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symptoms and their impact on quality of life in Parkinson’s disease.
Mov. Disord. 2009, 24, 1641–1649.
[55] Stuart, S, Lawson, RA, Yarnall, AJ, Nell, J, Alcock, L, Duncan, GW,
Khoo, TK, Barker, RA, Rochester, L, Burn DJ, ICICLE-PD study
group. Pro-Saccades Predict Cognitive Decline in Parkinson's
Disease: ICICLE-PD. Mov. Disord. 2019, 34, 1690-1698.
[56] Amir, G, Ron, N. Pulmonary pathology in Gaucher’s disease. Hum.
Pathol. 1999, 30, 666– 670.
[57] Mistry, PK, Sirrs, S, Chan, A, Pritzker, MR, Duffy, TP, Grace, ME,
Meeker, DP, Goldman, ME. Pulmonary hypertension in type 1
Gaucher’s disease: Genetic and epigenetic determinants of phenotype
and response to therapy. Mol. Genet. Metab. 2002, 77, 91–98.
[58] Collins, LM, Williams-Gray, CH, Morris, E, Deegan, P, Cox, TM,
Barker, RA. The motor and cognitive features of Parkinson's disease
in patients with concurrent Gaucher disease over 2 years: a case
series. J. Neurol. 2018, 265, 1789-1794.
[59] Ruskey, JA, Zhou, S, Santiago, R, Franche, LA, Alam, A, Roncière,
L, Spiegelman, D, Fon, EA, Trempe, JF, Kalia, LV, Postuma, RB,
Dupre, N, Rivard, GE, Assouline, S, Amato, D, Gan-Or, Z. The GBA
p. Trp378Gly mutation is a probable French-Canadian founder
mutation causing Gaucher disease and synucleinopathies. Clin.
Genet. 2018, 94, 339- 345.
[60] Detollenaere, C, Benghergbia, M, Brassier, A, de Villemeur, TB,
Amsallem, D, Berger, M, Stirnemann, J, Belmatoug, N, Rose, C.
Type 3 Gaucher disease, diagnostic in adulthood. Mol. Genet. Metab.
Rep. 2017, 13, 1-2.
[61] Horowitz, M, Wilder, S, Horowitz, Z, Reiner, O, Gelbart, T, Beutler,
E. The human glucocerebrosidase gene and pseudogene: structure
and evolution. Genomics. 1989, 4, 87- 96.
[62] Velez-Pardo, C, Lorenzo-Betancor, O, Jimenez-Del-Rio, M, Moreno,
S, Lopera, F, Cornejo-Olivas, M, Torres, L, Inca-Martinez, M,
Mazzetti, P, Cosentino, C, Yearout, D, Waldherr, SM, Zabetian, CP,
Mata, IF. The distribution and risk effect of GBA variants in a large
https://t.me/medicina_free
Parkinson’s Disease Association with Gaucher Disease …
273
cohort of PD patients from Colombia and Peru. Parkinsonism Relat.
Disord. 2019, 63, 204-208.
[63] Aharon-Peretz, J, Badarny, S, Rosenbaum, H, Gershoni-Baruch, R.
Mutations in the glucocerebrosidase gene and Parkinson disease:
phenotype-genotype correlation. Neurology. 2005, 65, 1460-1461.
[64] Clark, LN, Ross, BM, Wang, Y, Mejia-Santana, H, Harris, J, Louis,
ED, Cote, LJ, Andrews, H, Fahn, S, Waters, C, Ford, B, Frucht, S,
Ottman, R, Marder, K. Mutations in the glucocerebrosidase gene are
associated with early-onset Parkinson disease. Neurology 2007, 69,
1270-1277.
[65] Do, J, McKinney, C, Sharma, P, Sidransky, E. Glucocerebrosidase
and its relevance to Parkinson disease. Mol. Neurodegener. 2019, 14,
36.
[66] Sato, C, Morgan, A, Lang, AE, Salehi-Rad, S, Kawarai, T, Meng, Y,
Ray, PN, Farrer, LA, St George-Hyslop, P, Rogaeva, E. Analysis of
the glucocerebrosidase gene in Parkinson's disease. Mov. Disord.
2005, 20, 367-370.
[67] Cilia, R, Tunesi, S, Marotta, G, Cereda, E, Siri, C, Tesei, S,
Zecchinelli, AL, Canesi, M, Mariani, CB, Meucci, N, Sacilotto, G,
Zini, M, Barichella, M, Magnani, C, Duga, S, Asselta, R, Soldà, G,
Seresini, A, Seia, M, Pezzoli, G, Goldwurm, S. Survival and
dementia in GBA-associated Parkinson's disease: The mutation
matters. Ann. Neurol. 2016, 80, 662-673.
