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S. Sundaram, S. V. Chandrasekharan and S. S. Nair
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In: Neurochemistry of Metabolic Diseases ISBN: 978-1-53618-339-9
Editor: Sankar Surendran © 2020 Nova Science Publishers, Inc.
Chapter 8
PARKINSON’S DISEASE ASSOCIATION
WITH GAUCHER DISEASE
AND THERAPEUTIC EFFECT
Srinivasagam Rajasankar
1,*
,
Veerappachetty Venkateshgobi
2
and Sankar Surendran
1
1
Velammal Medical College Hospital and Research Institute,
Tamil Nadu, India
2
Department of Anatomy, Sivaraj Medical Colleges, Tamil Nadu, India
ABSTRACT
Parkinson's disease (PD) is a neurodegenerative disorder with a
progressive loss of dopaminergic neurons in the substantia nigra pars
compacta. The motor and non-motor symptoms in the disease include
movement disorder, depression, dementia, hypnotics and autonomic
dysfunction. Elevated levels of NAA is reported in the brain of patients
with PD. Glucocerebrosidase gene mutations lead to Gaucher disease, a
*
Corresponding Author’s Email: anatomysrs@yahoo.com.
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lysosomal storage disorder. Mutations in the same gene also contribute to
PD. Hence, lysosomal dysfunction is one of the events in the
pathophysiology seen in PD. Autophagy is found to be affected in some
subtypes of PD and therefore, regulating autophagy function is important
to protect cells against toxicity of aggregate-prone proteins.
1. INTRODUCTION
Parkinson disease (PD) is a progressive neurodegenerative disease
affecting one million people in the United States. After Alzheimer’s
disease, Parkinson disease is a major neurodegenerative disorder with
approximately one percentage of the population above sixty years are
affected by the disease [1]. The clinical symptoms seen in PD include gait
disturbance, tremors, impaired handwriting, speech disturbance, rigidity,
grip force, mild cognitive impairment and dementia. Fatigue,
hallucinations, cognition, and urinary problems were symptoms seen in
patients with PD with increasing disability and reducing quality of life [2-
5]. Progressive supranuclear palsy is an atypical Parkinsonism resembling
PD. Patient’s pain increases when parkinsonian symptoms become severe
[6]. Movement disorder mainly seen in the disease is associated with the
accumulation of intracytoplasmic aggregate prone protein. Impairment of
autophagy is one of the events seen in some subtypes of PD. Autophagy is
a degradative pathway that delivers cytoplasmic content to lysosomes for
degradation of aggregated cellular proteins and dysfunctional organelles.
2. FACTORS CAUSING PARKINSON’S DISEASE
AND GAUCHER DISEASE
More than 25 genes have been ascribed with the cause of PD
pathophysiology [7-9]. However, a common mutation found worldwide in
the late-onset of PD is G2019S in the leucine-rich repeat kinase 2 gene.
The Juvenile parkinsonism is caused by mutations in the Parkinson’s
disease genes of Parkin, protein deglycase DJ-1/Parkinson disease protein
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Parkinson’s Disease Association with Gaucher Disease …
255
7 or PTEN-induced kinase 1. Two cannabinoid receptors, cannabinoid
receptor type 1 and cannabinoid receptor type 2 have major role in the
basal ganglia involved in the pathogenesis of PD. Therefore, these two
receptors have been proposed as a target in treating the disease [10].
N-acetyl aspartic acid (NAA) is the second abundant metabolite in the
brain and is rich in neurons [11-14]. N-acetyl aspartic acid is vital for the
maintenance of healthy neurons. While NAA is converted into aspartate
and acetate in the central nervous system, kidney metabolizes NAA to
carbon dioxide and mammary gland converts NAA to lipids [15]. The
NAA is rich in food items including vegetables, soy beans, coffee, tea,
cocoa, corn and meats. Increased levels of NAA also induce inflammation
and contractility [13, 14, 15-18]. N-acetyl aspartic acid level is slightly
elevated in the brain of Patients with PD. Elevated levels of NAA with
sustained activity affects potential genes and proteins associated with
oxidative stress to lead oxidative stress and thus contribute in the disease
pathophysiology [15-19].
Gaucher disease (GD) is an autosomal recessive disorder, caused by
deficiency of glucocerebrosidase activity, a lysosomal enzyme, resulting
elevated levels of the substrate, glucosylceramide. The disease frequency is
approximately one in fifty thousand births and the disease is most
prevalence in Ashkenazi Jews. Infiltration of the bone marrow, spleen, and
liver by Gaucher cells is ascribed with the splenomegaly, cytopenia,
hepatomegaly and bone lesions seen in the disease. Glucocerebrosidase
gene mutations not only causing Gaucher disease but also contribute in
Parkinson’s disease pathophysiology by affecting lysosomal functions.
