Friday, 22 December 2017

A brief history of HSP

I was having a brief look at papers in the "new research tool" I became aware of at the drug repurposing conference in 2016.

This pointed me to this article which is a brief history of HSP.

I have copied and pasted the article below, and shortened for this aspects most of interest to me - which is principally understanding the earlier part of the HSP story. If you're interested in the more recent aspects, the click the link and read away!

The article is called: Hereditary spastic paraplegia from 1880 to 2017: an historical review

It is written by: Ingrid Faber, Eduardo Rafael Pereira, Alberto R. M. Martinez, Marcondes França Jr and Hélio Afonso Ghizoni Teive from Universidade Estadual de Campinas and Universidade Federal do Paraná in Brasil.

The diagnosis of an inherited spastic paraplegia is based essentially on the clinical picture, together with the investigation of other, potentially affected, members of the kindred. 

In the last three decades, advances in molecular genetics have revealed that HSPs constitute a large and heterogeneous group of diseases. These frequently overlap clinically and/or genetically with other degenerative disorders such as ataxias, leukodystrophies, spinal muscular atrophy, amyotrophic lateral sclerosis (ALS) and peripheral neuropathies. Historically, the differentiation between HSPs and inherited ataxias has been the most challenging. The key to differentiating complicated HSP from ataxias with associated corticospinal tract dysfunction is to focus on the patient's main disabilities. As a rule, individuals with HSP are overtly spastic and have mild or no complaints relating to the upper limbs. Whereas, in the ataxia group, there is no pronounced dissociation between upper and lower limbs. 

Hereditary spastic paraplegia - first descriptions
In 1880, the Baltic-German (region known today as Estonia and Latvia) neurologist Ernst Adolf Gustav Gottfried von Strümpell published the first case series of patients with HSP. Strümpell reported on two siblings with a probable AD-HSP whose symptoms manifested at 37 and 56 years of age. Clinically, these patients showed a pure form of spastic paraplegia. After the death of one of the siblings, neuropathology showed degeneration of the lateral corticospinal tract, fasciculus gracilis and spinocerebellar tract. In 1888, Maurice Lorrain, a French neurologist, published a more detailed contribution to the anatomical and clinical study of HSPs; hence HSP also being known as Strümpell-Lorrain disease.

Clinical phenotype
Rhein was the first, in 1916, to drive attention to the exquisite clinical heterogeneity some families with HSP displayed. His observations were accompanied by many case series describing pleomorphic clinical pictures encompassing: retinal degeneration, dementia, extrapyramidal symptoms, mental handicap, hand amyotrophy and other features. The term Strumpell's familial spastic paraplegia was reserved for families that displayed only spastic paraparesis, a condition that was thought to be much rarer. Currently, it is recognized that pure forms are more prevalent than complicated ones, their relatively benign clinical course, not affecting life expectancy, greatly contributed to their underdiagnosis at that time. Most epidemiological studies were based on postmortem or hospitalization records.

Anita Harding, a professor of neurology at the University of London, was an important pioneer in the field of molecular neurogenetics. In the 1980s, she published a series of groundbreaking works addressing HSP. In 1981, she presented what was, at the time, the largest investigation into pure HSP, with 22 families studied. She also reinforced the knowledge that spasticity, and not weakness, is the main source of disability in this scenario, an aspect that remains useful in differentiating HSP from other myelopathies. Harding's major contribution to the field of HSP was published in The Lancet journal in 1983. Entitled “Classification of the hereditary ataxias and paraplegias”, this paper established an accurate differentiation between ataxias and HSP, providing a workable base for the etiological investigations that would come. Harding defined that, besides the spastic paraparesis, additional mild signs such as vibration and segmental position sense deficits, slight distal amyotrophy and sphincter dysfunction were also conceivably present in the pure phenotype. This work also provided refinement of the HSP phenotype, emphasizing the variability of disease progression, even within the same family. Sadly, Harding's outstanding career ended prematurely at the age 42 when she succumbed to a cancer. 

In 2006, the German Network for Hereditary Spastic Paraplegia presented the spastic paraplegia rating scale, developed to quantify the disease progression clinically. Validated measures of disease severity are essential to understanding the disease's natural history. Additionally, by their ability to measure treatment impact, they are decisive in the development of future clinical trials.
Structural characterization
While the clinical descriptions of HSP flourished during the 1980s, the pathological comprehension of the disease saw flourishing moments 100 years before. We return to Adolf von Strümpell, the first to identify the disease clinically, who was also the first to describe its pathological hallmarks six years later, in 1886. An unrelated case was also documented by him in 1904. Both pathological specimens showed degeneration of the corticospinal tract in the spinal cord with a distal-proximal gradient. Since then, the disease has been understood as a distal axonopathy of the longest large myelinated fibers of the spinal tract. 

In 1952, Schwarz gave an extensive review of the pathologic literature, highlighting the contributions of Newmark (1904, 1906, 1911), Jakob and Kahlstorf, that culminated with the differentiation of Strümpell's disease from other conditions such as cerebellar ataxias and motor neuron disorders, establishing that, at first, lesions are restricted to the spinal cord and affecting the corticospinal and posterior tracts

Advances in genetics
After the accurate clinical classification developed by Harding, the research involving HSP evolved from anecdotal case descriptions to the systematic study of families alike. Numerous HSP genetic studies have been published since the 1980s. Several genetic subtypes of HSP have been described and numbered sequentially, based on the order of the gene discovery (SPG1, SPG2, SPG3, etc. In 1994, Jouet et al., reported that three disorders; X-linked spastic paraplegia, MASA syndrome (mental retardation, aphasia, shuffling gait and adducted thumbs) and X-linked hydrocephalus were, in fact, allelic conditions, all resulting from mutations in the gene for neural cell adhesion molecule (L1CAM or SPG1). This was the first gene discovered that caused HSP; Also in 1994, Hazan et al., identified the locus implicated in the majority of cases of dominantly inherited HSP.

In 1998, the first gene for autosomal recessive HSP was identified, when the HSP-SPG7 gene was cloned. In 2007, SPG11 was identified as the gene most commonly related to spastic paraplegia with mental impairment and thin corpus callosum. HSP-SPG11 has been recognized as the most common AR-HSP. Surprisingly, SPG11 mutations can also primarily present with other phenotypes, such as parkinsonism or ALS.

No comments:

Post a Comment