[68] Lubomski, M, Hayes, M, Kennerson, M, Ellis, M, Chu, S, Blackie, J,
O'Sullivan, JD, Nicholson G. A novel Parkinson's disease risk
variant, p. W378R, in the Gaucher's disease GBA gene. Mov. Disord.
2018, 33, 1662-1664.
[69] Mullin, S, Hughes, D, Mehta, A, Schapira, AHV. Neurological
effects of glucocerebrosidase gene mutations. Eur. J. Neurol. 2019,
26, 388-e29.
[70] Li, H, Ham, A, Ma, TC, Kuo, SH, Kanter, E, Kim, D, Ko, HS, Quan,
Y, Sardi, SP, Li, A, Arancio, O, Kang, UJ, Sulzer, D, Tang, G.
Mitochondrial dysfunction and mitophagy defect triggered by
heterozygous GBA mutations. Autophagy 2019, 15, 113-130.
https://t.me/medicina_free
S. Rajasankar, V. Venkateshgobi and S. Surendran
274
[71] Pitcairn, C, Wani, WY, Mazzulli, JR. Dysregulation of the
autophagic-lysosomal pathway in Gaucher and Parkinson's disease.
Neurobiol. Dis. 2019, 122, 72-82.
[72] Thaler, A, Bregman, N, Gurevich, T, Shiner, T, Dror, Y, Zmira, O,
Gan-Or, Z, Bar-Shira, A, Gana-Weisz, M, Orr-Urtreger, A, Giladi, N,
Mirelman, A. Parkinson's disease phenotype is influenced by the
severity of the mutations in the GBA gene. Parkinsonism Relat.
Disord. 2018, 55, 45-49.
[73] Oshima, H, Katayama, Y, Morishita, T, Sumi, K, Otaka, T,
Kobayashi, K, Suzuki, Y, Fukaya, C, Yamamoto, T. Subthalamic
nucleus stimulation for attenuation of pain related to Parkinson
disease. J. Neurosurg. 2012, 116, 99–106.
[74] Jung, YJ, Kim, HJ, Jeon, BS, Park, H, Lee, WW, Paek, SH. An 8-
year follow-up on the effect of subthalamic nucleus deep brain
stimulation on pain in parkinson disease. JAMA. Neurol. 2015, 72,
504–510.
[75] Honey, CR, Stoessl, AJ, Tsui, JK, Schulzer, M, Calne, DB. Unilateral
pallidotomy for reduction of parkinsonian pain. J. Neurosurg. 1999,
91, 198–201.
[76] Loher, TJ, Burgunder, JM, Weber, S, Sommerhalder, R, Krauss, JK.
Effect of chronic pallidal deep brain stimulation on off period
dystonia and sensory symptoms in advanced Parkinson’s disease. J.
Neurol. Neurosurg. Psychiatry. 2002, 73, 395–399.
[77] Andrejeva, J, Kasradze, M, Misiukeviciute, L, Radziuviene, R. The
effect of physical therapy with use of muscical elements in patients
with Patients with Parkinson’s disease. Georgian Med. News. 2019,
291, 82-85.
[78] Abrams, SB, Hallett, M. Clinical utility of different botulinum
neurotoxin preparations. Toxicon. 2013, 67, 81–86.
[79] Foppa, AA, Chemello, C, Vargas-Peláez, CM, Farias, MR.
Medication therapy management service for patients with Parkinson's
disease: a before-and-after study. Neurol. Ther. 2016, 5, 85–99.
https://t.me/medicina_free
Parkinson’s Disease Association with Gaucher Disease …
275
[80] Schneider, RB, Iourinets, J, Richard, IH. Parkinson's disease
psychosis: presentation, diagnosis and management. Neurodegener.
Dis. Manag. 2017, 7, 365-376.
[81] Karabiyik, C, Lee, MJ, Rubinsztein, DC. Autophagy impairment in
Parkinson's disease. Essays Biochem. 2017, 61, 711-720.
[82] Beutler, E, Demina, A, Laubscher, K, Garver, P, Gelbart, T, Balicki,
D, Vaughan, L. The clinical course of treated and untreated Gaucher
disease. A study of 45 patients. Blood Cells Mol. Dis. 1995, 21, 86-
108.
[83] Weiss, K, Gonzalez, AN, Lopez, G, Pedoeim, L, Groden, C,
Sidransky, E. The clinical management of Type 2 Gaucher disease.
Mol. Genet. Metab. 2015, 114, 110–122.
