Juvenile Parkinson’s Disease (JPD) is a rare movement disorder, that present before the age of 21 years. Kufor-Rekab syndrome (KRD) is one of the distinct types of JPD caused by ATP13A2 mutation and inherited as an autosomal recessive. The pathogenesis of KRD is related to inter-related metabolism of ATP13A2 with Mn2 and Zn2, bioenergetics of mitochondria, autophagy lysosomal dysfunction and synuclein metabolism. Clinically, KRD has a variable phenotype and may present with pyramidal or extrapyramidal symptoms and cognitive impairment. Early diagnosis of KRD is important as most of these patients are levodopa responsive and genetic counseling and screening is important for the whole family. We present a case of a 16-year-old boy who presented with tremors and walking difficulty and was later diagnosed as KRD.
Parkinson Disease (PD) is a movement disorder caused by degeneration in the basal ganglia. It has four cardinal symptoms of tremor, rigidity, bradykinesia and postural instability. The incidence of PD increases with age, with an incidence of 0.5 per 100,000 in the < 40-year age group compared to 13.4 per 100,000 in the overall age group . Early-Onset Parkinson’s Disease (EOPD) is defined as the onset of PD symptoms before the age of 60 years. EOPD is further divided into Juvenile Parkinson’s Disease (JPD) if it the patient presents before the age of 21 and Young-onset Parkinson Disease (YOPD) if onset is between 21 and 40 years of age . Several genetic mutations have been identified as a cause of JPD. Kufor-Rekab syndrome (KRD) is one of the distinct types of JPD that is caused by ATP13A2 mutation with an autosomal recessive pattern of inheritance. It is one of the rare diseases with less than 50 cases reported so far . We attempt to report a case of KRD and highlight the importance of rare movement disorders, thereby justifying the need for high suspicion in the management of such patients.
A 16 years old adolescent boy presented in our neurology clinic with tremors in left hand for 8 months followed by difficulty
in walking for 3 months. The tremors are only present during rest without any change in frequency. Similarly, no exaggerating or initiating factors were identified. For the last two years, patient has experienced increased restlessness, sweating and nervousness, especially during social gatherings. The patient was born to a consanguineous marriage and has no significant past medical and family history. The patient was prescribed propranolol, but no improvement was seen. The patient has also gone under cognitive-behavioral therapy without any beneficial outcomes.
On clinical examination, GCS was 15/15 (E4, V5, M5). His vitals were blood pressure = 120/70, heart rate = 80/minute, respiratory rate = 18/minute, and afebrile. He had an expressionless face with a decrease in eye blink frequency. Tremors were noticeable in his left hand while resting on the table. Cranial nerves examination showed slow vertical saccadic eye movements. His vision and funduscopic examination were normal. Slit-lamp examination showed no Kayser‐Fleischer ring. Limbs examination showed the grade 2 rigidity (UPDRS‐III) on the left upper and lower limb with power (5/5) and reflexes (DTR+2). Slowness was observed during hand movement, finger tapping, and toe-tapping. During walking, patients had difficulty maintaining the balance with swaying on the left side.
The patients also had difficulty in writing and letters became
Multiple investigations were carried out that involved
complete blood profile, comprehensive metabolic panel, serum
iron, copper, ceruloplasmin and 24-hour urine copper, which
appeared to be normal. MRI of the brain and spinal cord along
with visual evoked potential was also normal. On the basis of
history, physical examination (tremor, rigidity, bradykinesia,
mask-like face, micrographia, and upgaze palsy) and age of onset
symptoms a clinical diagnosis of Juvenile Parkinsonism (KRS)
were considered. Molecular screening of the ATP13A2 gene
on DNA extracted was performed. Sequence analysis revealed
homozygous deletion on exon 22 that results in the replacement
of serine with threonine followed by a stop codon. This confirms
the diagnosis of autosomal recessive juvenile parkinsonism.
Patient parents consented for the testing of gene mutation which
showed heterozygous mutation of ATP13A2 gene, confirming an
autosomal recessive pattern of disease.
