The history behind ALS type 8: from the first phenotype description to the discovery of VAPB mutation

ABSTRACT Over the past 68 years, the Finkel type late-onset adult autosomal dominant spinal muscular atrophy (SMA) that is allelic with amyotrophic lateral sclerosis-8 (ALS8) gained a genotype-phenotype correlation among the motor neuron diseases through the work of groups led by Zatz and Marques Jr.


INTRODUCTION
Motor neuron diseases (MND) encompass several neurological disorders characterized by progressive degeneration of the corticospinal tract, anterior horn cells of the spinal cord, and motor neurons of brainstem 1 . The main progressive and neurodegenerative disease in this group with adult onset is amyotrophic lateral sclerosis (ALS), which results in progressive loss of function of the upper and lower motor neurons of the brain, brainstem, and spinal cord, leading to atrophy and fatal motor paralysis 1,2 . Survival rate in most patients is two to five years 2,3 . Jean-Martin Charcot first described this disease in 1874, after correlating a series of cases that occurred from 1865 to 1869 4 . After 146 years of description, knowledge on ALS has expanded greatly with the discovery of biomarkers, genes, and new phenotypes 2,3 . Approximately 10% of ALS cases are hereditary 2,3 . More than 20 genes associated with ALS have been identified so far, starting with mutation of the Cu/Zn superoxide dismutase gene (SOD1) in 1993 2,3,5,6 . The most recent gene discovery -KIF5A/ALS 25 (kinesin family member 5A) -in 2018 also has an autosomal dominant inheritance pattern 5 . Along with the SOD1 mutation, mutations in the C9orf72, FUS, and TARDBP genes are most frequently associated with ALS 2,3,5,6 . Meanwhile, spinal muscular atrophy (SMA) is the most common group of inherited motor neuronopathies, and also the second most common autosomal recessive disorder in clinical practice 7 . Today, late adult-onset SMA represents an important group of inherited neurodegenerative disorders with different genetic causes, including SMN1-related proximal SMA, Kennedy's disease and Finkel type SMA, an autosomal dominant adult-onset SMA linked to a specific heterozygous pathogenic mutation (p.Pro56Ser) in the VAPB (vesicle-trafficking protein B) gene in chromosome 20q13.32, coding the VAMP-associated membrane protein type B 7 .

FINKEL'S CONTRIBUTION TO DESCRIBING A LATE-ONSET NEURODEGENERATIVE LOWER MND
In 1962, Nunjo Finkel ( Figure 1), a renowned Brazilian neurologist, described a series of four cases of patients in the same family with an atypical manifestation of MND, which he classified as a "late pseudomyopathic form of heredo--familial progressive muscle atrophy" 8 . The cases originated in the southeastern Brazilian town of Guarani, in the state of Minas Gerais. All patients presented with slowly progressive atrophy and proximal weakness associated with low back lordosis, abdominal bulge, and postural tremor 8 ( Figure 2). Finkel insightfully noticed that the atrophy of these cases was neurogenic in origin rather than myogenic, due to the significant fasciculation that was present, and initially attributed an autosomal recessive inheritance pattern 8 . (Figure 3) Later, in 1982, Richieri-Costa et. al. 9 described two other families with 80 individuals affected with the same atrophy phenotype described by Finkel. Although this could not be confirmed, an ancestral correlation was suggested considering that the disease was extremely rare outside Brazil, the phenotypes were identical, and the two families came from the same rural area in Brazil 9 . The paper also refuted the possibility that inheritance was autosomal recessive. It stated that, in fact, it was autosomal dominant. 9 In addition, Richieri-Costa described other less common symptoms, such as cramps and myotonic phenomena 9 . From this work, the disease Finkel described in 1962 became known as Finkel type late-onset autosomal dominant spinal muscular atrophy (MIM #18980), considered a familial motor neuron disease with an absolutely higher frequency in the southeastern region of Brazil. 6,8,10

DISCOVERY OF THE VAPB MUTATION IN BRAZILIAN PATIENTS -THE CONTRIBUTION FROM THE UNIVERSITY OF SÃO PAULO (USP)
Almost 40 years after Finkel's description, Nishimura et al.
(of the group led by Dr Mayana Zatz) described the P56S mutation in a highly conservative domain of the VAPB (vesicle-trafficking protein B) gene in 24 individuals from seven families affected by motor neuron disease 11 (Figure 4). Of these individuals, three families (eight patients) had the phenotype described by Finkel (late-onset SMA). The other families had distinct phenotypes, such as atypical ALS (with the presence of essential tremor) and typical ALS (clinically severe, with rapid progression) 11 . This type of genetically determined ALS was later defined as ALS8, a rare autosomal dominant subtype of familial ALS (FALS) originally identified in Brazilian families. Zatz's group found wide phenotypic heterogeneity related to the mutation, including within the families, broadening the clinical spectrum of the disease and expanding knowledge on the pathophysiological aspects of and potential treatments for this disease 11 13 . The patients exhibited proximal and axial muscle weakness and atrophy, fasciculations, and cramps associated with abdominal protrusion defined the motor phenotype. These patients also presented with distal tremor as well as autonomic abnormalities, including choking, chronic intestinal constipation, sexual and sudomotor dysfunction 13 . Furthermore, in 2008, the same group described neurophysiological findings for six members of this same family, detailing late-onset, dominant, proximal spinal muscular atrophy with dysautonomia related to the VAPB Prof56Ser mutation 14 . The electroneuromyographic findings were consistent with the II motor neuron disorder, and the abdominal muscles were severely affected from a topographical standpoint, which is considered the most frequent clinical tool when the disease initially emerges 14 .

Contributions from the groups led by Zatz and Marques
Jr. on Finkel type late-onset adult autosomal dominant SMA allelic with ALS8 broadened our understanding of motor neuron disease 8,9,10,11,12,13,14 . More recently, different brazilian neurological groups have published studies about ALS8 emphasizing different clinical aspects. [15][16][17][18][19] With each new discovery, ALS and SMA prove to be more complex than previously imagined. Remarkable advances in neurogenetics are transforming the knowledge generated by these distinguished researchers into hope for disease-modifying treatments in the near future.