C1 WHAT HETEROGENEITY OF ALS PHENOTYPE MAY BE TELLING US ABOUT PATHOBIOLOGY
RAVITS J
University of California, San Diego, USA
Email address for correspondence: [email protected]
Keywords: phenotype, propagation, pathobiology
Introduction: The marked heterogeneity of motor phenotypes of ALS is well recognized and implies the existence of an underlying unified explanation. In the earliest clinical stages, motor phenotypes are simpler than at later stages because upper and lower motor neuron (UMN and LMN) neuropathology has not summated. At such stages, several observations can be formulated.
Formulation:
Nearly all patients have focal onset of symptoms, suggesting motor neuron degeneration has a discrete anatomic origination.
The affected UMN and LMN both share the same body region, suggesting the synaptic connectivity between them was important when disease triggered.
The degrees to which the UMN and LMN are affected are highly variable, suggesting stochastic distribution of the pathogenic factor between them.
The degree to which the UMN and LMN are affected early in disease seems to remain constant throughout the disease, suggesting no further recruitment between UMN and LMN occurs after disease triggers.
The progression of UMN and LMN clinical deficits spreads outward contiguously along respective neuronal anatomy. In this regard, the incongruities between the two levels explain the seemingly complex phenotypes. One type of incongruity involves somatotopic anatomy: At the UMN level, for example, the arm area is contiguous to the ipsilateral leg area while at the LMN level, the arm area is contiguous to the contralateral arm area. The other type of incongruity involves anatomic spread distances: The UMN level, organized as laminar sheets, spans 12 cm in each hemisphere while the LMN level, organized as a column, spans 55 cm rostral to caudal. Because of these incongruities, the superimposed clinical effects of a spreading neuropathology become complex-signs of motor dysfunction summate both within and between levels.
The highly variable rates of progression are independent of the anatomy of the neuropathology. In this regard, it is important to note that progression rate and survival are independent measures of disease: progression rate is largely determined by the kinetics of motor neuron degeneration while survival is determined by this and the anatomy of the neuropathology (distance to spread to respiratory motor neurons and UMN/LMN distribution).
Conclusion: The fundamental defect in ALS could be a focally triggered and outwardly propagating process and thus the molecular biology of propagation could be fundamental in pathogenesis. The fact that a single genetic defect in FALS (even the same mutation in the same gene) causes marked phenotype heterogeneity supports the idea that a single process such as focal propagation could underlie disease. It is also worth noting that frontotemporal dementia, now recognized to be closely related to ALS, has discrete anatomic onsets-left or right frontal or temporal regions-and thus it too can be characterized as a disease with an anatomically spreading pathology.
C2 THE CONTRIBUTION OF GENETIC FACTORS TO SPORADIC ALS/MND
NICHOLSON GA
University of Sydney, ANZAC Research Institute, Sydney, Australia
Email address for correspondence: [email protected]
Keywords: sporadic ALS, genetic penetrance, risk factor
Like most other diseases the majority of ALS/MND subjects occur sporadically in the population where no other affected family members are known. In only about 5-10% of cases is another at risk family member known to have had ALS.
In families with more than one affected individual, all modes of inheritance (dominant, recessive or X-linked) are found, indicating that the disease in these families has a number of different genetic causes. In some dominantly inherited families 50% of at risk individuals eventually develop ALS. In most families only a few members develop the disease, suggesting reduced effect (penetrance) of a weak gene variation which could be regarded as a ‘genetic risk factor’. These intermediate penetrance families are part of a spectrum extending from fully dominant disease to sporadic cases.
Dominantly inherited families are themselves genetically heterogeneous and are caused by a number of genes with disease causing variations (mutations). In our clinic, mutations in SOD1, FUS and TDP43 account for nearly all of our fully penetrant families but these families represent less than 30% of all our families. Most recently reported ALS genes, such as VCP and OPTN account for less than 1% of familial cases (or less than 0.1% of all cases). It is therefore likely that the remainder of our ALS families have weakly penetrant mutations in many, as yet undiscovered genes. These gene variations are hard to find. Such weakly penetrant mutations are also a possible cause of sporadic ALS cases. Whether all sporadic cases have weakly penetrant risk factor genes remains to be determined.
This suggests that sporadic ALS will prove to be very heterogeneous with many risk factor genes. Determining whether these interact with each other and environmental factors is a challenge for the future. Hopefully, common mechanisms or a final common pathway leading to motor neurone death will be found, thus opening up prospects for a simple treatment. Because of the heterogeneity of ALS it is possible that specific treatments for different causes of ALS may be required.