**5. Angiogenin (ANG)**

Angiogenin is a angiogenic ribonuclease whose activity is related to its ability in regulating ribosomal RNA (rRNA) transcription. ANG induces angiogenesis by activating vessel endothelial and smooth muscle cells and triggering a number of biological processes, including cell migration, invasion, proliferation, and formation of tubular structures [52].

#### **5.1. Genotype**

The human *ANG* gene (Entrez Gene ID 283) is located on chromosome 14q11.1-q11.2, and it codes for a protein of 147 amino acids.

*ANG*, encoding a 14 kDa angiogenic ribonuclease, is the first loss-of-function gene identified in ALS. Since original discovery of *ANG* as an ALS candidate gene, a total of 15 missense mutations in the coding region of ANG have been identified in 37 of the 4,193 ALS patients. Among them, 10 have been characterized in detail and shown to be loss-of-function mutations. ANG gene has been found mutated in 2.3% of FALS and 1% of SALS patients [53].

The percentage of *ANG* gene mutations has been confirmed in the Italian ALS population [11].

#### **5.2. Phenotype**

Gellera et al. [11] identified 9 patients with new ANG mutation, 6 SALS and 3 FALS. Two patients presented bulbar onset, while 7 patients spinal onset. Patients with P-4S mutation presented signs of LMN involvement in both legs at age of 55 years and subsequently a rapidly progressive course with signs of UMN and LMN involvement. Two patients had G20G mutation but two different clinical course: first patient had slowly progressive lower limb onset MND at age 62 with prevalence of LMN signs and 3 years later manifested cognitive dysfunc‐ tion of frontal lobe type, second patient presented distal weakness of upper limb at age 21 with a slowly progressive course characterized by prevalence of LMN signs. SALS Patient with V113I mutation developed spasticity of the right arm and atrophy of the right hand muscles at age 51, one year later the same symptoms appeared in the controlateral upper limb with prevalence of UMN signs. Patient with H114R mutation started with bulbar signs at age of 68. Patients with previously described I46V mutation presented distal weakness of lower limbs, predominance of LMN signs, slow course of disease (only in one case more rapid with bulbar involvement). Age at onset was between 50-60 years.

So there was a wide phenotypic variability in these patients, for both district of onset and involvemenent of UMN/LMN.

Greenway et al. [53] reported that bulbar onset was more frequent in patients with ANG mutations.