The patient was started on a low dose of Carbidopa/
Levodopa, resulting in a gradual improvement in tremor and
walking. After 4 months of follow-up, the patient was dose-peak
dyskinetic movement of tongue and foot. We lowered the dose
of levodopa and started patient on pramipexole (the dopamine
agonist). He was followed for a year after that and his symptoms
were stable but little difficulty in writing still persisted.
Kufor Rakeb Disease (KRD) is an autosomal recessive,
juvenile-onset, levodopa-responsive Parkinsonism that is
characterized by the onset of extrapyramidal, pyramidal and
cognitive dysfunction. It was first identified in 1994 when five
cases of a Jordanian family was reported living in Kufr Rakeb
hence gain the name of the disease . There are multiple genes
identified in 2006 as a causative factor behind KRD disorder.
Th. These genes defect could be autosomal dominant (VPS35,
LRRK2, SNCA), autosomal recessive (PINK1, PRKN, PARK7,
ATP13A2, SLC6A3, and FBX07) or X-linked (TAF1). The gene
that has been identified in KRD is Parkin-9 or ATP13A2. The role
of ATP13A2 is in Mn2+ and Zn2+ metabolism, mitochondrial
bioenergetics, and autophagy lysosomal dysfunction have
helped us understand the pathogenesis involved in KRS. Also,
ATP13A2 is related to synuclein metabolism, which is the major
component in the pathogenesis of Lewy body dementia .
Clinically KRS manifest as parkinsonian signs of tremor,
bradykinesia, rigidity and postural instability. In addition,
slow saccadic eye movement, supranuclear gaze palsy, ataxia,
partial or total paralysis of legs, spasticity, dystonia, dyskinesia,
and hyperreflexia. Neurodegeneration involving multiple
organs is evidenced by the presence of pyramidal signs and
cognitive impairment. Many patients first present with learning
difficulties and intellectual disability, and it is the most common
non-motor symptom. Other non-motor symptoms include
anxiety, hyposmia or anosmia, panic attacks, auditory and visual
KRD can confuse with many diseases such as Dopa-responsive
dystonia (DRD), Wilson’s disease, a juvenile form of Huntington’s
disease, Parkinson-plus syndromes, Neuroacanthocytosis and
several toxic and metabolic causes of PD. Few cases that have
been reported in the literature has been delayed in diagnosis due
to the variability of presentation. Jha et al.  reported a case of
a 12-year-old male who presented with jerky movements of the
left leg that progressed to generalized weakness and made the
patient bedridden. After 5 years, he was diagnosed with juvenile
PD and responded to Levodopa. Prashanth et al.  reported a
case of 18 years old boy who presented with hand tremors and
difficulty in balance and responded to levodopa. Suleiman et al.
 reported a case of compound heterozygosity of the novel
mutation in ATP13A2. He was presented with gait disturbance,
tremors, dystonia, and cognitive impairment. Noch et al. 
reported two Chinese brothers, the older one had symptoms at
the age of 8 years as learning difficulties and later developed
dysarthria and gait abnormalities. Younger one initially had
language deficits, but he developed limb ataxia and dysarthria.
This phenotypic variability among patients of KRS is largely
unknown, but it can be due to the degree of impairment or type
of mutation in ATP13A2.
The mainstay of treatment is the symptomatic treatment
of PD, with the aim of maximizing functional recovery and
minimizing medication-related side effects. Levodopa has shown
an important effect in the resolution of symptoms, but long-term
use and high doses can cause dyskinesia and motor fluctuations
. Further investigations on the treatment of KRD that can
target metabolic derangements due to ATP13A2 mutation may
provide a beneficial effect in these patients.
Our case highlights the importance of diagnosing juvenile
Parkinson’s disease with such a rare genetic cause. KRS may
present with phenotype variability, which may delay the
diagnosis. However, young patients who have any kind of
pyramidal and extrapyramidal symptoms must be screened for
ATP13A2. Since most of these patients respond to levodopa,
early diagnosis can then prevent long-term sequelae in these