Fifty six percent of Parkinson's disease patients have at least one lysosomal
storage disorder gene variant and twenty one percent carry multiple alleles
[20]. Hence, lysosomal storage disorder is also one of the events in PD
pathophysiology.
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3. BIOCHEMICAL DIAGNOSIS OF THE
PARKINSON’S DISEASE
Some biochemical assays used to determine PD are symptomatic.
Measuring blood and cerebrospinal fluid levels of α-synuclein and protein
deglycase DJ-1/Parkinson disease protein 7 is useful to determine PD or
Parkinsonism. Nicotinamide phosphoribosyl transferase, an adipokine
regulating lipid and glucose metabolism, is higher in early-stage and drug-
naïve patients with PD [21]. Urate levels in the serum is correlated with PD
[22-23]. Reduction in microRNA19b is associated with patients with rapid
eye movement sleep behavior disorder [24].
Measuring dopamine transporter appears to be an accurate method to
determine dopamine neuron loss seen in PD [25]. Manifestation of
homovanillic acid level with xanthine is proposed to determine PD [26].
Lower level of plasma apolipoprotein A1 is related with a high risk of PD
[27]. Measurement of α-synuclein oligomers in the cerebrospinal fluid of
patients with PD by α-synuclein protein misfolding cyclic amplification is
useful to determine PD [28].
4. SUBTYPES OF PARKINSONISM
Over eighty percentage of patients diagnosed with Parkinson's disease
have primary parkinsonism/idiopathic Parkinson's disease. The word
idiopathic means cause of the disease is not known. Idiopathic Parkinson
disease worsens with increase in time. Patients with PD shows the
symptoms of impairment of normal balance, gait and posture [29].
Diagnosing these symptoms is important to distinguish Parkinson's disease
from vascular parkinsonism and atypical parkinsonism such as progressive
supranuclear palsy, corticobasal syndrome and multiple system atrophy.
Vascular parkinsonism is generally caused by strokes resulting clot in the
brain. Vascular parkinsonism affects the lower body to lead gait
abnormality rather than tremor. Atypical Parkinsonism shows some of the
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symptoms seen in Parkinson's disease, but that may not respond to
levodopa drug treatment. Drugs containing benzamide derivatives have
been ascribed as one of the major causes of drug induced parkinsonism.
Patients who stopped eating these drugs could improve symptoms seen in
drug induced parkinsonism. Drug induced parkinsonism shows symptoms
such as postural instability, rigidity, and gait disturbance as seen in
idiopathic Parkinson disease [30]. Approximately 300,000 people with
idiopathic Parkinson's disease are living in Germany [31]. The patients
with juvenile parkinsonism develop parkinsonian symptoms before twenty-
one-year-old. The symptoms in Juvenile parkinsonism include cognitive
decline, movement disorder and psychiatric disorder [32]. Dystonia is seen
in atypical parkinsonian disorders such as progressive supranuclear palsy,
multiple system atrophy, and corticobasal degeneration. The body
distribution, severity, timing of appearance and relationship to
dopaminergic and other medications may differ among atypical
parkinsonian types [33]. Dopamine has a role on wake-promoting efficacy,
as administration of dopaminergic analogues leads to increased activation
of cortical electroencephalogram (EEG) and behavioral excitation.
5. SUBTYPES OF GAUCHER DISEASE
Gaucher disease (GD, OMIM #230800, ORPHA355) is an autosomal
recessive disorder caused by mutations in the glucocerebrosidase 1 gene
(GCase 1) resulting decreased levels of glucocerebrosidase (EC: 4.2.1.25)
enzyme activity. The enzyme deficiency leads to the accumulation of the
substrate, glucosylceramide. Elevated levels of the substrate forms fibrillar
aggregates in macrophages and these cells are called as Gaucher cells. The
disease is characterized by hepatosplenomegaly, cytopenia and severe bone
involvement [34]. Type-1 Gaucher disease is mainly seen in patients from
Europe and USA. The disease is characterized by the viscera effects such
as splenomegaly [35-36], hepatomegaly [37], fatigue and delayed puberty
[38], acute pain in the pelvis and lower limbs [39] with normal
neurological function. Meanwhile, type 2 and type 3 Gaucher disease
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develop neurological impairment [40]. Type-2 Gaucher disease is
characterized by severe neurological impairment starting at age 2–6
months old with hepatosplenomegaly, rigidity of the neck and trunk,
oculomotor paralysis, bulbar signs and bilateral fixed strabismus [41].
