Spectrums of Amyotrophic Lateral Sclerosis. Группа авторов

linked to primary muscle disorders as well. Mutations in valosin‐containing protein (VCP), previously identified in a proportion of patients with hereditary inclusion‐body myopathy (IBM), were later detected in a subset of sALS and fALS cases [29]. Additional genes, including MATR3, hnRNPA1, hnRNPA2B1, and SQSTM1, have been identified, which are responsible for an ALS/myopathy spectrum with overlapping phenotypes [30–32]. Interestingly, most myopathies associated with ALS are distal myopathies with evidence of rimmed vacuoles at muscle biopsy. These structures represent the accumulation of autophagic vacuoles due to lysosomal dysfunction or protein accumulation.

Paget's disease of the bone, extrapyramidal syndromes, psychiatric disorders, and peripheral neuropathies are additional conditions that are mechanistically linked to ALS. The spectrum of clinical phenotypes associated with major ALS‐associated genes is listed in Table 1.1 [24, 25, 29, 30,32–66].

PLEIOTROPY OF ALS GENES

SOD1 is the only ALS‐associated gene that has been associated exclusively with an isolated motor phenotype. A common phenomenon for all other ALS genes is pleiotropy, which means a genetic variant can be associated with multiple phenotypic traits. The same genetic variant can cause not only different ALS subtypes in families, in terms of age of onset and disease course, but also different diseases. Examples of pleiotropic genes are C9orf72 and VCP. In the same family, C9orf72 carriers can have only ALS, only FTD, or overlapping ALS/FTD phenotypes. Furthermore, the same pathogenic variant in VCP has been detected in patients with ALS, FTD, IBM, and Charcot‐Marie‐Tooth type 2 (CMT2) [67]. The opposite is also true: different pathogenic variants in the same ALS‐associated gene can cause an identical phenotype.

TABLE 1.1 Spectrum of clinical disease phenotypes associated with genetic variants.

	ALS	FTD	Myopathy	Parkinson's disease	Paget's disease	Others
SOD1	+44	–	–	–	–	–
C9orf72	+24,25	+24,25	–	+45	+/−46	Psychiatric disorders [33], Huntington disease [34]
TARDBP	+47,48	+49	–	+50	–	–
FUS	+51,52	+53	–	–	–	Hereditary essential tremor 4 [35]
NEK1	+54	–	–	–	–	Short‐rib thoracic dysplasia [36]
TBK1	+55	+56	–	–	–	Herpes simplex encephalitis [37]
MATR3	+32	+32	+57	–	–	–
VCP	+29	+58	+58	–	+58	Charcot‐Marie‐Tooth type 2 [38]
SQSTM1	+30	+59	+60	–	+61	Childhood‐onset neurodegeneration with ataxia, dystonia, and gaze palsy [39]
OPTN	+62	+63	–	+64	+65	Open angle glaucoma [40]
KIF5A	+66	–	–	–	–	Hereditary spastic paraplegia [41], Charcot‐Marie‐Tooth type 2 [42], neonatal intractable myoclonus [43]

      Presence (+) or absence (−) of clinical signs in patients with variants in different genes is reported in the table.

      High‐throughput sequencing studies have shown that a consistent number of patients with the C9orf72 expansion have additional variants in other ALS‐associated genes, suggesting that pleiotropy can be explained by an oligogenic model [5, 27,68–70].

With rare exceptions, it is not possible to establish a genotype–phenotype correlation in ALS. The variants p.D11Y, p.D90A, and p.G93D in SOD1 are associated with a relatively benign form of motor neuron disease with distal limb distribution [71–74], while p.A4V and p.G85S are associated with a rapid course [75, 76]. Some mutations in FUS, including p.P525L and frameshift mutations, are frequently associated with juvenile‐onset ALS with an aggressive course [77–79].

GENETIC MODELS TO STUDY ALS

      In Vivo Models

      ALS is currently untreatable. Riluzole and edaravone, the two drugs approved by the US Food and Drug Administration (FDA), increase survival by a few months, blocking excessive glutamatergic neurotransmission and preventing oxidative stress damage, respectively, but they are not able to halt or cure the disease [80]. Genetic models represent a very useful tool to identify the concrete target of new drugs. Of course, no model can fully reproduce the human condition, especially its clinical heterogeneity, but a combination of in vitro and in vivo models can help to investigate the mechanisms underlying the disease and explore epistatic interactions.