Tagged: Henri Huchard

Juvenile-onset Parkinson’s disease

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A community in New Brunswick (Canada) was recently shocked to discover that a 2 year old boy in their midst had been diagnosed with Parkinson’s disease (Click here to read more).

Yes, you read that correctly, it’s not a typo: a 2 year old boy.

Juvenile-onset Parkinson’s disease is an extremely rare version of the condition we discuss here at the Science of Parkinson’s. It is loosely defined as being ‘diagnosed with Parkinson’s disease under the age of 20’. The prevalence is unknown, but there is a strong genetic component to form of the condition. In today’s post we will review what is known about Juvenile-onset and look at new research about a gene that has recently been discovered to cause a type of Juvenile-onset Parkinson’s disease.


Henri_Huchard

Dr Henri Huchard. Source: Wikipedia

In 1875, Dr Henri Huchard (1844-1910; a French neurologist and cardiologist) described the first case of a child who, at just 3 years of age, presented all the clinical features of Parkinson’s disease. Since that report, there have been many studies detailing the condition that has become known as ‘juvenile-onset Parkinson’s disease’.

What is juvenile-onset Parkinson’s disease?

Basically, it is a form of Parkinson’s disease that affects children and young people under the age of 20. The defining feature is the age of onset. The average age of onset is approximately 12 years of age (with the majority of cases falling between 7 and 16 years) and males are affected by this condition more than females (at a rate of approximately 5:1).

The actual frequency of juvenile-onset parkinson’s is unknown given how rare it is. When researcher look at people with early onset Parkinson’s disease (that is diagnosis before the age of 40; approximately 5% of the Parkinson’s community), they have found that between 0.5 – 5% of that group of people were diagnosed before 20 years of age. This suggests that within just the Parkinson’s community, the frequency of juvenile-onset parkinson’s is at the most 0.25% (or 2.5 people per 1000 people with Parkinson’s). Thus it is obviously a very rare condition.

It is interesting to note that Lewy bodies (the clusters of aggregated protein that classically characterise the brains of people with Parkinson’s disease) are very rare in cases of juvenile-onset parkinson’s disease. To our knowledge there has been only one case of Lewy bodies in juvenile-onset parkinson’s disease (Click here to read more on this). This suggests that the juvenile-onset form of Parkinson’s disease may differ from other forms of the condition in its underlying biology.

Do we know what causes juvenile-onset parkinson’s disease?

There is a very strong genetic component to juvenile-onset parkinson’s disease. In fact, the incidence of Parkinsonism in relatives of people with juvenile-onset parkinson’s disease is higher than in the general public AND in the relatives of people with other forms of Parkinson’s disease.

Genetic mutations in three genes are recognised as causing juvenile-onset Parkinson’s disease. The three genes are known to the Parkinson’s world as they are all PARK genes (genetic variations that are associated with Parkinson’s). Those three genes are:

  • Parkin (PARK2)
  • PTEN-induced putative kinase 1 (PINK1 or PARK6)
  • DJ1 (PARK7)

In juvenile-onset Parkinson’s disease, all of these mutations are associated with autosomal recessive – meaning that two copies of the genetic variation must be present in order for the disease to develop.

Parkin mutations account for the majority of juvenile-onset Parkinson’s disease cases. Affected individuals have a slowly progressing condition that is L-dopa responsive. Dystonia (abnormal muscle tone resulting in muscular spasm and abnormal posture) is very common at the onset of the condition, particularly in the lower limbs.

Can the condition be treated with L-dopa?

The answer is: ‘Yes, but…’

L-dopa (or dopamine replacement) treatment is the standard therapy for alleviating the motor features of Parkinson’s disease.

The majority of people with juvenile-onset parkinson’s respond well to L-dopa, but in the Parkin mutation version individuals will typically begin to experience L-dopa-induced motor fluctuations (dyskinesias) early in that treatment regime.

What research is currently being done on this condition?

Given that cases are so very rare and so few, it is difficult to conduct research on this population of individuals. Most of the research that is being conducted is focused on the genetics underlying the condition.

And recent that research lead to the discovery of a new genetic variation that causes juvenile-onset Parkinson’s disease:

Juvenile

Title: Discovery of a frameshift mutation in podocalyxin-like (PODXL) gene, coding for a neural adhesion molecule, as causal for autosomal-recessive juvenile Parkinsonism.
Authors: Sudhaman S, Prasad K, Behari M, Muthane UB, Juyal RC, Thelma BK.
Journal: Journal Med Genet. 2016 Jul;53(7):450-6.
PMID: 26864383           (This article is OPEN ACCESS if you would like to read it)

The researchers who wrote this article were presented with a 10 member Indian family from Aligarh, Uttar Pradesh. Of the 8 children in the  family, 3 were affected by Parkinsonian features (tremor, slowness, rigidity and gait problems) that began between 13 and 17 years of age. The researchers conducted DNA sequencing and found that none of the three affected siblings had any of the known Juvenile-onset Parkinson’s disease genetic mutations (specifically, mutations in the genes PARK2, PINK1and DJ1).

They then compared the DNA from the three siblings with the rest of the family and found a genetic variant in a gene called podocalyxin-like (or PODXL). It must be noted that PODXL is a completely novel gene in the world of Parkinson’s disease research, which makes it very interesting. PODXL has never previously been associated with any kind of Parkinson’s disease, though it has been connected with two types of cancer (embryonal carcinoma and periampullary adenocarcinoma).