[84] Aerts, JM, Hollak, CE, Boot, RG, Groener, JE, Maas, M. Substrate
reduction therapy of glycosphingolipid storage disorders. J. Inher.
Metab. Dis. 2006, 29, 449–456.
[85] Belmatoug, N, Burlina, A, Giraldo, P, Hendriksz, CJ, Kuter, DJ,
Mengelm E, Pastoresm GM. Gastrointestinal disturbances and their
management in miglustat-treated patients. J. Inherit. Metab. Dis.
2011, 34, 991–1001.
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In: Neurochemistry of Metabolic Diseases ISBN: 978-1-53618-339-9
Editor: Sankar Surendran © 2020 Nova Science Publishers, Inc.
Chapter 9
PHENYLKETONURIA:
DIAGNOSIS AND THERAPEUTICAL OPTIONS
Jaume Campistol
1,*
and Sankar Surendran
2
1
PKU Unit, Department of Neurology,
Hospital Sant Joan de Deu, Barcelona. Spain
2
School of Medicine, Louisiana State University,
Health Sciences Center, New Orleans, LA, US
ABSTRACT
Phenylketonuria is a genetic disorder of autosomal recessive
transmission, in which an alteration occurs in the metabolism of
hydroxylation of phenylalanine (Phe) to tyrosine (Tyr), by the
phenylalanine hydroxylase (PAH) activity. As a consequence, there is an
increase in plasma Phe levels and a decrease in Tyr concentration.
Although Phe is an essential amino acid, elevated levels of Phe
concentrations in the plasma and tissue resulting toxicity affects the
central nervous system. The PAH gene is located on chromosome 12q
*
Corresponding Author’s Email: campistol@hsjdbcn.es.
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Jaume Campistol and Sankar Surendran
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(q22-q24.1) and there are more than 700 different mutations. The
tolerance to Phe intake depends on the residual activity of the enzyme.
The most severe form of hyperphenylalaninemia (HPA) is classical
phenylketonuria (PKU). Nutritional treatment in this disease aims to
control the intake of Phe to achieve non-toxic levels, provide Tyr and to
offer the correct amount of carbohydrates, lipids, proteins and trace
elements to achieve a normal growth and development. Some patients
respond to administration of BH4 which acts as a chaperone. Enzyme
replacement therapy is now available for some PKU patients and other
therapies are in course.
1. INTRODUCTION
Hyperphenylalaninemia (HPN) is a generic term for a biochemical
phenotype in which there is a persistent increase in the plasma
concentration of phenylalanine (Phe) caused by disorders of hepatic
hydroxylation of this amino acid [1]. This system of hydroxylation of Phe
to tyrosine essentially involves the enzyme phenylalanine hydroxylase
(Phe 4-monooxygenase, PAH; EC 1.14.16.1) and the coenzyme
tetrahydrobiopterin (BH4), which is reduced in the hydroxylation reaction
and must be regenerated by another enzyme, dihydropterin reductase
(DHPR; EC 1.6.99.7) [1]. Any defect that interferes with the hydroxylation
system (deficiency of phenylalanine hydroxylase, dihydropterin reductase
activity, or defects in tetrahydrobiopterin biosynthesis) will cause
persistent HPN. This system is the main determinant of Phe homeostasis in
human beings. The main cause of HPN is the defect in phenylalanine
hydroxylase activity that causes PKU (OMIM 261600), which constitutes
98% of diagnosed cases [2].
2. HISTORY
In 1934, Fölling described the disease for the first time in two brothers
with intellectual disability and a special body odor, by the observation of
their acidified urine, turned into an intense green color, when added with
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Phenylketonuria
279
ferric chloride. Fölling deduced that what determined the color and smell
of urine was phenylpyruvic acid [3]. The study of other patients with
intellectual disabilities admitted to special institutions showed that eight of
them belonging to three families excreted urine, with the same odor and
color, when added with ferric chloride [3]. Based on these data, he
described the disease as a hereditary metabolic disorder, calling it
“phenylpyruvic idiocy”, and relating intellectual disability for the first time
to a congenital error in metabolism.
In 1937 the disease was called phenylketonuria (PKU) by Penrose and
Quastel [4]. In 1953, Jervis demonstrated a defect in the activity of the
liver enzyme phenylalanine hydroxylase. In the same year, Bickel
described the first possibility of therapy, by restricting the Phe of the diet,
which is the basis of treatment for these patients [5, 6].
