A Systematic Review of Genotype-Phenotype Correlation across Cohorts Having Causal Mutations of Different Genes in ALS

Abstract

Amyotrophic lateral sclerosis is a rare and fatal neurodegenerative disease characterised by progressive deterioration of upper and lower motor neurons that eventually culminates in severe muscle atrophy, respiratory failure and death. There is a concerning lack of understanding regarding the mechanisms that lead to the onset of ALS and as a result there are no reliable biomarkers that aid in the early detection of the disease nor is there an effective treatment. This review first considers the clinical phenotypes associated with ALS, and discusses the broad categorisation of ALS and ALS-mimic diseases into upper and lower motor neuron diseases, before focusing on the genetic aetiology of ALS and considering the potential relationship of mutations of different genes to variations in phenotype. For this purpose, a systematic review is conducted collating data from 107 original published clinical studies on monogenic forms of the disease, surveying the age and site of onset, disease duration and motor neuron involvement. The collected data highlight the complexity of the disease's genotype-phenotype relationship, and thus the need for a nuanced approach to the development of clinical assays and therapeutics.

Keywords: ALS; ALS genes; ALS variants; MND; genotype–phenotype.

Figure 1

Clinical features of amyotrophic lateral sclerosis (ALS) and their role in prognosis. Diagram summarising the heterogeneity of clinical features in ALS. Multiple features have been associated with a poor prognosis, with an elderly onset being associated with a rapid progression of symptoms and a poor prognosis, especially among elderly females presenting with bulbar-onset phenotype [12]. Disease progression can be assessed either by diagnostic delay or by the ALS functional rating score (ALSFRS: amyotrophic lateral sclerosis functional rating scale). Poor prognosis is associated with patients whose ALS diagnosis has been given less than 8 months after symptom onset, or among those patients losing more than 1.4 points/month on the ALSFRS scale [13].

Figure 2

The role of upper and lower motor neurons in different ALS variants. ALS is a disease with high variability in clinical phenotype. “Classic ALS” patients will present with signs of both UMN and LMN degeneration. However, patients with progressive muscular atrophy (PMA) and primary lateral sclerosis (PLS) present with LMN-predominant or UMN-predominant signs, respectively. LMN-predominant patients also include flail-arm syndrome and flail-leg syndrome ALS variants where LMN signs are present in upper or lower limbs, respectively. ALS patients might present symptoms in bulbar-innervated muscles, if UMN signs are predominant, patients are diagnosed with pseudobulbar-palsy. Blue colour circles indicate motor neurons of the corticospinal tract. Green colour circles indicate motor neurons of the corticobulbar tract. Solid circles indicate UMNs and open circles indicate LMNs. Colour of ticks corresponds to colour of variant label and tick location indicates the motor neuron populations affected. ALS: amyotrophic lateral sclerosis. PLS: primary lateral sclerosis. PMA: progressive muscular atrophy. CS: corticospinal. CB: corticobulbar.

Figure 3

PRISMA flow chart showing how studies have been selected.

Figure 4

Table summarising the phenotypes observed in ALS patients with different mutations. A detailed version of this table is accessible as supplemental data (Table S2). PubMed was searched to identify published studies reporting genotype–phenotype data for 23 genes. Column 2 indicates the frequency of genes observed in Caucasian populations described in previous reviews (Volk et al. [18] and Chia et al. [167]). The ethnicity/origin of cohorts reported across studies is specified in Table S2 and summarised in column 3. For each parameter reported in this table, the number of patients is given in the first subcolumn for each category. For age of onset, motor neuron impairments, disease duration, and FTD, the weighted mean ± SD, and weighted percentages are given, taking into account the numbers of patients studied. Data for each gene were collected from the following reference studies, then summarized: hnRNPA1: [168]; SETX: [169,170,171,172,173]; SOD1: [24,92,160,161,171,172,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188]; TBK1: [189,190,191,192]; FUS: [24,92,145,146,148,170,171,172,179,180,187,188,193,194,195,196]; OPTN: [171,180,187,197,198,199,200,201,202,203]; TUBA4A: [123,188,204,205]; TARDBP: [171,172,179,180,187,188,192,206,207,208,209,210,211]; ATXN2: [101,102,171,180,188,212,213,214]; C9orf72: [114,170,171,175,180,188,206,215,216,217,218,219,220,221,222,223,224,225,226]; MATR3: [227,228,229,230,231]; FIG4: [171,192,232]; ANG: [171,180,187,233,234,235]; NEK1: [131,236]; KIF5A: [137,141,143,237]; CCNF: [135]; PFN1: [238,239,240,241]; VAPB: [171,242,243]; UBQLN2: [244,245]; SQSTM1: [171,175,192,246]; VCP: [170,171,175,192,247]; SPG11: [179,248]; ALS2: [55,170]. Results from each separate study are shown in Table S2. Gradient colour for age of onset from dark blue to dark red: dark blue, 16 years; dark red, 60 years. Gradient colour for site of onset and for motor neuron impairment distributions: white, 0%; green, 100%.