 Siena, Italy e-mail: [email protected] L. Monti Unit NINT Neuroimaging and Neurointervention, AOU Senese, Policlinico Santa Maria Alle Scotte, Viale Bracci 2, 53100 Siena, Italy
123
amyloid was 529 pg/ml, (nv [ 600), phosphorylated-TAU was normal (21 pg/ml, nv \ 50). Amino acid analysis evidenced increased phenylalanine (Phe) (serum 947 lmol/ L, nv 37–94, urinary 49 mmol/mol-creatinine, nv 2–19), with normal tyrosine. Molecular analysis of the proband and her sister confirmed a compound heterozygosity for the mutations IVS10-11G[A/IVS4?4A[G of PAH gene, reported with classical PKU phenotype. Immediately after Phe-restricted diet with amino acid supplementation introduction (daily Phe intake: 600 mg), patient showed rapid improvement; 6 months later (still under Pherestricted diet), only mild cognitive deficit and visual reduction remained, despite unvaried Phe levels (serum 868 lmol/L, urinary 55 mmol/mol-creatinine). One-year brain MRI and MR spectroscopy follow-up showed marked reduction of white matter abnormalities and increased relative NAA/Cr ratio (Fig. 1b). Adult-onset PKU represents an uncommon event after the late 1960s, since newborn screening identifies the affected individuals; however, up to 10 % false negatives have been reported before the recent use of tandem-mass spectroscopy method. Few patients with cognitive, motor and visual disturbances were described with adult onset of PKU symptoms [2–6]; diffuse white matter abnormalities have been reported [3–5], either related to hypomyelination or intramyelinic edema [7]. Clinical and MRI changes are often reversible after therapy [8]. In our patient, the learning difficulties may have been a not-recognized disease sign that should have been evaluated and treated before; during the acute phase, beside dementia and extrapyramidal changes, she showed prosopagnosia, as a prominent sign. Brain MRI evidenced mild cortical atrophy, unusual for the age. H1-MR spectroscopy showed different NAA/Cr ratio before and after diet, without increased choline/creatine (Cho/Cr) ratio: this finding,
J Neurol (2014) 261:2446–2448
2447
Fig. 1 a Brain MR imaging and MR spectroscopy before therapy. Coronal T2-weighted, axial FLAIR images demonstrate a diffuse leukoencephalopathy. Multivoxel MR spectroscopy data set (TE 30 ms; 135 ms) using spin-echo (SE) acquisition was acquired. Spectroscopy (TE 135 ms) shows a decrease of the relative ratio NAA/Cr without an increase of Cho/Cr relative ratio. b After therapy the diffuse white matter signal abnormalities are strongly reduced and MR spectroscopy confirmed the metabolic recovery of the white matter by a significant increase of the relative ratio NAA/Cr
uncommon in PKU, in which only increased Phe values are usually present, could have been related to intramyelinic edema [9]. Increased levels of CSF TAU protein, related to axonal damage, were similarly described in many neurodegenerative diseases [10]. Despite carrying the same mutation, our patient showed a different disease progression, compared to her sister. This phenotypic heterogeneity has been previously observed in other PKU families and could be partly related to different brain uptake of Phe [1, 2, 11]. In our case, the unbalanced diet performed for slimming might have altered the unstable metabolic equilibrium. Rapid improvement of clinical and MRI abnormalities confirms this hypothesis, despite persistence of elevated Phe levels, possibly due to not-perfect home adherence to therapeutic diet. In conclusion, genotype–phenotype discordance is to be contemplated among members of the same family. Adult onset of PKU symptoms, not previously present (asymptomatic individuals) or recognized (as in our patient), should be considered in differential diagnosis of acute dementia, motor and visual disturbances, MRI white matter changes. Biochemical amino acid analysis should be performed in patients and family members, despite eventual negativity of family history and/or newborn screening. Prompt, life-lasting Phe-restricted diet leads to clinical amelioration, preventing brain damages. Acknowledgments This research has been in part supported by a grant from Regione Toscana and National Ministry of Health to AF. Authors kindly thank Dr. F. Calı`, Laboratorio di Genetica Molecolare, U.O.C. di Genetica Medica, Associazione OASI Maria SS. ONLUS— IRCCS, Troina, EN, for the execution of the genetic testing.
Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical standard report.
Patient’s anonymity was protected in this case
References 1. Weglage J, Mo¨ller HE, Wiedermann C, Cipcic-Schmidt S, Zschocke J, Ullrich K (1998) In vivo NMR spectroscopy in patients with phenylketonuria: clinical significance of interindividual differences in brain phenylalanine concentrations. J Inherit Metab Disord 21:81–82 2. Kasim S, Moo R, Zschocke J, Jinnah HA (2001) Phenylketonuria presenting in adulthood with progressive spastic paraparesis and dementia. J Neurol Neurosurg Psichiatry 71:795–797 3. Weglage J, Oberwittler C, Marquardt T, Schellscheidt J, von Teeffelen-Heithoff A, Koch G, Gerding H (2000) Neurological deterioration in adult phenylketonuria. J Inherit Metab Dis 23:83–84 4. Ishimaru K, Tamasawa N, Baba M, Matsunaga M, Takebe K (1993) Phenylketonuria with adult-onset neurological manifestation. Rinsho Shinkeigaku 33:961–965 5. Jousserand G, Antoine JC, Camdessanche´ JP (2010) Musty odour, mental retardation, and spastic paraplegia revealing phenylketonuria in adulthood. J Neurol 257:302–304 6. Narayanan D, Barski R, Henderson MJ, Luvai A, Chandrajay D, Stainforth C, Bradley J, Rogozinski H, Sharma R (2014) Delayed diagnosis of phenylketonuria—a case report of two siblings. Ann Clin Biochem 51:406–408 7. Anderson PJ, Leuzzi V (2010) White matter pathology in phenylketonuria. Mol Genet Metab 99:S3–S9 8. Cleary MA, Walter JH, Wraith JE, White F, Tyler K, Jenkins JP (1995) Magnetic resonance imaging in phenylketonuria: reversal of cerebral white matter change. J Pediatr 127:251–255 9. Pietz J, Kreis R, Schmidt H, Meyding-Lamade´ UK, Rupp A, Boesch C (1996) Phenylketonuria: findings at MR imaging and
123
2448 localized in vivo H-1 MR spectroscopy of the brain in patients with early treatment. Radiology 201:413–420 10. Oka M, Hasegawa S, Matsushige T, Inoue H, Kajimoto M, Ishikawa N, Isumi H, Ichiyama T (2014) Tau protein concentrations in the cerebrospinal fluid of children with acute disseminated encephalomyelitis. Brain Dev 36:16–20
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J Neurol (2014) 261:2446–2448 11. Weglage J, Wiedermann D, Denecke J, Feldmann R, Koch HG, Ullrich K, Moller HE (2002) Individual blood-brain barrier phenylalanine transport in siblings with classical phenylketonuria. J Inherit Metab Dis 25:431–436