In 1963, Guthrie published a method of screening Phe in blood to be
applied to the entire population in the neonatal period, which allowed the
early treatment of PKU and avoided the intellectual disability of patients
treated prematurely [7]. In 1980, Lenke and Levy described maternal PKU
embryopathy and in 1983, Woo located the PAH gene on chromosome
12q24.1 [2, 8, 9]. More than 700 mutations have been identified in the
PAH gene. Kure in 1999 described treatment with BH4 in some patients
with PKU and that has opened a new therapeutic strategy [10].
3. BIOCHEMICAL DIAGNOSIS OF THE DISEASE
The Guthrie test is based on the fact that a high concentration of Phe in
blood impregnated in a filter paper (Guthrie card) causes the cancellation
of the inhibitory action of bacterial growth of a compound added to the
culture medium, producing a growth halo around from the patient’ s blood
[2, 3, 7]. It was soon applied in numerous American states and spread
throughout Europe. The first early detection programs appeared in the
1960s by semi-quantitative determination of Phe in blood samples
impregnated on filter paper. Early detection procedures were based on the
Guthrie method (still used in some countries) and later on
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Jaume Campistol and Sankar Surendran
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chromatographic, fluorometric, immunoassay, and spectrophotometric
methods, but they are gradually being displaced by the use of tandem mass
spectrometry (MS/MS). This method allows the detection of a large
number of aminoacidopathies, organic acidurias and beta-oxidation defects
of fatty acids in the same dried blood sample, which is why it is currently
being adopted in most neonatal screening centers [2, 7]. If the detected
concentrations of Phe exceed 120-150 µmol/L, the patient is referred to the
referral center for PKU, where they will proceed to check, differential
diagnosis and start treatment, if necessary.
The biochemical tests necessary for differential diagnosis are initiated
with verification of the result of early diagnosis in the patient’ s blood, by
rapid determination of plasma Phe concentrations (by HPLC or
fluorimetry). This allows evaluating the variation of the Phe concentration
in the period of time (10-15 days) required for the result of early diagnosis,
at the same time that treatment is started if high plasma Phe concentrations
are verified, while continuing with differential diagnosis.
Once hyperphenylalaninemia has been verified, the differential
diagnosis continues basically focused on two aspects: 1) ruling out a defect
in the metabolism (synthesis or recycling) of BH4, and 2) if there is no
such defect, the patient’ s response to BH4 treatment, to check whether it
can be treated totally or partially with said cofactor or the restricted diet
should be immediately introduced into Phe [2].
Tetrahydrobiopterin (BH4) is a cofactor, can increase residual PAH
activity, has a major role in the conversion of Phe to tyrosine and in the
production of neurotransmitters [10-14] (Figure 1). Tetrahydrobiopterin is
synthesized from guanosine triphosphate in a three-step process. First,
guanosine triphosphate is converted into dihydroneopterin triphosphate by
GTP cyclohydrolase I. Subsequently, dihydroneopterin triphosphate is
converted into 6-pyruvol tetrahydropterin by 6-pyruvoyl-tetrahydropterin
synthase. Finally, 6-pyruvol tetrahydropterin is converted into
tetrahydrobiopterin by sepiapterin reductase (Figure 2). Thus, reduced
levels of BH4 in PKU affects normal conversion of Phe to tyrosine to
contribute in PKU pathophysiology.
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Phenylketonuria
281
The determination of the dihydropterin reductase activity makes it
possible to exclude the defect in the activity of this enzyme, that is, the
recycling of BH4. The assessment of pterins in urine is essential to
diagnose the different defects of tetrahydrobiopterin metabolism.
Figure 1. Phenylalanine hydroxylase catalyzes L-Phenylalanine to L-Tyrosine.
The BH4 oral overload test (20 mg/kg body weight) can be performed
simultaneously with the differential diagnosis and allows the response to
this cofactor to be checked. Complete and rapid normalization of HPN
(before 8 hours post-overload) suggests a deficiency in metabolism to
BH4, whereas gradual reduction of Phe or the absence of reduction of the
amino acid is related to the response to BH4, and they allow choosing the
appropriate treatment option [2, 5, 15].
In addition to PAH, BH4 also acts a co-factor for other agents. BH4 is
a cofactor for tyrosine hydroxylase, an enzyme required for the conversion
of L-tyrosine to L-DOPA. Thus, BH4 deficiency can lead to decline in the
levels of dopamine, norepinephrine and epinephrine. BH4 is a cofactor for
tryptophan hydroxylase, an enzyme required for the conversion of L-
tryptophan to 5-hydroxytryptophan. Since normal levels of dopamine and
serotonin are important for the brain regulatory function [11],
tetrahydrobiopterin deficiency resulting reduced levels of dopamine and
serotonin may lead to central nervous system disorders. BH4 is a cofactor
for nitric oxide synthase, which catalyzes the conversion of guanidino
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