The researchers then turned to their genetic database of 280 people with Parkinson’s disease have had their genomes sequenced. The researchers wanted to determine if any genetic variants in the PODXL gene were present in other suffers of Parkinson’s disease, but had not been picked up as a major contributing factor. They found three unrelated people with PODXL mutations. All three had classical Parkinson’s features, and were negative for mutations in the Parkin, PINK1 and DJ1 genes.

The researchers concluded that the PODXL gene may be considered as a fourth causal gene for Juvenile-onset Parkinson’s disease, but they indicated that further investigations in other ethnic groups are required.

 


The banner for today’s post was sourced from ClipArtBest

Does the age of onset make a difference?

This is Dr Henri Huchard (1844-1910; a French neurologist and cardiologist):

Henri_Huchard

Source: Wikipedia

In 1875, he described the case was of a child who, at just 3 years of age, presented with all the clinical features of Parkinson’s disease. Since that report, there have been many studies detailing the condition that has come to be known as ‘juvenile Parkinsonism‘. Currently the youngest person diagnosed with Parkinson’s disease is a young lady from Oklahoma. She was diagnosed at 10-years of age, but had shown symptoms since the age of 2.

We are going to explore juvenile Parkinson’s disease in future post, but today’s post will review some new research that looks at the differences in Parkinson’s disease features of people diagnosed at different ages.


For most members of the general public, Parkinson’s disease is considered a condition of the elderly. And this is a fair line of thinking given what they probably observe out there in the big wide world.

 

A few years ago though, Parkinson’s UK commissioned and published a report of the statistics/demographics of Parkinson’s disease in the UK (Click here for a copy of that report). In that report, they present this table:

Table1

It illustrates the estimated number of people in each age bracket that have Parkinson’s disease. As you can see, the bulk of the people affected are over the age of 60. But this does not mean that Parkinson’s disease is simply a condition of the aged. It is believed that worldwide at least 5% of diagnoses are to people below the age of 50 – this is considered early onset Parkinson’s disease.

There are many people – actor Michael J Fox among them – who have been diagnosed below the age of 40.

leadership-fox-m-img_2

Actor Michael J Fox was diagnosed with Parkinson’s disease at age 30.
Source: MJFox foundation

Given this wide spectrum of age of onset, it is curious that more research has not been conducted comparing the differences in features of the condition between the different age groups. This situation, however was remedied recently:

Age-of-onset-PD

Title: Age at onset and Parkinson disease phenotype.
Authors: Pagano G, Ferrara N, Brooks DJ, Pavese N.
Journal: Neurology. 2016 Feb 10.
PMID: 26865518

The investigators in this study took 422 people who had recently been diagnosed with Parkinson’s disease (none of them were on any anti-Parkinson’s medication, eg. L-dopa). The subjects were divided into 4 groups according to their age at diagnosis:

  1. younger than 50 years (58 subjects)
  2. 50-59 years (117 subjects)
  3. 60-69 years (168 subjects)
  4. older than 70 years (79 subjects)

The researchers then investigated differences in:

  • side of onset (left or right; dominant or non-dominant side of the body)
  • type of symptoms (rigidity or tremor, etc)
  • localization of symptoms occurrence (eg. arms, legs, etc)
  • severity of motor features (rigidity, tremor,…)
  • severity of nonmotor features (memory, attention,…)
  • severity nigrostriatal function (brain imaging of the dopamine system)
  • CSF biomarkers (Chemicals in the cerebrospinal fluid which surrounds the brain)

Curiously in all of the four groups, a quarter of the people had a family history of Parkinson’s disease. Familial history could suggest a genetic connection, and the genetic aspect of Parkinson’s disease has generally been associated with the early onset group. But this does not appear to be the case in this  study – there was no bias towards the younger onset group.

Asymmetry of motor features onset (eg. tremor, etc) was apparent in 97.8% of the total population, with 55% of those subjects having symptoms on their dominant side. It is interesting to note here, however, that the young onset group were the only group in which the non-dominant side was more affected than the dominant. Similarly, almost all of the symmetrical onset individuals (exhibiting no asymmetry in their motor features) were in the oldest group.

In all four groups, the arm was the more likely site of motor features (this was the case in approx. 85% in all groups). When considering other sites of onset, the head was more frequent in the older groups than the younger group, while the leg was more common in the younger group than the older group.

The older the age at onset the more severe the motor (eg. resting tremor, and postural instability scores) and nonmotor features (including autonomic, olfactory, and cognitive functions). This was accompanied by a greater dopaminergic dysfunction on the brain scan, and a reduction of alpha synuclein floating around in the cerebrospinal fluid.

Rigidity was more common in the young-onset group.

There were no differences between the groups in terms of issues associated with activities of daily living, measures of depression and anxiety, impulsive control, or sleep problems.

What does it all mean?

Why these difference exist and what they might tell us about the condition is yet to be determined. The results are interesting when one considers that the subjects had similar disease duration (they had all just been diagnosed; within 6 months of diagnosis). This suggests that the observed differences may be specific to the different age groups. A direct contribution of the aging process, however, has to be considered when assessing the older group.

This kind of analysis is necessary as it is the only way small details about the disease can be determined. We thought this was an interesting study