Type-3 Gaucher disease phenotype differ among patients with less than
twenty percentage patients showed progressive myoclonus epilepsy, less
than sixty percentage patients had cerebellar ataxia or spasticity and
dementia [42-44].
6. BIOCHEMICAL DIAGNOSIS OF GAUCHER DISEASE
Prenatal diagnosis of GD can be performed by determining
glucocerebrosidase levels and gene mutation analysis of the cultured
amniotic cells [45]. The reduced levels of the enzyme activity can be
measured in leukocytes, mononuclear cells and cultured fibroblasts to
determine GD. Elevated levels of Chitotriosidase was used as a biomarker
of the disease [46]. However, the increased levels of chitotriosidase was
also reported in other diseases such as Niemann–Pick disease [47],
multiple sclerosis, β-thalassemia and visceral leishmaniasis. Therefore,
measurement of chitotriosidase along with other phenotypes will help in
determining GD. Measuring plasma C-C Motif Chemokine Ligand 18 [48-
49] and glucosyl sphingosine levels are useful, as these levels are elevated
in patients with GD [50]. These levels along with other phenotypes may be
used in diagnosing GD.
7. CLINICAL SYMPTOMS OF PARKINSON’S DISEASE
The Fear of Falling Scale is a valid method to assess fear of falling in
PD. Fear of falling score is associated with the presence of anxiety
disorder, major depression, poor balance-related motor ability, more severe
impairments in activities of daily living and increased motor fluctuations.
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The generalized anxiety disorder is useful to predict number of falls during
a 12-month period [51]. Floor patterns incorporating transverse oriented
large rectangular visual cues may help patients with PD. Transverse floor
stones are better than diagonal, whereas regular pattern stones were
excellent to irregular in walking factors [52]. Thickening of rhomboid
fossa is observed in patients with PD (Figure 1).
Figure 1. Parkinson disease patients brain showing thickening of rhomboid fossa.
Patients with PD show restless legs syndrome, leg motor restlessness
and other leg restlessness related to sensorimotor symptoms. Late-onset leg
restlessness when more than fifty-year old, including restless legs
syndrome, leg motor restlessness and other leg restlessness, particularly if
frequent and asymmetrical are early nonmotor manifestation of PD [53].
Pain and other non-motor symptom may severely affect normal life of
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Patients with PD compared to the motor symptoms [54]. Pro-saccadic
characteristics of duration, latency, peak and average velocity reduced in
executive function, attention, global cognition and memory over fifty-four
months in PD. Reduction in global cognition and attention were predicted
by pro-saccadic metrics in adults. Saccadic characteristics are affected in
early stage of the disease and therefore can be used to predict cognitive
decline in PD [55]. Parkinson’s disease patients show various
abnormalities including spondylitis of cervical vertebra, posterior lateral
thickening of rhomboid fossa and cuneus thickening of median occipital
cortex (Figure 2). Patients with PD have stiffness of muscles in hand and
fingers (Figure 3).
Figure 2. Parkinson disease patient showing abnormalities. A. spondylitis of cervical
vertebra. B. Posterior lateral thickening of Rhomboid fossa. C-D. Cuneus thickening of
median occipital cortex.
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Figure 3. Patients with PD showing stiffness of muscles in the hand and fingers.
Table 1. Parkinson’s disease patients showing clinical symptoms
Age
Sex
Onset of Symptoms
Tremor Rigidity
Bradykinesia
Posture & Gait
Unilateral or Bilateral
Initial presenting Symptoms
Speech Difference
Gastro-intestinal
Disturbances
Dementia
Psychomotor Abnormality
Sensory Symptoms
72
Female
The patient started with pain in
Left shoulder with numbness of
fingers on left side
Tremor on left 4 digits
Movs slowly with trembling of
both limbs
Mild stooping with slow
stepping gait
Initial trembling of limbs of
right sided with slurring of
speech
Bilateral, she had initial
trembling of limbs of right
sided with slurring of speech
Yes
No
Initial grade with illusion
conscious responds to
conversations
ND
70
Male
Watering of eyes right side
irritation, deviation of angle of
mouth, Stiffness of joints of
both lower limbs
Tremor started in lips
progressing to digits of fingers
and toes
Moves slowly with trembling
of digits
Slow stepping gait
Initial trembling of limbs of
right sided with slurring of
speech
Generalized stiffness of neck,
hands and toes
Initial symptoms of Aphonia
No
Initial grade with illusion
Responds to conversations
Irritable temperament
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